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CORD-19:f2b3c64a3494a044b1085845dcc4aedb6c4e7e6b JSONTXT

CHAP TER 1 Alimentary System


Examination of the oral cavity should be standard procedure during any postmortem examination. To obtain a clear view of the mucous membranes of the buccal and oral cavities, teeth, tongue, gums, and tonsils, it is essential to split the mandibular symphysis and separate the mandibles as far as possible. A thorough examination of all structures will reveal not only local lesions, but often those that may be due to systemic disease. Lesions may be associated with congenital anomalies (genetic and nongenetic); trauma (physical and chemical); bacterial, mycotic, viral, and parasitic infections; metabolic and toxic diseases; and immune-mediated, dysplastic, or neoplastic disease. The poor physical condition of an animal may be directly related to oral lesions that result in difficulties of prehension, mastication, or swallowing of food.
Congenital anomalies may occur as heritable conditions or be the result of nongenetic factors, including toxicity and infectious agents. The development of normal face, jaws, and the oral cavity requires the integration of many embryonic processes, most importantly the frontonasal, maxillary, and mandibular processes. The complexity and duration of this development may lead to a great variety of aberrations. These are usually expressed in the newborn in the form of clefts resulting from failures of integrated growth and fusion of these processes. A common failure of fusion is that of the maxillary processes to the frontonasal process. This may leave facial fissures, cleft lip (harelip, cheiloschisis) and unilateral or bilateral primary cleft palate involving the area rostral to the incisive papilla.
Facial clefts may involve the skin only, or the deeper tissues as well. They are variously located, and not all are obviously related to normal lines of fusion. All are rare. The most common is a complete cleft from one angle of the mouth to the ear of that side. This results from failure of fusion of the lateral portions of the maxillary and mandibular processes. A defect extending from a cleft lip to the eye results from failure arthrogryposis frequently occur together in Charolais calves, and appear to be hereditary (probably simple autosomal recessive), as in Hereford cattle. Cleft palate in lambs may be genetic in origin, but also is associated with the ingestion of Veratrum californicum. Secondary cleft palates have been induced experimentally in newborn pigs by feeding gilts seeds or plants of poison hemlock (Conium maculatum) during gestational days 30-45. Both tree tobacco (Nicotiana glauca) in the western United States and tobacco stalks (N. tabacum) when fed to gilts early in pregnancy can induce a high incidence of cleft palate and arthrogryposis in newborn pigs. Piperidine alkaloids (coniine, coniceine, and anabasine) in hemlock and tobacco plants are responsible for the teratogenic effects of these plants. Lupines (Lupinus formosus, L. arbustus) produce piperidine alkaloids, including the teratogen ammodendrine, which can cause cleft palate and arthrogryposis (crooked calf disease) in calves born of dams fed the lupine at days 40-50 of gestation. Palatoschisis in piglets has also been associated with consumption of feed contaminated with Crotalaria retusa seed by sows during gestation. Primary and secondary cleft palate of German Boxer dogs appear to be hereditary, probably because of a single autosomal recessive gene. A single autosomal recessive gene has been associated with cleft palate in Pyrenees Shepherd dogs. Secondary cleft palate occurs in Siamese and Abyssinian cats and is likely hereditary. Griseofulvin treatment of the pregnant queen and mare will result in palatoschisis in the offspring. The defect has also been reported in both parts of the doubled face in diprosopus cats. Anomalies in the growth of jaws are quite common. Brachygnathia superior, shortness of the maxillae, is an inherited breed characteristic among dogs and swine. It has been reported in the Large White or Yorkshire breed. The condition is progressive with age, resulting in malapposition of the incisor and cheek teeth, which interferes with prehension and mastication. In swine, brachygnathia superior may be confused with atrophic rhinitis. In Angus and Jersey cattle, brachygnathia superior occurs as a hereditary trait. In any species, it may be associated with chondrodysplasia and is also present with other facial defects.
Brachygnathia inferior or micrognathia, shortness of the mandibles, may be a mild to lethal defect in cattle and sheep and is a breed characteristic of long-nosed dogs. Brachygnathia inferior is a common defect in calves. It is inherited, probably as a simple autosomal recessive trait. There is a higher incidence in males. This condition in calves has been associated with cerebellar hypoplasia. In Aberdeen Angus cattle, the defect may occur concurrently with cerebellar hypoplasia, and with osteopetrosis in this and other breeds (see Vol. 1, Bones and joints). In Merino sheep, brachygnathia is associated with a cardiomegaly and renal hypoplasia syndrome that has an autosomal recessive inheritance pattern. Transplacental infection with Schmallenberg virus, an orthobunyavirus, will lead to brachygnathia among other congenital malformations in lambs and calves. Mild brachygnathia inferior, termed parrot mouth, is a common conformational defect in horses.
Prognathism refers to abnormal prolongation of the mandibles. It is rather common, especially in sheep. It may develop with recovery from calcium deficiency in this species (see Vol. 1, Bones and joints). The malformation is relative, and it is not always easy to determine whether the jaw is absolutely long or merely apparently so, relative to a mild brachygnathia superior.
of fusion of the maxillary and frontonasal processes, which may be a superficial defect with failure of closure of the nasolacrimal duct.
Primary cleft palate (harelip, cheiloschisis) includes developmental anomalies of the upper lips rostral to the nasal septum, columella, and premaxilla. They may be unilateral or bilateral and superficial or extend into the nostril. The defect arises from incomplete fusion of the frontonasal process with the maxillary processes.
Secondary cleft palate (cleft palate, palatoschisis) ( Fig. 1-1 ) is often associated with primary cleft palate. The normal hard palate is formed, except for a small rostral contribution from the frontonasal process, and by the bilateral ingrowth of the lateral palatine shelves from the maxillary processes. At the midline, they fuse with each other and with the nasal septum, and undergo intramembranous ossification, except in their caudal part, which becomes the soft palate. Inadequate growth of the palatine shelves leaves a central defect, in either or both of the hard and soft palates, which communicates between the oral and nasal cavities. Other manifestations of disordered palato-genesis include unilateral defects in the soft palate; bilateral hypoplasia of the soft palate; or dorsal displacement of the soft palate, with excess soft tissue on the caudal portion. Affected animals have difficulty sucking, may have nasal regurgitation, and usually die within the first few days of life from aspiration pneumonia. In dogs, malformation of the soft palate has also been associated with alterations in the tympanic bulla and middle ear dysfunction.
Cleft palates have been reported in most species of domestic animals. In one extensive survey of Thoroughbred foals, 4% of congenital defects were secondary cleft palates. Most of these foals had a complete cleft of the hard palate; a few had clefts or hypoplasia of the soft palate only. In calves, cleft palate is one of the most common anomalies, but is very uncommon in sheep. Primary cleft palate is less common than secondary cleft palate in swine, although the two anomalies often occur together. In dogs and cats, cleft palate is often associated with certain breeds, suggesting that these are heritable traits.
The etiology of cleft palate is usually unknown, but examples of hereditary causes, maternal ingestion of certain drugs, or maternal consumption of teratogenic plants during pregnancy have been demonstrated. Secondary cleft palate and Developmental Mechanisms and Malformations. Baltimore: Williams & Wilkins; 1985. p. 187-195. Shariflou M, et. al. Brachygnathia, cardiomegaly
Dental disease is common and often is a factor that limits the useful life-span of the animal, especially sheep. Evaluation of dental disease necessitates a thorough examination of the oral cavity. The comments on dental development and anatomy are intended to provide a brief overview and assist the understanding of dental disease. Teeth develop from a band of ectoderm deep to the mucosal epithelium that spans the length of the gingiva. This ectodermal band is called the dental lamina. In the initial stage of tooth development, neural crest cells beneath the dental laminae induce multiple nodular thickenings along the length of the dental lamina. These are the tooth buds. Next, ectomesenchymal cells aggregate at the base of each tooth bud. The tooth bud then becomes a bell-shaped structure that grows down over the ectomesenchymal cells and becomes the enamel organ, which will give rise to enamel-producing ameloblasts. The ectomesenchyme below the enamel organ develops into the dental papilla, which will give rise to dentin-producing odontoblasts and also the tooth pulp. Ectomesenchyme cells also move around the periphery of the enamel organ to form a limiting sac called the dental follicle or dental sac. The dental sac will ultimately give rise to cementum-producing cells (cementoblasts), the periodontal ligament, and alveolar bone.
The cells of the enamel organ differentiate into 3 layers: outer epithelium, stellate reticulum, and inner epithelium. The cervical loop forms where the outer and inner epithelium of the enamel organ join. As the enamel organ develops, the dental lamina begins to disintegrate, leaving the tooth separate from the overlying oral mucosa. Remnants of the dental lamina can persist and give rise to dental cysts or neoplasms.
Hard tissues (dentin and enamel) are deposited on the developing tooth. The inner enamel epithelium of the enamel organ induces differentiation of odontoblasts from the ectomesenchyme of the dental papilla. Odontoblasts produce dentin, which in turn induces differentiation and enamel formation by the ameloblasts of the inner enamel epithelium. Thus formation of dentin is essential for the formation of enamel. These inductive interactions of epithelium and ectomesenchyme are considered important in the histodifferentiation of some tumors of dental tissues.
The crown of the tooth will ultimately be shaped by the inner enamel epithelium. The shape of the tooth roots will be determined by the cervical loop through epithelial extensions called Hertwig's epithelial root sheath (HERS) . The HERS guides the formation of the developing root by inciting differentiation of odontoblasts from the dental papilla. Typically the HERS will disintegrate after it initiates dentin formation. As the HERS fragments, it allows ectomesenchymal cells from the dental sac to contact the root dentin, differentiate into Agnathia is a mandibulofacial malformation characterized by absence of the lower jaw, caused by failure of development of the first branchial arch and associated structures. The defect is one of the most common anomalies in lambs but is rare in cattle. Associated malformations in lambs may include ateloprosopia (incomplete development of the face), microglossia or aglossia, and atresia of the oropharynx. Concurrent anomalies affecting other body systems also may be evident.
A lethal glossopharyngeal hereditary defect, termed bird tongue and caused by a simple autosomal recessive gene, has been reported in dogs. Affected pups have a narrow tongue, especially the rostral half, where the margins are folded medially onto the dorsal surface. The pups are unable to swallow. The muscle fibers of the affected tongues are normal histologically. In dogs, there is a congenital defect leading to a thickened short lingual frenulum called ankyloglossia. This lesion may be most pronounced at the rostral tongue, and the tip of the tongue may be notched. Hypertrophy of the tongue occurs as a congenital anomaly in pigs.
Epitheliogenesis imperfecta is an anomaly that causes widespread defects in cutaneous epithelium, and also affects the epithelial lining of the oral cavity, especially the tongue ( Fig. 1-2 ) (see Vol. 1, Integumentary system). The condition is characterized by irregular, well-demarcated, red areas from which the epithelium of the oral mucosa is absent. Histologically, these consist of abruptly defective areas in the squamous mucosa with inflammation of the submucosal connective tissues. The anomaly occurs in most species and is inherited as a simple autosomal recessive character in cattle, horses, and pigs; the mode of inheritance is unknown in the other species. There are several hereditary skin conditions in animals, such as epidermolysis bullosa simplex in Collie dogs, ovine epidermolysis bullosa in Suffolk and South Dorset Down sheep, and familial acantholysis of Aberdeen Angus calves, which have minor involvement of the lips and oral mucosa (see Vol. 1, Integumentary system).
Dentinal tubules are visible in histologic sections, but the anastomoses are not. Except for the processes, and nerve endings in the dentinal tubules near the pulp, dentin is acellular.
Normal dentin contains incremental or imbrication lines of von Ebner, which are fine basophilic lines running at right angles to the dentinal tubules. They represent normal variations in the structure and mineralization of dentin. Sublethal injury caused by certain infections, metabolic stresses, or toxic states may injure the odontoblasts, which then produce accentuated incremental lines known as the contour lines of Owen. Sometimes irregular zones of unmineralized or poorly mineralized dentin form between foci of normal mineralization. These are zones of interglobular dentin, which may be caused by hypophosphatemia.
There are 3 types of dentin. Primary dentin is produced by odontoblasts before tooth eruption. Secondary dentin is produced after root formation is complete by odontoblasts that remain active throughout life. Generation of secondary dentin is much slower than primary dentin. Tertiary dentin is produced in response to injury to the tooth. Tertiary dentin is called reactionary when it is produced by pre-existing odontoblasts. Reparative dentin is another type of tertiary dentin that is produced by newly differentiated odontoblasts. Reparative dentin may resemble bone and is sometimes called osteodentin. Sclerotic (transparent) dentin is formed when dentinal tubules are occluded by calcium salts. The junctions between primary, secondary, and reparative dentin are usually demarcated by basophilic lines.
Enamel has ~5% organic matter and ~95% mineral. It is produced by the tall columnar ameloblasts of the inner enamel epithelium. Enamel is produced in the form of prisms or rods, cemented together by a matrix. Mineralization begins as soon as it is formed and is a 2-stage process, somewhat similar to that in bone, but much more rapid. The cells of the inner enamel epithelium also move away from the dentin-enamel junction as the tooth is formed, but unlike odontoblasts, they do not have processes. Formation of enamel ends before tooth eruption. Enamel is hard, dense, brittle, and permeable, and is translucent and white. Mature enamel is not present in demineralized sections, but some of the matrix of immature enamel may be visible near ameloblasts of developing teeth.
Ameloblasts are very sensitive to environmental changes. Normal enamel contains incremental lines of Retzius, which are analogous to the incremental lines of von Ebner in dentin, and also reflect variations in structure and mineralization. The incremental lines are accentuated during periods of metabolic stress. More severe injury, as in fluorosis, or infections by some viruses can produce focal hypoplasia or aplasia of enamel. The reduced enamel epithelium protects the enamel of the formed tooth before eruption. Degeneration of this protective layer permits connective tissue to contact the enamel, and there may be resorption of enamel or deposition of a layer of cementum on it. This normally occurs during odontogenesis in horses.
Cementum is an avascular, bone-like substance, produced by cementoblasts; it contains ~55% organic and ~45% inorganic matter. In general the dentin of brachydont teeth is covered by cementum wherever it is not covered by enamel. When dentin formation has begun in the root, degeneration of Hertwig's epithelial root sheath begins and permits mesenchymal cells from the dental sac to contact dentin. They differentiate into cementoblasts, which produce cementoid, and later cementoblasts, and deposit cementum on the dentin of the root. Remnants of the HERS can persist and are called epithelial rests of Malassez. They persist in the periodontal ligament, and may give rise to tumors or cysts. They may be important in the induction or repair of cementum, and in periodontal reattachment following injury. In pigs and sheep, the rests may be incorporated into the junctional epithelium as it migrates apically in chronic periodontal disease. HERS cells of the root sheath that adhere to the dentin can produce enamel pearls.
As tooth development progresses, the crown of the tooth is covered by enamel, whereas the roots are covered by cementum. Dentin is present throughout the tooth. Fibroblasts in the dental follicle (sac) generate collagen that forms the periodontal ligament. The collagen of the periodontal ligament is intertwined with the cementum of the root surface and extends to the adjacent alveolar bone along the length of the root. The periodontal ligament is continually modified and reshaped with orientation of fibers in different directions during the life of the tooth.
The tooth will begin erupting while the roots are still developing. The mechanisms of tooth eruption are not fully understood. It is likely that the dental follicle plays a critical role in alveolar bone resorption and remodeling needed to allow the tooth to erupt. The inner enamel epithelium merges with the cells of the overlying stratum intermedium and the outer enamel epithelium to form the reduced enamel epithelium. This protects the enamel of the formed tooth before eruption. The reduced enamel epithelium will fuse with the mucosal epithelium as the tooth erupts, and after eruption a portion of the reduced enamel epithelium will persist along the gingival margin of the tooth as junctional epithelium. The process of tooth development is similar for deciduous and permanent teeth. Tooth germ for permanent teeth begins to develop along with the deciduous teeth. However, the permanent tooth germ is held dormant until later in life when the permanent teeth proceed with development and the deciduous teeth are lost.
There are important differences between the brachydont teeth of humans, carnivores, and swine, in which the enamel is restricted to the tooth crown, and the hypsodont teeth of herbivores. In hypsodont teeth, enamel extends far down on the roots, and is invaginated into the dentin to form infundibula. Also, the hypsodont teeth of herbivores, except the mandibular premolars of ruminants, are covered by cementum, which more or less fills the infundibula. Exceptions to these rules are provided by the tusks of boars, which are hypsodont, but not covered by cementum, and by ruminant incisors, which are brachydont but do have enamel covering part of the root dentin and cementum covering the root enamel.
The 3 hard tissues of teeth are dentin, enamel, and cementum. Dentin is light yellow and constitutes most of the tooth. It consists of ~35% organic matter and ~65% mineral. Thus its composition is similar to that of bone, and like bone, it contains type I collagen. Dentin is produced by columnar cells with basal nuclei called odontoblasts, which differentiate from ectomesenchyme of the dental papilla. It is formed as unmineralized predentin. The odontoblasts move away from the dentin-enamel junction, gradually encroaching on the pulp cavity as they produce dentin. Each odontoblast has a process extending into the dentin, encased in a dentinal tubule, which arborizes at the dentin-enamel junction. The process also anastomoses with the processes of other odontoblasts.
Heterotopic polyodontia is an extra tooth, or teeth, outside the dental arcades. The best-known example is the ear tooth of horses, which develops in a branchiogenic cyst. The cysts originate from failure of closure of the first branchial cleft, or from the inclusion of cellular rests in this area. They are lined by a stratified mucous or cutaneous-type epithelium, and may contain one or more teeth, either loosely attached in the cyst wall or deeply embedded in the petrous temporal bone. The tooth is derived from misplaced tooth germ of the first branchial arch, which is displaced toward the ear with the first branchial cleft. The cysts eventually form in the parotid region near the ear and may fistulate to the exterior. They are occasionally bilateral. Rarely the tooth may form a pedunculated mass enclosed by skin, and attached by a pedicle to the skin of the head. Heterotopic polyodontia also occurs in cattle, dogs, pigs, and sheep.
Developmentally misshapen teeth are classified as geminous (dichotomous) when there is a single root and partially or completely separate crowns; fused when the dentin of 2 teeth is confluent; and concrescent when the dentin is separate but the roots are joined by cementum. Gemination represents the embryologic partial division of a tooth primordium. It occurs in dogs, usually involving the incisors, and the affected tooth usually has a groove dividing the crowns, whose pulp chambers can be seen radiographically to merge in a common root. Misshapen teeth and missing teeth have also been reported in dogs as an X-linked recessive trait of ectodermal dysplasia. Fusion and concrescence represent the joining of 2 adjacent tooth primordia, one of which may be supernumerary. Malformation and malpositioning of teeth accompany abnormalities of the jaw bones. Aberdeen Angus and Hereford calves with congenital osteopetrosis have brachygnathia inferior, malformed mandibles, and impacted cheek teeth. Impacted molars occur as an inherited lethal defect in Shorthorns; an association with osteopetrosis apparently has not been investigated in this breed.
Odontogenic cysts are epithelium-lined cysts derived from epithelium associated with tooth development. This includes rests of Malassez, cell rests of dental laminae, reduced enamel epithelium, or malformed enamel organs. By definition, dentigerous cysts are cysts that contain part or all of a tooth. Dentigerous cysts usually are associated with permanent teeth. The cyst often forms over the developing tooth and the affected tooth then erupts into the preformed cysts. Dentigerous cysts enclose at least the crown of the tooth, but may include it all. Of the odontogenic cysts, all except those derived from cell rests of Malassez are potentially dentigerous (the rests of Malassez are the probable source of periodontal cysts). Dentigerous cysts originating in malformed enamel organs usually include malformed teeth. Teeth in cysts of reduced enamel epithelium or rests of dental laminae are also often abnormal. The most common forms of odontogenic dentigerous cysts in animals are those involving the vestigial wolf teeth of horses and the vestigial canines, especially of mares. The smaller cysts appear as tumors of the gums, whereas some of the larger ones may cause swelling of the jaw or adjacent maxillary sinus. In dogs, brachycephalic breeds often develop dentigerous cysts, which can be bilateral. The first premolar is often affected. Dentigerous cysts of animals are not as destructive as those in humans, in which species they are regarded as the most common benign destructive lesion of the skeleton. In dogs, a cyst that resembles odontogenic keratocyst of humans has been reported. This cyst is lined mineralize it. Some layers of cementum do not contain cells (acellular cementum), but in other layers, cementocytes are enclosed in lacunae. Sharpey's fibers from alveolar bone are embedded in the cementum. Cementum is more resistant to resorption than is bone, and unlike bone, normally is not resorbed and replaced as it ages; instead a new layer of cementum is deposited on top of the old layer. In some pathologic conditions, cementum is resorbed; subsequently, cellular or acellular cementum is deposited, and more or less repairs the defect.
Hypercementosis is abnormal thickening of cementum and may involve part or all of one or many teeth. When extra cementum improves the functional properties of teeth, it is called cementum hypertrophy; if not, it is called cementum hyperplasia. Extensive hyperplasia is often associated with chronic inflammation of the dental root.
The periodontal ligament is derived from the dental follicle. It is well vascularized and very cellular containing fibroblasts, cementoblasts, undifferentiated mesenchymal cells, and epithelial cells. The periodontal ligament contains type I collagen fibers with complex orientation. The periodontium comprises the periodontal ligament, gingival lamina propria, cementum, and alveolar bone. The ligament supports the tooth and adjusts to its movement during growth. It is well supplied with nerves and lymphatics, which drain into alveolar bone. The periodontal ligament is also a source of the cells that remodel alveolar bone and, in disease, cementum.
Epithelial rests of Malassez are present in the periodontal ligament and are particularly numerous in the incisor region of sheep. In all species, they may proliferate and become cystic when there is inflammation of the periodontium. The periodontium is also a site of origin of tumors. The periodontal ligament is normally visible in radiographs as a radiolucent line between tooth and alveolar bone. In prolonged hyperparathyroidism, alveolar bone is resorbed, and the ligament is no longer outlined radiographically, a change referred to as loss of the lamina dura.
Yellow to brown discoloration of teeth, and bright yellow fluorescence in ultraviolet light, caused by deposition of tetracycline antibiotics in mineralizing dentin, enamel, and probably cementum, occurs in all species. Treatment of the pregnant dam may cause staining of deciduous teeth in the offspring. Tetracyclines are toxic to ameloblasts in late differentiation and early secretory stages and, at high dose rates, may produce enamel hypoplasia. Black discoloration of ruminant cheek teeth is extremely common, and is caused by impregnation of mineral salts with chlorophyll and porphyrin pigments from herbage.
Dental attrition. Dental attrition is loss of tooth structure caused by mastication. The mature conformation of teeth is largely the outcome of opposed growth and wear, and the degree of wear depends on the type of tooth, the species of animal, and the material chewed. Wear is most evident in herbivores, and irregularities of wear are perhaps the most common dental abnormalities, especially in horses. In general, with normal occlusion and use, the extraalveolar portion of the tooth does not shorten. Its length is maintained initially by growth, the period of growth depending on the species, then by hypertrophy of the root cementum and/or dentin and by proliferation of alveolar bone, which serves to push the tooth out. Finally, senile atrophy of the alveolar processes and gingival recession may maintain or increase the length of the clinical crown. Cementum hypertrophy and alveolar atrophy may also result in loss of teeth in senility, or, if combined with subnormal wear, produce teeth that in old age are excessively by keratinized epithelium and has a high rate of reoccurrence after removal.
The ear tooth of horses is probably the most common nonodontogenic dentigerous cyst. Occasionally true dentigerous cysts form when normal tooth eruption fails or when there is maleruption resulting from odontodystrophy. Tooth eruption can be interrupted by trauma, including fractures to the mandible and maxilla.
Cystic dental inclusions about vestigial supernumerary teeth also occur in juxtamolar positions in cattle, but are insignificant. These too may be dentigerous, or they may be primordial cysts developed before the stage of enamel formation, and hence contain no mineralized tooth structures. Either type of cyst may give rise to ameloblastomas.
A high incidence of dentigerous cysts involving incisors occurs in some sheep flocks in Scotland, Australia, and New Zealand. A congenital disease involving the jaws and teeth of calves in Germany (odontodysplasia cystica congenita) is characterized by massive fibro-osseous enlargement of the maxillae and horizontal rami of the mandibles. Some teeth are malformed, misshapen, or absent. Cystic spaces in the jaws are lined by fibrous tissue or epithelium, the latter probably derived from enamel organs. The dental changes are thought to be secondary to those in bone. Most affected calves are aborted or stillborn, and many have ascites and hydrocephalus. The disease may be caused by environmental influences.
The permanent teeth are unique in that they continue to develop for a long time after birth. Thus, inflammatory and metabolic disease of postnatal life, for instance canine distemper virus infection ( Fig. 1-3A) , can produce hypoplasia of dentin and enamel. Hypoplasia of the enamel of deciduous teeth occurs in some calves with intrauterine bovine viral diarrhea virus infection ( Fig. 1-3B ). It has also been described in calves and pigs following irradiation of the dam during gestation. Dysplastic proliferation of dentin and enamel involving mandibular premolars and molars has been seen in young uremic dogs. Extreme fragility of deciduous teeth is a feature of bovine osteogenesis imperfecta (see Vol. 1, Bones and joints) . Dental dysplasia, characterized by normal dentin, absence of enamel matrix, and excess irregular cementum, was described in a foal with epitheliogenesis imperfecta involving the oral mucosa.
Pigmentation of the teeth. Normal enamel is white and shiny, but normal cementum is off-white to light yellow, and normal dentin is slightly darker yellow. Depending on the tooth, or the part of the tooth being examined, the normal color may be any one of these. Normal enamel is never discolored. Hypoplastic enamel of chronic fluorosis is discolored yellow through brown to almost black. Discoloration of brachydont teeth results from pigmentation of dentin, which is then visible through the semitransparent enamel, or pigmentation of the cementum of the root. Dentin may be colored red-brown by pulpal hemorrhages or inflammation, gray-green in putrid pulpitis, and yellow in icterus. Amelogenesis imperfecta is a disorder of enamel formation that leads to inadequate mineralization of enamel and usually yellow discoloration of teeth. This condition has been reported in cattle and in Standard Poodle dogs. Congenital erythropoietic porphyria of calves, cats, and swine discolors the dentin red in young animals (pink tooth) and darker brown in adults, although in swine, the discoloration may disappear with aging. A B thus discontinuous nutritional deficiencies often result in unequal wear. Certain vices, such as crib biting, also produce abnormal wear. In severely worn ruminant incisors, a central black core may be visible, which is secondary dentin deposited in the pulp cavity. It is not carious, but stains darker than the surrounding primary dentin.
Odontodystrophies. Odontodystrophies are diseases of teeth caused by nutritional, metabolic, and toxic insults. They are manifest by changes in the hard tissues of the teeth and their supporting structures and often occur during the period of tooth development. Lesions of enamel and dentin are emphasized here. The most prominent effects of odontodystrophies appear in enamel, and lesions of enamel are most significant because they are irreparable.
Formation of enamel occurs in a set pattern. It begins at the occlusal surface and progresses toward the root. Mineral maturation occurs in the same sequence, but for each level, it begins at the dentin-enamel junction and moves toward the ameloblast. Deleterious influences have their most severe effects on those ameloblasts that are forming and mineralizing enamel. Depending on the severity on the insult, ameloblasts may produce no enamel, a little enamel, or poorly mineralized enamel. Removal of the insult permits those ameloblasts that were not yet active to begin making normal enamel. Thus enamel defects vary in severity from isolated opaque spots or pits on the surface to deep and irregular horizontal indentations. These defects are most clearly seen on the incisor teeth and canine teeth and are usually bilaterally symmetrical. Similar lesions are also produced by infectious agents that injure ameloblasts, such as canine distemper virus and bovine viral diarrhea virus (see Fig. 1-3) .
Odontoblasts are susceptible to many of the same influences as ameloblasts, but they can be replenished from the undifferentiated cells of the dental pulp. Thus lesions in actively forming dentin may be repaired, whereas those in enamel are permanent.
Because of their close anatomical association with the bones of the jaws, teeth are very susceptible to disruption in the harmony of growth. This harmonious arrangement is often upset in the odontodystrophies and osteodystrophies, which may lead to malocclusion, anomalous development of teeth, and tooth loss.
Several nutritional and toxic conditions produce odontodystrophy. Fluorine poisoning is exemplary (see Vol. 1, Bones and joints). In vitamin A deficiency, ameloblasts do not differentiate normally, and their organizing ability is disturbed. As a result, odontoblastic differentiation is abnormal. Several lesions develop, including enamel hypoplasia and hypomineralization, vascularized dentin (osteodentin), and retarded or failed tooth eruption.
Calcium deficiency retards eruption and causes enamel hypoplasia and mild dentin hypoplasia. Teeth formed during the period of deficiency are very susceptible to wear. In sheep, recovery from prolonged calcium deficiency results in malocclusion caused by inferior prognathia. This reflects inadequate maxillary but normal mandibular repair during the recovery phase.
Phosphorus deficiency, combined with vitamin D deficiency, depresses dentin formation slightly, but has virtually no effect on enamel, at least not in sheep. Hypophosphatemia is associated with formation of interglobular dentin in humans. Malocclusion and abnormalities of bite in rachitic sheep are secondary to mandibular deformity.
long. Normal wear of the complicated cheek teeth (premolars and molars) of horses and cattle causes smoothing of the occlusal surfaces. As soon as wear of enamel exposes the dentin, which, being softer, wears more rapidly, secondary or tertiary dentin is deposited to protect the pulp. In time, this may fill the pulp cavity and cause death of the tooth. Abnormalities of wear are most common in herbivores ( Fig. 1-4) . Excessive wear of the deciduous and permanent central incisors occurs in certain sheep flocks in New Zealand. The wear is intermittent and may be severe enough to expose the pulp cavity. The cause is unknown but may be related to delayed eruption of adjacent teeth, leading to increased use of the affected pairs. Subnormal wear, caused by loss of the opposing tooth, occurs in oligodontia, abnormal spacing of adjacent teeth, and acquired loss of teeth; it results in abnormal lengthening. Such elongated teeth may grow against the opposing gum or, if deviated, into an adjacent soft structure such as cheek or lip. These teeth usually wear in abnormal places because complete loss of antagonism is unusual, and, because the upper and lower arcades do not coincide exactly, the coincidence is further reduced by the displacement of chewing.
Abnormal wear resulting from abnormal chewing is caused by voluntary (as in painful conditions) or mechanical impairment of jaw movement. Incomplete longitudinal alignment of the molar arcades allows irregular wear and hook formation on the first and last cheek teeth. Lateral movements of the jaws without the normal rotary grinding movements allow the ridges of the teeth of herbivores to become accentuated. Steep angulation of the occlusal surfaces results from inadequate lateral movement of the jaws, and sharp edges form on the buccal aspect of the maxillary teeth and the lingual aspect of the mandibular teeth. This may be unilateral when the animal chews with only one side of its mouth, the other side then being affected. The teeth wear progressively sharper, and can result in the teeth passing each other like shear blades; hence the term shear mouth. Subnormal resistance to wear on the part of the molar teeth is common, and results in wave mouth (weave mouth) or step mouth, in which successive teeth in an arcade wear at different rates. The wave or step form of the antagonistic arcade is reversed, so that the teeth of the 2 arcades interdigitate. This pattern of attrition is caused by variation in the hardness of opposing teeth, and is usually caused by intermittent odontodystrophy. Opposing teeth of the upper and lower jaws do not develop at the same time; host secretions to adhere to the pellicle, whereas others attach to bacteria of a different species that are already fixed to the tooth. Plaque increases in mass with time, and its composition becomes more complex as anaerobic gram-negative bacteria join the streptococci and actinomycetes that initiated plaque formation.
Supragingival plaque is metabolically active. It utilizes dietary carbohydrates to produce the adhesive polymers and the acids needed to demineralize enamel, and as energy sources for maintenance and for production of various enzymes and stimuli for inflammation. Extensive deposits of supragingival plaque are virtually invisible unless treated with a disclosing solution.
Subgingival plaque is less organized than supragingival plaque, and many of the organisms involved are gram-negative anaerobes that are asaccharolytic, weakly adherent, and motile. They derive their nutrients from the crevicular fluid. The flora of subgingival plaque is less well characterized than that of supragingival plaque. Culture results vary with sample collection technique, site of collection, and selectivity of media, and appear to under-represent the flora detected by molecular means in humans. A number of species including Bacteroides spp., Actinomyces spp., Porphyromonas spp., Tannerella forsythia, and spirochetes have been associated with gingivitis and periodontal disease in animals.
Dental calculus (tartar) is mineralized supragingival and subgingival plaque. In supragingival plaque it is formed by the deposition of mineral, mainly from saliva, in dead bacteria. In subgingival plaque, mineral is generated from gingival crevicular fluid. In horses and dogs, calculus is predominantly calcium carbonate. Calculus is often found in old dogs and cats, occasionally in horses and sheep, and rarely in other species. The distribution is often uneven, but it is usually most abundant next to the orifices of salivary ducts. Calculus on horses' teeth is chalky and easily removed. In dogs, it is hard, firmly attached, and often discolored. Red-brown to black calculus with a metallic sheen develops in pastured sheep and goats. It usually involves all the incisors, principally on the neck of the buccal surface. Minor amounts are common along the gum-tooth junction of the molar teeth, but occasionally larger (up to 2 cm) hard, black, rounded concretions may protrude from between opposed surfaces of the premolars. A high prevalence of calculus in sheep on the Scottish island of North Ronaldsay was related to their predominantly seaweed diet. Calculus was most severe around the cranial cheek teeth, increased in severity with age, was associated with periodontal disease, and contained large amounts of calcium, magnesium, and phosphorus.
Materia alba, which adheres to teeth, is a mixture of salivary proteins, desquamated epithelial cells, disintegrating leukocytes, and bacteria. The bacteria are not organized, and materia alba is easily removed. It is distinct from dental plaque, and from food debris, which also accumulates between uncleaned teeth.
Dental caries. Dental caries is a disease of the hard tissues of teeth, characterized by demineralization of the inorganic part and enzymatic degradation of the organic matrix. Erosions of teeth are characterized by removal of hard tissues layer by layer. These definitions permit the inclusion of equine infundibular necrosis as a form of caries (see following sections). Caries is common in horses and sheep but rare in dogs. Cats are commonly subject to caries-like odontoclastic resorptive lesions of uncertain etiopathogenesis.
Severe, experimental malnutrition also produces malocclusion. Recovery from malnutrition does not correct the lesion, and in addition, is associated with misshapen, malformed teeth, oligodontia, and polyodontia.
The major effects of odontodystrophies in herbivores are malocclusion, and/or accelerated attrition. Sometimes a high incidence of these abnormalities is attributable to one of the causes previously discussed, but often they are idiopathic.
A syndrome of dental abnormalities of sheep in the North Island of New Zealand is characterized by excessive wear of deciduous teeth, maleruption and excessive wear of permanent teeth, periodontal disease involving permanent teeth, and development of dentigerous cysts involving permanent incisors. Mandibular osteopathy is also present. Animals older than 5 years are culled for dental problems. The odontodystrophy (and osteodystrophy) is possibly caused by deficiencies of calcium and copper, and perhaps other nutrients, such as protein, and energy. This syndrome exemplifies the naturally occurring odontodystrophies, in that it probably has a complex pathogenesis, and is associated with an osteodystrophy. The latter association is to be expected, because bones and teeth are usually susceptible to the same insults.
Although dental lesions are not described, tooth loss caused by periosteal dysplasia and osteopenia occurs in Salers cattle afflicted with hereditary hemochromatosis.
The role of viruses in enamel hypoplasia is mentioned previously. Bacterial plaque, along with other tooth-accumulated materials, is discussed here.
Bacterial diseases involving tooth surfaces are caused by the development of supragingival and subgingival plaque. Supragingival plaque is located on the exposed crown of the tooth and causes dental caries. Subgingival plaque is found in the crevicular groove and causes periodontal disease. Tooth enamel is covered by a translucent pellicle, the acquired enamel pellicle, which is formed by selective adsorption of complex salivary proteins, and that is essential to the development of supragingival plaque. This is a dense, nonmineralized, bacterial mass, firmly adherent to tooth surfaces, which resists removal by salivary flow and prevents the buffering capacity of saliva from influencing plaque metabolites. Formation of this plaque involves adhesion of bacteria to the pellicle, and adhesion of bacteria to each other, producing a biofilm. Initial bacterial binding to the tooth surface is reversible through electrostatic and hydrophobic interactions, but this transitions to permanent receptor mediated binding.
Only organisms with the ability to adhere to the pellicle can initiate the formation of supragingival plaque; those that cannot are removed by oral secretions and mechanical action. Pathologic reduction of salivary flow, or regions of teeth where flow is reduced (interproximal regions and areas of pits or fissures) increases the prevalence of caries in some species.
The bacteria in supragingival plaque are members of the indigenous oral flora and are usually gram-positive aerobes. Most are streptococci and Actinomyces spp., which form an organized array on the tooth surface. Some plaque-forming bacteria synthesize extracellular polymers, which constitute the matrix of the plaque and permit adhesion between organisms of the same species. Some utilize polymers derived from the dentinal tubules. Production of reparative dentin in the pulp cavity is expected. Horses may also develop peripheral caries outside of the infundibulum. This typically occurs in the caudal cheek teeth and leads to loss of cementum that may contribute to irregular wear and periodontal disease.
In sheep, the proximal surfaces of mandibular teeth are usually affected by caries, which is commonly accompanied by periodontitis. Erosions of the neck region of the deciduous teeth occurred in sheep in New Zealand. The lesions were mainly located apical to the enamel-dentin junction on the labial or lingual surface. They did not seem to be related to the usual causes of localized tooth destruction.
Cattle develop loss of dentin just below the crown of incisor teeth at increasing frequency with age. This usually follows recession of the gingiva, and is not considered to be a form of caries, but proteolytic digestion of dentin by chyme in an alkaline pH.
In dogs, caries most commonly involves the fourth premolar and the first and second molars. Although relatively uncommon, when caries occurs, defects are often multiple and advanced, leading to therapeutic extraction.
Cats, whose teeth do not have centers where food can collect, very commonly develop multiple caries-like odontoclastic resorptive lesions, initially involving the subgingival neck or upper root, most often of cheek teeth, and increasing in prevalence with age. This is not a true caries lesion. Odontoclasts are similar to osteoclasts and participate in absorption of roots of deciduous teeth. For reasons that are not entirely clear, they are recruited or form at the tooth and begin to There are 2 types of caries: 1. Pit or fissure caries develops in irregularities or indentations, which trap food and bacteria, usually on the occlusal surface of the tooth. Plaque is not essential for initiation of this form of caries, of which equine infundibular necrosis is an example. 2. Smooth-surface caries usually occurs on proximal (adjacent) surfaces of teeth, typically just below contact points, or around the neck, and requires dental plaque for its initiation.
The organic acids, principally lactic, which initiate demineralization, are produced by bacterial fermentation of dietary carbohydrates. In smooth-surface caries, plaque produces the acid and maintains a low pH on the surface of the tooth. Progression of lesions depends on various factors such as salivary pH, hardness and resistance to demineralization of enamel, and frequency of access to carbohydrate. Demineralization of enamel often occurs in the subsurface enamel but progresses to caries only with prolonged exposure to acid. Infrequent exposure allows remineralization of enamel between meals. The enzymes that lyse the organic matrix are probably produced by plaque, but may be derived from leukocytes, for which plaque is chemotactic. Carious enamel loses its sheen and becomes dull, white, and pocked. When dentin is exposed, it becomes brown or black. Dentin is softer and more readily demineralized than enamel, and a pinpoint lesion in enamel may lead to a large defect when the carious process reaches the dentin. Enamel loss to caries is permanent, whereas odontoblasts at the pulp/dentin junction can generate tertiary dentin in response to dentin damage and loss. Nerve endings have not been identified at the enamel-dentin junction, and the pain of caries is thought to be caused by chemical or pressure changes in the dentinal tubules. Neuropeptides, including substance P, are generated in the pulp and may enhance pain during caries. Spread of infection along the dental tubules to the pulp cavity may result in formation of reparative dentin, pulpitis, or periapical inflammation and tooth loss.
In horses, infundibular necrosis is the most common form of caries. It develops most often on the occlusal surface of the maxillary first molar. The enamel invaginations (infundibula) in the cheek teeth of horses are normally filled with cementum before the teeth erupt. Filling proceeds from the occlusal surface toward the apex, but often is not completed before eruption. At this time the blood supply is cut off, and ischemic necrosis of any residual cementogenic tissue in the infundibula occurs ( Fig. 1-5A ). The deficiency of cementum is called hypoplasia.
Teeth with incompletely filled infundibula may accumulate food material and bacteria. This can lead to bacterial fermentation and lactic acid production that demineralizes the cementum over the infundibulum (Fig. 1-5B ). In some animals, the cavitated area expands to involve all the cementum and the adjacent enamel and dentin. This may result in coalescence of adjacent infundibulum and creation of a large defect in the occlusal surface. Decay of the mineralized tissues and coalescence of infundibula may progress to fracture of the tooth, root abscess, and empyema of the paranasal sinuses. The incidence of infundibular necrosis increases with age, and 80-100% of horses older than 12 years may have the lesion. Most are without signs, and in most, the lesion does not progress. Inflammation of the dental pulp, in horses and in other species, may result from direct expansion of caries from penetration of bacteria and bacterial degradation products along A B The exposed pulp canal is healed in 30-50 days by deposition of reparative dentin and secondary dentin. Similar healing presumably occurs in most piglets. Maxillary (malar) abscess of dogs involves the periapical tissues usually of the carnassial tooth, and may cause a discharging sinus beneath the eye. The pathogenesis of the abscess is obscure, but it may be a sequel to crown fractures or to pressure necrosis of periapical tissues. Some chronic inflammations of the pulp become slowly expansive spherical granulomas about the root apex (root granulomas). Occasionally these granulomas are enclosed by an epithelial cyst (periodontal cyst) derived from cell rests of Malassez. The epithelium contains plasma cells, and the combination may have a protective role in periapical sepsis.
Periodontal disease. Periodontal disease is the most common dental disease of dogs and sheep, and an important problem in other ruminants, horses, and cats. Although there are minor differences among species, in general, periodontal disease begins as gingivitis associated with subgingival plaque, and may progress through gingival recession and loss of alveolar bone to chronic periodontitis and exfoliation of teeth.
The gingival sulcus, or crevice, is an invagination formed by the gingiva as it joins with the tooth surface at the time of eruption. Clinically normal animals have a few lymphocytes, plasma cells, and macrophages under the crevicular epithelium of the gingiva, which forms the outer wall of the crevice. Low numbers of lymphocytes, plasma cells, and macrophages are also present under the junctional epithelium, which is apposed to the enamel of the tooth.
Clinical gingivitis is usually initiated by accumulation of plaque in the crevice, but may be associated with impaction of feed, especially seeds, between teeth. Gingivitis is initially characterized by increased numbers of leukocytes and fluid in the gingival crevice, and then by acute exudative inflammation and accumulation of neutrophils, plasma cells, lymphocytes, and macrophages in the marginal gingiva. If the disease progresses, marked loss of gingival collagen fibers, which hold the gingiva to the adjacent tooth, occurs in a few days. This is probably related to the activity of prostaglandins and matrix metalloproteinases generated in inflamed tissue, or possibly enzymes from plaque bacteria, such as Porphyromonas gingivalis, which also produce enzymes (gingipains) thought to damage junctional epithelium. Porphyromonas spp. are implicated as obligate pathogens for canine gingivitis, and as probable participants in feline gingivitis/periodontitis. Grossly the gingiva is red and swollen because of the hyperemia and edema of inflammation. Acute gingivitis may become quiescent, with lymphocyte aggregations beneath the junctional epithelium. Halitosis is associated with gingivitis in small animals.
Continuation and exacerbations of the inflammation cause apical recession of the tooth-gingiva junction, and resorption of alveolar bone ( Fig. 1-6) . Alterations in the periodontal flora may be responsible for these exacerbations. A major part of chronic periodontal disease is resorption of alveolar bone, which modifies the attachment site of the periodontal ligament. If concomitant bone loss precedes gingival recession, the sulcus is deepened to form a periodontal pocket, which is lined by transformed junctional "pocket" epithelium, and becomes the site of chronic active inflammation. When gingival recession precedes loss of alveolar bone and gingival collagen, pockets do not form, but tooth roots are exposed. In either case, destruction of the periodontium and periodontal ligament, resorb enamel and eventually dentin. A reddened swollen area of gingiva or granulation tissue often lies over the lesion, which may be on the labial or buccal aspect, and frequently is painful to touch. The resorptive lesions begin as shallow defects in the cementum, lined by odontoclasts, facing a somewhat disorganized periodontal ligament. They progress into the underlying dentin, and, with time, into the root canal. Either or both coronal and apical extension of lesions may occur. Extension of the process coronally more superficially undermines the enamel, which is resorbed or breaks off, causing destruction or loss of the crown. Extension of the dentinal lesion apically leads to resorption of the root. Remnants of the root may persist, often overgrown by gingiva, following loss of the crown. Conversely, destruction primarily of the root may result in obliteration of the periodontal ligament, resorption of adjacent alveolar bone, but with odontoalveolar ankylosis by reparative hard tissues, retaining the crown in the dental arcade. In addition to the odontoclasts that line the resorbing cementum or dentinal surfaces of the lesion, more advanced defects contain a mixed leukocyte population, macrophages, and disordered granulation tissue. Repair is often superimposed, with cementoblastic or osteoblastic cells producing new mineralized tissue of varied osteoid, bone, cementum, or osteodentin morphology. Pulpitis may occur in the affected root canal, and reparative dentin may be deposited there. The prevalence of such lesions has increased markedly in the past 40 years, suggesting an association with changes in form of diet, but the lesion is idiopathic, with no clear relationship to periodontitis, mechanical trauma, viral infections, or nutritional or metabolic disturbances. A number of factors have been proposed to be involved with feline resorptive lesions, including local inflammatory mediators, increased vitamin D intake, and local pH.
Pulpitis. The dental pulp is derived from the dental papilla. It is surrounded by odontoblasts and dentin, except at the apical foramen, through which vessels and nerves pass. Pulp is a loose syncytium of stellate fibroblasts, and contains histiocytes and undifferentiated mesenchymal cells. The latter are odontoblastic precursors.
The apical foramen is located at the apex of the root and is where blood vessels and nerves enter the tooth. The apical foramen is narrow, and this predisposes to vascular occlusion, ischemic necrosis of the pulp, and death of the tooth. Production of abundant secondary dentin and reparative dentin can cause occlusion, but the usual cause is inflammation. Normally, pulp is the only vascular tissue of the tooth, and, along with the periodontium, the only site of conventional inflammation. Pulpitis is always related to infection, the effect of bacteria or their products entering through the surface of fractured teeth, carious perforations (especially in teeth with enamel defects), perforations resulting from abnormal wear or trimming, from periodontitis, and possibly hematogenously. In herbivores, in which the pulp is divided by enamel foldings, inflammation is usually limited to one division, and is usually purulent. Very mild pulpitis may heal, but usually it terminates in tooth necrosis, periapical abscessation, perhaps with fistula formation, osteomyelitis, or gangrene as inflammation of the pulp extends to the periodontium and the jaws.
Periapical abscess and osteomyelitis of the jaws are complications of pulpitis that may follow clipping the tusks ("needle teeth") of piglets. Trimming of the incisor teeth of sheep to avoid the effects of broken mouth often exposes the pulp cavity, but the pulpitis that ensues is rarely chronic.
The sequelae of suppurative periodontitis are many, being mainly variations on a theme of osteomyelitis. The osteomyelitis of actinomycosis is discussed in Vol. 1, Bones and joints. If the mandible is involved, the fistula usually develops on the ventral margin. If the maxillary molars are involved, fistulation may occur into the maxillary sinus. If the premolars are involved, fistulation may develop into the nasal cavity or externally. In dogs, involvement of the canine teeth may produce internal or external fistulae, and involvement of the maxillary carnassials usually produces a fistula beneath the eye, and orbital inflammation. Fistulation may be prevented for some time, or permanently, by ossifying periostitis over the involved bone. Fistulae in the upper jaw tend to be persistent. In the lower jaw, they may heal, usually with extensive deposition of new bone. Occasionally, especially in horses, chronic mild periodontitis may be confined by the periodontium, which is, however, expanded by granulation tissue to form a root granuloma. Under the same circumstances, there may be hyperplastic exostosis of the cementum. and resorption of alveolar bone, cementum, and root dentin, lead to exfoliation of teeth.
Gingivitis is common in dogs. Usually it is proliferative, the gingiva being replaced by collagen-poor, highly vascular granulation tissue, which appears as a red, rolled edge next to the tooth. In dogs, gingival pocket formation is quite unpredictable and may be present on one root of a tooth and absent on the other. Bone loss in dogs is often more severe at the bifurcation of two-rooted teeth than in interproximal areas (gingiva between teeth). Resorption of bone is associated with osteitis as the inflammation extends from the periodontium into alveolar bone. In dogs, the premolars and, to a lesser extent, the first molars and central incisors are most severely affected, whereas the second molars and mandibular canines are quite resistant.
Gingivitis is among the most common veterinary problems in cats. In general, it resembles that in dogs. Gingivitis in cats is also associated with the feline stomatitis/glossitis complex addressed in the following sections.
In sheep, periodontal disease may involve all teeth, but the effects are most severe on the incisors, and periodontal disease is a major cause of premature exfoliation. Sheep develop acute gingivitis during tooth eruption, in association with accumulation of subgingival plaque around the tooth. In some sheep, chronic gingivitis involving the lingual aspect of the incisors ensues, and on farms with a high incidence of broken mouth (lengthening of the incisor crown, forward protrusion, and loosening of the teeth), this progresses to chronic active periodontal disease.
Cara inchada (swollen face) is an epidemic periodontitis of cattle, formerly common in the west-central part of Brazil. Animals of 2-14 months were mostly affected, and herd prevalences of more than 50% were recorded. When progressive, cara inchada causes loss of teeth, leading to malnutrition. It is associated with dental eruption, and ingestion of forage thought to contain low levels of antibiotics derived from soil actinomycetes that permit colonization of the periodontal space by a variety of gram-negative bacteria, including Prevotella (Bacteroides) melaninogenica.
Severe periodontitis and tooth loss are an important part of the syndrome associated with bovine leukocyte adhesion deficiency.
embedded in the ulcers. The ulcers vary in size from 1 mm to 5 cm in diameter and are mainly located at the junction of the labial and gingival mucosa adjacent to the upper corner incisors, the lingual frenulum, the sublingual folds, the base of the dorsum of the tongue, and the soft palate. Similar lesions in horses have been associated with contamination of hay by foxtail.
Swine have a diverticulum of the pharynx in the caudal wall immediately above the esophagus, and barley awns and other rough plant fibers occasionally lodge here and penetrate the pharynx. This occurs mainly in young pigs, and death follows pharyngeal cellulitis. Similar problems occur in sheep following improper use of drenching guns, and in cattle injured by balling guns.
Inflammatory processes of the oral cavity (stomatitis) may be diffuse or focal and they may predominantly affect certain regions to produce, if (1) the pharynx is involved, pharyngitis;
(2) the tongue, glossitis; (3) the gums, gingivitis; (4) the tonsils, tonsillitis ( Fig. 1-8) ; and (5) the soft palate, angina. Lesions limited to the mucosa of the oral cavity are termed superficial stomatitides. Processes seated in connective tissues of the mouth, the deep stomatitides, are usually sequelae to transient superficial lesions.
Superficial stomatitis. Inflammatory changes may be associated with ingestion of irritating chemicals such as caustic or toxic compounds. An example is paraquat, a herbicide that may cause severe erosive stomatitis in dogs. Dogs and cats that chew on the plant Dieffenbachia may develop oral erosions and ulcers. Electrical burns are occasionally seen in puppies or kittens that chew through electrical wires. It is often not possible to differentiate the cause of diffuse stomatitis, but an attempt to do so is important because it may indicate a systemic disease state. Viral diseases causing stomatitis will be considered in detail in the section on Infectious and parasitic diseases of the alimentary tract later in this chapter.
Inflammatory disease, localized to the buccal cavity and not part of systemic viral disease, is also common and important. It is generally caused by the indigenous bacterial flora. The oral microbiota ordinarily contains many microbial species, indicative of septicemia, and larger ones may accompany local inflammation, trauma, and the hemorrhagic diatheses. Petechiae on the ventral surface of the tongue and frenulum in horses are consistent with equine infectious anemia, or other thrombocytopenic or purpuric conditions. The active hyperemia that gives the diffuse pink coloration to the mucosa in diffuse stomatitis disappears immediately at death, so that at autopsy the inflamed mucosa is disappointingly blanched.
The presence of feed in the mouth of a cadaver is abnormal, except in ruminants, which may eructate and have feed in the caudal pharynx at the time of death. In most cases it is attributable to disease, which results in paralysis of deglutition or semiconsciousness. It is common in horses with encephalitis, leukoencephalomalacia, and hepatic encephalopathy. The food in such cases is usually poorly masticated and readily differentiated from that refluxed postmortem. Bones or other large foreign bodies lodged in the pharynx of cattle suggest pica of phosphorus deficiency. They may cause asphyxiation or pressure necrosis in the wall of the pharynx. Large portions of root crops may also lodge in the pharynx. Dogs often have bones and sticks that tend to be wedged across the palate behind the carnassial teeth.
In dogs, foreign-body stomatitis occurs, caused by plant fibers, burrs, or quills ( Fig. 1-7) . In mild cases, gingivitis surrounds the incisors and canine teeth. Small papules or vesicles and shallow ulcers may be evident on the tongue. Plant fibers may protrude from the lesions. Chronic cases are characterized by exuberant granulomas associated with lingual ulceration and gingival hyperplasia with plant fibers deeply embedded in these lesions. Long-haired dogs are especially prone to develop this type of lesion when they attempt to remove plant material that is trapped in their hair coat. The granulomas must be differentiated from neoplasms.
Sharp foreign bodies that cause laceration of the mucosa predispose to necrotic and deep stomatitis. Grass seeds and awns frequently impact between the retracted gingival margin and teeth in periodontitis of ruminants and exacerbate the local initial lesion, perhaps predisposing to the development of osteomyelitis. Metallic objects, including wire, may lacerate the oral mucosa, especially in cattle. Horses fed dry triticale hay may develop severe oral ulceration, with masses of awns Traditionally, vesicular stomatitides in animals were associated with viral infections, and these are still important causes. Vesicular stomatitis and foot-and-mouth disease are associated initially with vesicle formation; however, rinderpest, bovine viral diarrhea, and malignant catarrhal fever produce sharply demarcated erosive/ulcerative lesions without initial vesicle formation. Oral erosions and ulcers in horses, ruminants, and swine should be regarded as indicating one of the vesicular diseases to which the species is susceptible, until proved otherwise (see section on Infectious and parasitic diseases of the alimentary tract, later in this chapter). Sunburn, photoirritation associated with grazing on celery and related crops, and lesions associated with parvovirus infection in swine may cause lesions of the snout resembling vesicular diseases. Animals exposed to irritant chemicals in feed or bedding may develop vesicles and erosions of the face and oral cavity, for example, toxicity in horses and dogs associated with irritant quassinoids found in wood shavings derived from Simaroubaceae species.
Bullous immune skin diseases are recognized with increased frequency, especially in dogs, and some of these have severe oral lesions, which are described here (see also Vol. 1, Integumentary system).
Pemphigus vulgaris is a severe, acute or chronic, vesiculobullous autoimmune disease mediated by autoantibodies to the desmosome protein desmoglein 3, which is involved in joining adjacent epithelial cells to each other. Desmoglein is highly expressed in suprabasal oral epithelium. Pemphigus vulgaris is most common in dogs and cats with rare reports in horses. It is characterized by acantholysis of the epidermis, which results in formation of flaccid bullae and erosions involving mainly mucocutaneous junctions, oral mucosa and, to a lesser extent, skin. Canine pemphigus vulgaris follows a similar pathogenesis to that of humans with overexpression of the proto-oncogene c-Myc before acantholysis and bullae formation. c-Myc overexpression is likely a consequence of anti-desmoglein 3 antibody binding to its target on basal keratinocytes. Clinically affected dogs and cats have erosions/ ulcerations of the oral mucosa and may drool. The oral lesions are generally more prominent than, and precede, the skin lesions. They are most obvious on the dorsal surface of the tongue, which is bright red, with a few scattered pink raised areas representing islands of normal mucosa. The lesions vary greatly in severity and distribution, although the hard palate is often severely ulcerated. Bullae are rarely seen in the oral cavity, because they ulcerate rapidly. Oral pemphigus vulgaris lesions have also been associated with drug reactions in dogs and cats.
Microscopically, the earliest lesion consists of suprabasilar acantholysis, which is followed by the formation of clefts. These lead to ulceration of the mucosa. The basal cells of the epidermis remain attached to the basement membrane and form a so-called "row of tombstones." A few neutrophils and eosinophils may infiltrate the epithelium. There is a variable lymphocytic and plasmacytic lichenoid reaction in the propria. The presence of suprabasilar clefts and bullae caused by acantholysis is considered to be diagnostic of pemphigus vulgaris. However, extensive erosion and ulceration of the mucosa and secondary bacterial infections frequently obscure these clefts and bullae. Several biopsies from different areas of the oral mucosa may be required to demonstrate the characteristic lesions. A presumptive histologic diagnosis should be supported by direct immunofluorescence tests that show mainly anaerobes such as Actinomyces, Fusobacterium, and spirochetes, which exist in balance with each other and in harmony with the host. Disruption of this microfloral balance may lead to stomatitis. The oral mucosa is quite resistant to microbial invasion for several reasons. These include the squamous mucosal lining; antibacterial constituents of saliva such as lysozyme; immunoglobulins, especially immunoglobulin A (IgA), in oral secretions; and the presence of a rich submucosal vascular network and inflammatory cells. Factors altering the balance of indigenous organisms are not well delineated. Systemic illness, stress, and nutritional and hormonal imbalances may alter the microbial population by altering the amount, composition, and pH of saliva. The integrity of the oral epithelium depends on a high rate of epithelial regeneration to balance loss resulting from a high rate of abrasion and desquamation. Rapid epithelial replication promotes quick healing of superficial lesions.
The lamina propria of the oral epithelium is well vascularized, but generally dense and relatively inelastic. For this reason, there is little distention of lymphatics and tissue spaces with fluid exudate, and therefore swelling resulting from edema is not a significant part of stomatitis involving hard palate and gums, with the exception of the gingival margins.
Catarrhal stomatitis. Catarrhal stomatitis is superficial inflammation of the oral mucosa, which usually involves the caudal fauces and may be associated with mild gingivitis. It is a common nonspecific lesion, which often develops in the course of debilitating diseases. The mucosae are hyperemic, and the loose texture of the submucosa in the fauces permits development of edema. The swelling is aggravated by edema and hyperplasia of the abundant lymphoid tissues of the soft palate, tonsil, and pharyngeal mucosa. The epithelium accumulates, producing a dull gray mucosal surface. Palatine glands produce excessive mucus. Catarrhal stomatitis resolves with the return of normal oral function.
Thrush, or oral candidiasis, occurs most commonly in foals, pigs, and dogs. It involves the proliferation of yeasts and hyphae in the parakeratotic superficial layers of the oral epithelium. It appears grossly as patchy pale-gray pseudomembranous material on the oral mucosa and back of the tongue, and probably reflects alterations in epithelial turnover and oral microbiota (see section on Infectious and parasitic diseases of the alimentary tract, later in this chapter). Mold products of Stachybotrys alternans cause catarrhal and necrotizing stomatitis, as well as colitis, if feed is contaminated. Gingivitis and ulceration of the oral mucosa may rarely be associated with infection caused by Nocardia spp. in dogs.
Vesicular stomatitides. Stomatitis characterized by the formation of vesicles occurs in most species of domestic animals. The vesicles develop as accumulations of serous fluid within the epithelium or between the epithelium and the lamina propria. These may coalesce to form bullae, and the elevated epithelium is easily rubbed off during chewing to leave raw eroded patches with bits of epithelium adherent. The transition from vesicle to erosion occurs rapidly, so that, in individual animals, vesicles may not be seen. This is especially so in dogs and cats because the oral mucosa is very thin. Because the basal epithelium or basement membrane remains intact, regeneration and healing are complete in a few days unless the local lesions are complicated by bacterial or mycotic infections. However, foci of previous erosion may be identifiable for some months by their slight depression and lack of pigmentation. mucous membrane pemphigoid, but the autoantibodies may be recognized binding to the lower part of the basement membrane.
The oral lesions of pemphigus vulgaris and of the subepidermal blistering diseases must be differentiated from lesions caused by trauma, toxic epidermal necrolysis, drug eruptions, chronic uremia, mucocutaneous candidiasis, and lymphoreticular malignancies.
Feline calicivirus causes mainly a respiratory infection in cats. The disease is complicated by lingual and oropharyngeal ulcers, which start out as vesicles. They are 5-10 mm in diameter, smooth, and well demarcated from the surrounding normal mucosa. They occur mainly on the rostrodorsal and lateral surfaces of the tongue and each side of the midline of the hard palate. The palatine lesions are apparently more severe in cats fed dry food. Microscopically, the earliest lesions consist of foci of pyknotic cells in the stratum corneum and superficial stratum spinosum. They progress to foci of necrosis with vesicle formation and subsequent erosion and ulceration of the mucosa. Regeneration of the oral mucosa in the ulcerated areas generally occurs within 10-12 days. A single layer of squamous epithelial cells extends from the margins of the ulcer beneath a layer of exudate. Active viral replication also takes place in the tonsillar crypt epithelial cells, and virus may be recovered from these areas for weeks postinfection. Viral inclusions have not been observed in oral epithelial cells. The virus is isolated from a high percentage of cats with chronic stomatitis. Concurrent infection with felid herpesvirus 1 may also occur.
Erosive and ulcerative stomatitides. This form of stomatitis is characterized by local epithelial defects of the oral mucosa and nasolabium and is usually associated with acute diffuse stomatitis and pharyngitis. Erosions are circumscribed areas of loss of epithelium, which leave the stratum germinativum and basement membrane more or less intact. They are usually associated with acute inflammation in the underlying propria. The erosions vary in size and shape. Although they are often a nonspecific development in a wide variety of conditions, they are also an essential part of a number of important diseases. They heal cleanly and quickly, but if secondarily infected or complicated, may develop into ulcers.
Ulcers, in contrast to erosions, are deeper deficiencies that extend into the substantia propria. They too vary greatly in size and shape; the edges tend to be elevated and ragged, and when they heal, it is with scar formation.
The causes of ulcerative stomatitis are in general those of erosive stomatitis. There are, however, a number of recognized syndromes and specific diseases in which the predominant change is ulceration. Phenylbutazone intoxication in horses may cause oral ulcers in concert with ulcers of the stomach, intestine, and colon; the syndrome is discussed with ischemic diseases of the gut.
Chronic gingivostomatitis-a progressive stomatitis that involves the palatoglossal arches, gingiva, palate, and tongueis most common in cats, but occurs at a lower frequency in dogs. A number of terms have been used to describe these clinical entities, including lymphoplasmacytic stomatitis and plasma cell gingivitis-stomatitis-pharyngitis. There are commonalities and differences among the manifestations of these entities, and it is likely that they represent a continuum of disease processes. Two broad categories are described in the following, with the understanding of their overlapping clinical signs, gross and microscopic pathology, and potential etiologies.
autoantibodies (usually IgG) and complement in the intercellular spaces of stratified squamous epithelium.
Bullous pemphigoid is a term that has been applied generically to superficial autoimmune vesiculobullous or ulcerative disease of mucous membranes (including the oral mucosa) and skin, characterized by subepithelial clefting; acantholysis is not a feature. It has been reported in humans, horses, dogs, and cats. It is now recognized that there is a complex of autoimmune subepidermal blistering diseases, varying in their target antigen, clinical manifestations, and prognosis. Those involving the oral cavity of cats and dogs include bullous pemphigoid, mucous membrane (cicatricial) pemphigoid, and canine epidermolysis bullosa acquisita. All are characterized by circulation of IgG and IgE autoantibodies against specific basement membrane antigens. The characteristic microscopic lesions of all are transient subepidermal blisters, which may contain fibrinocellular exudates with variable numbers of neutrophils and eosinophils. Differentiation and diagnosis of each is by the detection of circulating antibody directed at appropriate antigens, using ELISA or immunofluorescent tests, or by identification of immunoglobulin fixed to basement membrane. Paraneoplastic bullous stomatitis characterized by subepithelial clefting has been reported in a horse with a hemangiosarcoma.
Bullous pemphigoid is retained as the name for the second most common of the autoimmune subepidermal blistering disease in dogs and cats. The lesions mainly occur on haired skin, and a minority of cases involve the mucocutaneous junctions or mucosae, including the mouth, which is affected about one-third of the time. Microscopically, there is a rich neutrophilic and eosinophilic dermal infiltrate adjacent to, and sometimes spilling into the subepidermal bullae. The targets for the autoimmune response are epitopes on canine collagen XVII (also called bullous pemphigoid antigen 2 or BPAg2). Collagen XVII is an epithelial transmembrane protein that is a component of the hemidesmosome that joins basal keratinocytes to the lamina densa of the basement membrane.
Mucous membrane pemphigoid is the most common autoimmune subepidermal blistering disease of small animals, causing about half of all cases. Adults are predominantly affected, and among dogs, German Shepherds are overrepresented. The oral mucosa is a common site for lesion development, including gingiva, palate, and tongue. Typically, subepidermal vesicles in mucous membrane pemphigoid are associated with a relatively sparse inflammatory infiltrate. The antigen targeted by autoantibodies is collagen XVII or, in a low number of cases, laminin-5. Basement membrane-fixed immunoglobulin is detected by direct immunofluorescent or immunoperoxidase staining of formalin-fixed paraffinembedded tissue.
Epidermolysis bullosa acquisita is a rare disease of dogs, representing about 25% of cases of autoimmune basement membrane diseases, with a poor prognosis. The associated autoantibodies are directed against collagen VII, which makes up the anchoring fibrils that join the lamina densa of the basement membrane to the type I collagen of the dermis. The lesions are most common on skin, and advance rapidly to erosions at points of friction, but the oral epithelium often sloughs extensively. Intact subepidermal vesicles may contain no inflammatory cells, or neutrophils may accumulate at the basement membrane, sometimes forming subepidermal microabscesses. The results of serum or cutaneous immunofluorescent tests resemble those in bullous pemphigoid or neutrophils at the periphery of the ulcers, with plasma cells and mast cells in the lamina propria. Eosinophils and macrophages may not be prominent, especially in the chronic stages of the lesion.
Eosinophilic ulcer is one of the 3 different types of lesions that have been associated with the so-called eosinophilic granuloma complex. The other 2 conditions, eosinophilic plaque and linear granuloma, cause mainly skin lesions, which are different clinically and morphologically from eosinophilic ulcer (see Vol. 1, Integumentary system).
Oral eosinophilic granuloma (collagenolytic granuloma) in dogs occurs as a familial disease in young Siberian Huskies. Sporadic cases have been reported in other breeds, especially Cavalier King Charles Spaniels. Affected dogs have single or multiple firm, often ulcerated, raised plaques, which are covered by yellow-brown exudate, on the lateral or ventral surfaces of the tongue. Lesions on the soft palate are less common, and here they tend to be oval to circular ulcers with slightly elevated borders.
Microscopically, foci of collagenolysis in the mid and deep zones of the lingual submucosa are surrounded by a mainly granulomatous inflammatory reaction, with macrophages, giant cells, lymphocytes, plasma cells, and mast cells. Eosinophils are a constant feature, but their numbers vary from few to many. The lesions are identical to those seen in linear granuloma of cats.
The cause is unknown, although the morphology of the lesion and the response to corticosteroid therapy suggest hypersensitivity. The familial tendency in Siberian huskies indicates that hereditary factors are involved. Eosinophilic granuloma must be differentiated from oral mast cell tumors, which also affect the tongue in dogs. Degeneration of collagen fibers is often a feature of mast cell tumors; however, in mastocytoma, the characteristic mixture of mast cells and eosinophils infiltrates the tongue and connective tissues more diffusely. The mast cells may be in various stages of degranulation, and inflammation is minimal or absent in mast cell tumors.
Horses with eosinophilic epitheliotropic disease (see Vol. 1, Integumentary system and the later section on Eosinophilic enteritis in cats and horses) may also have eosinophilic stomatitis and lingual ulceration.
Ulcerative stomatitis can be a presenting lesion in erythema multiforme in dogs, and must be differentiated from oral epitheliotropic T-cell lymphoma.
In dogs there may be foci of ulceration in the mucosa of the lip or cheek that overlies areas of severe periodontal inflammation. This has been termed chronic ulcerative stomatitis or chronic ulcerative paradental syndrome.
Feline viral rhinotracheitis is a common upper respiratory tract infection of cats caused by felid herpesvirus 1 (see Vol. 2, Respiratory system). This virus may cause ulcerative lesions in the mouth, especially on the tongue. Rarely, oral and skin ulcers may occur, without evidence of concurrent respiratory tract infection. Microscopically, foci of cytoplasmic vacuolation in squamous epithelium evolve into areas of necrosis and ulceration. The ulcers are often covered by a layer of fibrinocellular exudate. Herpetic inclusions may be present in epithelial cells at the periphery of the ulcers.
Uremia associated with chronic renal disease often causes fetid ulcerative stomatitis in dogs, and less commonly in cats. Dirty gray-brown ulcers occur on the gums, lateral surface, and margin of the tongue, and on the inner surface of the lips Feline ulcerative stomatitis and glossitis or lymphocyticplasmacytic stomatitis, is an ulcerative and chronic inflammation of the mucosa of the fauces, the angle of the jaws and, less commonly, the hard palate, gingiva, and tongue. Microscopically, there is diffuse inflammation of the oral mucosa and submucosal connective tissues, dominated by lymphocytes and plasma cells. The syndrome is more common in older cats and may accompany periodontitis. The cause is unknown, but is probably multifactorial, involving imbalance in the oral microbiota, with predominance of gram-negative anaerobes and spirochetes, leading to an overall decrease in the microbial diversity at inflammatory lesion sites. Some have reported the isolation of feline calicivirus and felid herpesvirus 1 from more cats with lesions of chronic stomatitis compared with those without, but the role of these viruses in the etiology is unresolved. Feline calicivirus can persist as a sequel to previous disease episodes and in the face of prior vaccination. Feline leukemia virus and feline immunodeficiency virus may predispose some cats to chronic stomatitis because of their immunosuppressive effects, but evidence of infection is not consistently found.
Feline plasma cell gingivitis-pharyngitis or feline chronic gingivostomatitis is characterized by raised erythematous, proliferative lesions, mainly in the glossopalatine arches, extending caudally to the palatopharyngeal arch and rostrally to the gingiva. The lesions may involve Eustachian tubes and also can affect the conjunctiva. Histologically the mucosa is hyperplastic and frequently ulcerated, with a marked submucosal inflammatory cell reaction, mainly plasmacytes, including binucleate cells and cells containing Russell bodies. Neutrophils, lymphocytes, and histiocytes are scattered among the plasma cells. Inflammation is most intense at the epidermallamina propria junction. Affected cats have elevated polyclonal serum gamma-globulin levels. The polyclonal gammopathy and the plasmacytic, lymphocytic reaction are suggestive of an immune-mediated lesion, and differentiation from mucosally associated lymphoid neoplasia may be challenging. The etiology and the relationship of this syndrome to feline ulcerative stomatitis and glossitis (see previous section) are unclear; the 2 syndromes probably form a continuum, although the plasma cell predominance and the hypergammaglobulinemia attributed to plasma cell gingivitisstomatitis are distinguishing. Similar stomatitis occurs in dogs.
Eosinophilic ulcer (eosinophilic granuloma, lick granuloma, labial ulcer, rodent ulcer) is a chronic, superficial ulcerative lesion of the mucocutaneous junctions of the lips, and, to a lesser extent, the oral mucosa and skin, in cats of all ages. The cause is unknown. A number of etiologies have been considered, including allergic disease and primary eosinophil dysfunction. The lesions may respond to corticosteroid, oral progestagens, cryosurgery, or radiation therapy, although recurrences are common. Typically, well-demarcated, redbrown, shallow ulcers, often with elevated margins, occur on the upper lip on either side of the midline. They are usually a few millimeters wide and several centimeters long. Occasionally, ulcers are present elsewhere in the mouth, such as on the gums, palate, pharynx, and tongue. Skin lesions are located in those areas that are frequently licked, such as the neck, lumbar area, and abdomen. Microscopically, the squamous mucosa is ulcerated, with large areas of necrosis of the underlying connective tissues and accompanied by a marked inflammatory cell reaction. The cellular reaction consists predominantly of fistulate through the mucosa or skin. Abscesses in the wall of the pharynx may result from necrosis of retropharyngeal lymph nodes. Necrotic stomatitis with simple necrosis of the epithelium and lamina propria may be produced by thermal or chemical agencies, but in animals, it is usually caused by Fusobacterium necrophorum and other anaerobes.
Fusobacterium necrophorum is the principal cause of oral necrobacillosis or necrotic stomatitis in animals. It is also associated with necrotizing lesions elsewhere in the upper and lower alimentary tract, and liver. Wherever it occurs, it is usually a secondary invader following previous mucosal damage ( Fig. 1-9A) . The organism produces a variety of exotoxins and endotoxins; among the latter are leukocidins, hemolysins, and a cytoplasmic toxin, all of which probably enhance the necrotizing ability of the organism. Once established in a suitable focus, F. necrophorum proliferates, causing extensive coagulative necrosis.
The best-known form of necrobacillary stomatitis is calf diphtheria, an acute necrotizing ulcerative inflammation of the buccal and pharyngeal mucosa, and also of the laryngeal mucosa (necrotic laryngitis). The predisposing lesions may include trauma, infectious bovine rhinotracheitis, and papular stomatitis. Necrosis of palatine and pharyngeal tonsils may be seen. The incidence of diphtheria in slaughtered beef cattle may be as high as 1.4%. The same syndrome is rather common in housed lambs as a complication of contagious ecthyma. The infection also may be initiated in the gums about erupting teeth in any species, and by the trauma produced in baby pigs by removing the needle teeth. It is frequently fatal in young animals, in which extension often occurs to other organs. In adults, oral necrobacillosis tends to remain localized to the oral cavity, where it may complicate vesicular and ulcerative stomatitides. It is not unusual, however, for the infection to spread down the alimentary tract. and cheeks, often adjacent to the openings of salivary ducts. The margins of the ulcers are swollen and hyperemic.
The pathogenesis of the oral lesions in uremia is poorly understood. Elevations in blood and salivary urea in combination with urease-producing bacteria, normally present in the oral microflora, may generate ammonia from salivary urea. Ammonia has a caustic effect on the oral mucous membranes. Experimental antibody production against urease renders some intestinal bacteria nonpathogenic and prevents uremic colitis, providing evidence of the importance of urease. However, there is poor correlation between the levels of blood urea and the development of uremic stomatitis, suggesting other important factors. Uremic vasculitis and impaired microvascular perfusion may contribute to the pathogenesis of uremic stomatitis.
Salivary glucose levels may be elevated in dogs and cats with diabetes mellitus, resulting in an imbalance of the oral microflora and predisposing to chronic gingivitis in diabetic animals.
Ulcerative glossitis and stomatitis in swine is commonly part of exudative epidermitis (greasy pig disease) of preweaning pigs (see Vol. 1, Integumentary system). In addition to the characteristic skin lesions, about a third of the piglets may develop ulcers on the dorsum of the tongue. Erosions and ulcers of the hard palate occur in a small number of piglets. Microscopically, there is ulceration of the squamous mucosa with coagulative necrosis, and vesicle and pustule formation in the superficial epithelium over the rete pegs. A pleocellular inflammatory reaction is evident in the connective tissue below the ulcers.
tongue." Entry of actinobacilli to the tongue may be gained through traumatic erosions along its sides, but often the primary lesion is in the lingual groove. Here, trapped grass seeds and awns may provoke the initial trauma. Lesions elsewhere in the soft tissue of the mouth may be attributed to disruption of the mucosa by similar types of insults, and eruption of, or abrasion by, teeth.
Microscopically, the lesion is a pyogranuloma, centered on a mass of coccobacilli, surrounded by radiating eosinophilic clubs made up of immune complexes ( Fig. 1-10) . The club colonies, in turn, are surrounded by variable numbers of neutrophils, and are invested by macrophages or giant cells. Lymphocytic and plasmacytic infiltrates are present in the surrounding reactive fibrous stroma or granulation tissue. An individual inflammatory focus appears grossly as a nodular, firm, pale, fibrous mass a few millimeters to 1 cm in diameter, containing in the center minute yellow "sulfur" granules, which are the club colonies.
Lymphogenous spread is common. Affected lymphatics are thickened, and nodules are distributed along their course. This distribution is best seen beneath the mucosa of the dorsum and the lateral surface of the tongue and often can be traced through to the pharyngeal lymphoid tissue ( Fig. 1-11) . Some of these more superficial nodules erode the overlying epithelium, and coalescence may produce quite large ulcers. The most common form of lingual actinobacillosis consists of The early lesions are large, well-demarcated, yellow-gray, dry areas of necrosis, surrounded by a zone of hyperemia ( Fig. 1-9B ). They are found on the sides or dorsal groove of the tongue, on the cheeks, gums, palate, and pharynx, especially the recesses beside the larynx. Primary foci may occur in the laryngeal ventricles. Lesions near the larynx often lead to respiratory distress and death may be associated with asphyxia. The necrotic tissue projects slightly above the normal surface, and is friable but adherent and is not easily detached. In time it may slough and leave deep ulcers, which may heal by granulation. The necrotic tissues are histologically structureless and are surrounded at first by a zone of vascular reaction, later by a dense but narrow rim of leukocytes, and finally by thick encapsulating granulation tissue. The bacteria are arranged in long filaments, particularly at the advancing edge of the lesions. The submucosal extension of the lesions may take them deeply into the underlying soft tissues and bone.
Spread from the oral foci occurs down the trachea (causing aspiration pneumonia), down the esophagus, and via blood vessels. Death may occur acutely in septicemia with only multiple small serosal hemorrhages as evidence, or metastases may occur in other tissue. Venous drainage from the face to the vascular sinuses of the meninges may lead to pituitary and cerebral abscessation. A gross diagnosis of oral necrobacillosis is ordinarily possible, but may be confirmed by a smear from the margin of the lesion. The organism is difficult to cultivate because it is a strict anaerobe.
Fusobacterium equinum is a recently described bacterial opportunist that is closely related to F. necrophorum. It is a component of the normal microbiota of the equine gastrointestinal, reproductive, and respiratory mucosa. F. equinum produces a leukotoxin and is associated with necrotizing lesions, including the oral cavity in horses.
Noma (cancrum oris) is a rapidly spreading pseudomembranous or gangrenous stomatitis; it is not caused by a specific pathogen but is associated with tissue invasion by the normal oral flora, particularly fusobacteria and spirochetes with widespread local tissue destruction. The predisposing factors are unknown, but they are probably nonspecific and associated with mucosal trauma and debility. The disease, which is occasionally observed in horses, dogs, and monkeys, is in many respects similar to oral necrobacillosis. In the lesions, the spirochetes can be found in large numbers at the advancing margins as well as in peripheral viable tissue. In the deep layers of necrosis, fusiforms predominate, and toward the surface, there is a variety of other organisms, chiefly cocci. The initial lesion is a small tattered ulcer of the cheek or gum, which spreads rapidly and may involve much of the buccal surface of the gums and the mucosa of the cheek. It is intensely fetid and consists of a dirty necrotic pseudomembrane surrounded by a zone of acute inflammation. The necrotic tissue may slough to leave deep ulcers; the cheek may be perforated to leave a gaping defect, or gangrene may supervene.
Actinobacillosis is a disease mainly of cattle, sheep, and pigs, leading to stomatitis, glossitis, lymphadenitis, and sometimes pyogranulomas in the wall of the forestomachs of ruminants. Actinobacillus lignieresii is part of the normal oral flora, and in cattle is associated with deep stomatitis.
Actinobacillosis is typically a disease of soft tissue, spreading as a lymphangitis and usually involving the regional lymph nodes. This distinguishes it from actinomycosis, which causes mostly bone lesions. The tongue is often involved in actinobacillosis, and the chronic condition produces clinical "wooden
The tonsils are normally prominent and protrude slightly from the tonsillar fossa in the dog and cat. In these species, tonsils are compact, fusiform structures with a finely stippled, pale pink mucosal surface. In swine, tonsillar lymphoid tissue is granulation tissue in which are embedded many small abscesses surrounded by a dense connective tissue capsule. The epithelium overlying these large granulomas may be intact or ulcerated. Diffuse sclerosing actinobacillosis of the tongue (wooden tongue) is firm because of extensive proliferation of connective tissue, which replaces the muscle fibers. Granulomatous nodules are sparsely scattered in the fibrous stroma.
Although actinobacillosis in cattle is best known as a disease of the tongue, the infection may occur in any of the exposed soft tissues, especially those of mouth and esophagus; occasionally it involves the wall of the forestomachs, the skin, or the lungs. Lesions in these sites resemble those described in the tongue. Actinobacillosis causes regional lymphadenitis. The cut surface of the node reveals small, soft yellow or orange granulomatous masses that project somewhat above the capsular contour and contain "sulfur" granules. There is also sclerosing inflammation of the surrounding tissues, which may cause adhesion to overlying skin or mucous membranes. The retropharyngeal and submaxillary nodes are most often affected, as well as the lymphoid tissues of the submucosa of the soft palate and pharynx. Involvement of the pharynx and the retropharyngeal lymph nodes may cause dyspnea and dysphagia.
Oral actinobacillosis in swine causes lesions similar to those in cattle, including glossitis. Actinobacillosis may also occur sporadically or as outbreaks in sheep, but in this species the tongue seems to be exempt. The characteristic lesions in sheep occur in the subcutaneous tissue of the head, especially of the cheeks, nose, lips, and submaxillary and throat regions, and on the nasal turbinates. They may also occur on the soft palate and pharynx as complications of wounds received at drenching. The organism has rarely been isolated from horses.
Lesions morphologically similar to actinobacillosis may be caused by a variety of organisms. Trueperella (Arcanobacterium) pyogenes may be isolated from lingual ulcers and granulomas in lambs. Microscopic examination of these lesions reveals well-demarcated submucosal granulomas with plant fibers in the center, surrounded by a marked neutrophilic reaction. The organisms most likely gain entry after the mucosa is damaged by hard fibrous plant fibers from the weed lambsleeve sage (Salvia reflexa), present in the bedding. Actinomyces bovis, a gram-positive filamentous organism, causes pyogranulomatous mandibular and maxillary osteomyelitis in cattle and mastitis in sows. Actinomyces weissii has been isolated from dogs with stomatitis/gingivitis. Staphylococci may cause pyogranulomatous lesions (botryomycosis) in any species. Less common causes of similar microscopic lesions include Nocardia and the various agents associated with mycetomas (see Vol. 1, Integumentary system).
Oral dermatophilosis-oral infection by Dermatophilus congolensis-has been reported in cattle and cats. D. congolensis commonly causes exudative dermatitis in a wide variety of species (see Vol. 1, Integumentary system). In cattle, oral dermatophilosis has been associated with A. bovis infection. In cats, the organism is uncommonly associated with oral granulomas, especially affecting the tongue and tonsillar crypt. Large numbers of gram-positive, filamentous, branching organisms, with longitudinal and transverse divisions, may be demonstrated in the necrotic centers of submucosal granulomas. The organisms probably enter through damaged mucosa. The lesion must be differentiated from the more common squamous cell carcinomas of the tongue.
Inflammatory polyps of the tonsils occur infrequently in old dogs. They are flat to pedunculated rubbery masses (1-3 cm in length), attached to the tonsillar sinus, with a smooth to verrucous surface. Histologically, the lesions are composed of mature, sometimes edematous, highly vascularized connective tissue that is covered by squamous epithelial cells. Aggregates of lymphocytes and plasma cells are scattered throughout the connective tissue. The lesions are probably the result of chronic recurrent episodes of subclinical tonsillitis. They are usually asymptomatic but may cause gagging and retching. A tonsillar lymphangiomatous polyp has been reported from a dog.
Tumors, especially lymphosarcomas and squamous cell carcinomas, are common causes of tonsillar enlargement in dogs. Bilaterally enlarged and soft, pale swollen tonsils are usual with lymphosarcoma, and these may become clinically obvious before the development of peripheral lymphadenopathy.
Some of the lumps, bumps, and cysts that develop in and around the oral cavity are malformations, hyperplasias, and neoplasias originating in tooth germ or teeth. Malformations of dental origin have been considered previously under developmental anomalies of teeth. Gingival masses of all types, many of which are of tooth germ origin, are common in dogs, but occur much less frequently in other species. In this discussion we follow revisions in the nomenclature of lesions that formerly were included with epulis, placing those that clearly are of dental origin with other such tumors, and consigning the remainder to hyperplastic and reactive lesions. Prognostic implications for such masses have not changed, despite some reclassification.
Epulis is a generic clinical term for tumor-like masses on the gingiva. Epulis has, in the past, been used to describe developmental, inflammatory, and hyperplastic lesions, as well as several neoplastic lesions of tooth germ origin, which are numerous in dogs, and develop occasionally in cats. It has no specific pathologic connotation, and preferably, the term should not be used in a morphologic diagnosis, except in the context of fibromatous epulis of periodontal ligament origin, discussed in Tumors of dental tissues, which follows.
In evaluating lesions of the gums and jaws, a potentially confusing element is the nature of the epithelium and of the hard tissues that are often found in the stroma. In interpreting these, it is important to recall the inductive pattern of tooth development. Epithelial remnants from tooth organogenesis occur commonly in the gingiva and the periodontium, and nests of dental epithelium can be found incidentally in any concentrated in the caudal soft palate, and forms a plaque of raised and pitted thickened mucosa. In horses, tonsillar tissues are dispersed over pharyngeal and epiglottic mucosal surfaces and consist of a series of plaques and nodules in the mucosa. In cattle, there are multiple sets of tonsils, including palatine, lingual, soft palate and pharyngeal tonsils. In other species, the tonsils are diffuse. They are subject to the usual conditions involving lymphoid tissue, and undergo progressive atrophy with age.
Tonsils are part of the mucosal-associated lymphoid tissue (MALT) and are constantly exposed to antigenic stimuli, by virtue of their function in immune surveillance in the oropharynx. As a result, they are a site of functional lymphoid hyperplasia and physiologic inflammation. Many bacteria native to the oropharyngeal mucosa probably inhabit the tonsillar crypts. Consequently they may serve as portal of entry for a variety of bacterial agents and viruses. A significant percentage of swine may carry Erysipelothrix rhusiopathiae and Salmonella spp. in the tonsils, and Streptococcus suis type 2 can be cultured from tonsils.
Desquamated epithelium, bacteria, necrotic debris, and neutrophils may normally be present to moderate degree in tonsillar crypts. This reaction is exaggerated, and may be associated with ulceration of the crypt and suppuration of involuted tonsillar lymphoid tissue, in certain bacterial infections, causing the formation of visible yellow nodules. Conditions in which such bacterial tonsillitis may occur include pasteurellosis in sheep and pigs, Actinomyces and Tonsillophilus in tonsils of swine, and necrobacillosis in all species (see . In porcine anthrax, hemorrhagic necrotizing tonsillitis is reported.
Prion proteins have been identified in tonsillar tissue of infected animals. Scrapie-associated prion protein is consistently detected by immunohistochemistry in the center of primary and secondary lymphoid follicles of sheep with clinical and histologic lesions of scrapie, and this may be a useful antemortem diagnostic approach in this and other prionassociated diseases of animals. The prion protein of chronic wasting disease has been identified in tonsils of elk and deer. The prion protein of bovine spongiform encephalopathy has been shown to accumulate in palatine tonsils 10 months after experimental infection.
The tonsil is the site of primary virus multiplication in pseudorabies (Aujeszky's disease) in swine. The virus causes necrotizing tonsillitis, and intranuclear viral inclusions may be seen in cryptal epithelial cells.
Involution of B-dependent tonsillar lymphoid follicles resulting from viral lymphocytolysis may occur during the early phase of a number of lymphotropic diseases such as feline panleukopenia, canine parvoviral enteritis, canine distemper, bovine viral diarrhea, and swine vesicular disease. Numerous karyorrhectic nuclei, lymphocyte depletion, and prominent histiocytes signal such damage. In distemper, involuted tonsils are susceptible to secondary bacterial invasion and suppuration. Compensatory lymphoid hyperplasia may occur during the postviremic phase of parvoviral infections and distemper. The tonsil often appears to be the preferred organ of viral persistence in a symptomatic carrier infected with feline calicivirus. In porcine circovirus 2 infections (postweaning multisystemic wasting syndrome), involution of lymphoid tissue and accumulation of macrophages and giant cells containing basophilic cytoplasmic circoviral inclusions occur, as they do in other lymphoid organs.
Further reading Lucke VM, et al. Tonsillar leukocytes, and bleeds easily. The cause is not completely understood. Pyogenic granuloma is probably an exaggerated response to local trauma, irritation, and/or infection. In horses, exuberant granulation tissue of periodontal origin sometimes develops at the site of extracted teeth to produce a tumor-like mass in the dental arcade. Epithelial remnants and proliferative bone may be associated with the granulation tissue in such cases. Peripheral giant cell granuloma (formerly giant cell epulis) occurs in dogs and cats as gingival masses, often red, that may be smooth and sessile, or pedunculated. Giant cell granuloma is the second most common gingival tumor in cats after fibromatous epulis. These lesions may not be true granulomas. Very occasionally, similar lesions, described as central giant cell granulomas, occur more deeply in the jaw. The gingival epithelium is hyperplastic or ulcerated and extends deeply into the underlying mass, which is well vascularized and often contains hemosiderin-laden cells. Characteristic of the tumor are numerous multinucleated giant cells, with multiple central nuclei and abundant eosinophilic cytoplasm, which are located in a densely cellular stroma. The nature of the giant cells is not fully known, and it is suggested that they may be osteoclastic in origin. Foci of hard tissue, including mineralized osteoid, may be present. Giant cell granulomas are regarded as hyperplastic, and have occurred at the site of tooth extraction.
Fibrous hyperplasia (formerly part of fibrous or fibromatous epulis, gingival hypertrophy) is common in dogs, and may be generalized and diffuse, or focal, localized to one or more teeth. When focal, it is a discrete tumor-like mass and, whether local or general, may cover part of the crown ( Fig. 1-12) . The stromal component of the mass consists of mature fibrous tissue with low cellular density. Foci of hard tissue and epithelial nests may be present. Local enlargement may be promoted by chronic, probably painless, inflammation. It may be associated with periodontal disease. Characteristically there is a band of mononuclear cells, predominantly plasma cells, in the gingival stroma adjacent to the epithelium, which is often hyperplastic, sometimes markedly so. Where the epithelium is ulcerated, neutrophils may be prominent, marginating in vessels, in the stroma, and migrating through the epithelium.
Diffuse fibrous hyperplasia is familial in Boxer dogs, and a more severe overgrowth, termed hyperplastic gingivitis, occurs as a recessive inherited disease in Swedish silver foxes. In the foxes, both jaws are affected and the lesion causes proliferative lesion in this region. Characteristically, dental epithelial cells show reverse polarity, their nuclei being located at the apex of the cell, distal to the basement membrane. Often the cell nests are surrounded by a relatively clear halo that contains a few strands of collagenous tissue. Also, gingival epithelium commonly proliferates extravagantly in response to irritation, and may form complex plexiform patterns. Unless there is neoplastic change; the epithelial component is not of primary significance. Similarly, many stromal masses in the regions of the jaws include mineralized tissues or amorphous, apparently mineralizable tissues, which may develop by metaplasia of fibrous tissue or by de novo cellular differentiation. It is often difficult to determine whether this is bone, cementum, dentin, or their precursors, but in any case this is prognostically irrelevant, as is the abundance of such tissues themselves. In describing lesions of the gums and jaws, the adjective "peripheral" refers to an origin in the gingiva, whereas "central" implies a deeper origin in the jaw bone.
The oral and pharyngeal mucosa is a common site of malignant tumors in the dog, as it is in cats. Malignant oral tumors account for ~6% of all canine and ~7% of all feline neoplasms. Large domestic animals have a low prevalence of malignant oral tumors, and when they do occur in ungulates, they are usually relatively nonaggressive. There are regional geographic differences in the prevalence of certain oral tumors, especially in dogs and cattle. Such differences may be related to the distribution of carcinogens in the environment, and warrant further investigation from the point of view of comparative oncology.
The most common types of malignant oral tumors in dogs and cats are squamous cell carcinoma, fibrosarcoma, and, in dogs only, malignant melanomas. They vary somewhat in their behavior depending on the species in which they occur, and the type and location of the tumor. Dogs and cats with mean ages over about 6 or 7 years of age are mainly affected. The canine population with fibrosarcomas has a mean age of about 8 years. Melanomas in dogs tend to occur in a notably older age class than the other tumors, with the mean of the distribution at about 11-12 years. Typical clinical signs, determined by the location, behavior, and stage of the tumor, are drooling, halitosis, pain, dysphagia, anorexia, weight loss, loose teeth, mandibular fractures, oral bleeding, noisy respiration, coughing, and a change in voice.
Boxers, Cocker Spaniels, German Shorthaired Pointers, Weimaraners, and Golden Retrievers apparently have a higher prevalence of malignant oral tumors than other breeds of dogs, whereas Dachshunds and Beagles apparently have a very low prevalence. The male-to-female ratio has been reported to be as high as 6 : 1 for melanomas, 3 : 1 for tonsillar carcinomas, and 2 : 1 for fibrosarcomas. The ratios have to be interpreted with some caution because they may be partly related to differences in the ratio of males to females in the general population.
All types of malignant oral tumors in dogs and cats tend to progress rapidly, and regardless of the type of malignancy, the prognosis is generally poor, unless the lesion is completely resected early in its clinical course, before metastasis.
Pyogenic granuloma is a bright red or blue mass on the gums of dogs. It is composed of extremely vascular granulation tissue covered by gingival epithelium, and is not genuinely granulomatous, despite the name. It ulcerates, is infiltrated by Viral antigen can be demonstrated in nuclei of koilocytes and in intranuclear, but not cytoplasmic, inclusions by specific immunohistochemistry. Electron microscopy reveals intranuclear 50-55 nm viral particles, sometimes forming paracrystalline arrays.
Malignant transformation of infected papillomavirusinfected epithelium to produce squamous cell carcinomas can occur, but its importance in the etiology of canine oral squamous cell carcinomas is unclear. Injections of live CPV1 vaccine into the skin of dogs may result in a spectrum of lesions, including epidermal hyperplasia, papillomas, epidermal cysts, basal cell tumors, and squamous cell carcinomas, and some cutaneous squamous cell carcinomas in dogs contain CPV1 genetic material.
In domestic and wild species of cats, oral and cutaneous papillomas and fibropapillomas are very occasionally identified. In the oral cavity they are most common on the ventral aspect of the tongue, and typically they are multifocal, pink, and more sessile than verrucous. Microscopically, raised areas of thickened mucosa are comprised of hyperplastic keratinocytes with occasional fibrovascular stalks. Typical degenerative changes are seen in infected keratinocytes, and papillomavirus antigen can be detected by immunohistochemistry in a high proportion of such cases.
In cattle, oral papillomas, caused by bovine papillomavirus 4 (a strain of bovine papillomavirus 3, genus Xipapillomavirus), can occur commonly in endemic areas. Their morphology and distribution in the oral cavity are similar to the papillomas of dogs, but because they infect the esophagus and forestomachs extensively, they are considered more fully later in the section on Neoplasia of the esophagus and forestomachs.
Tumors of dental tissues are classified either as epithelial (with or without odontogenic ectomesenchyme) or mesenchymal neoplasms, and malformations. Tooth development provides the classic example of epithelial-mesenchymal interactions, and inductive influences appear to be active in some tumors. Familiarity with dental embryology assists an understanding of the origin, appearance, and classification of the tumors discussed later.
Tumors of dental tissues are rare, other than fibromatous epulis of periodontal ligament origin and canine acanthomatous ameloblastomas (acanthomatous epulides). All are nonmalignant, and infiltrative or expansive. However, their location predetermines destruction of bone and displacement of teeth, and they are difficult to remove.
Tumors of odontogenic epithelium include the ameloblastoma, which is a slowly progressive invasive but nonmetastatic tumor, consisting of proliferating odontogenic epithelium in a fibrous stroma. The proportions of epithelium and stroma vary widely. The terms adamantinoma and enameloblastoma are obsolete synonyms. These tumors are more common in dogs than in cats and horses, and seem to occur more often in the mandible than the maxilla. Tumors formerly described as ameloblastomas in young cattle are now considered to be ameloblastic fibromas, discussed in the following.
Ameloblastomas occur at any age. They originate from the dental lamina, the outer enamel epithelium, the dental follicle around retained unerupted teeth, the oral epithelium, or odontogenic epithelium in extraoral locations. They are predominantly intraosseous and, because of their location, they displacement and malalignment of teeth, eventually reaching such proportions that the mouth cannot be closed.
These benign epithelial tumors (warts) in dogs, cats, and cattle are caused by papillomaviruses.
In dogs, they are caused by canine papillomavirus 1 (CPV1), and mainly occur in young animals, although older dogs in close contact may become infected. The lesions are unsightly, are often multicentric, and may be traumatized and bleed, but only heavy infections that interfere with swallowing or respiration cause other than cosmetic problems.
The virus is host- and fairly site-specific. Injury to the oral mucosa often precedes viral infection. Infection of basal epithelium of the squamous mucosa stimulates increased mitosis, whereas viral genome replicates in the differentiating keratinocytes of the stratum spinosum and granulosum, which degenerate, with viral assembly and expression in superficial squamous layers. The incubation period is generally about 2 months. Spontaneous recovery, mediated by CD4 and CD8 T cells, usually occurs within 1-2 more months, followed by solid antibody-mediated immunity to reinfection. The warts first develop as single, smooth papular elevations which are pale or the color of the mucosa. These lesions progress to multiple, proliferative cauliflower-like, firm, white to gray growths ( Fig. 1-13 ). They develop on the lips, gingiva, buccal mucosa, tongue, palate, and walls of the pharynx. The esophagus and the skin of the muzzle also may be involved. Persistent and progressive infections, which may also involve haired skin remote from the mouth, are attributable to immunocompromise of the host, rather than an unusually virulent strain of virus.
The microscopic structure of fully developed lesions is typically verrucous, with very thick keratinizing squamous epithelium covering thin, branching, often pedunculated cores of vascularized proprial papillae. There is also marked acanthosis. Individual epithelial cells or small groups in the upper areas of the stratum spinosum and granulosum degenerate (koilocytes), developing koilocytic atypia, with clear cytoplasm around or adjacent to an often somewhat condensed nucleus, and large cytoplasmic granules or inclusions, with loss of intercellular bridges. Basophilic intranuclear viral inclusions may be found in cells in the outer spinose layers, but they can be rare; intracytoplasmic inclusions also may be present. Regressing lesions are infiltrated by moderate numbers of T lymphocytes. Histologically, the tumor is composed of solid sheets, nodules, and anastomosing cords of polyhedral epithelium (acanthocytes) bordered by a row of palisading cuboidal to columnar cells with round to oval nuclei and moderate amounts of cytoplasm. Prominent intercellular bridges, the defining feature of the lesion reflected in the name, are present between many of the acanthocytes. The solid sheets/cords of acanthocytic neoplastic cells and prominent intercellular bridges distinguish acanthomatous ameloblastoma from ameloblastoma described previously (Fig. 1-17) . In some tumors, intraepithelial cysts contain vacuolated, otherwise structureless, eosinophilic material and cellular debris. These cysts probably form from degenerate epithelium. Small masses of hard tissue may develop in the stroma between the epithelium.
It is sometimes difficult to distinguish an acanthomatous ameloblastoma developing in the gingiva from the epithelial proliferation accompanying gingivitis. Besides the usual prudence required when identifying neoplastic cells in areas of inflammation, other criteria for differentiation include the predominance of broad sheets of epithelium and the mitotic figures 1-16 Acanthomatous ameloblastoma in a dog. This is an exophytic tumor that is also invading and destroying mandibular bone and displacing teeth. (Courtesy Noah's Arkives.) may destroy large amounts of bone, and extend into the oral cavity or sinuses. Large tumors may undergo central degeneration and become cystic.
Odontogenic epithelium is the criterion for diagnosis of ameloblastoma. Neoplastic odontogenic epithelium has peripheral palisading of epithelial cells. There is typically basilar cytoplasm with an apical nucleus ( Fig. 1-14) . Odontogenic epithelium may form any one of several patterns. Follicular and plexiform patterns are most common, consisting of discrete islands, or irregular masses and strands of epithelium, respectively. Many tumors contain both patterns. In both, central masses of cells, often resembling the stellate reticulum of the enamel organ, are surrounded by a single layer of cuboidal or columnar cells that resemble inner enamel epithelium. Cysts originate from degeneration of the centers of epithelial islands, or from stromal degeneration. Small cysts may coalesce to form grossly evident cavities. Ameloblastomas occasionally undergo keratinization and are termed keratinizing ameloblastomas. In some, stromal osteoid and bone develop, which may be an epithelial inductive effect.
Amyloid-producing odontogenic tumors are rare tumors that occur as unencapsulated gingival masses in dogs and cats. They are characterized by odontogenic epithelium, with deposits of amyloid, and sometimes prominent trabeculae of osteoid/dentinoid. The epithelium may be arranged in strands, nests, or masses and may contain areas of stellate reticulum. Occasionally there is mineralization of epithelium or stroma, in the form of small nodules or amorphous masses. The amyloid also may be nodular or amorphous and may be intermingled with the mineral. Distinguished histologically, but not prognostically, from ameloblastomas by the presence of amyloid, these tumors are cured by surgical excision.
Acanthomatous ameloblastoma (acanthomatous epulis, peripheral ameloblastoma, adamantinoma, basal cell carcinoma) is a common tumor of odontogenic epithelium arising from the gingiva or epithelial rests of dogs; it does not occur in other species. It is easily confused clinically with the benign stromal masses found in the canine gingiva, but it often behaves aggressively, invading local alveolar bone ( Fig. 1-15 ), causing tooth loss, and recurring in many animals following conservative treatment. Grossly, they are gray-pink papillary to sessile gingival masses in the vicinity of the alveolus (Fig. 1-16) .
tooth-like structures (denticles) are present, each containing enamel, dentin, cementum, and pulp, arranged as in a normal tooth. Distinction of the two may be arbitrary. Separate areas of ameloblastic epithelium are not present in complex and compound odontomas. A tumor that contains ameloblastic epithelium and separate areas of complex or compound odontoma is an odontoameloblastoma.
Odontomas are usually located in the mandibular or maxillary arch, and are less rare in cattle and horses than in other species. They are connected with existing dental alveoli and are detected when they bulge the contour of the host bone or interfere with other teeth. They may originate from normally or abnormally placed dental lamina as well as from a supernumerary dental lamina.
Fibromatous epulis of periodontal ligament origin is a peripheral odontogenic neoplasm, indistinguishable clinically from fibrous hyperplasia, and most common in dogs. Although uncommon, fibromatous epulis is the most frequent epulis in cats. The distinction between fibrous hyperplasia and fibromatous epulis is academic because prognosis following surgical removal is good for both lesions. Fibromatous epulis of periodontal ligament origin is a neoplasm, however, comparable to the rare human tumor called peripheral odontogenic fibroma. Similar tumors occur rarely in cats. Fibromatous epulides of periodontal ligament origin are firm to hard, gray-pink neoplasms, often projecting from between the teeth or from the hard palate near the teeth. Often they are mushroomshaped and have a smooth, lobulated surface. They are attached to the periosteum, and may displace teeth mechanically, but do not invade bone. Fibromatous epulides are most common around the carnassial and canine teeth of brachycephalic breeds, and usually occur in dogs over about 3 years of age.
Fibromatous epulides of periodontal ligament origin are stromal tumors consisting of interwoven bundles of cellular fibroblastic tissue that is often well vascularized ( Fig. 1-18 ). They are distinguished from fibrous hyperplasia by the immaturity of this stroma, which is comprised of small stellate to fusiform fibroblasts dispersed in a dense collagen matrix, and by their tendency to contain less inflammatory tissue and more hard tissue, which may resemble bone, cementum, or dentin. About 60% contain branching cords or islands of sometimes present in the acanthomatous ameloblastoma. Evidence of invasion of bone is clearly relevant to the diagnosis, care being taken to differentiate alveolar bone from stromal hard tissues.
Some acanthomatous ameloblastomas show characteristics of squamous cell carcinoma when they escape the influence of the subgingival stroma and invade bone, but metastases are not recorded, and complete surgical resection is curative. Squamous cell carcinoma, and occasionally fibrosarcoma or osteosarcoma, has been reported from the site of irradiated acanthomatous ameloblastomas, several months to many years after treatment.
Dental tumors containing both odontogenic epithelium and ectomesenchymal tissue (mixed odontogenic tumors) are rare in domestic animals. The ameloblastic fibroma (fibroameloblastoma) occurs in horses, dogs, and cats, often in young animals, but is the most common odontogenic tumor of cattle, where it is found in the vicinity of the mandibular incisors of calves. It consists of cords of odontogenic epithelium resembling dental lamina, intimately associated with an ectomesenchymal component consisting of spindle cells resembling dental pulp. Where the epithelium is well differentiated, resembling the enamel organ, it may be associated with enamel and dentin; such variants are termed ameloblastic fibro-odontomas, in contrast to ameloblastic fibromas, which contain no mineralized tissue. These tumors generally behave like ameloblastomas, although malignancy has been reported once in a dog.
Feline inductive odontogenic tumor is a rare tumor specific to cats that is most frequent in kittens, where they occur as osteolytic masses in the rostral maxilla, causing tooth loss or facial distortion. They are distinguished by the presence of aggregates of neoplastic odontogenic epithelium partially enveloping somewhat spherical masses of cellular ectomesenchyme, forming structures resembling the cap stage of tooth development, when dental epithelium invests the dental papilla but odontoblasts have not yet differentiated.
Odontomas are malformations (hamartomas) in which fully differentiated dental tissues are represented, and are classified as complex and compound odontomas. In complex odontomas the tissues are disorganized, and in dogs, cementum is not evident, although it is in horses. In compound odontomas, Grossly, tonsillar carcinoma usually appears unilateral. The earliest lesion visible is a small, slightly elevated, granular plaque on the mucosal surface, but it is rarely recognized. In the advanced stages, the affected tonsil is replaced by neoplastic tissue, 2-3 times normal size, nodular, firm and white, and the surface often is ulcerated. There is usually extensive infiltration of the surrounding tissues by microscopically typical SCC. Histologic examination of the grossly unaffected tonsil may also reveal early carcinoma. SCCs originating in the tonsils have a higher metastatic potential than other SCC of the oral cavity of dogs. They often metastasize early to the regional nodes, initially the retropharyngeal nodes, and to the thyroid, with distant metastases to many visceral organs, but especially the lungs, and to bone. Tonsillar SCCs must be differentiated from involvement of the tonsil in lymphosarcoma.
Gingival SCCs may be associated with chronic periodontitis in dogs. It is not always clear whether they have predisposed to periodontitis, or resulted from chronic irritation of the gingiva. It is assumed that some originate in the gingiva and others in subgingival or periodontal epithelial rests. They appear as pink or white nodular masses around the mandibular or maxillary dental arcade, often around canine or carnassial teeth, extending to form larger masses or ulcerative plaques; sometimes they involve adjacent hard palate. Their microscopic appearance is conventional, although the degree of keratinization, and formation of keratin pearls, may be lower than in similar cutaneous tumors. They may often be obscured by chronic active inflammation, as well. They are locally invasive, and may invade bone ( Fig. 1-20) , maxillary tumors sometimes extending into the sinuses and orbit. However, they are much less likely to have metastasized at presentation than SCC of the tonsil.
In horses, SCC are found rarely on the gums and hard palate, possibly arising in chronically irritated hyperplastic alveolar epithelium in cases of chronic periodontitis. They are slow-growing, exceedingly destructive, and metastatic mainly to the regional lymph nodes. Such tumors are large when first observed and may project from the palate or gums as gray extensively ulcerated masses, or appear as craterous ulcers. The large ones are extensively necrotic, and the teeth are lost or loosely embedded in the tumor. These tumors of the maxilla epithelium, which may be continuous with the gingiva, or originate in epithelial rests of Malassez. The epithelium is bordered by a row of cuboidal cells somewhat resembling odontogenic epithelium ( Fig. 1-19 ). Although such masses are sometimes categorized as fibromatous or ossifying, depending on the abundance of the hard tissue, there is no prognostic value in this distinction because these are all benign tumors that are cured by excision.
Squamous cell carcinoma (SCC) is by far the most common oral malignancy of cats, and although there seems to be some geographic variation, it is generally most frequently located on the ventral surface of the tongue, on the midline near the frenulum. The gingiva is the next most common site, and other locations, including the tonsils, are generally much less frequently involved. In the early stages, gingival SCCs are often mistaken for gingivitis. Oral SCCs in cats are generally advanced at presentation. The tumor is locally invasive, especially into bone and local soft tissues, but at presentation is less frequently metastatic to regional lymph nodes, and rarely to the lungs, although the survival rate of animals following surgical resection alone is only about 20%. Larger tumors at presentation signal a poorer prognosis. Paraneoplastic hypercalcemia has been reported. Grossly, these tumors are irregular, slightly nodular, red-gray, friable masses, often with an ulcerated surface that bleeds easily. Microscopically the tumor is a conventional SCC in appearance. Infection with feline immunodeficiency virus, feline leukemia virus, or feline sarcoma virus is not clearly a factor in the etiology, which is presumably multifactorial and in some cases may involve exposure to environmental tobacco smoke.
In the dog, most studies have found that SCC is second to melanoma in prevalence in the oral cavity. It most frequently involves the tonsils, although the gums are also common sites. Lips, tongue, and other oropharyngeal mucosae are involved much less often. The etiology is likely multifactorial, including epithelial hyperplasia associated with chronic gingivitis, and carcinogens associated with smog and smoke in the case of tonsillar tumors in urban dogs, but, as alluded to previously, infection with canine oral papillomavirus may have a part to play in some cases. epithelial-like and spindle-shaped cells, which have a marked tendency to form nests supported by a light stroma, extending deep into the submucosa. Multinucleated giant cells also may be present. Osteoid and cartilage have been reported in the stroma of a low number of canine melanomas. Most melanomas have melanin pigment, but detection of this pigment, which also may be concentrated in melanophages, often requires careful examination of individual tumor cells. Cytologic evaluation of melanotic tumors may require bleaching, but any difficulty in interpretation is more likely to involve poorly pigmented variants. They are DOPA-positive (3.4-dihydroxyphenylalanine) in frozen section, and react immunohistochemically (vimentin 100%, melan A >90%). Melan A is considered sensitive and specific for melanocytes, differentiating them from melanophages in oral tumors. A panel of immunohistochemical stains that includes melan-A, tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2), and PNL2 has been shown to be highly accurate for diagnosis of canine oral melanoma.
Most oral melanomas in the dog are malignant. However, a small subset of well-differentiated canine oral melanomas has been associated with prolonged survival times after complete resection. Mitotic index, nuclear atypia and Ki67 have been shown to be useful as prognostic markers for canine oral melanoma.
In cats, oropharyngeal malignant melanoma is rare. It occurs in older animals, involves the same regions affected in rapidly fill the adjacent sinuses and cause bulging of the face and may extend further, into the nasal, orbital, and cranial cavities. The microscopic appearance of the tumors varies considerably, from well differentiated with keratinization of individual epithelial cells and formation of keratin "pearls," to poorly differentiated with little evidence of keratinization.
In cattle, oral SCCs are very rare, with the exception of a few geographic areas where they are associated with oral papillomatosis and ingestion of bracken fern. A similar association is made in the etiology of SCC of the esophagus and forestomachs in cattle, and is considered more fully in that section. There are sporadic reports of this tumor on the lower lip of sheep.
Malignant melanomas are the most common oral tumors in dogs in many parts of the world. Although cutaneous melanomas are common in gray horses and certain breeds of swine, these species have no tendency to develop oral melanomas, although rare cases are reported. These tumors are also rare in cattle, sheep, and cats.
Most oral melanomas in dogs are malignant and highly aggressive neoplasms, and the majority have metastasized by the time they are diagnosed. They arise from melanocytes in the mucosa or superficial stroma, mainly on the gingiva and labia, and less often on the buccal mucosa, palate, tongue, and pharynx. There is variation in the outcomes of studies of sex and breed association. Males have been overrepresented in some studies, but not others. Some consider that melanomas are more common in smaller breeds or in those with a dark hair coat and/or pigmented mucous membranes, such as Scottish and Boston Terriers, black Cocker Spaniels, Dachshunds, Miniature Poodles, and Chow Chows, but not all studies have found size or breed associations. The degree of pigmentation of these tumors varies considerably, and many are at least partially amelanotic, but there appears to be no relationship between the amount of pigment and biological behavior. Metastases are usually pigmented, but in some cases the primary tumor is pigmented and the metastases are not, and vice versa.
Symptomatic lesions usually are ~3-4 cm in diameter when discovered. They grow rapidly; necrosis and ulceration are common ( Fig. 1-21A ), as is invasion of bone by gingival tumors. More than 70% metastasize to the regional lymph nodes. An approximately equal number spread via hematogenous and lymphatic routes to more distant sites, especially the lungs, where they may be evident at autopsy, but too small to be detected radiographically. The median survival time for untreated dogs is reported as 2 months, and survival following treatment is little better, at about 3 months. The median survival time of dogs with no bone, lymph node, or distant involvement detected at diagnosis is about 8 months after surgical resection.
The histologic appearance of melanomas varies greatly, from a fairly well-differentiated heavily pigmented type, to a highly anaplastic amelanotic type. The diagnosis of the latter is often difficult. However, certain features are evident in most of these tumors. Anaplastic melanocytes show junctional activity, infiltrating the junction between the basilar epithelial cells and the submucosa (Fig. 1-21B ). Round or polyhedral cells with a large nucleus and extensive cytoplasm with well-demarcated borders predominate in some tumors. Others are comprised of spindle-shaped cells with oval nuclei containing small nucleoli. Most frequently there is a characteristic mixture of
A round epithelioid cells that have abundant acidophilic granular cytoplasm. The cytoplasmic granules are strongly periodic acid-Schiff-positive, and ultrastructurally are phagolysosomes. The nuclei are round to oval, centrally or eccentrically located, and have 1-2 nucleoli. Mitotic figures are rare. The tumor cells have a marked tendency to form nests or cords that are separated by a delicate network of reticulin fibers, although some are arranged as sheets of cells. None of these tumors in dogs have recurred after excision, and there is only one record of metastasis, to thoracic organs. There are a few reports of this tumor in the tonsil, tongue, gingiva, and palate of cats. In horses, granular cell tumors are located in the lungs (see Vol. 2, Respiratory system).
Neuroendocrine cells of the dispersed neuroendocrine system are present at a low density throughout most levels of the gastrointestinal tract, as well as at other sites, in several mammalian species. In older literature they may be referred to as Merkel cells.
Very rarely, they form tumors of the skin and the oral/nasal pharyngeal mucosa in the dog. In the latter site they tend to be pedunculated, and are located on the gums, lips, and pharynx. Their behavior is aggressive, with metastasis to local nodes and distant sites, and local recurrence if margins around the resected tumor are not adequate. Histologically, they consist of well-circumscribed, densely packed nests and sheets of polygonal to round cells in the submucosa, resulting in an organoid appearance. The cells have a moderate amount of pale basophilic cytoplasm. The nuclei are pleomorphic, the nuclear membrane is indented, and there are 1-2 centrally located nucleoli. The mitotic index varies from few to 2-3 mitotic figures per high-power field. Multinucleated giant cells are often present. The cells stain negatively with the periodic acid-Schiff stain but have a positive argyrophilic reaction. These are useful features to differentiate this tumor from granular cell tumors. The tumor must also be differentiated from malignant melanoma. Immunohistochemical reactions are usually positive for synaptophysin and neuron-specific enolase, and more variably for chromogranin-A and cytokeratin. Ultrastructurally, the tumor cells contain cytoplasmic secretory granules characteristic of neuroendocrine cells.
Extramedullary plasmacytomas are uncommon tumors of the oral mucosa and skin of mainly older dogs (mean age 9-10 years). They arise as primary tumors from plasma cells in the soft tissue, or rarely as metastases from primary osseous myeloma.
This tumor has probably been under-diagnosed in the past, being mistaken for undifferentiated round cell tumor, histiocytic sarcoma, or a variant of dermal lymphoma. In the oral cavity, it has been misdiagnosed as malignant melanoma. Grossly the tumor is a red, lobulated raised mass usually located on the gingiva or lips. It can invade bone, rarely. Plasmacytoma also occurs sporadically in the stomach, colon, and rectum.
Histologically, the tumor is well circumscribed, nonencapsulated, and the overlying mucosa is usually intact, unless it has been traumatized in large tumors. The tumor cells are pleomorphic with variable amounts of amphophilic to basophilic cytoplasm. The nuclei are round to oval and the nuclear dogs, resembles the mixed tumor cell phenotype of dogs, and has a short median survival time.
Pigmented basilar epithelial cells are frequently present in superficial areas of the submucosa in a variety of nonneoplastic lesions resulting from irritation to the mucosa. This so-called "pigmentary incontinence" must be differentiated from malignant melanoma.
In dogs, fibrosarcoma is the third most common oral malignant tumor, comprising about 15-25% of such lesions, but the most common sarcoma of the oral cavity. It frequently occurs in younger dogs; for example, one report indicated 25% occurred in dogs <5 years of age, and the median age is ~7 years. Larger breeds appear to be predisposed, perhaps especially the Golden Retriever. It occurs mainly on the gums of the maxilla and adjacent palate and the rostral mandible, and less often in the buccal mucosa, lips, and tongue. Despite a relatively benign histologic appearance in large breeds, it grows rapidly, invading maxillary and mandibular bone in the majority of cases, and frequently recurs after surgical removal. About 20-35% have metastasized to regional nodes, and pulmonary metastases have occurred in about 10-20% at diagnosis. Median survival times after surgical resection are reported to be near 25 months.
The tumors are solitary gray to red, firm, irregularly shaped to nodular fleshy masses >4 cm in diameter that may ulcerate and become secondarily infected. They are usually fixed to any underlying bone. Microscopically, the submucosa is diffusely infiltrated by densely cellular sheets of pleomorphic fusiform fibroblasts arranged in interwoven bundles with variable, but often relatively small, amounts of collagen. The mitotic index is high in high-grade tumors, and there may be multinucleated giant cells scattered throughout.
In cats, this tumor is the second most frequent oropharyngeal malignancy, but it is not common. The gingiva and palate have been reported as sites of predilection by some, but others did not observe any specific location. The tumor resembles that in dogs, and invasion of bone is common.
This tumor occurs occasionally in the oral cavity of middleaged dogs, and, less frequently, in cats. Most commonly they are found on the lip of dogs, but they may arise in the submucosa of the tongue, gum, and hard palate. The tumor is diagnosed using the same criteria as cutaneous mastocytomas, and all should be considered potentially malignant, with metastasis to regional lymph nodes a possibility. Mast cell tumor should be considered in the differential diagnosis of oral lesions resembling granulation tissue or eosinophilic granuloma in dogs and cats. Lymph node metastasis may be higher in oral mast cell tumors compared with the cutaneous counterpart, and metastasis is associated with a poorer prognosis.
This rare tumor occurs in older (mean age 9 years) dogs, mainly in the base of the tongue, but also in the gingiva, lips, and palate. Most granular cell tumors are thought to be derived from neuroectodermal precursor cells. They are elevated, usually less than ~2 cm in size, red, and granular or smooth on the mucosal surface. The cut surface is white and firm. Microscopically the mass consists of large, polyhedral to de Bruijn N, et al
Salivary glands are a complex set of secretory structures, present both as large discrete glands in the head and cranial neck region, and as an extensive series of submucosal minor salivary glands in the oral cavity, including the tongue, oropharynx and larynx. Gland structure is variable, depending on whether the gland produces serous or mucous secretion, or both. Common acute reactions to injury include hypersecretion, necrosis, edema, and inflammation. Gland atrophy, ductular fibrosis and obstruction, and squamous metaplasia may develop following chronic injury. Oncocytic metaplasia is a benign age-related lesion of salivary duct epithelium wherein eosinophilic granular swollen cells (oncocytes) containing abundant cytoplasmic mitochondria replace normal ductal epithelial cells.
The most common conditions of the salivary glands are functional. Ptyalism is increased secretion of saliva; aptyalism is reduced or absent secretion. Ptyalism is seen as abnormal accumulation of saliva in the mouth, and should be differentiated from failure to swallow. It occurs in a variety of conditions including stomatitis, organophosphate or heavymetal poisoning, and encephalitis. Aptyalism is less common but may accompany fever, dehydration, and salivary gland disease. membrane is indented. The cells are densely packed into nests and sheets that are divided by scant fibrovascular stroma. Anisokaryosis, binucleated and multinucleated cells are frequently present in the center of the tumor, and the most differentiated plasma cells are usually evident at the periphery. The mitotic index varies widely from one tumor to another. Immunoglobulin, especially IgG, can frequently be demonstrated in the neoplastic cells, and AL amyloid (amyloid immunoglobulin light chain) is occasionally present among the tumor cells. Electron microscopic examination reveals features typical of plasma cells.
In spite of the anaplastic appearance and the presence of mitotic figures, the biological behavior of these tumors is benign, and they are cured by simple resection.
Lesions variously considered vascular hamartomas or hemangiomas have been described in the gums of neonatal calves and in the oral cavity of puppies. Hamartomas are focal disorganized overgrowths of mature tissue endogenous to the organ involved. Because of their location, they usually have an inflamed surface, and may resemble, superficially, granulation tissue or pyogenic granuloma. They are pink to red lobulated masses, up to several centimeters in diameter, often pedunculated, on the rostral mandibular gingiva adjacent to the incisors, which may be displaced. They also may be located in the tongue. Microscopically, the tumors consist of irregular thinwalled vascular channels containing erythrocytes or proteinaceous material, and lined by well-differentiated endothelial cells. The vascular spaces are separated by loose fibrous stroma. Vascular hamartomas are benign, but a single hemangiosarcoma in a young calf has been described that involved the palate and gums, as well as distant sites.
Hemangiomas occur rarely in the oral cavity of mature horses, dogs, and cats. Rare hemangiosarcomas have been recorded in the oral cavity of cats and a few dogs, the latter with cutaneous hemangiosarcomas.
Various benign and malignant neoplastic and like lesions in the oropharynx have been reported sporadically. In the dog, benign masses include dermoid cysts, histiocytoma, lipoma, lymphangioma, hemangioma, rhabdomyoma, ganglioneuroblastoma, and calcinosis circumscripta (of the tongue). Malignant tumors that have been reported in the oral cavity, mainly in the lip and tongue, are hemangiosarcoma, leiomyosarcoma, histiocytoma, ectopic thyroid carcinoma, hemangiopericytoma, schwannoma, osteosarcoma, rhabdomyosarcoma, and highly malignant undifferentiated tumors.
In cats, benign tumors include hemangioma and fibroxanthoma, and malignant examples are oral and tonsillar lymphosarcoma, schwannoma, and osteosarcoma. Pharyngeal, lingual, and gingival lymphomas have been described in horses. Salivary tumors are described later in the section on salivary glands.
Pharyngeal sialoceles are uncommon but affected dogs may present with dyspnea. Zygomatic and palatine sialoceles also occur, and can be associated with inflammation and cause exophthalmos and soft palate swelling, respectively. Small sialoceles, seldom exceeding 0.5 cm in size, are occasionally observed on the side of the bovine tongue. They presumably result from rupture of the fine tortuous ducts of the dorsal part of the sublingual gland.
The wall is soft, pliable, well-vascularized connective tissue with a glistening lining and the contents are initially mucinous but become progressively inspissated and tenacious. The histologic appearance of sialoceles varies greatly, apparently depending on the stage of development. Centrally there is abundant amorphous amphophilic material with a mixed inflammatory reaction, which may be very mild. Initially, the wall consists of an outer well-vascularized layer of immature connective tissue and an inner layer of loosely arranged fibroblasts. As the sialocele ages, mature fibrous connective tissue forms the wall, plasma cells or lymphocytes are the most numerous inflammatory cells, and the material in the center becomes progressively more basophilic.
Anomalous regression of pharyngeal pouches or clefts results in pharyngeal (branchial) cysts, sinuses, or fistulae that can manifest in a variety of ways. The lining of these cysts can vary from squamous to pseudostratified ciliated epithelium; occasionally more than one type of epithelium is observed. Congenital cervical sinuses, cysts and fistulae have been reported in veterinary species. Thyroglossal duct cysts have been reported in cats: These are remnants of pharyngeal thyroid primordium, occur directly on the midline, and are readily distinguishable histologically because they are lined by thyroidogenic epithelium.
Sialoadenitis, inflammation of the salivary glands, is uncommon, but after malignant neoplasms is the second most frequently diagnosed salivary gland lesion of dogs and cats. The submandibular gland is usually affected. Inflammation of the zygomatic gland in dogs is a cause of retrobulbar abscess. The route of infection is usually via the excretory duct, although it also may be hematogenous or localized trauma. Duct obstruction is due to inflammatory exudate, desquamated epithelial cells, and mucus, which may be expressed from the duct orifice. Partial or complete obstruction of the duct produces secondary atrophic changes in the glands, although there is initial gland enlargement resulting from the combined effects of retained secretion and inflammation. Ducts throughout the gland initially become dilated and inflamed. Acini swell and rupture from retained secretion, and this often leads to marked neutrophilic inflammation. In chronic cases, there is marked glandular atrophy with only remnants of atrophic epithelium embedded within inflamed fibrous connective tissue.
Specific inflammations of the salivary glands in domestic animals are few. Examples include rabies, where there is often focal lysis of acinar cells, mononuclear infiltration and rare Negri bodies in ganglionic neurons; strangles in horses; and distemper in dogs. Eosinophilic sialoadenitis may be a component of eosinophilic epitheliotropic syndrome in horses discussed in the section on Eosinophilic enteritis in cats and horses. Sjögren's-like syndrome has been diagnosed in cats and dogs, characterized by plasmacytic inflammation of salivary glands. Sialoadenitis can also occur secondary to squamous metaplasia of interlobular salivary ducts, which is an early lesion of vitamin A deficiency. Exposure to highly chlorinated Ptyalism in cattle and horses may be an expression of mycotoxicosis. Rhizoctonia leguminicola has a wide geographic distribution, and infestation of legumes is associated with "slobbers syndrome." Mycelial growth on well-cured hay is not grossly visible. Two biologically active alkaloids-slaframine and swainsonine-are produced by the fungus. Slaframine, a parasympathomimetic alkaloid, is associated with excessive salivation, lacrimation, anorexia, diarrhea, frequent urination, bloat, reduced milk production, and weight loss. No specific lesions have been associated with slaframine toxicosis. Guinea pigs are extremely sensitive to the toxin. Presumptive diagnosis may be based on feeding trials in that species, if chromatographic analysis for slaframine is not readily accessible.
Ptyalism may be associated with neurointoxication, particularly those agents that affect the trigeminal nuclei. Known causes include ingestion of Paspalum destichium (knotgrass) and Prosopis glandulosa (honey mesquite), poisoning with cholinergic stimulants, snake envenomation, neurotropic viruses, especially rabies virus, and in dogs exposure to the toad Bufo marinus cause neurologic abnormalities and ptyalism.
Vesicular and ulcerative diseases that affect the oral cavity, such as foot-and-mouth disease are usually associated with ptyalism.
Foreign bodies such as plant awns or fiber are occasionally present in the ducts; the parotid duct is more often affected than the submaxillary duct. They invariably cause some degree of inflammation or secondary infection and if the duct epithelium is destroyed, localized cellulitis occurs. Salivary calculi (sialoliths) may also cause obstruction and inflammation. They are more common in horses than other species; the parotid duct is most commonly affected. Microliths are formed routinely and undergo regular turnover; however, secretory inactivity can cause microliths to accumulate more material, leading to formation of large calculi that may cause obstruction. Calculi in horses are usually single hard white laminated structures composed largely of calcium carbonate; in dogs the composition varies. Many lodge at the orifice and cause some degree of salivary retention, glandular atrophy, and predisposition to infection and further inflammation.
Dilations of the duct are due to stagnation of flow or obstruction resulting from congenital atresia, foreign bodies, calculi, or inflammatory strictures. The dilated ducts appear as fluctuating cords, sometimes with local diverticula. Ranula is the term applied to a smooth, rounded, fluctuant cystic distention of the duct in the floor of the mouth. The lining epithelium may or may not be intact and cyst contents may be serous fluid or thick tenacious mucus. Rupture of a duct or a gland to an epithelial surface results in a permanent fistula as the continued flow of saliva prevents normal restoration, and the duct epithelium eventually fuses with the surface.
Salivary mucocele or sialocele is an accumulation of salivary secretions in single or multiloculated cavities, not lined by secretory epithelium, in the soft tissues of the mouth or neck. Sialoceles are often thought to be the result of trauma to the duct, and there may be a history of ranula-like swelling in the mouth. Most sialoceles are subcutaneous and may be large and pendulous, up to 10 cm in diameter. They can be located anywhere from the mandibular symphysis to the middle of the neck, but most are ventrolateral along the midline. They arise most commonly from the sublingual salivary gland, but sialoceles in other locations have been sporadically described.
intermediate cells, which may line cysts, sometimes in a papillary pattern. Cyst rupture initiates a granulomatous response, including giant cells. Tumors with infiltrative peripheral growth pattern are likely to recur locally or metastasize to distant organs.
Acinic cell carcinomas are less common than adenocarcinomas, occurring mainly in dogs and sporadically in the cat, horse, and sheep. An essential criterion for diagnosis of this tumor is the presence of well-differentiated salivary epithelial cells (acinar, intercalated duct, vacuolated, clear or glandular cell subtypes). There is minimal cellular pleomorphism and a low mitotic index. They are at least partially encapsulated masses but often display infiltrative growth along the margins; however, metastases occur only late in course of disease.
Pleomorphic adenomas, or mixed tumors, have been described rarely in the dog, cat, cow, and horse. Analogous to mixed mammary tumors, they are composed of neoplastic myoepithelial and epithelial cells along with myxoid, chondroid, or osseous stromal transformation. They are considered benign, but complete excision is difficult and local recurrence is common. Development of malignant epithelial foci within benign tumors is described and represents malignant transformation (carcinoma in pleomorphic adenoma).
Rarely, other epithelial (myoepithelioma, squamous cell carcinoma, cystadenocarcinoma) and mesenchymal (angiolipoma, fibrous histiocytoma, osteosarcoma, fibrosarcoma) malignancies appear to arise in the salivary glands.
The esophagus is comprised of an inner circular layer and an outer longitudinal layer of skeletal muscle for much or all of its length. In the pig, there is a short segment near the cardia that is comprised of smooth muscle, and in horses and cats, smooth muscle is found in the distal third of the esophagus. The esophagus is lined by stratified squamous epithelium with a variable number of submucosal mucous glands, depending on the species and location along the esophagus. Esophageal protection against aggressive insults resides mainly in mucus and bicarbonate in salivary secretion and is produced by esophageal submucosal glands. The esophagus merits particular attention during the examination of animals with inadequate growth rate, cachexia, ptyalism, dysphagia, regurgitation, vomition, and aspiration pneumonia. In ruminants, tympany may be a sequel naphthalenes is now rare, but can lead to hypovitaminosis A and subsequent squamous metaplasia.
Necrotizing sialometaplasia is a distinct and rare disease of dogs, cats and humans. There is characteristic ischemic necrosis of salivary gland lobules with inflammation and squamous metaplasia of the ducts, features easily and often misinterpreted as malignant transformation. The cause is thought to be vascular compromise induced by trauma, although immunemediated destruction of blood vessels or infection have also been hypothesized. The disease is seen in a number of small breed dogs, primarily terriers; the submandibular gland is preferentially affected. Affected dogs are presented in extreme pain with enlarged firm salivary glands. Recurrent vomition is reported, and this is thought to be centrally mediated. Benjamino KP, et al. Pharyngeal
Neoplasms of the salivary glands are rare in all species. They have been reported in cattle, sheep, goats, horses, dogs, and cats, but not swine; only in dogs and cats do salivary tumors occur often enough to permit generalization. Tumors are usually unilateral, and they may arise from any salivary gland, but the parotid and mandibular glands are most commonly affected. Neoplasms develop mostly in aged animals and are almost exclusively carcinomas. Cats tend to have more aggressive disease at the time of diagnosis and metastasis to regional nodes and distant sites, especially the lungs, is more common. Adenocarcinomas that have metastasized to the nodes or beyond at diagnosis have a worse prognosis than those with tumor localized to the gland. The histologic structure of salivary tumors in animals is as diverse as humans, and morphology typically mimics cell types of normal salivary glands. The phenotype of salivary tumors has little bearing on prognosis, with notable exceptions being acinic cell carcinomas, which are tumors of low grade malignancy, and pleomorphic adenomas (or mixed salivary tumor), which have potential for malignant transformation. The most frequent variety is adenocarcinoma, and although there are various structural patterns (acinar, ductular, trabecular, solid) sometimes within the same tumor, an acinar or nested arrangement is usually evident somewhere, embedded in an often extensive fibrous stroma.
Mucoepidermoid carcinomas are composed of a combination of squamous epidermoid cells, mucus-producing cells and esophagus by variously sized, often slit-like apertures. Most are probably acquired, and they occur most often in the lower cervical esophagus near the thoracic inlet and the distal thoracic esophagus just cranial to the diaphragm. Increased intraluminal pressure associated with foreign bodies, obstruction or stenosis are potential causes of pulsion diverticula, in which the mucosa is forced out through the distended or ruptured muscularis. Such diverticula may be large spherical structures with a narrow neck and are most common in the horse and dog. The rare traction diverticulum is the result of contraction of a paraesophageal fibrous adhesion, following perforation and inflammation, drawing with it a pouch of esophageal mucosa that is usually small and inconsequential. In contrast to pulsion diverticula, which have a layer of epithelium lining the inner aspect of a wall of fibrous connective tissue, traction diverticula have a wall comprised of all layers of the esophagus. Ingesta and foreign bodies may accumulate in diverticula, causing gradual enlargement with the potential for local esophagitis, ulceration, and perforation or formation of a fistula.
Other rare anomalies of the esophageal mucosa include epithelial inclusion cysts and distal esophageal papillae in cattle resembling those of the rumen, and gastric heterotopia.
Hyperkeratosis and hyperplasia of the esophageal epithelium may be signs of vitamin A deficiency or chlorinated naphthalene toxicity, which has been described in herbivores. This is accompanied by squamous metaplasia of mucous glands and ducts of the esophagus and throughout the body. Mild hyperkeratosis may be difficult to assess in herbivores because some degree of keratinization is normal and anorexia or failure to swallow results in loss of the abrasive effect of food passage leading to accumulation of keratinized squames. Parakeratosis and epithelial hyperplasia is indicative of response to epithelial injury (see later section on Esophagitis). In the distal esophagus of pigs, this lesion is often observed concomitant with ulceration of the pars esophagea of the stomach. Esophageal parakeratosis can also occur in pigs with cutaneous parakeratosis caused by zinc deficiency. Adami C, et
Erosive and ulcerative esophagitis is a common finding associated with viral diseases causing similar lesions in the oropharynx or reticulorumen, including bovine viral diarrhea, rinderpest, bovine papular stomatitis, infectious bovine to esophageal disease. The presence of a bloat line in the esophagus at the thoracic inlet may indicate a condition causing increased intra-abdominal pressure such as gastric dilation or ruminal tympany. The squamous mucosa is frequently eroded or ulcerated in viral diseases that cause similar lesions elsewhere in the upper alimentary tract. Conditions of striated muscle, such as nutritional myodegeneration and eosinophilic myositis in the ruminant, or polymyositis, systemic lupus erythematosus, and trypanosomiasis in the dog, involve the esophageal muscle. Envenomation following snake bite may lead to myopathy of the esophageal musculature in dogs. Diseases of the neuromuscular junction, as in myasthenia gravis, and peripheral neuropathies, such as giant axonal neuropathy and polyneuritis, result in esophageal disease.
The mucosa of the distal portion of the feline esophagus normally has a herringbone pattern of superficial folds. Hypertrophy of the smooth muscle of the distal esophagus, most commonly the inner smooth circular layer, occurs in horses. It is usually found incidentally at autopsy, although some cases also have concurrent terminal ileal muscular hypertrophy. The lesion is considered idiopathic, but potential factors in the pathogenesis include autonomic imbalances or defects in the smooth muscle pacemaker cells normally found at these sites. Congenital anomalies of the esophagus are very rarely recorded in domestic animals, and their interpretation as such can be difficult because similar defects may develop as sequelae of esophageal trauma or inflammation.
Congenital duplication cysts of the esophagus have been reported in horses and dogs. Esophageal cysts are classified as duplication by 3 essential criteria. The cyst must (1) be located within the esophageal wall, (2) be lined by columnar, squamous, cuboidal, ciliated, or pseudostratified epithelium, and (3) have a double muscle layer in the wall. Esophageal duplication cysts may be clinically silent; however, they manifest as space-occupying lesions if they fill with cellular debris and secretion. Potential complications are associated with compression of adjacent structures or cyst rupture.
Rare segmental aplasia of the proximal esophagus may be apparent in the neonate. A short blind pouch communicates with the pharynx, and a thin fibrous band connects it to the distal patent esophagus that follows a normal course to the stomach. Esophageal atresia and congenital esophagorespiratory communications result from anomalies occurring when the respiratory primordium buds from the embryonic foregut.
Esophagorespiratory fistulae without esophageal atresia are also rare in animals. Esophageal fistula formation is likely acquired following foreign body perforation of the esophagus; however, in calves and dogs, some are likely congenital. Short fibrous bands with a narrow epithelial-lined lumen connecting an esophagus of normal diameter with the trachea or bronchus are reported, as are small apertures connecting the lining of esophageal diverticula with the respiratory tree. The lining of such defects changes from stratified squamous to columnar respiratory epithelium in the fistula or wall of the diverticulum. Gastric distention by air in calves, and pneumonia resulting from aspiration, have been associated with esophagorespiratory fistulae.
Esophageal diverticula are irregular outpouchings or herniations of the esophageal mucosa through a defect in the esophageal tunica muscularis. They communicate with the erosions, ulcers, or superficial fibrinonecrotic debris. Such damage is most common in the distal esophagus, but in some instances can extend to the pharynx. Epithelial hyperplasia and neutrophilic exocytosis occur in response to mild superficial epithelial necrosis. A consequence of chronic gastroesophageal reflux, well recognized in humans and described in dogs and cats, is columnar and mucous cell metaplasia of the distal esophagus. In humans, the lesion is known as Barrett esophagus and is an important risk factor for development of esophageal adenocarcinoma, but this has not been clearly demonstrated in animals.
Hiatus hernia usually involves sliding herniation of all or part of the abdominal esophagus, cardia, and stomach into the thoracic esophagus, rather than periesophageal herniation. It is generally self-reducing, but usually results in lower esophageal sphincter failure and reflux, rather than gastric herniation and obstruction. Gastroesophageal intussusception is a rare event, most reported in puppies of large breeds of dogs, and is associated with recurrent vomition that may lead to aspiration pneumonia.
Thrush, or mycotic esophagitis caused by Candida albicans, is seen in piglets and weaner swine, and may involve the squamous mucosa of the entire upper alimentary canal. C. albicans is an opportunist seen secondary to antibiotic therapy, inanition, or esophageal gastric reflux, and is considered more fully in the later section on Mycotic diseases of the gastrointestinal tract. Gibson CJ, et
Esophageal obstruction can have intrinsic or extrinsic causes, and the lesions are generally obvious. The esophagus proximal to the stenotic area may be dilated, contain retained ingesta, or have evidence of erosion, ulceration or inflammation. Choke, or esophageal impaction, is the most common example of intrinsic obstruction, and occurs when large or inadequately chewed and lubricated foods, masses of grain or fibrous ingesta, or medically administered boluses lodge in the lumen of the esophagus ( Fig. 1-23 ). Predisposed sites are where the esophagus deviates or is slightly restricted normally: the area overlying the larynx, the thoracic inlet, the base of the heart, and just cranial to the diaphragmatic hiatus.
Complications of obstruction include pressure necrosis and ulceration of the mucosa, which may progress to perforation or less commonly development of esophageal diverticula or fistulae. Sharp objects, such as bones, are most likely to cause perforation. Severe cellulitis of the periesophageal tissue ensues, and depending on the site of perforation, may involve rhinotracheitis, and feline calicivirus. Epithelial proliferation or granulation tissue during healing of ulcers may result in raised opaque areas at the lesion margin or surface, respectively.
Caustic or irritant chemicals, ionizing radiation, electrochemical reactions (batteries), or heat may cause mucosal injury, the severity of which depends on the nature of the insult and duration of exposure. Mild acute insult may result in reddening of the mucosa. More severe insult results in liquefactive necrosis associated with alkalis, and coagulative necrosis associated with exposure to acids and toxins (paraquat, oak toxicosis) and may result in deep esophageal ulceration and sloughing of the mucosa.
Superficial epithelial damage heals uneventfully, though repeated insult may cause irregular epithelial hyperplasia. Ulcerated mucosa heals by granulation, and raised islands of surviving proliferative epithelium may be observed on the surface. The inflammatory reaction in ulceration frequently involves tunica muscularis and adventitia. Fibrosis and scarring may cause stricture or stenosis, if the original defect involved a significant portion of the esophageal circumference.
Reflux esophagitis occurs because of a loss of functional integrity of the lower esophageal sphincter associated with airway occlusion and increased intra-abdominal pressure, the pharmacologic effects of preanesthetic agents, or abnormality of the hiatus. Esophagitis is due to the action of gastric acid, pepsin, and probably regurgitated bile salts and pancreatic enzymes, on the esophageal mucosa. Reflux esophagitis is most common in dogs and cats as a sequel to surgery involving general anesthesia, although it may follow chronic gastric regurgitation or vomition for any cause ( Fig. 1-22) . In swine and horses, it may be associated with ulceration of the squamous portion of the stomach. In dogs, it can be associated with hiatus herniation. A high prevalence of apparent gastroesophageal reflux disease in the distal esophagus of premature calves was demonstrated by endoscopy; however, the pathogenesis remains unclear.
Stratified squamous epithelium appears more susceptible to the corrosive effects of gastric secretion than other types of mucosa in the lower gastrointestinal tract. Relatively short duration of exposure to refluxed gastric content is required to induce epithelial damage characterized by hyperemia, linear
Deglutition is a complex and highly coordinated physical act, which may be conveniently divided into three phases-oral, pharyngeal, and esophageal. Oral dysphagia occurs because of painful lesions involving the oral cavity and tongue, such as stomatitis, glossitis, and gingivitis, or lesions that impair movement of the tongue or delivery of the bolus to the oropharynx, such as loss of hypoglossal nerve function associated with hydrocephalus, trauma, or myasthenia gravis. Cleft palate can result in nasal regurgitation. Pharyngeal dysphagia may be associated with painful inflammatory or neoplastic lesions involving the pharynx, tonsils, or retropharyngeal region, which may physically intrude on the pharyngeal space required for swallowing. Encephalitis involving the medulla oblongata and nuclei or tracts of the major cranial nerves involved in pharyngeal contraction and lingual function (V, IX, X, XII) should be carefully examined in cases of pharyngeal dysphagia unexplained by other lesions. Rabies and brain abscess in all species, infectious bovine rhinotracheitis and listeriosis in ruminants, are important central causes of pharyngeal paralysis. Retropharyngeal abscesses or other lesions of the equine guttural pouch may cause peripheral nerve damage and paralysis. Idiopathic myodegeneration, muscular dystrophies, and myasthenia gravis have been reported to impair pharyngeal muscle function.
Cricopharyngeal dysphagia is recognized in dogs as a swallowing disorder of the upper esophageal sphincter characterized by cricopharyngeal muscle asynchrony or achalasia (failure of the muscle to relax). The cause is unknown but this may be a primary muscular disorder because cricopharyngeal myotomy or myectomy is curative.
Megaesophagus, or esophageal ectasia, is recognized as dilation of the esophageal lumen, and is the result of atony and flaccidity of the esophageal muscle ( Fig. 1-24 ). This occurs as the result of segmental or diffuse motor dysfunction of the body of the esophagus, and results in failure of peristaltic propulsion of the food bolus through the lower esophageal sphincter into the stomach. Ingesta accumulates in the esophageal lumen, which may lead to putrefaction and esophagitis in dilated or dependent areas; undigested food is eventually regurgitated. The volume of the dilated thoracic and cervical esophagus may greatly exceed that of the stomach causing ventral displacement of the intrathoracic trachea and heart. Animals with megaesophagus may have signs of malnutrition, including emaciation, dehydration, and osteopenia as well as rhinitis and aspiration pneumonia resulting from regurgitation.
Congenital idiopathic megaesophagus (CIM) is relatively common in dogs; it may improve functionally to some extent with time. CIM has its highest prevalence in Great Danes, the mediastinum directly or by extension along fascial planes from the cervical region. Perforation of the thoracic esophagus may lead to pleuritis. Sharp objects, such as needles, quills, grass seeds, and awns, may penetrate and track from the esophagus through adjacent tissues.
Removal or dissolution of an obstruction may allow healing of the segmentally ulcerated esophagus. As for reflux esophagitis, fibrosis and scarring of large ulcers may result in narrowing of the lumen, stricture, or stenosis. Although hypertrophy of internal and external muscle layers is seen occasionally in the distal esophagus of cattle and horses (in which species the distal esophageal muscle is normally relatively thick), this change is usually not clearly the result of obstruction. Stenosis rarely is caused by intramural or intraluminal neoplasia, or more commonly by external compression which can be due to enlarged thyroid glands, thymus, and cervical or mediastinal lymph nodes.
The most common causes of external compression and constriction of the esophagus are vascular ring anomalies seen in dogs, occasionally in cats, and rarely in other species. Persistence of the right fourth aortic arch is the most common of these anomalies, and occurs when the right aortic arch develops instead of the normal left aortic arch. With this condition, the ligamentum arteriosum forms a vascular ring around the esophagus, resulting in entrapment and constriction of the esophagus against the trachea. Other vascular anomalies that may constrict the esophagus are reported only in the dog and include: persistence of both right and left aortic arches, persistent right ductus arteriosus, aberrant left subclavian artery in association with persistent right aortic arch, and aberrant right subclavian artery arising distal to the left subclavian artery and passing dorsally over the esophagus. The Irish Setter, German Shepherd, German Pinscher, and Boston Terrier are breeds most commonly afflicted with vascular ring anomalies.
Further reading Dechant JE, et German Shepherds, and Irish Setters. In Miniature Schnauzers, the condition has an inheritance pattern of simple autosomal dominant with incomplete (60%) penetrance. With very rare exceptions, it is not secondary to physical obstruction or failure of the lower esophageal sphincter to open. Motor stimulation to the striated esophageal muscle, despite being carried in the vagus, is not autonomic, and seems intact. There is strong evidence that CIM results from a selective defect in the distension-sensitive afferent autonomic arm of the reflex that coordinates esophageal function. Idiopathic megaesophagus can develop in mature dogs, and based on some studies, this represents the majority of cases. Most cases of idiopathic megaesophagus in dogs are not comparable with humans, in which esophageal achalasia is a significant primary motor disorder.
Megaesophagus may be acquired secondary to glycogen storage disease in Lapland dogs, localized or systemic myasthenia gravis, administration of cholinesterase inhibitors, hypoadrenocorticism, canine giant axonal neuropathy, immune-mediated polymyositis, polyradiculoneuritis, canine distemper, systemic lupus erythematosus, lead poisoning, Chagas disease, and snake envenomation.
Megaesophagus in the cat may be congenital, and it appears most common in the Siamese breed. The pathogenesis is unclear. Neuronal degeneration or neurogenic atrophy of muscle is not recognized in the esophageal wall. Acquired megaesophagus in cats has been associated with functional pyloric stenosis, hiatus hernia, upper respiratory obstruction/ nasopharyngeal polyps, and lead poisoning.
Presumed congenital megaesophagus has been reported in foals. Histologic examination of the segmentally dilated proximal esophagus revealed no significant lesions of muscle or ganglia. Aganglionosis has also been implicated in megaesophagus in foals. Megaesophagus also may be acquired in foals; in such cases there is usually ulceration of the distal esophagus, as well as the pars esophagea of the stomach.
Megaesophagus in cattle has been described as congenital, or more commonly an acquired lesion associated with hiatus hernia, or pharyngeal trauma presumably causing vagus nerve damage. Megaesophagus is rarely reported in small ruminants.
Sarcosporidiosis occurs in the striated esophageal muscle of sheep. Esophageal sarcocysts appear as ovoid white thinwalled nodules ~1 cm long projecting from the esophageal muscle. Sarcocystis gigantea, the species producing large esophageal cysts and similar large cysts in skeletal muscle, is spread by cats. Microscopic sarcocysts of other species also may be encountered in esophageal striated muscle of a variety of hosts (see section on protistan infections, and Vol. 1, Muscle and tendon). Sarcocysts in esophageal muscle normally incite little or no local inflammatory reaction and are only of significance in meat inspection. Eosinophilic myositis can be observed in the esophageal muscle and, although the cause of this lesion is not certain, it is thought to be associated with rupture of cysts of this parasite. In horses, Gasterophilus spp. larvae may be temporarily attached to the caudal pharyngeal, cranial esophageal or distal esophageal mucosa adjacent to the cardia; ulcers may occur at the sites of attachment.
The larvae of the warble fly Hypoderma lineatum reside for some time in the submucosa or adventitia of the bovine esophagus before they migrate to the dermis of the back. Here the small 2-4-mm translucent larvae grow up to 6 times before migrating toward the back of the host, but can cause local hemorrhage and inflammation. Death of first-stage larvae in the esophageal wall following systemic insecticide treatment, for example, can lead to severe acute inflammation in the esophageal submucosa and potentially esophageal obstruction, tympany, and perforation.
Spirurid nematodes of the genus Gongylonema may be encountered in the stratified squamous mucosa of the upper alimentary tract, including the esophagus, in ruminants and swine. These white thread-like worms up to 10-15 cm long burrow in the epithelium or propria of the esophagus and produce white or red, blood-filled serpentine tracks ( Fig. 1-25) . Their presence is inconsequential to the host.
Spirocerca lupi is a spirurid nematode that parasitizes the esophageal wall of Canidae and some other carnivores. It is most common in warm climates where dogs ingest third-stage larvae either via the dung beetle intermediate host or one of several insectivorous vertebrate paratenic hosts such as rodents, chickens, or reptiles. Larvae penetrate the gastric mucosa and migrate along arteries to the aorta, then subintimally to the caudal thoracic area, which they attain within worm. The granulomas around S. lupi contain highly reactive pleomorphic fibroblasts with large open nuclei and numerous mitotic figures. Neoplasms arising from such lesions have cytologic characteristics typical of fibrosarcoma and osteosarcoma, with local tissue invasion, and in many cases, pulmonary metastasis. The carcinogenic stimuli associated with the development of these tumors are unknown. Hypertrophic pulmonary osteopathy is occasionally found in animals with Spirocerca-associated sarcoma and, rarely, granuloma. Kirberger RM, et al. Spirocerca lupi-associated
The rumen represents the central processing unit for ingesta and as such is critical to the animal's well-being. However, because most of this occurs as a chemical process with minimal morphologic correlates, it is an organ that often seems to be overlooked by pathologists. Examination of ruminal contents may provide critical cues with respect to general metabolic states. Overly dry contents are an excellent indicator of dehydration. Voluminous frothy contents occur with primary bloat. Urea toxicity can be detected by an ammoniacal odor and alkaline pH. An odor of cooked turnips or a pungent insecticidal smell is suggestive of organophosphates. In grain overload, contents have a fermentative odor and pH may be <5.0. However, with putrefaction and release of toxic amines into the rumen, pH in cases of acidosis may return to near-normal levels. In these animals, the ruminal epithelium remains adherent to the submucosa despite any intervening postmortem changes, and it is an important clue to mucosal disease. Vagus indigestion, often associated with dysfunction of the esophageal groove, leads to accumulation of large volumes of watery fluid within the forestomachs. The rumen content of animals with Taxus spp. toxicity will have an aromatic odor like cedar several weeks of infection. Following 2-4 months in a granuloma in the aortic adventitia, worms migrate to the subjacent esophagus where they develop to adulthood. Here the adult nematodes are found within large, thick-walled cystic granulomas in the submucosa of the distal esophagus or gastric cardia. A fistula leading to the esophageal lumen is usually present, through which the tail of the female worm may protrude, and which provides the outlet for ova to the gastrointestinal tract ( Fig. 1-26 ). Larvae that adopt aberrant migratory pathways may be found in granulomas in sites such as the subcutis, bladder, kidney, spinal cord, as well as stomach and intrathoracic locations. Aortic lesions associated with Spirocerca are described in Vol. 3, Cardiovascular system, but include intimal and medial hemorrhage and necrosis with eosinophilic inflammation; intimal roughening with thrombosis; aneurysm with rare aortic rupture; intimal and medial mineralization, and heterotopic bone deposition. The presence of persistent aortic lesions in the dog, even in the absence of esophageal granuloma, is evidence of prior infection with S. lupi. Caudal thoracic vertebral body spondylitis occurs in greater than half of cases and is characterized by exostoses or bony spurs arising from the ends of the vertebral bodies. The pathogenesis is unclear, but may by initiated by migrating worms or inflammatory mediators.
In some animals with S. lupi, mesenchymal neoplasms develop in the wall of the esophageal granuloma ( Fig. 1-27) ; pulmonary fibrosarcoma has been associated with an ectopic
Further reading Berry
The ruminal mucosal epithelium usually sloughs within a few hours after death. It separates from the lamina propria in large gray patches, which cover the ingesta when the rumen is opened. Persistent firm attachment of the ruminal epithelium is abnormal. This undue adhesion occurs in acute and chronic rumenitis, especially if caused by fungi, and about scars of healed rumenitis. Adhesion may not occur in the early stages of ruminal acidosis.
Tympanitic distention of the forestomachs (tympany, hoven, bloat) may be acute, or chronic and recurrent. The acute or primary tympany of cattle fed legumes or high-concentrate rations is characterized by foaming of the rumen contents, which prevents gas from being eructated, whereas in chronic or recurrent (secondary) tympany, the gas is free but retained because of some physical or functional defect of eructation. Primary tympany is also called frothy bloat. Foam production in ruminal contents occurs normally. However, the amount of foam produced is small and unstable. There is apparently a delicate balance between profoaming and antifoaming factors in the rumen. These factors are multiple, and there is considerable controversy as to the extent to which each one influences the production of the foamy, viscous ruminal content so characteristic of frothy bloat, the most common cause of rumen distension.
The formation of foam is dependent on soluble proteins, especially fraction I proteins, which are present in high levels (up to 4.5%) in bloat-inducing legumes, such as alfalfa and clover, especially in the prebloom stage of growth. Other legumes, notably sainfoin, trefoil, and cicer milk vetch, are not associated with bloat. Soluble proteins, released from chloroplasts, are degraded by the rumen microflora, and they rise to the surface where they are denatured, become insoluble, and stabilize the foam. The optimal pH (isoelectric point) for foam production by soluble proteins ranges from 5.4 to 6.0. Pectins are considered to increase viscosity of ruminal fluid and may act as foam-stabilizing agents. Plant lipids may act as antifoaming agents by competing for metal ions with the soluble proteins, thus inhibiting the denaturation of these proteins and resulting in decreased foam production.
Eructation is a complex series of muscular contractions in which gas is forced from the rumen through the cardia and is released through the esophagus. The eructation sequence is oil and needles will be present in the ingesta. Recognition of characteristic foliage in rumen content may lead to a diagnosis of poisoning by several different toxic plants, including cyanogenic plants of the genus Prunus, oleandrin-containing plants of the genus Nerium, and so on. Motor oil, paint flakes, or metallic lead present in the rumen would help to support a diagnosis of lead poisoning. Several other toxic substances can be identified by visual inspection of the ruminal contents.
The ruminal mucosa is unique in that it has a stratified squamous epithelium that functions in absorption as well as protection from the vat of fermenting bacteria contained within. Langerhans cells are distributed within the mucosa throughout all compartments of the ovine rumen. T lymphocytes are found individually, and in aggregates, in both intraepithelial and subepithelial locations, with most in the cranial sac and relatively few dorsally.
Ruminal papillae in newborn calves are rudimentary and their subsequent development is dependent on diet, possibly as a consequence of stimulation by insulin-like growth factor-1. The end products of ruminal carbohydrate fermentation, propionate and butyrate, stimulate papillary growth. Papillae can take a variety of shapes, including long and flat, conical, spade-shaped, or hair-like. High-concentrate rations, which provide abundant propionate and butyrate, tend to produce papillae that are club-shaped, clumped ( Fig. 1-28) , and may be dark. Microscopically, these papillae are covered with epithelium displaying acanthosis, hyperkeratosis, orthokeratosis, and parakeratosis, and hyperpigmentation. Secondary papillae may be hyperplastic as well, creating the clumped appearance or rosette-like configurations. Rumens in animals fed barley rations have similar changes. Hairs from the rachilla of the barley adhere to the mucosa, especially in the interpapillary areas, giving it a distinct matted appearance. These penetrate the mucosa and lamina propria, where they evoke a leukocytic reaction, often causing microabscesses. A diffuse pleocellular reaction is evident in the thickened fibrotic wall.
Roughage also plays a role. When animals receive adequate levels (~15%) of coarse roughage, propionic and butyric acids
Josefsen TD, Landsverk T. T cell subsets and Langerhans cells in the forestomach mucosa of adult sheep and sheep foetuses. Vet Immunol Immunopathol 1996;51:101-111. Shen Z, et al. An energy-rich diet causes rumen papillae proliferation associated with more IGF type 1 receptors and increased plasma IGF-1 concentrations in young goats. J Nutr 2004; 134:11-17. is the so-called bloat line in the esophageal mucosa ( Fig. 1-29A ). This lesion is formed because of congestion with petechial and ecchymotic hemorrhages in the mucosa of the cervical esophagus, which changes abruptly or gradually to a pale mucosa at the level of the thoracic inlet. Although the presence of this line is usually considered highly suggestive of bloat, a similar change can apparently be seen in other conditions and some pathologists do not interpret this line as diagnostic for bloat. The tracheal mucosa is hemorrhagic, especially cranial to the thoracic inlet. Blood clots are frequently seen in the bronchi, and paranasal and frontal sinuses. The lungs are pale and compressed into the cranial thorax by the bulging diaphragm. There is pressure ischemia of the abdominal viscera, especially the liver, though the extreme margins of the hepatic lobes may be congested. Lymph nodes and the muscles of the hind legs are pale.
There may be marked subcutaneous edema, particularly of the vulva, inguinal region, and perineum, and intestines may herniate through the inguinal canals. If the autopsy is done soon after death, the ruminal contents are bulky and foamy ( Fig. 1-29B ). The foam gradually disappears after death and is usually absent if the autopsy is delayed for 10-12 hours. Inguinal hernia and diaphragmatic rupture may occur after death.
Secondary tympany (free gas or secondary bloat) may be acute, but is generally chronic, with periods of acute initiated by the presence of free gas in the dorsal sac of the rumen. Thus, if ruminal conditions prevent normal contractions from occurring in the reticulorumen or if movement of free gas through the cardia or esophagus is obstructed, bloat occurs. Excessive foam production causes distention of the rumen because it prevents formation of a free gas cap and the clearing of the cardia, which is essential for normal eructation to take place. When foam enters the esophagus, it stimulates the swallowing reflex, which also interferes with normal eructation. Gassy froth accumulates in the rumen as a consequence.
The variation among animals in their susceptibility to bloat may be determined in part by variations in the amount and composition of saliva. Saliva apparently has properties that may promote or prevent foaming in the rumen. When secretion of saliva decreases, the viscosity of ruminal contents increases, which in turn promotes foaming. Cows that have high susceptibility to bloating produce less saliva than cows that have low susceptibility. Succulent and high-concentrate feeds reduce salivary secretion, thus increasing viscosity of rumen contents. The composition of saliva also affects foam production in several ways. Combination of salivary bicarbonate with organic acids such as citric, malonic, and succinic, which are present in high levels in legumes, results in the production of large amounts of carbon dioxide, enhancing bubble formation. Carbon dioxide accounts for 40-70% of the total gas produced in the rumen.
High and low susceptibility to bloat can be temporarily transferred between animals by exchange of total reticulorumen contents. The understanding of the full role played by these various factors in bloat is incomplete, and other factors may be involved.
Rations high in concentrate and low in roughage not only reduce saliva secretion, but also change the ruminal microflora. They promote the growth of large numbers of encapsulated bacteria, which increase the concentration of polysaccharides, and these, in turn, increase the viscosity, promoting foam. These bacteria are also often mucinolytic and may destroy salivary mucins. Perhaps this explains the more gradual onset of feedlot bloat, because it takes time for the ruminal flora to change. Particle size of the grains fed may be one factor in feedlot bloat, with smaller particle size predisposing more to bloat.
The cause of death in bloat is probably a combination of physical and metabolic effects. Increased intra-abdominal pressure on the diaphragm inhibits respiration, and adversely affects cardiac function. Hypoxia may be caused by respiratory embarrassment. Increased intra-abdominal pressure also has a marked effect on the hemodynamics of the abdominal viscera, which are compressed, driving blood out of them. The caudal vena cava is also compressed, decreasing venous return to the heart. Distention also affects mucosal permeability and alters vagosympathetic reflexes.
The bloated animal is often found dead and distended with gas; blood exudes from the orifices, and because of the gaseous distention, the carcass often rolls on its back and assumes a sawhorse posture, with forelegs extended forward and rear legs pointing backward. The blood is dark and clots poorly; both features are indicative of death from anoxia. Subcutaneous hemorrhages are prominent in the cranial extremities, which are congested. There is marked edema, congestion, and hemorrhage of the cervical muscles and of the lymph nodes of the head and neck. An inconsistent but suggestive finding A B prehended with the food, to be deposited in the forestomachs. Sheep are largely immune because of their more selective eating habits. Foreign bodies are rarely found in the rumen of goats, despite their reputation for indiscriminate feeding habits. In consequence, a large proportion of adult cattle, and very few goats or sheep, have metallic, wood, or plastic foreign bodies in the rumen and reticulum, but rarely in the omasum.
Spherical masses consisting largely of hair or wool (trichobezoars) or plant fibers (phytobezoars) may also form in these compartments. Hairballs are most common in younger ruminants, the hair being swallowed after licking, particularly by animals deprived of dietary fiber. They may have some other foreign body as a nucleus and contain a proportion of plant fibers, the whole mass concreted by organic substances and inorganic salts. The same general comments apply to phytobezoars. Being smooth, neither are important unless regurgitated to lodge in the esophagus or passed on to obstruct the reticulo-omasal orifice, the pylorus, or the intestine, which is very infrequent. Otherwise, these bezoars are an incidental finding.
The important foreign bodies are those (such as lead) that cause intoxication when dissolved, and those that (being abrasive or sharp) penetrate the mucosa. In calves on diets low in roughage, ingestion of wood shavings or straw may lead to diffuse transmural inflammation of the forestomachs and sometimes the abomasum. A mixed bacterial flora containing clostridia and other organisms is responsible, presumably following mucosal trauma. The sequel to penetration by sharp objects in adult cattle is traumatic reticuloperitonitis.
Abutarbush SM, Naylor JM. Obstruction of the small intestine by a trichobezoar in cattle: 15 cases (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002)
Perforation of the forestomachs by foreign bodies is virtually always caused by a long, thin, and sharp foreign body, usually a wire or nail, penetrating the reticular wall. Incomplete perforation is usually inconsequential, although in some cases focal suppurative or granulomatous inflammation develops in the wall of the reticulum, with or without minor overlying peritonitis. There are no adequate answers as to why perforation occurs, but it is probably caused by forceful contraction of the reticulum, and many cases seem to be predisposed by the increased intra-abdominal pressure of late pregnancy and parturition.
The prophylactic use of magnets has become common in many herds, and this probably contributes to the marked decrease in fatal cases of traumatic reticuloperitonitis observed over the past few years. Frequently, these magnets are found incidentally in the reticulum, completely covered by metal foreign bodies, including nails and wires, which might otherwise have penetrated the reticular wall. The replacement of baling wire with twine in many parts of the world is another reason for the apparent decline in the prevalence of this disease. exacerbation. It is usually the result of a physical or functional defect in eructation of gas produced by normal rumen fermentation. The more common physical problems include internal or external obstructions of the esophagus or esophageal groove by tumor, foreign body, or esophageal stenosis of any cause. Reticular adhesions, abscesses, peritonitis, or tumor masses that interfere with contractions of the forestomach can result in bloat. Functional causes of secondary tympany include organophosphate intoxication, and vagal damage caused by adhesions, lymphosarcomatous infiltrates, or right-sided abomasal displacement and volvulus. Secondary tympany is a component of the syndromes collectively termed vagus indigestion. Bloat caused by muscular dystrophy of the diaphragmatic muscles has been described in both Meuse-Rhine-Issel and Holstein-Friesian breeds of cattle.
Secondary tympany, which is sometimes fatal, occurs in bucket-fed calves. This may be a persistent problem in some veal calves, which are known as ruminal drinkers. They ingest large amounts of milk, which escapes the reticular groove and flows into the rumen, where it putrefies because of digestion by proteolytic bacteria involving transformation of lactose into lactate by lactobacilli causing ruminal and metabolic acidosis. Casein clot formation in the abomasum is partly inhibited. The clinical signs are characterized by inappetence, unthriftiness, recurrent tympany, abdominal distention, and clay-like feces. Because of butyric and lactic acid accumulation in the epithelium of the reticulorumen, ruminal drinking leads to hyperkeratotic parakeratosis and severe reticulorumenitis accompanied by epithelial loss, erosions, and necrosis.
Animals fed rations that have too much indigestible roughage may have recurrent episodes of bloat. Feed must contain adequate portions of protein, starch, and/or sugars, and cellulose to stimulate growth of the cellulolytic microflora. Indigestible roughage accumulates in the rumen and reticulum when the intake of digestible nutrients (starches and sugars) is inadequate. As a result, the forestomachs become dilated, which in turn inhibits reticuloruminal contractions that are required for clearance of the cardia and subsequent eructation.
A postmortem diagnosis of secondary bloat is based on autopsy findings, which are similar to those described in primary bloat, but without frothy rumen content, and with the addition of any physical causes of impaired eructation. Postmortem distention of the rumen must not be mistaken for antemortem tympany. Braun
Further reading Abutarbush lesions may be in the pharyngeal and cervical areas, or intrathoracic, such as lymphosarcomatous infiltration, or abdominal. The latter are usually investment of the nerve in adhesions following reticular perforation, or trauma following abomasal volvulus. In other cases, degeneration of the vagus is not evident. In these, the dysfunction and lesions are more likely to be due to peritonitis and the subsequent abscessation, or adhesions that disrupt the normal tension-receptor activity or cause a pain response that interferes with normal motility of the forestomachs and abomasum.
In failure of omasal transport (type II vagus indigestion), there is impairment of movement of ingesta from the reticulorumen to the omasum, associated with abscesses adjacent to the reticulo-omasal orifice. There, lesions probably result in mechanical or neural interference to emptying of the reticulorumen.
A diagnosis of vagal indigestion at autopsy is ordinarily dependent on evidence of abnormal abomasal, omasal, or reticuloruminal motility, in association with morphologic lesions of the vagus nerves, adhesions, or neoplasms involving the forestomachs and abomasum.
Traumatic pericarditis is a less common sequel now, perhaps because many of the initial penetrations are diagnosed and the foreign body removed surgically, and also because, as explained previously, the cases of traumatic reticuloperitonitis themselves have decreased. The pericardial reaction is copious and fibrinopurulent. There are usually additional lesions of traumatic pneumonia and pleuritis. Braun U. Traumatic The outcome of complete perforation is common, but variations in the pattern are frequent. The perforation is usually in the cranioventral direction and is followed immediately by acute local peritonitis. If the foreign body is short or bent, it may progress no further, and some foreign bodies are apparently withdrawn with the next reticular movement; in such instances, only chronic local peritonitis with adhesions develops. The foreign body may advance to perforate the diaphragm and pericardium, resulting in traumatic pericarditis.
A ventral penetration may result in subperitoneal and subcutaneous abscess near the xiphoid. Rare perforation of one of the larger regional arteries may result in sudden death from hemorrhage, and sudden death may also occur if there is penetration of the myocardium or rupture of a coronary artery. Septicemia is also a possible but uncommon complication. Penetration of the thoracic cavity may occur without perforation of the pericardium, causing pneumonia and pleuritis. Right lateral deviation of the penetrating agent involves the wall of the abomasum. It is unusual for the liver or spleen to be penetrated, but metastatic abscesses in the liver are common.
As soon as the foreign body penetrates the serosa, local fibrinous peritonitis develops, which later leads to dense adhesion of variable extent between the reticulum and adjacent structures. Further progression of the foreign body is ordinarily slow and produces a canal surrounded by chronic granulation tissue and containing, besides the foreign body, ingesta, purulent exudate, and other detritus. The bacteria commonly active in the tract are Trueperella (Arcanobacterium) pyogenes, Fusobacterium necrophorum, and a variety of putrefactive types. In many cases, a foreign body cannot be found, perhaps because it has rusted away or been withdrawn into the reticulum.
One of the variants in the usual pattern of migration of the foreign body is penetration of the right side of the reticulum, leading to suppurative inflammation in the grooves between the reticulum, omasum, and abomasum. The acute local peritonitis causes immediate cessation of ruminal movements; however, persistent ruminal atony or irregular motility with gradual onset of bilateral abdominal distention, inappetence, and decreased milk production may ensue. Clinically this is referred to as vagus indigestion, which also may be a sequel to abomasal displacement. At autopsy, there are very characteristic changes in the stomachs with this syndrome. The rumen is distended with enough fluid to cause sloshing if the carcass is jolted. There is no ruminal fermentation or normal odor, and bits of unmacerated straw and food particles float on the watery fluid; the more-normal ingesta has sedimented. The omasum can be very large and impacted with dehydrated ingesta. The abomasum may be distended and impacted with dry ingesta, presumably because of functional pyloric stenosis or abomasal stasis.
The question of the importance of vagal nerve damage in the pathogenesis of vagus indigestion remains unresolved. The consensus is that this syndrome is associated with mechanical or functional impairment of outflow of ingesta from the forestomachs or abomasum, but in some cases the primary defect appears to reside in flaccidity of the reticular groove and in degeneration of its muscle and intramuscular nerve plexus. The rumen and reticulum are dependent on intact vagi for normal movement, and a minority of cases of vagus indigestion appears to be associated with damaged nerves. Vagal Rumenitis assumes significance in subclinical disease or in survivors of acute episodes, by providing a portal for the entry for fungi and Fusobacterium necrophorum, which cause secondary infections. These complications are discussed later. Other complications include coexisting primary tympany (frothy bloat), which may be the fatal partner of grain overload in feedlot cattle.
Ruminal acidosis usually follows the ingestion of excess carbohydrate in the form of grain, or other fermentable feedstuffs occasionally used, such as root crops, bread, waste baked goods, brewers' waste, and apples. There is wide variation in the amount of carbohydrate necessary to kill an animal, because tolerance to rations high in starch does develop if they are introduced gradually. Sudden increments in the amount of carbohydrate ingested are of more importance than the actual amount. Sudden changes from concentrates with lower energy values to those with higher values may predispose to acidosis. Extreme environmental temperature changes, either hotter or cooler, may result in temporary reductions in feed consumption, and acidosis may develop once such animals return to full feed.
Shortly after the ingestion of a toxic amount of carbohydrate, ruminal pH begins to fall. The decrease in pH during the first few hours is mainly caused by an increase in dissociated volatile fatty acids, not lactic acid. The production of the latter increases after there has been a marked change in the ruminal flora, which is very responsive to the substrate available for fermentation. In cattle and sheep, the normal pH of ruminal fluid varies between 5.5 and 7.5, depending on the diet fed.
The gram-negative bacteria that predominate in the normal flora, and the protozoa, are very sensitive to changes in the pH; most die at a pH of 5.0 or less. Once the pH of the ruminal contents starts to fall, streptococci, mainly Streptococcus bovis, proliferate rapidly, acting as a major source of lactic acid. When the pH reaches 5.0-4.5, the numbers of streptococci decrease, with a concomitant increase in lactobacilli. The pH of rumen content may fall as low as 4.0-4.5 in fatal cases.
As ruminal pH drops, ruminal atony develops, mainly as the result of an increase in the concentration of the nondissociated volatile fatty acids, lactic, propionic, and butyric. They act on receptors that mediate inhibition of reticuloruminal motility via a vagovagal reflex. Loss of forestomach motility in ruminal acidosis is apparently not dependent on the development of systemic acidosis. There is also cessation of salivary secretion, so that the buffering effect of saliva is absent.
The increase in ruminal organic acids, mainly lactate, causes an increase in ruminal osmotic pressure. This results in movement of fluid from the blood into the rumen, producing bulky and liquid ruminal contents and severe dehydration. Plasma volume is reduced; hemoconcentration, anuria, and circulatory collapse follow. Serum protein levels, urea, inorganic phosphorus, lactate, pyruvate, and liver enzymes are all elevated. The osmotic pressure of the intestinal contents also increases when the ingesta with the high lactate concentrations arrives there. Loss of fluid at this level probably contributes further to the dehydration, and it may also play a significant role in the development of the diarrhea that is commonly seen clinically. In addition to the osmotic effects, there is acidosis caused by the absorption of lactate from the rumen, and possibly from the intestine.
The low ruminal pH is lethal to much of the normal flora and fauna. The protozoa appear to be particularly sensitive, they can occur subsequent to chemical rumenitis, primary viral rumenitis, sepsis, or intensive antibiotic treatment.
Mild inflammation of the forestomachs occurs in some young calves fed milk from a pail, when, because of laxity of the reticular groove reflex, the milk spills into the rumen and reticulum in large quantity. A similar problem occurs with feeding by stomach tube. Putrefaction in these compartments leads to mild rumenitis, with edema and mild neutrophil infiltration of the mucosa.
Accidental consumption of excessive quantities of urea, in the form of nonprotein nitrogen supplement, or fertilizer, in liquid or powder form, results in the production of ammonia in the rumen. The toxic effect is accelerated by urease in soybased rations, and is based on the production of high blood levels of ammonia. Rumen contents smell ammoniacal when the organ is opened; the content is alkaline (pH 7.5-8); and there may be congestion or coagulative necrosis of the cranioventral wall of the rumen. Elevated ruminal and abomasal pH values (7.0), without specific lesions, have been associated with ingestion of boron fertilizer by cattle and goats.
Ingestion of toxic levels of sulfur results in chemical rumenitis because of the conversion of sulfur to hydrogen sulfide, and possibly sulfurous acid, in the rumen. Large amounts of yellow sulfur particles are usually found in the rumen and abomasum. Eructation and subsequent inhalation of hydrogen sulfide result in acute alveolitis. Absorption of sulfides from the lungs leads to marked depression of the respiratory and cardiovascular centers in the central nervous system. Affected animals also develop acidosis, probably caused by the absorption of acids, and impaired renal function associated with the direct toxic effects of sulfur metabolites on tubular epithelial cells.
Inflammation of the forestomachs may be associated with certain plant toxicoses, mainly in Australia, Africa, and South America. Examples are Kikuyu grass (Pennisetum clandestinum), prickly paddy melon (Cucumis myriocarpus), and several species of Bryophyllum, Lupinus, and Phytolacca.
Feeding rations deficient in fiber, which is increasingly the case in developed countries, can alter the microflora, predisposing the animals to metabolic disorders or rumenitis. In addition, acute chemical rumenitis develops after overeating on rapidly fermentable carbohydrate, usually grain. Pessoa CR, et
Ruminal acidosis and rumenitis associated with ingestion of excess carbohydrate are problems mainly of intensive beef and dairy production. Sheep, and especially goats, are also susceptible to this problem. Its importance lies partly in loss of production and partly in mortality because of the acute disease, in which rumenitis is of minor significance and lactic acidosis is the major cause of morbidity and mortality. but many types of bacteria are also lost. In those animals that survive the acute phase of ruminal acidosis, recovery is not complete until a normal ruminal flora is re-established through contact with other animals or by transplant of ruminal content from healthy animals. Temporary recovery may be followed by what appears clinically to be a relapse in acidosis, but which is a developing mycotic rumenitis. If treatment of the initial fluid imbalance is delayed, death may occur in a week or so from ischemic renal cortical necrosis. The gross findings in this metabolic disease are not specific, and a practical diagnosis requires knowledge of access to fermentable carbohydrate and a clinically observed circulatory failure. At autopsy, the eyes are sunken, the blood may be thick and dark because of dehydration and hypoxia, and there is general venous congestion. The appearance of the ruminal contents varies with the time interval between ingestion of the carbohydrate and the autopsy. In the early stages, there is a copious amount of porridge-like rumen content, which has a distinct fermentative odor. The amount of grain, corn, or other source of starch varies considerably and is an unreliable indication of acidosis, and the presence of finely ground concentrate may be overlooked. Ruminal pH is only helpful when it is low (<5.0) because it may rise in later stages of the disease. Although the ruminal contents may appear relatively normal in more advanced cases of acidosis, intestinal contents tend to remain very watery. Absence of protozoa is consistent with chemical rumenitis, but is also influenced by the interval between death and the postmortem examination.
The diagnosis of ruminal acidosis at autopsy can be difficult. The most suggestive abnormality is the rumenitis. It is probably chemical and dependent on the low pH, and is not readily discerned grossly. There may be a slight poorly defined blue discoloration in the ventral sac of the rumen, reticulum, and omasum, visible through the serosa. When the epithelium is detached, the lamina propria may be hyperemic in patches. In some cases, the epithelium appears to have undergone fixation because of low pH and is difficult to peel.
Microscopic examination of the ruminal mucosa is the most reliable way of confirming a diagnosis of chemical rumenitis. The ruminal papillae appear enlarged. There is marked cytoplasmic vacuolation of the epithelial cells, often leading to vesiculation. A mild to marked neutrophilic reaction is evident in the mucosa and submucosa ( Fig. 1-30 ). Focal areas of erosion and ulceration may or may not be present.
Fusobacterium necrophorum is a normal inhabitant of the anaerobic ruminal environment. This bacterium is commonly responsible for complications of ruminal acidosis, producing characteristic lesions in the forestomachs ( Fig. 1-31A ) and in the liver. Invasion of the wall of the rumen takes advantage of the foothold provided by the superficial necrosis and inflammation of acidosis. Inflammatory changes favor the adherence of F. necrophorum to ruminal epithelium.
Necrobacillary rumenitis is common in feedlot cattle, probably a product of mild acidosis following a too-rapid introduction to a high-concentrate ration. It affects the papillated areas of the ventral sac and occasionally the pillars. On the mucosal surface, the early lesions are visible as multiple irregular patches 2-15 cm across, in which the papillae are swollen, dark, slightly mushy, and are matted together by fibrinocellular inflammatory exudate. Affected papillae are necrotic, but ulceration may be delayed if there is ruminal atony and stasis. If the animal recovers from the immediate effects of overeating, the necrotic epithelium sloughs, the ulcer contracts, and
A central area, thickened to 1 cm or more, firm and leathery. There is acute fibrinohemorrhagic inflammation of the overlying peritoneum, and beneath it in the grooves there is bloodstained, inflammatory edema. The spleen also may be affected.
On the inner surface of the rumen, the lesions are more hemorrhagic than those of necrobacillosis, and more irregular in outline ( Fig. 1-33B) , and the necrotic epithelium is difficult to detach. Histologically, the rumenitis is characterized by hemorrhagic necrosis of all structures in the wall; by copious fibrinous exudate; and by rather scant leukocytic reaction. Fungal hyphae with nonparallel walls are readily visible in the necrotic tissues and the lumina of the thrombosed blood vessels. More chronic cases are characterized by granulomatous inflammation in the deeper parts of the mucosal lesion.
Mycotic rumenitis and omasitis may occur in cows that do not have a history of acidosis. It has been suggested that these cases may be a sequel of sepsis, with reflux of abomasal fluid into the forestomachs, and therapy with broad-spectrum antimicrobials acting as predisposing factors for mycotic infections. It can also be a sequel to ruminal damage in survivors of bovine viral diarrhea virus infection. Roughly circular and dark areas of infarction, most of them with a pale center, involving rumen and reticulum. Notice that the spleen is also affected. B. Appearance of mucosal surface of rumen; superficial necrosis overlies congested submucosa.
A B epithelial regeneration begins from the margins. The regenerated epithelium is flat and white, and the papillae do not return completely. A stellate scar often remains, but many of the smaller lesions may disappear completely ( Fig. 1-31B ). Liver abscesses are the main complication of the F. necrophorum rumenitis and the term "rumenitis-liver abscess complex" is frequently used to describe this condition. Although the precise mechanism is not fully understood, it is recognized that bacterial emboli are released from the F. necrophoruminfected ruminal wall into the portal circulation, followed by bacteria being filtered by the liver, resulting in hepatic infection and abscess formation. Hepatic lesions are initially the typical coagulative necrosis of necrobacillosis, but in time they liquefy to form abscesses ( Fig. 1-32 ), and these often persist long after the initial ruminal lesions have cicatrized or disappeared.
It is unusual for ruminal necrobacillosis in cattle to be more than a superficial infection, and although the muscle layers are involved in the inflammation, they are not ordinarily invaded by the organism. However, perforation of the omasal leaves is common. In sheep, the infection is more aggressive, although less frequently observed, than it is in cattle. Fusobacterium varium has also been reported to produce liver abscesses associated with rumenitis in sheep.
Mycotic infection should be suspected when inflammation in the wall of the forestomachs extends to the serosa and is hemorrhagic and angiocentric. The fungi, which, like F. necrophorum, are opportunists, are usually zygomycetes of the genera Mucor, Rhizopus, and Absidia, which cannot be differentiated from each other in histologic sections.
Mycotic rumenitis is much more severe and extensive than necrobacillary rumenitis, and is often fatal. The basis for the lesion is submucosal venular thrombosis caused by fungal invasion, causing venous infarction of the tissue field involved. The inflammation extends to the peritoneum, causing hemorrhagic and fibrinous peritonitis that mats the omentum to the rumen. In fatal cases, most of the ventral sac and parts of the reticulum, omasum and/or abomasum are involved. The lesions are very striking and suggest on initial inspection that the walls have been massively infarcted, which in part they have ( Fig. 1-33A ). The margins are well demarcated, usually by a narrow zone of congestive swelling. The affected areas are roughly circular, red to black, sometimes with a pale Paramphistomum spp. Larval paramphistomes in the duodenum can cause disease. The biology and pathogenicity of paramphistomes are discussed in detail the section on Infectious and parasitic diseases of the alimentary tract, later in this chapter.
Myiasis of the rumen caused by larvae of the screwworm fly Cochliomyia hominivorax is occasionally a cause of mortality in young calves in South America. The larvae are presumed to be licked from cutaneous wounds and swallowed. They lodge in the rumen and perforate it. Gordon DK, et
Neoplasia of the esophagus and reticulorumen is, with the exception of papilloma, rare in domestic animals. Papillomas of the esophagus in dogs are uncommon and may be associated with oral papilloma. In cattle, papillomata of the esophagus and forestomachs are common in some areas. They are caused by bovine papillomavirus 4 (BPV-4), which infects only squamous mucosa of the mouth, pharynx, esophagus, and forestomachs. Bovine alimentary papillomatosis in healthy immunocompetent animals is usually mild with solitary papillomata, although a minority of infected animals may have multiple lesions. Most are small (<1 cm), broadly pedunculate tapering acuminate masses. They are composed of a number of closely packed fronds of squamous epithelium, each supported by a light core of fibrous stroma, and arising from a common fibrous base. Viral replication and the microscopic changes in infected epithelium are typical, as described earlier for canine oral papillomas, although the characteristic koilocytes and intranuclear inclusions can be sparse. These papillomas are usually rejected by a cell-mediated immune response within approximately 12 months. However, severe Metastases sometimes occur in the liver and cause necrotizing thrombophlebitis of the portal radicles visible as small irregular tan areas of infarction surrounded by a deep red margin.
Other conditions that have been associated with ruminal acidosis are laminitis and an encephalopathy which morphologically resembles the lesions of early polioencephalomalacia (see Vol. 1, Integumentary system; Vol. 1, Nervous system). Foster AP, et
Gongylonema spp. occur in the epithelium of the rumen. They appear as described in the esophagus, and are not pathogenic.
More important parasites are the conical rumen flukes belonging to the family Paramphistomatidae. Although several species of Paramphistomum have been described, Paramphistomum cervi is probably the most widespread species; Calicophoron daubneyi is reported to be common in cattle and sheep in Great Britain. Paramphistomum parasites are found in cattle and sheep in warm temperate, subtropical, and tropical regions. These red, plump, droplet-shaped flukes are about the size of the papillae between which they reside in the rumen, where they are usually considered to be mostly nonpathogenic ( Fig. 1-34A ). However, if present in very high numbers, they can cause rumenoreticulitis, with atrophy of papillae and excessive cornification of the stratum corneum and granulosum ( Fig. 1-34B ). Loss of condition has been observed in adult cattle with massive ruminal infestation of esophagus and adjacent mediastinum. In horses, squamous cell carcinoma of the stomach may also involve the adjacent terminal esophagus. Rare squamous cell carcinoma, and adenocarcinomas arising from the esophageal glands, are reported in dogs. Invasion of, or metastasis to, the canine esophagus by thyroid, respiratory, and gastric carcinomas is also reported.
Mesenchymal tumors of the esophagus, with the exception of the Spirocerca-associated fibrosarcomas and osteosarcomas in dogs, referred to previously in the section on parasitic diseases of the esophagus, are very rare. However, leiomyoma, osteosarcoma, and plasmacytoma have been reported in dogs. Connective tissue tumors of the ruminant forestomachs are similarly rare, although fibromas of the reticular groove have been reported. Occasional involvement of the rumen, omasum, and reticulum may occur in cattle with lymphosarcoma, usually also involving the abomasum and more distant sites.
The stomach should be carefully examined in animals of any species with a history of inappetence or anorexia, cachexia, hypoproteinemia, diarrhea, regurgitation, or vomition. Abdominal distention may be associated with gastric dilation or displacement. Hematemesis, melena, or anemia may signify gastric bleeding. Many infectious diseases, with major systemic or alimentary tract signs elsewhere, produce gastric lesions. Systemic states such as uremia and endotoxemia cause characteristic gastric lesions in some species. The stomach has long been considered to lack a normal bacterial population (microbiota). However, bacteria have been identified in the glandular stomach of healthy animals, including members of the genus Helicobacter. In the horse and pig, an obvious smooth white or yellow esophageal region is present. It is covered by stratified squamous epithelium, with susceptibility to insult and reparative capacity similar to that of the esophageal lining. Chronic inflammatory infiltrates and lymphoid follicles are normally present in the lamina propria and submucosa of the cardiac gland mucosa abutting the esophageal region, especially in the pig. The cardiac gland zone is gray and is particularly well developed in this species, lining the gastric diverticulum, fundus, and about half the body of the stomach. In the dog, cat, and ruminant, cardiac glands are limited to a narrow zone at the cardia or omasal opening. Cardiac glands are branched tubular structures, lined almost exclusively by columnar mucous cells.
The fundic, or oxyntic, gland acid-secretory mucosa in the horse and pig is red-brown and slightly irregular but not highly folded. More prominent longitudinally oriented rugae, or plicae, are present in the dog and cat, and in the abomasum of ruminants. Gastric secretion undiluted by ingesta in the dog or cat normally should be pH <3.0. Abomasal content should be pH <3.5-4.0. papillomatosis, often accompanied by development of squamous cell carcinomas (see later) in the same location has been described in the esophagus and forestomachs of bracken fern immunosuppressed, BPV-4 infected cattle in Scotland and England.
Fibropapillomas, limited to the esophagus, esophageal groove and rumen of cattle, are caused by bovine papillomavirus 2 (BPV-2), normally associated with cutaneous papillomas and fibropapillomas. Alimentary fibropapillomas are smooth nodular pearly-white masses, usually about 0.5-1.0 cm in diameter, but occasionally up to 3.0 cm and plaque-like. They are comprised of fibromatous stroma covered by acanthotic epithelium, which occasionally may be ulcerated. No evidence of expression of BPV-2 is found in alimentary fibropapillomas, the viral genome being identified by molecular probes.
Papillomas and fibropapillomas are normally asymptomatic, though large lesions of the reticular groove and esophagus may interfere with eructation and deglutition, causing bloating or loss of condition.
Malignant neoplasms of the esophagus and forestomachs in ruminants are ordinarily extremely rare. However, in several localities, squamous cell carcinoma is relatively common in cattle, associated with BPV-4-induced papilloma (but not with fibropapilloma because of BPV-2). However, BPV-4 viral antigens or genome are not detected in these carcinomas. An interaction between papillomavirus and ingestion of carcinogens in bracken fern predisposes to the development of squamous cell carcinomas of the esophagus and forestomachs in Scotland and England. Immunocompromise caused by bracken fern intoxication, which is permissive of severe papillomatosis, is also a co-factor in neoplastic transformation to squamous carcinomas. In Brazil and Bolivia, a similar association is made with carcinomas of the oropharynx and esophagus. A high prevalence of carcinoma of the esophagus and forestomachs has also been reported from a single valley in Kenya, in association with papillomata not confirmed as viral, and with a yet undetermined carcinogen apparently ingested with or derived from native forest plants.
Esophageal and ruminal carcinomas are associated with dysphagia or difficult deglutition, ruminal tympany, and apparent abdominal pain with progressive cachexia. Concurrent papillomas, carcinomas, and hemangiomas of the bladder, like those causing enzootic hematuria, but associated with BPV-2, are often found in cattle with esophageal or ruminal cancer. In Scotland, intestinal adenomas or adenocarcinoma also occur in many cases.
Esophageal and ruminal carcinoma may be seen developing from recognizable papillomas; as brown irregular roughened hyperplastic epithelium; or as ulcerated or irregular proliferative fungating lesions. Distal esophagus, reticular groove, and the adjacent ruminal wall are the sites most commonly affected with carcinoma. Microscopically, they are typical squamous cell carcinomas, and invade locally, their scirrhous nature causing induration of the wall of the organ. They may metastasize to local lymph nodes, and to distant sites such as liver and lung.
In sheep and goats, alimentary papillomas and squamous cell carcinomas are rare, and little is known of their etiology.
Rarely, squamous cell carcinomas also may be encountered in the esophagus of aged cats, where they develop in the midthoracic portion, forming proliferative plaques of neoplastic cells that eventually ulcerate and invade the wall of the mucosae in the stomach of cats. The cause and significance are unknown.
Hydrolysis of protein in preparation for subsequent intestinal digestion and absorption is accomplished in the stomach by acid and by pepsin, activated by autocatalysis from pepsinogen at low pH. Secretion of acid is the function of the oxyntic, or parietal cells, about one billion of which are present in the stomach of a 20-kg dog. Regulation of the volume and acidity of gastric secretion is physiologically complex and highly integrated, involving neurocrine, endocrine, and paracrine mechanisms.
The parietal cell secretes hydrochloric acid in response to stimulation by histamine, acetylcholine, and gastrin. All 3 agonists are probably continuously present and involved in basal acid secretion. However, the effects of acetylcholine and gastrin are largely dependent on concurrent stimulation by the permissive agonist, histamine.
Histamine is a paracrine stimulant, continuously present in the environment of the oxyntic cells, and secreted by mast cells and enterochromaffin-like cells. Occupation of the H 2 histamine receptor on the oxyntic cell causes enhanced generation of cyclic adenosine monophosphate. This in turn stimulates protein kinase cascades culminating in translocation of the proton pump to the apical cell membrane, where acid is secreted.
Acetylcholine, the neurocrine agonist, is released near the oxyntic cell from processes of parasympathetic postganglionic neurons. Its release is enhanced by vagal activity during the central stimulation of the cephalic phase-the Pavlovian response. Gastric distention also stimulates the parietal cell via vagovagal and short intramural reflex pathways. Acetylcholine acting on muscarinic M 3 receptors elevates intracellular Ca 2+ , which stimulates acid secretion.
Gastrin is released into the bloodstream by G cells, many of which are in the pyloric antrum. Calcium, amino acids, and peptides in ingesta, impinging on G cells, stimulate gastrin release. Vagal stimulation during the cephalic phase, and fundic-pyloric vagovagal reflexes, in concert with local pyloric reflexes, initiated by distention, also cause G cells to release gastrin. Gastrin acts mainly by a receptor-mediated process to release histamine from the enterochromaffin-like cells. Gastrin alone is a weak stimulant of acid production, but it synergizes secretion by oxyntic cells exposed to histamine and acetylcholine. In addition, gastrin has an important trophic effect, increasing the number of parietal and endocrine cells in fundic mucosa. In turn, parietal cell mass seems to impact on chief cell differentiation.
Acid production during the gastric phase of secretion is depressed by the negative-feedback effect of acid in the antrum, through the inhibitory effect of somatostatin on the G cell below pH 3.0. Acid, fat, and hyperosmolal solutions in the proximal small intestine also inhibit acid secretion, perhaps by the mediation of neural reflexes, secretin, gastric-inhibitory polypeptide, epidermal growth factor, transforming growth factor-α, or other enterogastrones. Prostaglandin E 2 also inhibits acid production by parietal cells.
The chief cell is probably susceptible to the same general stimuli for secretion as the parietal cell.
Gastric motility is the outcome of an interaction among myogenic, hormonal, and neuronal factors, the latter two impinging directly or indirectly on smooth muscle. Mediating at least part of the neural component of this control system, by as yet uncertain mechanisms, are the interstitial cells of Tall columnar mucous cells cover the gastric surface, and line pits or foveolae. The junction of the base of the foveola and the upper portion of the neck of the fundic gland proper is termed the isthmus. Cuboidal or low columnar pluripotential stem cells in a narrow zone in this area undergo mitosis. Three lineages are identified: (1) pit (foveolar) cells; (2) parietal cells; and (3) zymogen (chief) cells. Daughter cells of the pit cell lineage differentiate into foveolar mucous cells, migrating up on to the gastric surface, where they are lost, probably in about 4-6 days. The neck of the oxyntic gland below the isthmus is lined by pyramidal, peripherally located acid- and intrinsic factor-producing parietal cells. Interspersed are inconspicuous mucous neck cells, mainly in the upper neck and probably stages in the differentiation of chief, and perhaps, parietal cells, and scattered endocrine cells. In the base of the gland the pepsinogen-producing zymogen, or chief, cells are concentrated.
Mucous neck cells, like foveolar mucous cells, contain periodic acid-Schiff-positive mucus. Parietal cells differentiate from cells proliferating at the isthmus, and appear to be relatively long-lived, that is, of the order of weeks to months. A complex tubulovesicular/canalicular structure upon which the hydrogen ion-secretory proton pump is inserted opens at the luminal apex of the cell in the secretory state. A number of long-lived enteroendocrine cells, derived from proliferative cells at the isthmus, are recognized in the oxyntic gland, secreting histamine, serotonin, and somatostatin, among other endocrine/paracrine agents. Endocrine cells usually abut the basement membrane of the gland, lack exposure to the gland lumen, and have characteristic basal granules. The chief cells are apparently long-lived cells, derived from stem cells at the isthmus. Ultrastructurally they have extensive rough endoplasmic reticulum, a prominent Golgi zone, and numerous zymogen granules.
Normally, mitotic figures are not common in cells at the isthmus of fundic glands, and are virtually never seen at any distance from the isthmus. However, the fundic mucosa of newborn ruminants and especially piglets may be relatively poorly differentiated and proliferative. The proliferative compartment, if active, is sensitive to radiomimetic insults, such as cytotoxic agents and parvoviral infection. This is reflected by narrowing of the isthmus and upper neck and attenuation of the epithelium lining the gland.
The pyloric mucosa forms a slightly pitted or irregular surface in the distal portion of the stomach; it extends further cranial along the lesser than the greater curvature. The knoblike torus pyloricus at the pylorus of the pig is a normal structure. The tubular glands of the pyloric mucosa open into deep gastric pits that may extend half the thickness of the mucosa. The glands are lined by pale mucous cells, with interspersed endocrine elements, mainly G (gastrin) and D (somatostatin) cells. Scattered parietal cells may be present, especially in glands in the zone intergrading with fundic mucosa.
The stromal elements of the gastric lamina propria are relatively inconspicuous, in fundic mucosa in particular. Normally, a few lymphocytes and plasma cells, and scattered mast cells are present, mainly deep between glands. Occasional lymphocytic nodules or follicles may be present, usually near the muscularis mucosae. Lymphoid infiltrates are more common in antral mucosa. A thick band of amorphous hyalinized connective tissue, sometimes termed the lamina densa, is seen sporadically on the luminal aspect of the muscularis
Restitution of acute erosive physical or chemical trauma to the mucosal surface is by rapid (minutes to hours) immigration of surviving attenuated surface and foveolar cells. Under the initial control of transforming growth factor-β and later influenced by epidermal growth factor, repair by proliferation of cells in the isthmus follows, if the erosive lesion is superficial and spares the progenitor cells. The "sonic hedgehog" protein is secreted by parietal cells and has been shown to be important in epithelial cell differentiation and gastric wound repair in animal models. A cap of mucus, exfoliated epithelium, and fibrin over a mucosal defect may form a protective barrier conducive to effective restitution of the mucosal epithelium. An acute inflammatory reaction demarcates severely eroded or superficially necrotic mucosa, and hemorrhage may be evident on the surface and in adjacent mucosa. Mitoses become common in the upper gland. After a gastric insult, mucosal blood flow rapidly increases. This is protective by aiding in dilution and removal of back-diffusing acid and injurious substances from the mucosa.
During the early phase of repair, cells lining shallow foveolae and covering the surface are basophilic, poorly differentiated, and flattened, cuboidal, or low columnar. Sites of epithelial exfoliation and neutrophil transmigration or effusion into the lumen may be evident. Congestion, edema, mild neutrophilia, and fibroplasia are seen in the superficial lamina propria. The evolution and repair of gastric ulceration, to which erosion may be antecedent, are discussed later. The progenitor cells of the fundic mucosa have the potential to produce tall columnar mucous cells of the foveolar or surface type, to produce mucous neck cells, and by further differentiation, to evolve into parietal cells.
Cajal, pacemakers that are variously found between the layers of gastric smooth muscle, or among smooth muscle cells.
The gastric mucosal barrier to acid back-diffusion and autodigestion resides largely in the single layer of foveolar and surface mucous cells and its products. Tight junctions are present between epithelial cells and are critical in maintenance of barrier function. Integrity of the gastric mucosal barrier implies continuity of the mucosal surface epithelium. The capacity of these cells to maintain tight junctions, to migrate rapidly to fill defects, and to secrete mucus, bicarbonate, and a hydrophobic phospholipid surface layer, is central to protecting the gastric mucosa against progressive injury by insults arising in the lumen.
Gastric mucus is freely permeable to hydrogen ions and has little innate buffering capacity, but it resists hydrolysis by intraluminal pepsin, protecting the integrity of the mucosal surface. Mucus forms a layer immediately over the gastric epithelial cells termed the "unstirred mucus layer" and is the first line of defense from injury. This layer consists of a number of different types of mucin, bicarbonate, and phospholipids. Cardiac gland mucosa in the pig, and pyloric mucosa, secrete bicarbonate in considerable quantities, and normally resist acid attack. Fundic surface mucous cells also actively secrete bicarbonate into a thin unstirred layer of surface mucus. Bicarbonate and mucus secretion by mucous cells is stimulated by prostaglandin E 2 . Acid is buffered by bicarbonate in the thin unstirred layer of mucus, preventing back-diffusion into the mucosa. In addition, the "alkaline tide" of bicarbonate, released into the gastric interstitial space during the course of acid secretion, further buffers the mucosa against acid back-diffusion.
Prostaglandins, particularly of the E series, ubiquitous in gastric mucosal lamina propria, may have protective effects other than by stimulation of bicarbonate and mucus secretion by mucous cells, and by inhibition of histamine-stimulated acid secretion by parietal cells. They cause proliferation, resulting in an increased mass of foveolar mucous epithelium. They may promote incorporation of surfactant molecules into the apical cell membrane of surface mucous cells, increasing its hydrophobicity and imparting greater resistance to watersoluble insults. They also may be involved in gastric mucosal cytoprotection by sulfhydryl compounds, which may neutralize free radicals and other toxic metabolites.
Prostaglandins and basal nitric oxide production cause vasodilation and increased blood flow, in addition to inhibiting acid secretion by parietal cells, and promoting bicarbonate secretion by foveolar mucous cells. Bicarbonate in the local circulation, resulting from the alkaline tide generated by acid secretion in glands deeper in the mucosa, is probably important in buffering the superficial lamina propria against backdiffusion of acid; adequate blood flow flushes injurious free radicals from the vicinity of surface cells. Experimentally, high blood flow is protective against many mucosal insults, whereas ischemia is ulcerogenic.
Epidermal growth factor, originating in salivary glands, and transforming growth factor-α, produced locally in the gastric mucosa, also appear protective, in that they may promote cell proliferation and migration to fill defects, and suppress acid production. Bombesin is probably protective through stimulation of gastrin-mediated nitric oxide release, promoting gastric mucosal blood flow. The gastric microvascular network is also from fundic atrophy associated with the loss of appetite on the basis of the degree of mucous cell hyperplasia and differentiation, and the presence of inflammatory cells.
The cause and functional significance of gastric mucous metaplasia are unclear. Parietal cells are important for epithelial homeostasis and their loss during chronic inflammation may contribute to epithelial dysregulation and mucous metaplasia.
Presumably loss of parietal cells and hyperplasia of mucous neck cells is partly a response to soluble local immunemediated stimuli or products of inflammation because it is localized in the vicinity of glands containing larvae in gastric parasitism, but, as a general phenomenon, seems independent of parasite-specific factors. Tumor necrosis factorα, interleukin-1, and interferon-γ are candidate cytokines involved in inflammatory mucous metaplasia of the fundic stomach. In vitro, interleukin-1β and tumor necrosis factor-α inhibit acid secretion by isolated parietal cells, and tumor necrosis factor-α induces apoptosis of parietal cells. Replacement of parietal cells by mucous neck cells, or an apparently more fully differentiated mucous cell in chronic gastritis, may be a protective response. It may eliminate the threat of local acid corrosion, and promote the transfer into the lumen of protective soluble factors such as lysozyme and IgA or its analogues. In animal models, gastric mucous metaplasia has been identified as an early event in the progression to gastric neoplasia.
Achlorhydria ensues in severe chronic gastritis and mucous metaplasia. The pH of gastric secretion approaches or exceeds neutrality under some circumstances, as sodium ion replaces hydrogen ion in gastric content and bicarbonate is secreted. With diminished gastric acid concentration, progressive microbial colonization of the stomach and upper intestine ensues. Parietal cell atrophy and replacement by mucous neck cells in ruminants with anorexia caused by enteric disease may predispose to mycotic invasion of the mucosa if it is physically disrupted. However, mucous metaplasia and hyperplasia, as seen in chronic gastritis or conditions like ostertagiosis, do not seem to render the mucosa prone to mycosis. Loss of the hydrolytic effects of acid and pepsin, in achlorhydria, seems to have little effect on digestion of protein and uptake of nitrogen, at least in animals with ostertagiosis, and the effect on protein digestion of atrophic gastritis in humans appears to be minimal. Rather, at least in parasitic gastritis, inappetence diminishes nutrient intake on the one hand, whereas mucosal permeability permits protein loss through the mucosa (protein-losing gastropathy); together, these impact on the nitrogen economy of the animal to cause reduced productive efficiency, or loss of body condition, depending on whether the animal enters negative nitrogen balance or not.
Evaluation of gastric biopsies is governed by the same caveats discussed in the section on interpretation of intestinal and colonic biopsies. Rapid fixation of gastric biopsies is paramount. Gastritis, and the pathogenesis of gastrointestinal parasitism, are discussed later in this chapter. Atrophy of parietal cell mass without extensive mucous cell hyperplasia occurs in animals, particularly ruminants, which have signs of gastrointestinal disease, including inappetence. The change is not evident grossly. Microscopically, fewer parietal cells are seen in the upper neck of fundic glands, and often in the depth of the gland. This is accompanied by epithelial proliferation, indicated by moderate numbers of mitotic figures at the isthmus and in the neck of the gland. Mucous neck cells become the predominant cell in the upper gland. In extreme cases mucous neck cells are present to the base of glands, and achlorhydria occurs. Similar findings occur in animals with a wide variety of syndromes involving loss of appetite. Starvation of moderate duration does not produce comparable lesions. This lesion may be the result of reduced trophic stimulation of the fundic mucosa, and is not to be confused with atrophic gastritis, in which loss of parietal cell mass and atrophy of mucosal thickness are accompanied by usually chronic inflammation.
Mucous metaplasia and hyperplasia of glands in the fundic stomach in all species are associated with chronic inflammation of the mucosa. As the lesion evolves, parietal cells seem to be lost at an accelerated rate because they are only present in the basal portion of the glands, and they appear to be progressively displaced from above by hyperplastic mucous cells. Mitotic figures may be numerous throughout the neck of the gland, which elongates. The metaplastic epithelium in early lesions tends to resemble mucous neck cells. In established lesions, columnar mucous cells with regular nuclear polarity, similar to foveolar mucous cells, may be present. When inflammatory infiltrates are local, the mucous change is limited to a few surrounding glands. More diffuse inflammation is associated with the development of widespread epithelial mucous metaplasia. Focal or diffuse, superficial or mucosal, proprial infiltrates of plasma cells and lymphocytes are typical. Often, neutrophils, eosinophils, and Russell-body cells will be present in the lamina propria, and lymphocytes may be between epithelial cells in glands. Globule leukocytes may be present in the epithelium of glands, especially in the parasitized abomasum.
This mucous metaplasia, hyperplasia, and chronic inflammation is associated with a variety of causes, including chronic traumatic insults, such as those caused by implanted foreign bodies, as well as in the abomasa of ruminants infected with lentiviruses. The specific agency most commonly recognized is gastric parasitism by nematodes such as Ostertagia spp., Trichostrongylus axei, Hyostrongylus spp., and Ollulanus tricuspis, where the distribution of the lesion is often closely related to the physical presence of nematodes and to the interstitial inflammatory reaction that they incite. Mucous metaplasia and hyperplasia are also typically present around the healing margins of chronic ulcers, perhaps in response to local inflammation.
The mucosa affected in these circumstances is grossly thickened, as on the overhanging margin of an ulcer, or in an Ostertagia "nodule," with a pebbled or convoluted surface if the lesion is widespread. Gastric rugae or plicae are thickened, partially as a result of mucosal hypertrophy, perhaps with submucosal edema. The surface of the stomach is usually paler than normal in affected areas; however, local congestion or hyperemia may be evident. Although the surface may be glistening, profuse mucus secretion is not usually obvious. Achlorhydria is the consequence of widespread change of this type. Mucous metaplasia and hyperplasia are differentiated
Further reading Barker hypertrophy of glands, which may involve foveolar or deeper glandular elements alone, or in combination, perhaps with cystic dilation of deeper portions of glands. There is usually a concomitant chronic inflammatory infiltrate in the mucosa and occasionally submucosa, and small erosions of the mucosal surface may occur. If there is muscular hypertrophy, this is reflected on the cut surface of the pylorus by irregular firm thickening of the circular muscle. Microscopically, smooth-muscle fibers in affected fascicles are irregularly hypertrophic. Recognition of smooth-muscle hypertrophy requires a full-thickness biopsy, which will not be obtained by endoscopy.
Gastric dilation in the horse is often secondary to obstruction of the stomach, small bowel, or of colic with ileus, and is also part of the syndrome "grass sickness," discussed elsewhere in this chapter. Ingestion of Datura sp. seeds, which contain a parasympatholytic alkaloid, can also cause ileus, leading to gastric dilation. Primary gastric dilation in horses is a sequel to consumption of excess fermentable carbohydrate, sudden access to lush pasture, or excessive intake of water. Dilation associated with intake of fermentable feed is likely analogous to grain overload in cattle. Ingesta may swell through absorption of saliva and gastric secretion. Evolution of gas and organic acids, including lactic acid, by bacterial fermentation of carbohydrate, occurs in the cranial portion of the stomach. An influx of water follows as the result of increased osmotic pressure in the stomach, contributing to increased distension and to systemic dehydration. Animals surviving for any time with acute gastric dilation of this type may develop laminitis. Gastric rupture may follow primary or secondary dilation of the equine stomach; it may be idiopathic, in that no clear cause is identified. Gastric rupture is diagnosed in ∼5% of horses with colic admitted to veterinary hospitals. Rupture usually occurs along the greater curvature, parallel to the omental attachment, releasing gastric content into the omental bursa or the abdominal cavity. Death ensues acutely as the result of shock and peritonitis. The margins of the laceration show evidence of antemortem hemorrhage, which differentiates the lesion from postmortem rupture of a dilated stomach. There also may be congestion of the cervical esophagus and blanching of the thoracic esophagus, producing a prominent bloat line. This, and compression atelectasis of the lungs in some cases, attests to the tremendous increase in intraabdominal and intrathoracic pressure exerted by the dilated stomach before rupture. Perforation, as distinct from rupture, of the stomach in the horse is rare, and is associated with parasitism, gastric ulcer, or neoplasia.
Pyloric stenosis is a functional and sometimes anatomic problem, which in part represents probably the only anomaly of the stomach recognized in animals. Pyloric stenosis can be congenital or acquired. It is relatively common in dogs, and rare in cats and horses. Recurrent vomition and poor growth in recently weaned animals suggest the clinical diagnosis of a congenital lesion. Contrast radiographic studies will confirm delayed gastric emptying. There is limited critical functional information on congenital stenosis. An analogous condition in humans is associated with a lack of the interstitial cells of Cajal, but this association has not been clearly demonstrated in domestic animals, nor have morphological or significant immunohistochemical neural abnormalities been identified. In some dogs there may be hypertrophy of pyloric smooth muscle, which appears grossly thickened. Tonic stenosis of the pyloric sphincter may occur in dogs, perhaps because of alterations of the myenteric plexus or gastrin excess. Hypertrophy of the pyloric smooth muscle and stenosis has been reported in Siamese cats. An association with esophageal dilation has been made in the cat. Congenital pyloric stenosis in a foal was associated with signs of abdominal pain and reluctance to consume solid feed. In all species, the clinical problem is usually abolished by pyloromyotomy.
Physical causes of acquired pyloric stenosis or obstruction include: ulceration, granulation, and stricture of the pyloric canal in any species; foreign bodies; as a complication of polyps and tumors in the area; and chronic hypertrophic pyloric gastropathy in dogs.
Chronic hypertrophic pyloric gastropathy is the term coined for a syndrome of pyloric obstruction in dogs, associated with mucosal hypertrophy, hypertrophy of circular smooth muscle, or a combination of the two. Mucosal hypertrophy alone is the most common lesion; muscular hypertrophy alone is the least common, although some degree of muscular hypertrophy is seen in about half the cases. Affected animals are typically of small breeds, and those middle-aged or older. Males outnumber females. The pathogenesis is speculative, and it is not clear whether muscular hypertrophy is primary, as it seems to be in some cases, or whether it is secondary, in response to obstruction related to excess mucosa. Because mucosal and muscular lesions can be present independently, they may have separate causes. The mucosal hypertrophy has features in common with hypertrophic gastritis, described elsewhere. The cardinal presenting sign is chronic intermittent vomition, perhaps with weight loss, and with gastric distention in a few cases. Gross examination, by gastroscopy, at gastrotomy, or autopsy, in most cases reveals enlarged mucosal folds surrounding and obstructing the pyloric canal. This reflects completely occluded in volvulus, which may involve rotation of up to 270-360°. Venous infarction of the gastric mucosa ensues, as volvulus progressively constricts outflow of blood from the stomach. The mucosa, and usually the full thickness of the gastric wall, is edematous and dark red to black, and there is bloody content in the lumen of the stomach. Ischemic mucosa becomes necrotic, and the stomach may rupture. Hemoperitoneum may occur as a result of avulsion of gastric blood vessels.
Obstruction of veins by volvulus, and pressure exerted by the distended stomach, result in decreased venous return via the portal vein and caudal vena cava, causing reduced perfusion of intra-abdominal organs, reduced cardiac output, and circulatory shock. Increased intra-abdominal pressure impinges on the diaphragm and compromises respiration. A variety of acid-base and electrolyte abnormalities ensue in dogs with gastric dilation and volvulus, contributing to the physiologically precarious state. Cardiac arrhythmias as a sequel to gastric dilation and volvulus have been associated with putative release of myocardial depressant factor from an ischemic pancreas, and with myocardial necrosis, resulting from ischemia. Death is inevitable in dogs with acute gastric volvulus that are not treated early. Rare cases of chronic gastric volvulus are reported, with fixation of the spleen in the right side of the abdomen by omental adhesions.
In swine, gastric volvulus is a cause of sudden death in adult sows, perhaps with a brief premonitory period of anorexia, abdominal distention, dyspnea, and drooling. It is associated with excitement in anticipation of feeding among pigs that are fed at regular, often long, intervals, and may be a sequel to unduly rapid ingestion of feed, water, and air. The twist may occur in either direction about the long axis of the stomach, although clockwise torsion predominates.
Abomasal displacement and volvulus is a common clinical problem in high-producing, intensively managed dairy cattle, particularly around the time of parturition, but it also occurs in animals that are predominantly pasture fed. The displacement is usually ventral and to the left of the rumen. Many affected animals have concurrent problems, including ketosis, hypocalcemia, metritis, and retained placenta. Affected abomasa have decreased sensitivity to acetylcholine, and abomasal atony has been implicated as a prerequisite to displacement. Alterations in the enteric nervous system in the abomasum, including substance P levels, may also play a role. Evolution of gas in the abomasum is directly related to the amount of concentrate in the ration. Left displacement of the gas-filled abomasum is amenable to treatment, and is rarely encountered at autopsy. Handling of an affected animal postmortem may correct displacements in any case. Other than possible scarring of the lesser omentum, the abomasum may be unremarkable. Abomasal fistulae, draining in the right paramedian area, may ensue if, during abomasopexy to prevent recurrent displacement, nonabsorbable sutures fixing the abomasum to the abdominal wall penetrate the abomasal mucosa.
Simple right displacement, which accounts for ~15% of abomasal displacements, is probably caused by similar agencies. However, right displacement may be complicated in about 20% of cases by progression to abomasal volvulus, which is clinically serious.
Abomasal volvulus is probably the sequel to rotation of a loop formed by a distended abomasum and attached omasum and duodenum. The volvulus is counterclockwise about a Gastric dilation and volvulus ( Fig. 1-35 ) occur relatively commonly in dogs, and uncommonly in cats. In dogs, gastric dilation and volvulus are usually problems associated with eating, and probably aerophagia, especially in the deep-chested breeds, such as Great Danes, St. Bernards, Irish Setters, Wolfhounds, Borzois, and Bloodhounds. Predisposing factors are controversial but may include: increased laxity of the hepatogastric ligament; prior splenectomy; a diet of small food particles; recent kenneling; having a raised feed bowl; and infection with the nasal mite Pneumonyssoides caninum, which causes "reversed sneezing."
The gas that contributes to the development of dilation is probably the result of aerophagia, and possibly the evolution of carbon dioxide by physiologic mechanisms. Inability to relieve the accumulation of food, fluid, and gas in the stomach causes the organ to dilate and alter its intra-abdominal position, so that its long axis rotates from a transverse left-right orientation to one paralleling that of the abdomen. In simple dilation, the esophagus is not physically completely occluded, the spleen remains on the left side, and the duodenum is only slightly displaced dorsally and toward the midline. Repeated episodes of gastric dilation probably compromise splenic venous return during periods when the stomach is distended, and eventually lead to episodes of splenic ischemia and segmental infarcts.
For reasons that are unclear, gastric dilation may be converted to gastric volvulus. The stomach rotates about the esophagus in a clockwise direction, as viewed from the caudal aspect. The greater curvature of the distended organ moves ventrally and caudally, and then rotates dorsally and to the right. This forces the pylorus and terminal duodenum cranially to the right and clockwise around the esophagus. Ultimately they lie to the left of midline across and ventral to the esophagus, compressed between the esophagus and the dilated stomach. Depending on the degree of volvulus, the spleen, which follows the gastrosplenic ligament, usually ends up lying in a right-ventral position, between the stomach and liver or diaphragm. It is bent into a V shape by tension on its ligaments, becomes extremely congested, and may undergo torsion, infarction, and rupture. The esophagus becomes
A variety of foreign bodies may be encountered in the stomach and in the abomasum. Most are incidental findings, or at worst, associated with vomition, mild acute or chronic gastritis, or occasionally with ulceration. Trichobezoars (hairballs) are often found in the stomach of long-haired cats, and in calves reared on diets low in roughage, where most are in the rumen, with a few in the abomasum. Phytobezoars (nondigestible plant material) and trichophytobezoars have been implicated as the cause of pyloric obstruction and death in young lambs on pasture and, in some regions, in cattle grazing fibrous plants. Fine sand may accumulate in the abomasum in considerable amounts, usually with no detrimental effect.
Gastric impaction by inspissated content in horses is related to factors such as consumption of fibrous roughage and persimmons, inadequate water intake, and poor mastication. It may cause anorexia, mild colic, and loss of body condition, and is to be differentiated clinically and at autopsy from gastric impaction secondary to pyrrolizidine alkaloid poisoning, from dilation secondary to intestinal obstruction, and from primary gastric dilation.
Primary abomasal impaction in cattle may result from restricted water intake and coarse, high-roughage feed, such as wheat stubble or straw. Secondary abomasal impaction may follow pyloric stenosis, physical or functional, of any cause. It is perhaps most common as a functional abomasal stasis in one of the manifestations of vagus indigestion. Loss of abomasal motility may be the product of intrathoracic inflammatory or neoplastic vagal lesions; vagal involvement in adhesions following traumatic reticuloperitonitis; vagal trauma in surgically corrected abomasal volvulus; adhesions of the abomasum and omasum that may physically impair motility; or systemic disease that causes abomasal stasis.
The abomasum is impacted with thick porridge-like or inspissated coarse fibrous digesta, despite an apparently patent pylorus. Abomasal rupture may ensue, particularly in primary impaction associated with coarse feed, resulting in diffuse peritonitis. Most commonly, the laceration is near the omasalabomasal orifice, but it may be elsewhere. Omasal dilation and ruminal distention are also found in many of these cases; omasa usually contain inspissated digesta, while rumen content tends to be fluid. Metabolic derangement owing to sequestration of chloride in the rumen following regurgitation from the obstructed abomasum, and hypokalemia resulting from transverse axis through the lesser omentum, when viewed from the right side.
Rotation, buoyed by the gas-filled body of the abomasum, may be in the sagittal plane. With a 360° volvulus, the pylorus ends in the cranial right portion of the abdomen dorsal to the twisted omasum, with the duodenum trapped medial to the omasum and lateral to the partially rotated reticulum ( Fig. 1-36 ). Alternative modes of displacement and rotation are possible, but all may end in this relationship.
Obstruction of duodenal outflow in volvulus results in sequestration of chloride in the abomasal content and the development of metabolic alkalosis. Severe volvulus causes obstruction of blood vessels at the neck of the omasum, as well as causing trauma to the vagus nerves in the region. The abomasum becomes distended with blood-stained fluid and gas. Venous infarction of the deeply congested mucosa may result in ultimate abomasal rupture, often near the omasoabomasal orifice, and peritonitis. Damage to the vagal branches may prohibit return of normal abomasal motility in animals successfully withstanding surgery, resulting in vagus indigestion. Cases of abomasal volvulus are also occasionally reported in preruminant calves; these are usually fatal.
Sarcina-like bacteria have been associated with abomasal diseases in lambs and calves. Pathologic findings include various combinations of abomasal bloat, hemorrhage, and ulcers.
Gastroesophageal intussusception, gastroduodenal intussusception, and pylorogastric intussusception are uncommon displacements, involving the stomach of dogs with signs of upper alimentary tract obstruction that require surgical correction. Applewhite AA, et al but is not common. In such dogs there may be no gross gastric lesion, or variable edema and thickening of rugal mucosa, perhaps with focal ulceration, is evident. Microscopically, in dogs, the lamina propria between glands is edematous, and there are increased mast cells. Deposits of basophilic ground substance and mineral are found, especially on the basement membrane of vessels and glands, or on collagen fibrils and in degenerate smooth muscle. These changes occur particularly in the middle and deeper portions of the mucosa. Parietal cells in this area are usually mineralized as well. More extensive mineral deposition also involves the muscular coats and arterioles of the submucosa and serosa. Such vessels also show evidence of endothelial damage, medial necrosis, and, in some cases, thrombosis. Severe mucosal congestion, edema, and necrosis are possibly related to ischemia secondary to the vascular lesions, although perhaps not directly associated with arterial thrombosis and obstruction, which is often not readily found. In cats with uremic gastropathy, gastric fibrosis and mineralization occur, but not gastric ulceration, edema, or vascular fibrinoid change.
The cause of the vascular lesions associated with uremia is incompletely understood. Mineral deposition is probably the product of altered systemic metabolism of calcium in renal failure, perhaps coupled with the local microenvironment resulting from bicarbonate moving across the basal border of secreting parietal cells. Membrane lesions in metabolically compromised parietal cells may also act as foci of mineral deposition (see Vol. 2, Urinary system, for a discussion of uremia). Metabolic acidosis and inflammatory cytokines including tumor necrosis factor-α may also promote vascular mineralization. Mineralization is also a feature of vitamin D intoxication.
Gastric venous infarction is a common lesion in swine, and is also encountered in ruminants and horses. It is related to endothelial damage and thrombosis in venules, usually associated with endotoxemia or other bacterial or toxic damage. Salmonellosis and Escherichia coli septicemia in all species, and in addition, in swine, postweaning coliform gastroenteritis, erysipelas, swine dysentery, and Glasser's disease are associated with the lesion. Porcine dermatopathy and nephropathy syndrome has also been associated with gastric infarction. The fundic mucosa is bright red or deep red-black and may have excess mucus or perhaps fibrin on the surface. Occasionally the superficial mucosa is obviously necrotic, adopting a yellowbrown caseous appearance, and may lift off with the ingesta. In section there is thrombosis of venules in the mucosa and often at the mucosal-submucosal junction, usually with prominent fibrin plugs. Thrombosed capillaries and venules may be present at any level of the mucosa, along the base of the ischemic zone of superficial coagulative necrosis, with local hemorrhage and edema. There may be an acute inflammatory reaction delineating the necrotic area in the mucosa. Sometimes the full thickness of the gastric mucosa, focally or diffusely, may be necrotic. decreased intake in feed in the face of continued normal renal excretion, place these animals in perilous physiologic circumstances, often before inanition becomes a significant factor. A syndrome known clinically as abomasal dilation and emptying defect occurs in Suffolk and Hampshire sheep. The animals develop chronic inappetence and weight loss, and at autopsy they have a markedly distended abomasum containing digesta resembling rumen contents. No morphologic gross or microscopic lesions of the stomach, vagus nerve, or other organs have been found, except scattered chromatolytic and necrotic neurons in the celiacomesenteric autonomic ganglion. The cause is unknown, but it is suggested that it may be an acquired dysautonomia, possibly toxic, requiring a genetic predisposition for expression. Although rumen chloride levels are elevated, few animals become hypochloremic and alkalotic, as do cattle with abomasal impaction. Bird A, et
Edema of the gastric rugae occurs with hypoproteinemia in any species, in portal hypertension, and is found in the abomasum of cattle poisoned by arsenic, sheep ingesting tannic acid, and both cattle and sheep with ostertagiasis. Edema fluid collects in the submucosa of the folds, and is particularly obvious in the normally thin abomasal plicae. Edema may contribute to the thickening of rugae seen in gastritis. Edema of the submucosa of the stomach is a common and important lesion in edema disease of swine. It is best appreciated by making several slices through the serosa and external muscle to the submucosa on the greater curvature over the body of the stomach. Edema disease is considered fully in the later section on Infectious and parasitic diseases of the alimentary tract. Hyperemia of the gastric mucosa occurs with ingestion of chemicals, which usually also cause superficial erosion and necrosis, discussed later under chemical gastritis. Focal hyperemia may be related to local irritation of the mucosa by foreign bodies, and with focal acute viral lesions of the abomasum in cattle. Congestion of the mucosa can occur in conditions causing portal hypertension, including cirrhosis and shock in the dog.
Uremic gastritis, seen as severe congestion and hemorrhage of the body of the stomach, associated with signs of hematemesis and melena, is found in some dogs, and occasionally in cats and horses, with renal disease. In such animals, the mucosa is thickened and deep red-black. There may be granular material typical of mineral within the mucosa. Lesions vary in severity from case to case, and premonitory changes without severe hemorrhage and necrosis are present in animals euthanized earlier in the course of disease. Gastric ulceration may occur, or idiopathic insults. Following the discovery of Helicobacter pylori as a major cause of gastric ulceration in humans, there was a flurry of activity to document its significance as a cause of gastritis and/or gastric ulceration in other monogastric species. The picture that has emerged is a confusing one because of substantial flux in the taxonomy of the various gastric spiral organisms, and because of the existence of many different species of Helicobacter (only some of which have been successfully cultivated). At least 20 different Helicobacter species, distinguished by mRNA sequencing, have been reported from various mammalian species. It is safe to say that probably all mammals have one or more species of Helicobacter as part of the normal gastric flora, and thus determining a causal relationship between Helicobacter and gastric disease has proved very difficult.
Helicobacter pylori is a common cause of acute and chronic gastritis affecting antrum, corpus, or both, in humans and in other primates. In humans it is the leading cause of chronic peptic ulcers. This may progress in some cases to gastric mucosal atrophy, with loss of antral and/or oxyntic glands. Chronic Helicobacter infection in humans also significantly increases the risk for the development of gastric carcinoma and lymphoma. On the other hand, H. pylori appears to be a very uncommon infection in other species, and has never been proved to cause disease in nonprimates. Among nonprimates, the most convincing evidence for clinically significant gastric Helicobacter infection is in ferrets. Although virtually all adult ferrets have H. mustelae as part of the normal gastric flora, heavily colonized ferrets develop diffuse lymphocyticplasmacytic gastritis with lymphofollicular hyperplasia and sometimes with erosions. Progression to neoplasia has not been documented. H. heilmannii has been incriminated in development of gastric lymphoma in cats.
The role of Helicobacter in the development of gastritis or gastric ulceration in other species remains uncertain. Claims for the significance of Helicobacter acinonychis as a cause for gastritis in captive cheetahs remain unproved, in that antibiotic treatment improves the clinical disease but does not eradicate the gastric Helicobacter infection. Furthermore, wild cheetahs have the same Helicobacter colonization, but not the gastritis. In dogs and cats, it is routine to see various spiral organisms colonizing the gastric surface and within canaliculi in parietal cells in normal animals and in those with gastrointestinal disease. Depending on detection methods, the prevalence of colonization is at least 50% and may be nearly universal in adults. The prevalence of such colonization as determined by direct visualization or by culture is as high in clinically healthy animals as in those with clinical signs of gastritis. On the other hand, there are several studies claiming that dogs or cats with natural or experimental Helicobacter infection have a higher prevalence of mucosal mononuclear leukocytes and mucosal lymphoid follicles, and faster mucosal turnover, than is seen in animals in which Helicobacter infection could not be demonstrated. The problem is that the modest histologic changes have not been correlated with the development of clinical disease. The changes described resemble the kind of changes seen elsewhere in the intestinal tract with, for example, acquisition of the normal flora by germfree animals, or even as part of normal immunologic maturation of the gastrointestinal tract. Improvement in clinical signs following antibiotic therapy appropriate for the elimination of Helicobacter has not been documented convincingly.
Gastritis is a term used clinically as a presumptive diagnosis for those cases of vomiting that are thought to arise from gastric irritation rather than disease elsewhere. In pathology, the term is often used with equal imprecision, referring to a wide range of gastric injury in which histologic criteria of inflammation may not be particularly prominent. Under the broad umbrella of gastritis fall several different types of lesions: gastric mucosal necrosis, erosion or ulceration caused by mechanical, chemical, or ischemic insults, among which is uremic gastritis, described earlier; true gastritis, in which the lamina propria contains the leukocytic and vascular changes characteristic of inflammation; and finally, lesions of gastric mucosal atrophy, fibrosis, and lymphofollicular hyperplasia that arguably are the residual lesions of previous active inflammatory disease. Chemical gastritis or abomasitis, reflected in diffuse gastric congestion, hemorrhage, necrosis, and ulceration, may be induced by chemicals such as arsenic, thallium, formalin, bronopol, steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), phosphatic fertilizers, and by the toxic principle in bitterweed (Hymenoxon odorata). Blister beetle (Epicauta spp.) intoxication in horses, induced by the cantharidin contained in these insects, may cause necrosis and ulceration of the distal esophagus and pars esophagea, and intense hyperemia of the glandular mucosa of the stomach, and in some cases gastric ulcers and rupture. In addition, enterocolitis, nephrosis, hemorrhages of the urinary bladder, and myocardial hemorrhage and necrosis are reported with regularity in blister beetle toxicosis. Zinc may cause acute mortality, in which the mucosa of the abomasum and duodenum is a distinctive lime green and necrotic, with an underlying congested, edematous submucosa. Microscopically, radiating crystals are evident in the necrotic tissue. Subacute zinc intoxication may be reflected in abomasal damage characterized by exfoliation of glandular epithelium, ablation of glands in some areas, and reparative proliferation of mucous neck cells, in addition to fibrosing pancreatitis and mild nephrosis. In sheep, type-A trichothecene mycotoxin has been associated with rumenitis and abomasal ulceration in acute toxicity. Mechanical gastritis is most commonly seen in dogs after ingestion of coarse foreign materials and in cats with hairballs. The lesion is discovered as an incidental finding when careful clinicians biopsy the stomach via endoscopy when making the diagnosis of gastric foreign body, or at the time of surgical removal of that foreign material. Hairballs in the abomasum of ruminants are associated with lack of roughage in young animals, but virtually never with disease.
Eosinophilic infiltrates occur in the squamous stomach of horses with an eosinophilic epitheliotropic syndrome, discussed in the later section on eosinophilic enteritis in horses, and with dermatitis.
The majority of examples of genuine gastritis are seen in dogs and cats with more generalized gastrointestinal inflammatory disease, such as food allergy or idiopathic inflammatory bowel disease, and is discussed further with those topics (see later section on Idiopathic inflammatory bowel disease).
Infectious agents in small animals appear to be minor causes of gastritis, when compared with chemical, mechanical, usually occurring in temperate climates of the world. The factors initiating bacterial invasion are unknown, although local tissue damage in the abomasum is implicated. Cold weather is usually associated with the disease, but it is difficult to imagine feed being cold enough, by the time it reaches the abomasum, to cause significant mucosal trauma or hypothermia and necrosis. Production of exotoxin by C. septicum causes the signs and death, which usually ensues quickly. A similar gastritis has been associated with C. sordellii infection.
At autopsy, there may be blood-tinged abdominal fluid and the serosa of the abomasum may be congested or fibrincovered. Mucosal lesions may be diffuse, or involve demarcated foci of variable size and shape. Abomasal folds may be thickened, reddened, and occasionally hemorrhagic or necrotic. Most notable is the presence of extensive gelatinous edema and emphysema in the submucosa. Diffuse edema, and extensive areas of suppurative infiltrate demarcating areas of coagulative necrosis, with prominent pockets of emphysema, are evident in tissue sections. These involve mainly submucosa, and extend into adjacent mucosa and external muscle. There may be venous thrombosis and hemorrhage. Gram-positive bacilli are usually evident as individuals or colonies in affected tissue.
C. perfringens type A has been associated with a syndrome of tympany, abomasitis, and abomasal ulceration in calves in the western United States. However, the role of this pathogen in development of abomasal inflammation and ulceration is not completely understood. Animals have abdominal tympany and pain, depression, or may die suddenly. Grossly, there is variable congestion, hemorrhage, erosion, and ulceration of the abomasal mucosa, usually in the fundic area. Circular or linear perforating ulcers may develop. In association with the expected microscopic changes in erosion or ulceration, there is exfoliation and necrosis of mucosal epithelium, edema of the submucosa, dilation and thrombosis of submucosal lymphatics, and mild acute inflammatory infiltrates in the submucosa. Gram-positive bacilli may be on the mucosal surface, or in inflamed submucosa. Proliferation of C. perfringens in the rumen of calves with overflow of milk from the reticular groove is believed to promote colonization of the abomasum, and production of necrotizing exotoxin. Disease has also been associated with overeating, contaminated colostrum, and Chlamydophila (Chlamydia) have been recognized in surface mucous cells of otherwise normal fundic mucosa in cats with no signs of disease. Experimental infection produced conjunctivitis and respiratory disease, but only mild gastritis.
Gastric mucosal hypertrophy is a lesion within the stomach of dogs that may be focal or diffuse. The focal lesion is much more prevalent, occurring as an intraluminal papillary proliferation of pyloric antral mucosa causing clinical signs of pyloric obstruction. The proliferation is mostly by mucuscontaining cells of the mucosal surface and foveolae, forming papillary projections supported by a lamina propria that is either normal or that contains an increase in plasma cells and eosinophils. The significance of the eosinophilic inflammation in causing the regional mucosal hypertrophy is unknown, but many examples do not have any change in mucosal leukocytes. Surgical excision is curative. The diagnosis is usually obvious on the basis of endoscopic examination. Endoscopic biopsies may or may not permit the diagnosis, depending on the depth of mucosa captured by the biopsy forceps. The key to the diagnosis in an endoscopic biopsy is that the entire depth of the sample is taken up by surface epithelium and foveolae, whereas in a normal stomach a biopsy of similar size would capture at least some of the deeper gastric pyloric glands.
Diffuse gastric mucosal hypertrophy (chronic hypertrophic gastritis) of dogs, similar in many respects to Ménétrier's disease in humans, is rare. Vomition and weight loss, in some cases associated with inappetence or diarrhea, are described in the history. The characteristic lesion is marked gastric rugal hypertrophy involving part or most of the fundic gland mucosa in the body of the stomach. Grossly thickened folds of mucosa over an area 4-10 cm in diameter are thrown up in a convoluted pattern that may resemble cerebral gyri.
Microscopically, these areas are composed of hypertrophic/ hyperplastic mucosa that may or may not include secondary folds of muscularis mucosae and submucosa. Findings are variable in the few cases reported. There may be foveolar and glandular epithelial hyperplasia with progressive or total loss of parietal cells, which are replaced by mucous cells of various degrees of differentiation. Marked cystic dilation of mucous glands may occur, which may be evident grossly. Mononuclear cells infiltrate the lamina propria between glands and near the muscularis mucosae, and the propria may be edematous, especially superficially. If the gross appearance of the mucosa in animals with hypertrophic gastritis is not seen by endoscopy or at surgery, biopsies that do not sample the full thickness of the mucosa may be misdiagnosed as chronic superficial or diffuse gastritis.
The cause of chronic hypertrophic gastritis is unknown, but in part it may be mediated by immune events in the mucosa. The condition in humans is associated with proteinlosing gastropathy. Significantly, chronic gastritis and chronic hypertrophic gastritis have been reported in the Basenji, a breed of dog in which a syndrome of protein-losing gastroenteritis and diarrhea is well recognized (see later section on Idiopathic inflammatory bowel disease).
Hypertrophic antritis, producing a thickened, sometimes convoluted, mucosa in the antrum, is part of the syndrome of chronic hypertrophic pyloric gastropathy, associated with pyloric stenosis in dogs, considered earlier. Etiologic factors are unknown.
Braxy, or bradsot, is an acute abomasitis of sheep and, less commonly, calves, caused by infection with Clostridium septicum ( Fig. 1-37 ). It is a sporadic disease of young animals, Gasterophilus are found attached to small erosions and ulcers in the esophageal and glandular mucosa, which very rarely become complicated or perforate.
In swine, the spirurids Ascarops spp., Physocephalus spp., and Simondsia spp. are associated with mild gastritis in heavy infections. Gnathostoma may be embedded in inflammatory cysts in the submucosa. Ollulanus tricuspis may be encountered. Hyostrongylus rubidus can cause chronic gastritis and wasting in pigs.
In cattle, sheep, and goats, members of the genera Haemonchus and Mecistocirrus are large abomasal blood-sucking trichostrongyles, capable of causing severe anemia and hypoproteinemia. Ostertagia spp. and related genera, including Camelostrongylus, Teladorsagia, Marshallagia, and Trichostrongylus axei, in various ruminants, cause chronic abomasitis with mucous metaplasia, achlorhydria, diarrhea, and plasma protein loss. Cryptosporidium andersoni occasionally causes subclinical abomasitis in cattle, associated with elongation of the gastric glands, hyperplasia of the epithelium in the gland isthmus, attenuation of epithelium lining the neck of fundic glands, and dilation of glands. The small basophilic organisms are present on the surface of epithelium from the base of glands to the mucosal surface. Large schizonts of an incompletely decreased gut motility. In both calves and lambs, clostridial gastritis may be preceded by the development of superficial peptic micro-ulcers, which subsequently become colonized and progress to typical clostridial lesions.
Abomasitis associated with viral infection occurs in a number of the systemic viral diseases affecting the gastrointestinal tract, including infectious bovine rhinotracheitis in calves and, rarely, older animals, herpesviral infections of small ruminants, bovine viral diarrhea, rinderpest, malignant catarrhal fever, and bluetongue. Abomasal lesions are rarely the sole manifestation of these diseases, but form part of a picture at necropsy that may suggest an etiologic diagnosis. The appearance and pathogenesis of abomasitis in these diseases vary with the conditions (see Infectious and parasitic diseases of the alimentary tract, later in this chapter).
Mycotic gastritis or abomasitis is a sporadic problem almost invariably secondary to insults that cause achlorhydria, focal atrophy, necrosis, or ulceration under conditions in which mycotic colonization can occur. Compromised resistance, perhaps associated with endotoxemia, septicemia, endogenous or exogenous steroids, neoplasia, lympholytic viral disease, and altered gastrointestinal flora caused by antibiotic therapy, may further promote mycosis. Fungal hyphae attaining the submucosa typically invade venules and arterioles, causing thrombosis and hemorrhagic infarction. The agents involved are usually zygomycetes (phycomycetes) such as Rhizopus, Absidia, or Mucor; rarely, Aspergillus may be implicated. The lesions are areas of necrosis, with an intensely congested or hemorrhagic periphery, ranging in diameter from 1 to 2 cm, to confluence over much of the body of the stomach ( Fig. 1-38A ). Affected mucosa is thickened, red or pale in the necrotic zone, and may be covered by hemorrhage. Edema and hemorrhage are evident in the submucosa. The lesion may penetrate to the serosa, where it is typically seen as a roughly circular area of hemorrhage in the external muscle and subserosa. Hyphae, usually broad and nonseptate zygomycotic in type, are present in sections of the necrotic mucosa, submucosa, and invading vessels, where they initiate thrombosis ( Fig. 1-38B ).Candidiasis of the pars esophagea may occur in swine, often in association with preulcerative epithelial hyperplasia and parakeratosis. For an overview of mycosis of the digestive system, and its sequelae, see the later section on Infectious and parasitic diseases of the alimentary tract.
Parasitic gastritis is often subclinical in dogs and cats, but in a small number of animals can be associated with vomiting and mucosal ulceration. Members of the genera Physaloptera and Gnathostoma are found in dogs, where the former cause focal ulceration and the latter are the cause of submucosal inflammatory cysts containing suppurative exudate and worms. In cats, Physaloptera spp. may attach to mucosal ulcers, whereas Gnathostoma spp. and Cylicospirura felineus are found in nodules in the gastric wall. Ollulanus tricuspis is found on the mucosa of the stomach in cats, where it may cause mild to, rarely, severe chronic gastritis. Cryptosporidium infection of the gastric mucosa occurs rarely in cats and dogs, with uncertain significance.
In horses, Draschia megastoma is found in inflammatory nodules in the submucosa of the cardiac zone, especially along the margo plicatus. The nodules can be several centimeters in diameter and contain necrotic debris and worms. Habronema muscae and H. majus are found on the mucosa and have been associated with mild ulceration. Trichostrongylus axei may cause chronic gastritis in the horse. Bots of the genus A B NSAID inhibition of cyclooxygenase (COX). Additionally, NSAIDs (except aspirin) may promote gastric hypermotility. Hypermotility is associated with altered microvascular blood flow and decreased mucosal response to injury. This is especially true in the gastric folds. Phenylbutazone may also have a direct toxic effect on vascular endothelium in the mucosa, which also compromises circulation and predisposes to ulceration.
In humans, gastritis associated with Helicobacter pylori infection, and duodenal colonization with this agent, are associated with development of duodenal ulcer. Helicobacterassociated gastritis extending cranially in the stomach is associated with gastric ulcer. Similar associations between Helicobacter infection, gastritis, and peptic ulcer have not been demonstrated convincingly in domestic animals.
Reflux of duodenal contents containing bile salts has been implicated in the induction of gastritis and gastric ulcer. Under some experimental conditions, acid back-diffusion into the gastric mucosa, and morphologic damage, have been caused by the application of bile salts. The effects are dependent on the pK a of the bile salt, which must be soluble at acid pH, and on the concentration of hydrogen ion. Lipid solubility of bile salts, and associated damage to surface cell membranes, may mediate these effects. Alcohols, also lipid-soluble compounds, alter permeability of gastric mucosa and permit back-diffusion of acid. Lysolecithin, formed when pancreatic lipase hydrolyzes lecithin in bile, increases gastric mucosal permeability too.
Glucocorticoids and stress have been implicated in the genesis of ulcer, although the role of steroids is controversial. Experimentally, gastroduodenal hemorrhage and ulceration occur in some species of animals stressed by restraint or social factors, and they are a feature of "trap death syndrome" in small mammals. Severe gastric hemorrhage or ulceration may occur following neurosurgery, trauma to the spinal cord, and burns, and it is considered by some to be stress related. Administration of methylprednisolone sodium succinate to dogs was clearly acutely ulcerogenic. However, some experimental studies have demonstrated that glucocorticoids released during stress are more gastroprotective than ulcerogenic, although the rate of healing in pre-existing ulcers was decreased in the presence of steroids.
Reduced mucosal perfusion or ischemia may be a principal factor interacting in stress-associated ulceration, and in that initiated by other modalities, discussed previously. Reduced blood flow to the mucosa in local areas, under a number of circumstances, precedes mucosal hemorrhage or erosion. Ischemia will result in hypoxemic compromise of surface mucous cells. In combination with the effects of other insults, this may initiate mucosal permeability and back-diffusion of acid. Neutralization by blood-borne bicarbonate of acid diffusing into the mucosa also may be reduced in ischemia. Mucosal ischemia may result from reduction in local prostaglandin (as in NSAID administration) or nitric oxide concentration, thrombosis, as well as local or systemic hypotension. Ischemia may be more significant in the induction of fundic, rather than antral, ulcers.
Whatever the cause, the results of a breach of the gastric glandular mucosa have the potential to follow a common pathway to ulceration in all species. Acute superficial lesions, such as those associated with stress or following administration of aspirin, are often seen as areas of reddening and hemorrhage, especially along the margins of rugae in the fundic characterized coccidia in sheep and goats form pinpoint pale foci in the abomasal mucosa. The name Eimeria (Globidium) gilruthi has been applied. Infection has been associated with elongation of the gastric glands with hyperplasia of the mucous neck cells, and decreased numbers of parietal cells. Gastric parasitism is considered more fully in the later section on Infectious and parasitic diseases of the alimentary tract.
Gastroduodenal ulcer produces signs much less often in animals than in humans. The pathogenesis of peptic ulcer in both humans and animals in general seems to resolve into a relative imbalance between the necrotizing effects of gastric acid and pepsin on one hand, and the ability of the mucosa to maintain its integrity on the other. Impairment of mucosal integrity in the face of normal acid secretion is probably the predominant mechanism, although there are clear instances when hypersecretion of acid is causative.
Factors implicated in hypersecretion of acid include abnormally high basal secretion, possibly associated with an expanded parietal cell mass, perhaps the result of increased trophic stimulation by gastrin. Gastrinomas cause Zollinger-Ellison syndrome, characterized by elevated gastric acid secretion and severe gastroduodenal ulceration. Increased histamine levels associated with mastocytosis or mastocytoma also cause acid hypersecretion and ulceration.
Ulceration caused by compromise of mucosal protective mechanisms is attributed to nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, phenylbutazone, and indomethacin. Orally administered NSAIDs that are weak organic acids, such as aspirin, have a direct deleterious effect on the stomach. Active bicarbonate secretion is responsible for a pH gradient from acid in the lumen to near neutrality at the epithelial cell surface. Stimulation of this bicarbonate secretion is induced by prostaglandin E 2 and nitric oxide. Inhibition of bicarbonate secretion occurs in the presence of atropine and various NSAIDs. Decreased prostaglandin is due to ulcers in their microscopic appearance (allowing for their intestinal location), evolution, and sequelae.
Peptic ulcer in dogs is reported relatively infrequently in the literature. Signs associated with peptic ulcer include variable appetite, abdominal pain, vomition, melena, and anemia. Ulcers, a few millimeters to 3-4 cm in diameter, are found most commonly in the pyloric antrum or proximal duodenum. The gross and microscopic appearance of ulcers varies with their aggressiveness and duration, as previously described. Thrombosed arterioles and venules cut by the ulcerative process are often seen, and should be sought in the bed of gastric and duodenal lesions associated with anemia or obvious hemorrhage.
Perforation of gastric or duodenal ulcers may lead to massive hemorrhage or release of gastric contents into the abdomen. Perforating duodenal ulcer may instigate pancreatitis. Some ulcers perforate silently, the serosal lesion healing by granulation, or adhesion by, and fibroplasia in, the omentum. The irritant nature of gastric contents released in these circumstances may lead to chronic inflammation, granulation, and thickening of the serosa, even when previous perforation cannot be appreciated. A search for microscopic particles of food such as plant material or muscle fibers in the serosal inflammatory response confirms perforation in this circumstance. Chronic peptic ulcers with thickened mucosal margins, scirrhous bases, and perhaps serosal thickening associated with perforation or near perforation, must be differentiated from gastric adenocarcinoma in the dog.
Syndromes resulting from hypersecretion of acid occur in dogs. Mastocytoma is associated with peptic ulcer, presumably owing to histamine-stimulated acid hypersecretion and microvascular effects. The tumor and mastocytosis do not involve the stomach directly, and ulcers may occur in animals with solitary skin tumors. In one series of 24 dogs with recurrent or metastatic mastocytoma, gastric and duodenal erosions or ulcers, frequently multiple, were present in 20. In many cases such lesions are clinically silent, and they should be looked for at autopsy in animals with mastocytoma. Mast cell tumors have rarely been associated with gastric ulceration in the cow, and in the cat, where gastric ulcer is very uncommon.
Zollinger-Ellison syndrome, peptic ulcer caused by gastrinsecreting pancreatic islet cell tumors or gastrinomas, has been reported in a few dogs and fewer cats. The history usually includes inappetence, vomition, weight loss, and possibly diarrhea or melena. Reflux esophagitis and gastric or duodenal ulcer are present in most cases. Small nodular masses histologically confirmed as islet cell tumors may be found in the pancreas, and in most animals, metastases to the liver, spleen, or hepatic lymph nodes are present.
Firm diagnosis rests on demonstration of elevated serum gastrin levels by radioimmunoassay; by identification of gastrin-bearing cells in fixed or frozen tumor tissue by immunohistochemistry; or by demonstration of gastrin in extracts of frozen tumor.
The microscopic appearance of these islet cell tumors is not diagnostic for gastrinoma, nor is the ultrastructural appearance of tumor cells necessarily characteristic of the G cell. Pancreatic islet cell neoplasms may be difficult to find, and should be sought assiduously in suspect cases.
The cause in dogs of gastroduodenal ulcer possibly associated with decreased resistance to back-diffusion of acid is less clear. Hepatic disease is often present in dogs with gastric ulcer, but the basis for a causal association is obscure. Some mucosa. Acid treatment of hemoglobin gives blood on the surface or in the gastric lumen a red-brown or black color. In some instances, melena, presumably the result of a recent episode of gastric bleeding, may be present in the lower intestine, with minimal gross evidence of hemorrhage or ulceration in the stomach. The microscopic lesion associated with hemorrhage of this type is often subtle; bleeding seemingly results from diapedesis, with minimal mucosal damage. Usually there is superficial erosion of the mucosa, often difficult to differentiate from autolysis, with granules of brown acid hematin in debris on the surface. Inflammation is usually absent. Evidence for healing mild gastric erosion is the presence of basophilic, poorly differentiated, flattened, cuboidal or low columnar cells on the mucosal surface, with mitotic cells in the upper neck of the glands.
Lesions of any genesis proceeding to gastric ulcer do so by progressive, often rapid, coagulative necrosis of the gastric wall. Ulcers vary in microscopic appearance depending on their aggression, and the point in their development at which they are intercepted. Acute gastric lesions appear as erosions with superficial eosinophilic necrotic debris and loss of mucosal architecture to the depths of the foveolae, or as a depression in the mucosal surface with necrotic debris at the base. Necrosis usually extends rapidly to the muscularis mucosae, causing ulceration. Once the superficial portion of the mucosa is destroyed, natural local buffering is lost, and the proliferative compartment of the gland, which is near the surface, is obliterated, preventing a local epithelial regenerative response. Ulcers attaining the submucosa impinge on arterioles of increasing diameter, multiplying the risk of significant gastric hemorrhage. The ulcer may progress through the muscularis and serosa, culminating in perforation of the gastric wall. Severe gastric hemorrhage or perforation are relatively common sequelae of gastroduodenal ulceration in domestic animals.
Ulcers that come into equilibrium with reparative processes may do so at any level of the gastric wall below the mucosa, but usually at the submucosa. Subacute to chronic ulcers have a base and sides composed of granulation tissue of variable thickness and maturity, infiltrated by a mixed inflammatory cell population, and overlain by a usually thin layer of necrotic debris. Chronic ulcers wax and wane. Depending on the relative dominance of reparative processes and aggressive ulceration, the layer of granulation tissue may be thick and mature, or thinner, less mature, and with superficial evidence of recent necrosis. There is mucous metaplasia and hyperplasia in glands at the periphery of the ulcer, which, with time, overhang the edge of the lesion, whence epithelial cells may gradually migrate across, closing the defect. Restitution of mucosal integrity is a complex process that is promoted by local activity of cytokines and growth factors such as transforming growth factor-β, vascular endothelial growth factor, basic fibroblast growth factor, epidermal growth factor, interleukins-1β and -2, and interferon-γ. Secretion of growth factors is a coordinated response by gastric epithelium and mesenchymal cells. Angiogenesis, also driven by cytokines and growth factors within the healing ulcer and granulation bed, is important for restoration of the mucosal microvasculature. The mucosa of healed ulcers, even in the fundic zone, is comprised of mucous glands. Excessive scarring of healed ulcers located near the pylorus may lead to pyloric obstruction in any species.
Duodenal ulcers, which usually occur proximal to the opening of the pancreatic and bile ducts, resemble gastric The causes of abomasal ulcer are usually unclear, but they are most common in young calves, dairy cows, and feedlot animals. Viral agents including bovine viral diarrhea virus and malignant catarrhal fever virus are associated with abomasal ulcers. Abomasal ulcer occurred in about 34% of feedlot cattle in one study, with about half the cases symptomatic, whereas there are reports of over 6% of European dairy cows slaughtered with evidence of active or previous abomasal ulcers. A very high proportion, often in excess of 50%, of veal calves may have abomasal ulcers at slaughter. Ulcers often appear to be subclinical, and apparently without effect on growth or performance. However, about one-third of suckling calves dying under 4 months of age in western Canada had perforating abomasal ulcers. They were often associated with hairballs, which, it was concluded, were probably not causal. Mineral deficiencies, including copper and selenium, have been associated with abomasal ulcers in calves.
Ulcers often seem to occur under stressful circumstances, as in recently weaned and veal calves, postparturient cows, animals with concurrent disease such as abomasal displacement or mastitis, or after transportation. Lactic acid and histamine entering the abomasum from the forestomachs in animals poorly adapted to high-concentrate rations may contribute to mucosal damage. In veal calves, consumption of straw, shavings, or other roughage has been associated with an increased prevalence of ulcers, and there appears to be an increase in thickness and altered mucus production in the pyloric mucosa. Abomasal ulcers in range calves in western North America have been associated with Clostridium perfringens gastritis, consumption of roughage at pasture, and possibly copper deficiency. Perforating abomasal ulcers may develop in calves secondary to mycotic infection. Abomasal stasis may play a part in animals with physical or physiological abomasal obstruction or displacement. Ulceration of the abomasal mucosa infiltrated by lymphosarcoma will occur, and it may occur as a sequel to ingestion of toxins such as arsenic.
The presenting sign in many cases of abomasal ulceration is melena. Hemorrhage causing exsanguination, or perforation and septic peritonitis, is the usual cause of death resulting from abomasal ulcers. Bleeding abomasal ulcer should be looked for in cattle with melena or anemia, and perforating abomasal ulcer in animals presented with septic peritonitis, especially if digesta is in the abdominal cavity. Perforation may occur into the omental bursa, localizing contamination, and occasionally, points of perforation will be adherent to the abdominal wall, or occluded by superficially adherent omentum.
Gastric ulcers in swine are usually restricted to the pars esophagea; in a small proportion of affected pigs, lesions extend into the contiguous esophagus. Rarely are significant ulcers of the cardiac, fundic, or pyloric mucosa encountered in swine, sometimes in association with ulcer of the pars esophagea, occasionally with gastric parasitism or systemic disease. Venous infarcts in the body of the stomach in swine are not to be confused with gastric ulcer.
Under conditions of modern pig husbandry, the prevalence of ulcer and associated abnormalities of the pars esophagea is high. Weaned growers and feeders are commonly affected. Most lesions are subclinical; however, some prove fatal. Pigs die without premonition, or with a short history that may include anemia, weakness, inappetence, vomition, and melena. Other animals are affected chronically, with signs of anorexia, ulcers are associated with administration of glucocorticoids in high doses as anti-inflammatory, immunosuppressive, or antineoplastic therapy. Nonsteroidal anti-inflammatory drugs such as aspirin, naproxen, indomethacin, ibuprofen, flunixin meglumine, and piroxicam, sometimes given in excessive quantity, are also associated with spontaneous ulcers. Gastric hemorrhage and gastroduodenal ulceration are occasionally seen in dogs following trauma or major surgery. A syndrome of gastric hemorrhage, pancreatitis, and colonic ulceration and perforation is recognized in dogs following spinal trauma. The pathogenesis of this problem is obscure and undoubtedly complex.
Abomasal ulcers in cattle are common ( Fig. 1-39) ; duodenal ulcer is rarely encountered in this species. Acute ulcers or erosions considered to be the result of stress are frequently seen incidentally in animals, of any age, dying of a variety of causes. They are usually present as linear areas of brown or black hemorrhage or erosion along the margins of abomasal rugae, or as punctate hemorrhages and erosions scattered over the mucosa, especially of the fundus.
Ulcers may be present anywhere in the abomasum. They are common in the pyloric region in cattle, and especially at the torus pyloricus in veal calves, but they may scallop or perforate abomasal rugae and excavate the mucosa in the fundus as well. Often more than one ulcer is present. A B the entire pars esophagea. They usually spare only a microscopically visible margin of squamous epithelium adjacent to the cardiac gland mucosa. Ulcers of the pars esophagea, like peptic ulcer, have a floor of necrotic debris overlying exposed connective tissue ( Fig. 1-40) . Depending on the stage and aggression of the ulcer, there may be a well-developed inflammatory margin to the necrosis and a bed of granulation tissue.
Grossly, fully developed ulceration of the pars esophagea is apparent as a punched-out lesion with elevated rolled edges, obliterating the entire pars esophagea and obscuring the esophageal opening (see Fig. 1-40 ). The floor of the ulcer may be so smooth that it is misinterpreted as normal. Pigs with gastric ulcer at any stage of evolution tend to have fluid content in the stomach. Those with hemorrhagic ulcer may have red-brown gastric content, or massive hemorrhage into the stomach with large blood clots in the lumen, and smaller clots adherent to the base of the ulcer and its exposed bleeding points. Melenic content will often be present in the intestine, and the colon may contain firm black pelleted feces. The carcasses of animals that exsanguinate with gastric ulcer are very pale. Blood in the intestine associated with gastric ulcer in pigs must be differentiated from mesenteric volvulus and intermittent melena, and weight loss that may culminate in death or slow recovery with runting.
There is little disagreement over the morphology of ulceration of the pars esophagea, although its etiopathogenesis has been controversial. Many factors have been implicated in the etiology. Stressful husbandry practices have been considered to contribute to development of ulcer, although glucocorticoid administration results in lesions of the fundus, not pars esophagea, in pigs. Environment has been identified as a factor, for example, pigs held on slatted floors have a higher incidence of nonglandular ulcers than pigs on solid or straw flooring. High dietary copper levels, feeding of whey, starchy diets low in protein, high levels of dietary unsaturated fatty acids, and microbial production of short-chain fatty acids have been associated with the development of ulcers. Experimental infection with Ascaris suum has been associated with ulcer, but natural infection is not considered causally associated. Although an association between the presence of Helicobacter heilmannii and ulceration has been proposed in pigs, this has not been strongly substantiated, and gastric ulcers in pigs involve squamous, rather than glandular, mucosa. Experimentally in gnotobiotic pigs, H. heilmannii has been shown to induce ulcers in the squamous portion of the stomach of pigs fed a ration high in carbohydrate. Experimentally, factors stimulating acid secretion, especially histamine, consistently cause ulcers of the pars esophagea, suggesting that gastric acidity may play an etiologic role. Repeatedly, finely ground rations have been found to be ulcerogenic, and this may be the single most important predisposing factor. Squamous epithelium has no innate buffering capacity, and it is highly susceptible to attack by gastric acid, pepsin, and refluxed bile, as occurs in reflux esophagitis. Similar events may initiate ulceration of the pars esophagea. Swine with gastric ulcers usually have abnormally fluid stomach contents. Feeding of finely divided rations and prolonged fasting are associated experimentally with increased water in stomach content. Normally there is a declining gradient of pH from esophagus to pylorus in stomach ingesta. Abnormally fluid gastric content fails to partition properly, and the pH gradient from esophagus to pylorus is not established. Relatively low pH occurs at the esophageal end of the stomach, where hydrochloric acid, pepsin, and refluxed bile, along with short-chain fatty acids produced by microbial fermentation of carbohydrate, synergistically attack the squamous mucosa. Meanwhile, the pH at the pylorus is higher than normal. Under conditions of prolonged gastric distention and relatively high antral pH, gastrin-stimulated acid secretion may be excessive, promoting that insult.
Lesions of the pars esophagea may involve only a small part, or virtually all of the gastric squamous mucosa. The lesion evolves through parakeratosis, to fissuring and erosion, with ultimate ulceration in severe cases. All stages in this progression will be encountered at autopsy in pigs. The epithelium of the pars esophagea often appears yellow and is thickened, irregular, roughened, and may flake or peel off readily. Candida may be present over the epithelial surface, with hyphae invading the parakeratotic epithelium, perhaps because of favorable cystine or glycogen levels. Rete pegs and proprial papillae are elongate.
Erosion of the epithelium progresses to ulceration and exposure of papillae and deeper propria, which bleed as small vessels are disrupted. Such lesions begin as fissures in the hyperplastic parakeratotic epithelium, but advance to ulcerate B A ulceration, with evolution of the ulcer and ulcer bed, as described earlier in swine. In a low number of horses, glandular metaplasia has been observed in the ulcer bed.
Ulcers in the secretory stomach are less common. These ulcers are also often large and multiple, although a full range from focal punctate to extensive deep lesions may be seen.
Perforation may occur at any site of ulceration, and in one series represented 1% of 600 autopsies on foals. Some foals may exsanguinate because of bleeding ulcers, and occasionally clotted blood will fill the stomach, forming a cast.
Pyloric and duodenal stenosis have been associated with healing ulcers in horses. Ulcerative lesions involving the circumference, or the antimesenteric mucosa, of the proximal duodenum have been associated with gastric ulcers in foals, and duodenal stricture may represent a more chronic phase of this process. Severe esophagitis occurs in foals with ulcer and gastric reflux.
Many cases of gastric ulcers in horses are associated with enteric disease, colonic impaction, ileus, surgery, or other circumstances that can be considered stressful or could cause gastroduodenal reflux. Ulcers are common in horses held in stalls, and alternating periods of feeding and feed deprivation have been shown to induce ulceration of the gastric squamous epithelial mucosa. The pathogenesis of ulceration in the pars esophagea in horses probably resembles that in swine. Abnormally fluid content associated with feeding patterns and feedstuffs is permissive of acid, pepsin, and bile reflux to the cranial part of the stomach, where, at pH levels <4.0, volatile fatty acids generated locally may predispose further to damage to the squamous mucosa. A diet of bromegrass hay has been implicated in causing lower gastric pH, and thus facilitating ulcer formation. Exercise increases intra-abdominal pressure, resulting in gastric compression and reflux of acidic content into the cranial stomach, possibly contributing to ulceration associated with intensive training.
It is unclear whether the ulcerative duodenitis seen in some cases is a product of peptic ulceration, or whether it represents a process such as "proximal enteritis," which in turn results in stricture, gastric reflux, and ulceration. Administration of NSAIDs is commonly associated with gastroduodenal ulcers, and lesions of the glandular stomach, squamous stomach, and pylorus, among other lesions, have been induced in horses intoxicated with phenylbutazone. from proliferative hemorrhagic enteropathy associated with Lawsonia. A few pigs with parakeratosis, erosion, and ulceration of the pars esophagea have esophageal lesions suggestive of gastric reflux.
Gastric ulcers in some pigs resolve by granulation, and they may become re-epithelialized. Such lesions usually become scirrhous, puckered, and contracted as the ulcer closes from the periphery, and scarring may be visible from the serosa. In these circumstances, stenotic occlusion of the esophageal opening into the stomach may occur, and pigs with this problem can develop muscular hypertrophy of the distal esophagus.
In horses, ulcers in the stomach of foals and adults are often found at autopsy incidental to some other disease process. Gastric ulcer as a clinical entity is less commonly recognized, although a syndrome of abdominal pain, sometimes associated with gastric reflux, has been described in foals, and gastric ulcers are associated with colic in older horses. Ulcers are common in foals under 4 months of age; about half of a group of foals without signs of gastric disease had ulcers visible by endoscopy. Ulcers have been detected endoscopically in >65% of performance horses, in training, racing, or on endurance rides. They are often multiple, and although most frequent in the esophageal region, they can simultaneously involve all 4 mucosal zones of the stomach, and the duodenum, with no relationship apparent in the pattern of distribution. COX expression is altered in ulcers of the squamous regions, with decrease in COX1 and increase in COX2 expression; COX2 may be important in the healing response.
Ulcers of the esophageal zone are common. They are usually most severe at or adjacent to the margo plicatus, involving the edge of the squamous epithelium. They are often large and irregular in shape. There may be extensive fissuring, erosion, and ulceration of the squamous mucosa on the remainder of the pars esophagea, and in the esophagus, sometimes nearly to the pharynx, in foals with reflux. Often islands of thickened white proliferative mucosa are scattered as plaques on a predominantly ulcerated mucosa ( Fig. 1-41) . Microscopically, there is epithelial hypertrophy and hyperplasia in response to insult, marked in some islands of surviving mucosa, with prominent rete pegs and edematous proprial papillae. Parakeratotic hyperkeratosis is also an early lesion. Lesions then grade through increasing degrees of epithelial erosion to alpha-defensins. These molecules are now known to be key mediators of homeostasis, host-microbe interactions, innate immune defense, and regulation of epithelial stem cells and the regenerative response of injured intestinal epithelium.
Oligomucous cells are relatively intermediate cells which differentiate into mature goblet cells. Both are present in epithelium of crypts and villi, with variable prevalence and distribution at various levels of the intestine, and in the different species. They have basal nuclei with distended apical theca-containing mucin granules. These cells synthesize and secrete by exocytosis bioactive molecules such as mucins, which are components of mucus. Intestinal mucus provides lubrication and frontline host defense against irritants and microbes while allowing nutrient transport. Mucus also contains trefoil factor, which is produced by goblet cells and promotes epithelial restitution after injury; lysozyme and defensins produced by Paneth cells; resistin-like molecule β (RELMβ) produced by goblet cells is involved in immunoregulation and homeostasis; and immunoglobulin A secreted by epithelial cells. Goblet cell hyperplasia and mucus secretion are promoted in the acute phase by a variety of noxious stimuli, inflammatory mediators, and by cell-mediated immune events in the gut, whereas chronic infections can result in depletion of goblet cells and alteration of mucus layers.
Enteroendocrine cells comprise a heterogeneous population of approximately 16 amine-or peptide-secreting endocrine/paracrine cells, representing about 1% of the epithelial cell population. Formerly classified by the ultrastructural appearance of their secretory vesicles, subtypes of enteroendocrine cells are now classified based on the contents of their secretory vesicles and are named by letters. Serotonin, somatostatin, cholecystokinin, peptide YY, glucagon-like peptides, and secretin are produced by specialized EC, D, I, L, and S cells in the gastrointestinal tract and these molecules are involved in regulation of intestinal motility and peristalsis, secretions, visceral sensations, and appetite. Immunohistochemistry studies have demonstrated that enteroendocrine cells stain positively for chromogranin A. With the exception of carcinoid tumors of serotonin-secreting cell origin, and rare functional neoplasms of other enteroendocrine cells in humans, the pathologic implications of this class of cells are still poorly defined.
Poorly differentiated enterocytes undergo rapid amplification division and these cells are cuboidal or low columnar with relatively few, short microvilli. Daughter cells differentiate and move into the functional compartment of absorptive enterocytes lining the villus. Undifferentiated crypt epithelial cells also secrete electrolytes and water. Mature enterocytes are responsible for the final digestion and absorption of nutrients, electrolytes, and water, and are by far the predominant epithelial cell type in the intestine. They are normally tall columnar cells, polygonal in cross-section, with regular basal nuclear polarity. A tight junction, which is permissive to small molecule and water transport, joins the apical margins of adjacent cells. The barrier to transepithelial macromolecular movement is essentially maintained even at sites of extrusion of effete enterocytes at the tips of villi. Basal to the tight junction, the lateral cell membranes interdigitate loosely, and a long, narrow potential space exists between enterocytes. The basolateral cell membrane is the site of sodium-potassiumdependent adenosine triphosphatase that drives the sodium pump, and of carrier systems exporting monosaccharides from the cell. Absorptive epithelial cells lie on a basal lamina with
The microtopography of the small bowel is extensively modified to increase its surface area by spiral mucosal folds in some species, and by villi projecting into the lumen. The villi, projections of lamina propria covered by a layer of epithelium one cell thick, expand the absorptive surface of the small bowel 7-14 fold. In most species, villi are tallest in the duodenum, and decline somewhat in height toward the ileum. The length and shape of villi in normal animals vary with the species, age, intestinal microflora, and immune status. In general, villi in dogs, cats, neonatal piglets, and ruminants tend to be tall and cylindrical; those in horses and in young ruminants tend to be moderately tall and cylindrical; villi in weaned ruminants and swine may be cylindrical, leaf-or tongueshaped, or rarely ridge-like, with their broad surface at right angles to the long axis of the gut. Villus length typically declines somewhat after weaning.
Opening to the mucosal surface around the base of each villus are several crypts of Lieberkühn. Depending on the species and their proliferative status, crypts are straight or somewhat coiled and lined by a single layer of epithelium. The progenitor compartment of the enteric epithelium resides here, producing cells that differentiate and move up on to the surface of villi, mainly as absorptive enterocytes, ultimately to be extruded as effete cells from the tips of villi. Sloughed cells contribute to the enzyme content and complexity of the intestinal luminal content.
Stem cells are found near or at the base of the crypts, depending on species and the position in the gastrointestinal tract, and they give rise to rapid-cycling transit-amplifying cells, which eventually differentiate into 1 of 4 main lineages of cells, which undergo continuous cycles of renewal: Paneth cells, goblet cells, neuroendocrine cells, and enterocytes.
Paneth cells, a population of enigmatic cells turning over slowly (~20 days) in the base of the crypts in small intestine, are most obvious in horses among the domestic animals. They are not found in dogs, cats, or swine, nor prominent in the intestine of ruminants. Conspicuous eosinophilic secretory granules are present in their apical cytoplasm, and these contain a number of antimicrobial proteins and peptides including lysozyme, phospholipase, DNAse, ribonuclease, and Lymphocytes, neutrophils, and eosinophils are scattered in the lamina propria of villi and between crypts. Eosinophils are especially common in the intestine of ruminants and horses, with no specific pathologic connotation; they are highly variable in the intestine of small animals. Intraepithelial lymphocytes are frequently observed along villi and less commonly along crypts. Globule leukocytes may be found in the epithelium of crypts and low on villi, or sometimes in the lamina propria between crypts. Plasma cells are normally not numerous in villi, but are concentrated in the lamina propria between the upper portions of crypts.
The vascular supply to the small intestinal mucosa arises in submucosal arteries that give off arterioles at right angles, some of which send branches to a capillary plexus around crypts of Lieberkühn. Most arterioles arborize near the villus tip into a dense capillary plexus, which lies immediately beneath the basal lamina of the epithelium. Mucosal capillaries have fenestrations facing the basal lamina, which may be more permeable than the remainder of the endothelium. One or more venules drain blood from the capillaries in villi and between crypts, and flow into larger veins in the submucosa, which drain into mesenteric veins and the hepatic portal circulation. The lacteal, or central lymphatic vessel of the villus, is sufficiently permeable to permit the entry of macromolecules and chylomicrons, and is the main route of lipid transport from the villus.
The cecum and colon vary widely in anatomy and size among domestic animals, depending largely upon the significance of hindgut microbial carbohydrate fermentation. Production of volatile fatty acids from carbohydrate by colonic flora occurs in all species. This is a primary source of energy in the horse; it is significant in swine and ruminants as well. Extensive movement of electrolytes and water occurs across the colonic wall. In the horse, a volume of fluid approaching that of the extracellular fluid space may be in the large bowel, which must maintain a fluid medium for microbial fermentation; daily fluid absorption from the hindgut may exceed the extracellular fluid volume. Absorption of electrolytes and water, an electrolyte-conserving mechanism, is probably the major function of the colon in dogs and cats, and of the distal colon of herbivores.
The mucosa of the cecum and colon in all domestic mammalian species lacks villi, although there are ridges or folds on the mucosal surface. Colonic glands, or crypts, are straight tubular structures. The architecture of colonic glands and their cell population resembles that of small intestinal crypts. Epithelial cells differentiate progressively from stem cells deep in the glands to a single layer of columnar absorptive epithelial cells with basal nuclei that line the mucosal surface. Hindgut epithelial cells generally have sparse and irregular microvilli in comparison with those of the small bowel. Numerous glycoprotein-laden vesicles are observed in the apical cytoplasm of epithelial cells in most species. Oligomucous cells, also derived from basal stem cells, form a second proliferative population in the lower half of the colonic gland. Well-differentiated goblet cells are usually present in the upper half of colonic glands and on the surface. Goblet cells are present in variable numbers, depending on the species and a variety of other factors. Enteroendocrine cells of about a half-dozen types have been recognized, and are scattered in the cell column lining glands in the large bowel. Paneth cells are not found in normal colon; however, Paneth cell metaplasia has been proposed as a preneoplastic which they interact via integrins; they may be involved in communications with the underlying mesenchyme. Immediately beneath the basal lamina lies the sheath of syncytial myofibroblasts, alpha-smooth muscle actin-positive cells that mediate information flow between the epithelium and lamina propria through production of growth factors, cytokines, chemokines, prostaglandins, and extracellular matrix molecules. Myofibroblasts are thus involved in growth and tissue repair, tumorigenesis, inflammation, and fibrosis. Myofibroblasts are probably largely responsible for the remarkable plasticity of the villus during adaptive changes including villus atrophy and reconstitution of mucosal 3-dimensional morphology.
The apical surface of normal enterocytes is highly modified into microvilli, ∼0.5-1.5 µm long and 0.1 µm wide, which are regularly arrayed in close apposition to each other at right angles to the surface of the cell. They are visible as the "brush border" by conventional microscopy. Microvilli increase the surface area of absorptive epithelium by a factor of ∼15-40 times. The plasmalemma of microvilli is studded with massive numbers of enzyme molecules, including aminopeptidases and disaccharidases involved in terminal digestion of peptides and carbohydrates. These protrude as minute knob-like structures into the glycocalyx that coats the surface of microvilli.
In neonatal swine and ruminants, vacuolation of absorptive enterocytes is normal, and the nucleus is often also displaced into the apical cytoplasm. In piglets vacuolation is usual in the ileum but not in the duodenum, and seems to be a function of cell age. Such vacuolation should be differentiated from the presence of eosinophilic colostrum present in cytoplasmic vacuoles in the epithelial cells of neonates.
The cytoplasm of absorptive enterocytes is stabilized at the apical border by the filaments of the terminal web. Smooth endoplasmic reticulum is most prominent in the upper half of cells, whereas cisternal elements of rough endoplasmic reticulum are more uniformly distributed. The Golgi zone lies above the nucleus. Free ribosomes and polyribosomes are numerous in differentiating cells of the upper crypt and lower villus, and are relatively fewer in mature absorptive enterocytes.
The complex of endoplasmic membranes and Golgi apparatus is particularly active in handling absorbed lipid, which diffuses from micelles at the cell surface through the apical membrane, in the form of long-chain fatty acids or monoglyceride. These are re-esterified to triglyceride, appearing in the smooth endoplasmic reticulum, and are complexed with apoproteins produced in the rough endoplasmic reticulum to be excreted via the Golgi apparatus through the basolateral cell membrane as chylomicrons. Chylomicrons enter the extracellular space and leave the villus via the lacteal.
The lamina propria supports the epithelium of the small intestinal mucosa. It is composed of loose fibrous tissue within which blood vessels, smooth-muscle, inflammatory, and immune cells are interspersed. In addition to functioning in defense against microorganisms, macrophages phagocytose inert particulate matter reaching the lamina propria from the lumen. Bile pigment, perhaps derived from meconium, can be seen in macrophages in the tips of villi in neonates. Macrophages also phagocytose iron and may play a role in iron homeostasis. Apoptotic bodies, ceroid, and hemosiderin also may be observed in lamina proprial macrophages. This can be prominent in horses and is thought to represent detritus from apoptosis of upwardly migrating subepithelial myofibroblasts, and should not be mistaken for foci of necrosis.
intestinal disease is not indicated clinically, and to view critically their reliability in diagnosing such entities.
Biopsy interpretation is enhanced by increasing size and number of specimens, full-thickness sampling, careful tissue handling including minimizing trauma, rapid fixation, and optimal orientation. Sacrificing any of these attributes increases the subjectivity with which a biopsy is interpreted; hence exquisite care must be taken in tissue handling to reduce traumatic artefact and to optimize orientation. Clinicians and pathologists dealing with endoscopic, capsule, and forceps biopsies must remember the limitations in interpretation imposed by small sample size, fragmentation, unfavorable sample orientation, and failure to sample the deep mucosa, submucosa and muscularis. These costs are offset to some degree by the opportunity to obtain a greater number of samples than may be possible by other means, at arguably lower risk and cost, and possibly more focused on a lesion by direct endoscopic examination.
The gastrointestinal tract is presented continually with antigens in food, allergens, toxins, viruses, commensal and pathogenic bacteria and their products, and parasites with their excretions and secretions. The epithelial barrier of the gut is only one-cell thick and has enormous surface area; the enteric mucosal surface of the average human is about 400 m 2 . Therefore, it is not surprising that the epithelium and associated lymphoid and inflammatory cells in the mucosa and submucosa are components of a complex system for excluding, blocking, sampling, tolerating, or neutralizing and eliminating antigens or potential pathogens. Intestinal immune elements are sparse and quiescent at birth; immune activity in the gut is probably stimulated in response to colonization by normal bacterial flora beginning in the early neonatal period. In the mature animal, lymphoid tissue is estimated to comprise 25% of lesion in development of colonic epithelial neoplasia in humans.
The lamina propria of the colon is minimal between closely packed glands and contains a cell population similar to that in the small bowel. Normally, relatively few inflammatory and immune cells are present in the superficial mucosa in small animals and young herbivores; most plasma cells and lymphocytes are between deeper portions of glands. Older herbivores, especially horses, may have heavier superficial proprial inflammatory infiltrates, and macrophages containing phagocytosed debris may be present below the surface epithelium. In the equine colon, terminal arterioles entering the mucosa branch at right angles from the submucosal plexus. Capillaries ramify to surround colonic glands, and form an anastomosing network at the luminal surface, whereas sparsely distributed venules drain the superficial capillary plexus.
The connective tissue of the submucosa lies between the mucosa and the external muscle of the gut, which is formed by fascicles of smooth muscle cells arranged as inner circular and outer longitudinal layers. An extensive enteric nervous system with submucosal (Meissner's), and myenteric (Auerbach's) plexuses marked by ganglia, modulates external autonomic neural regulation and coordinates gastrointestinal motility and function. The neurons of the enteric system equal in number those in the spinal cord, and their ramifications sense and influence epithelial absorption and secretion, local endocrine/paracrine secretion, blood flow, immune events, and motility in the gut. Secretomotor neuron branches extend to individual crypts of Lieberkühn, where they stimulate secretion of electrolyte, water, and mucus. Excitatory and inhibitory effects are mediated by acetylcholine and by amine and peptide neurotransmitters such as substance P, adenosine triphosphate, and vasoactive intestinal peptide, which in some cases are also produced by endocrine cells of the gut and pancreas. Myofibroblastic pacemaker cells of the intestine, known as interstitial cells of Cajal, are distributed throughout the intestinal musculature, integrated with the extrinsic and enteric nervous systems. Abnormalities of these cells are thought to lead to disorders of motility, and to gastrointestinal stromal tumors, a specific entity described in dogs, horses, and cats. Disorders of motility associated with enteric neural lesions, such as the dysautonomias and grass sickness, are discussed in the later section on intestinal obstruction.
Interpretation of intestinal and colonic biopsies is often subjective, unless objective diagnostic criteria can be met, including recognition of an etiologic agent, a specific cell type, a characteristic pattern of inflammation or anatomic abnormality such as lymphangiectasia, or cytologic and morphologic abnormalities indicating malignancy.
There are significant variations in the microscopic morphology of the gut with age; between species and among individuals of a species; at different levels of the small and large intestine within species and within the same individual; and as a result of factors influencing mucosal cell trafficking in health and disease. Limited morphometric data are available in domestic animals, and interpretation is limited by the lack of standardized quantitative criteria defining morphological features during health and disease. Until more such information is available, and its application is validated, particularly in the diagnosis of inflammatory bowel disease, pathologists do well to expand their experience of intestinal morphology by close examination of tissues from animals in which gastro-products such as amylamines, and to damaged enterocytes. They also presumably participate in the adaptive response, responding to antigens entering from the lumen and in tumor surveillance. Some may kill compromised epithelial cells.
Most, but not all, intraepithelial lymphocytes appear to originate in Peyer's patches.
Globule leukocytes are visible in hematoxylin and eosinstained tissue sections as mononuclear cells with large eosinophilic cytoplasmic granules, in the epithelium of the crypt and lower villus, and sometimes in the lamina propria. They have been associated with parasitism, but their function remains poorly understood and their origin uncertain with some evidence suggesting they originate from mast cells or large granular lymphocytes.
The aggregated lymphoid follicles, or Peyer's patches, are scattered in the mucosa of the small intestine, and lymphoglandular complexes or solitary proprial lymphoid nodules may be grossly visible throughout the colonic mucosa. Peyer's patches are present throughout the length of the small intestine in all species, although they tend to be larger distally. They are grossly visible, usually as oval or elongate structures up to several centimeters wide, thickening the antimesenteric wall of the intestine. They may project slightly above the mucosal surface, or appear as cupped depressions that must not be mistaken for ulcers, especially in dogs. In neonates of some species, including swine, they may be poorly developed and not visible grossly. Continuous Peyer's patches are found in the distal ileum of calves, lambs, and piglets and develop during late gestation, as opposed to upper intestinal lymphoid tissue, which is dependent on colonization of the gut for postgestational development. They are similar morphologically but apparently functionally distinct from other gutassociated lymphoid tissue. Their role as a primary site of B-cell generation remains controversial and, given that they involute as the animal matures, they likely play an important role in host defense during early life.
Peyer's patches are comprised of follicular aggregates of B lymphocytes surrounded by aggregates of T lymphocytes in the submucosa, underlying a discontinuous muscularis mucosae. Overlying the lymphoid follicles is a mixed population of T and B lymphocytes and dendritic cells extending into the lamina propria in rounded mucosal projections known as subepithelial domes, which lie between villi. Cell populations of Peyer's patches in newborns and gnotobiotes of most species tend to be sparser than those in older or bacterially colonized animals, although those in neonatal calves appear relatively well developed.
Membranous or microfold cells, M cells, are flattened cells lacking a brush border found interspersed among the follicleassociated epithelium overlying the subepithelial dome region, which separates the epithelium from the submucosal Peyer's patches and intestinal lymphoid follicles. Within the dome region are populations of dendritic cell subsets, which probably play a major role in initiation of mucosal immunity. M cells actively sample and transport particulate matter and macromolecules from the lumen to their basolateral membrane pocket where they interact with cells of the underlying mucosal immune system to facilitate mucosal immune responses. Despite, or perhaps because of, its role in adaptive immunity, the M cell is exploited as a likely portal of entry to the mucosa by certain pathogenic bacteria, including Mycobacteria, Salmonella, Yersinia, and Listeria in some species, and for some viruses. Neutrophils are seen transmigrating the the intestinal mucosal mass, and to exceed that of the spleen in volume.
Elements of gastrointestinal mucosal defense are diverse, and include the volume of fluid secretion and peristalsis for dilution and flushing of contents, respectively, and gastric and bile acids and pancreatic secretions that break down ingested antigens. The indigenous microflora competitively inhibit or actively exclude intruding bacteria. Mucins on the luminal surface form a secretory barrier, and retain trefoil factor, antibody and soluble components of innate resistance, including those produced by Paneth cells. The epithelium provides a physical barrier, participates in innate resistance by production of proinflammatory cytokines, enables passive immunity by antibody uptake in the neonate, and contributes to active immunity by antigen uptake and presentation. Intraepithelial lymphocytes are an important first line of defense against pathogens and are recognized to play a significant role in epithelial barrier homeostasis. Soluble antibody in plasma and interstitial fluid neutralizes antigens penetrating the mucosal barrier and contributes to opsonization/phagocytosis, as do endogenous components of the innate immune system, such as complement. The organized elements of the mucosal immune system, Peyer's patches, and other mucosal lymphoid follicles, are sites for induction of intestinal immune responses, generating antigen-activated B and T cells that ultimately home back to the mucosa where they reside along with populations of macrophages and dendritic cells. Regional lymph nodes receive and trap free and phagocytosed antigens, and antigen-presenting cells activate more B and T cells, promoting mucosal and systemic immunity.
The epithelial cell of the neonate is uniquely capable of uptake and transport of macromolecules from the intestinal lumen to the basolateral cell surface. In all species of domestic animals, colostral transfer of immunoglobulins by this route provides the neonate with passive humoral immunity during the early postnatal period. The period of active uptake of macromolecules is short, usually only 24-48 hours in ungulates, and "closure" precludes further bulk transport of macromolecules.
Although bulk transport does not occur in mature animals, nutritionally inconsequential amounts of macromolecules continue to be transferred by enterocytes. Such molecules must escape both intraluminal hydrolysis and intracellular lysosomal degradation to permit their export from the cell. Fully differentiated small intestinal absorptive epithelial cells express major histocompatibility complex class II molecules on their basolateral membranes, and are capable of presenting antigen directly to T cells. Additionally, enterocytes detect pathogen-associated molecular patterns of bacteria and viruses via pattern recognition molecules, including surface toll-like receptors and cytosolic nucleotide-binding oligomerization domain (Nod) molecules for activation of cellular production of proinflammatory or immunomodulatory cytokines.
Intestinal intraepithelial T lymphocytes form a large population strategically located between the basolateral surfaces of epithelial cells and may comprise up to 10-20% of the cells within the epithelial layer. They are more numerous in the small intestine than the large intestine. In domestic animals they are comprised mainly of T cells uniquely expressing the homodimeric form of CD8α; most of these express the γδ T-cell receptor as opposed to the αβ T-cell receptor, especially in the small intestine. They function as a front line of defense, as part of the innate immune response to bacterial and plant German Shepherd, and Shar-Pei dogs, where it may be associated with increased susceptibility to intestinal and respiratory disease.
IgG-producing plasma cells are relatively uncommon in the intestinal lamina propria in species other than ruminants. However, locally produced and systemically circulating IgG may assume significance when vascular permeability and inflammation occur because of its ability to fix complement, facilitate antibody-dependent cell-mediated cytotoxicity, and to opsonize. IgE-producing plasma cells are present in the lamina propria in small numbers in most species. IgE is implicated in immune responses during intestinal parasitism. Its significance may be in IgE-dependent cytotoxicity by eosinophils, mast cells, and basophils, as well as in mediating immediate (type I) hypersensitivity reactions in the mucosa.
Intestinal mucosal mast cells differ histochemically and physiologically from mast cells in most other tissues. They are less demonstrable using standard stains after formalin fixation as are connective tissue mast cells from other tissues; they stain well in tissue fixed in basic lead acetate or Carnoy's fluid. In contrast to connective tissue mast cells they contain tryptase but not chymase, and their granules are few, and variably electron-dense by electron microscopy. Proliferation of intestinal mast cells is T-cell-dependent and occurs during some parasitic and bacterial infections. Histamine, serotonin, and other mediators released by mast cells have many and complex effects on vascular tone and permeability; on motility, chemotaxis, and effector function of leukocytes; on immune-active cells; and possibly on mucus release. Mast cells interact with the enteric nervous system, sensing antigen with their IgE immune probe, and communicating with the sensory arm of the enteric nervous system by degranulation, releasing stimulatory soluble mediators. They undoubtedly play a central role in regulation of physiologic, immune, and inflammatory processes in the gut.
Intestinal eosinophils probably do not differ functionally from eosinophils in other sites as cytotoxic effector cells and modulators of local inflammation, particularly during intestinal parasitism, immune-mediated, or hypersensitivity reactions.
Immunoinflammatory events in the large bowel are less well understood than those in the small intestine; presumably similar principles prevail. Lymphoglandular complexes consist of submucosal follicular lymphoid aggregates penetrated by glands extending from the mucosa, and presumably facilitate contact of surface epithelium of the large bowel with underlying lymphoid tissue. These occur in the cecum and proximal colon of the dog; in the colon of swine; at the cecocolic junction, proximal spiral colon, and terminal rectum of ruminants. Solitary mucosal lymphoid nodules, normally without penetrating glands, and generally restricted to the lamina propria and superficial submucosa, are also scattered throughout the cecum and colon in all species. epithelium of the dome, and are found in the lumen over the dome, in enteric bacterial infections of calves in particular. B and T lymphoblasts gain access to Peyer's patches via specific receptors in permeable postcapillary venules. The major cell population in Peyer's patches appear to be B lymphocytes committed mainly to IgA production, whereas among the T cells is a large proportion of T helper cell precursors. Lamina proprial T cells are mixed CD4+ and CD8+, are most numerous between upper crypts and villi, and are likely antigen-activated cells. Cytokine production by activated T lymphocytes is complex and multifactorial, and this plays a significant role in promotion of inflammation and tolerance, particularly toward commensal organisms (covered in more detail later).
Antigen is processed and presented to lymphocytes in Peyer's patches and mesenteric lymph nodes largely by dendritic cells trafficking from the mucosa where they initially acquire antigen. Dendritic cells compose 10-15% of leukocytes in the lamina propria and in neonatal calves, are more numerous in the ileum compared with jejunum. Dendritic cells acquire antigen by interactions with intestinal epithelial cells or M cells, and can also directly sample luminal contents by extending their dendrites between enterocytes. The cytokine context within which dendritic cells function is also important and contributes greatly to the differential capacity of dendritic cells to initiate and regulate host immune responses. Macrophages are more common in the lamina propria than in Peyer's patches. Macrophages are involved in mucosal protection by phagocytosis and/or killing of invading pathogens such as Mycobacterium avium subspecies paratuberculosis and Histoplasma capsulatum, regulation of inflammatory responses, and as scavengers of dead cells or foreign debris. Macrophages also sequester iron, inhibiting bacterial metabolism. Macrophages in colonic lamina propria are highly phagocytic, but have a low ability to activate T cells and promote T-cell-mediated immune responses.
IgA-producing lymphocytes leave the Peyer's patches or other mucosal-associated lymphoid tissues and home to mucosal surfaces, including the intestinal tract, respiratory tract, mammary gland, and salivary glands. In the lamina propria of the intestine, they differentiate into IgA-secretory plasma cells and localize adjacent to upper crypt epithelium. Dimeric IgA is transported via the polymeric Ig receptor from the basolateral border of columnar crypt epithelial cells onto the apical surface of epithelial cells. IgA-secreting cells are the predominant class of plasma cell in the lamina propria in most species. However, IgM-secreting plasma cells are prevalent in young calves, swine, and dogs; locally induced IgA class switching may actually occur in the lamina propria. IgM secretion is also facilitated by polymeric Ig receptor, and this may be significant in the young piglet and calf. Although IgA and IgM are secreted, IgG1 is the major antibody class in intestinal secretion of cattle and it appears to be selectively secreted by the gut and in the bile of that species.
The functions of IgA in the gut lumen are many and include blocking attachment of bacteria and viruses to epithelial cells, promoting pathogen clearance, neutralizing intraluminal toxins, maintenance of homeostasis, facilitation of antigen sampling, limiting absorption of food or microorganismderived antigens, and promotion of tolerance. Secretion of IgA complexed with antigen into the bile by hepatocytes may be a significant means of clearing the circulation of antigen absorbed from the gut. IgA deficiency is reported in Beagle, Normal flora are known to be important for development of the mucus layer properties, mucosal lymphoid structures, modulation of immune cell differentiation and regulation of cytokine and chemokine production in the gut. Host factors influencing gut flora include composition of the diet; peristalsis, which continually flushes the small intestine of a large proportion of its bacterial population; lysozyme; lactoferrin; gastric acidity if unbuffered or undiluted; and, in the abomasum of suckling calves, perhaps a lactoperoxidase-thiocyanidehydrogen peroxide system. Mucosal epithelial maturation is influenced by the microbiota: germfree animals have longer and thinner villi, less-developed proprial vascular network and shallow crypts with fewer proliferating stem cells, compared with conventional animals. The quantity and quality of IgA secretion plays an important role in shaping both composition and function of the gut microbiome.
The use of probiotics, deliberate oral administration of specific microbial cultures, has been shown to improve body weight gain and decrease diarrhea in newborn calves and pigs, as well as to protect adult animals from colonization with certain pathogens, including Escherichia coli O157:H7 and some Salmonella spp.
Water movement in the bowel is passive, following osmotically the transport of electrolyte and nutrient solutes. The small intestinal mucosa is highly permeable to the passive movement of small ions and water and is therefore considered leaky, despite the presence of tight junctions along the apical margins of absorptive enterocytes. This ensures that the content of the small bowel is approximately isosmolal with the interstitial fluid space. The permeability of junctional complexes appears to be sensitive to Starling forces, influenced by intravascular hydrostatic and oncotic pressure, so that fluid and solute actively absorbed may leak back into the lumen, thus modulating net absorption by the mucosa. Water is secreted into the gut with digestive juices and is almost entirely resorbed in the small and large intestine; aquaporins, transmembrane water channel proteins, are important in the rapid passage of water across cell membranes. Sodium absorption takes place by a number of active transcellular mechanisms, which vary in importance at different levels of the gut, and with the physiologic circumstance. Fundamentally, Na + absorption depends on electrochemical forces established by the adenosine triphosphate-dependent Na + pump on the basolateral cell membrane of the absorptive enterocyte. This pump moves Na + up a concentration gradient
After birth, no part of the gastrointestinal tract is sterile. Hundreds of species of microorganisms including mostly anaerobic bacteria but also archaea, eukaryotes, and viruses, many of them unidentified, inhabit the stomach and intestine, forming an ecosystem of enormous complexity. Known to be important during inflammatory intestinal disease, the microbiota also provide an array of biochemical and metabolic activities important for normal host physiology and homeostasis, including: facilitation of metabolism of indigestible compounds; synthesis of essential vitamins; required for development of intestinal epithelium and immune system; and protection from invasion of opportunistic pathogens. The microbiota thus contribute prominently to homeostasis, regulated inflammation during host defense, and dysregulated inflammation during autoimmunity.
Generally, bacterial populations are least in the stomach and upper small intestine of ruminants and carnivores, being limited by the acid gastric environment and by peristalsis. The anaerobes and facultative anaerobes increase to ∼10 7 per gram of content in the lower small intestine, and total bacterial populations >10 10 or 10 11 per gram of content are present in the cecum and colon. Prominent among colonic bacteria are coliforms, Lactobacillus, and strict anaerobes, including Bacteroides, Fusobacterium, Clostridium, Eubacterium, Bifidobacterium, and Peptostreptococcus. Spirochetes are found in swine and dogs. Anaerobic bacteria outnumber facultative anaerobes by a thousand-fold in the large bowel.
The complex ecology of the gut flora imparts upon it considerable stability. It is relatively resistant to the intrusion of new inhabitants and this is one of the major factors protecting against the establishment of pathogenic bacteria. It is no coincidence that bacterial diarrhea occurs most commonly in the neonate with a poorly established flora, or after changes in husbandry or antibiotic therapy, which may disturb the enteric bacterial population. The normal flora acts as a barrier to colonization by pathogens through several means, including secretion of host defense peptides such as colicins and bacteriocins. Short-chain fatty acids, particularly butyrate, generated by these microbes during carbohydrate metabolism are significant energy sources and trophic factors for colonocytes and are highly detrimental to members of the Enterobacteriaceae and therefore contribute to colonic barrier health in general. Competition for energy, and the effect of metabolites other than short-chain fatty acids produced by the native flora, also militate establishment of invasion by exogenous bacteria.
The intestinal surface is lined by a population of cells ultimately derived from stem cells that are present at or near the base of crypts or glands, but with its proximate source in amplifier populations of undifferentiated columnar or oligomucous cells in the lower half of the crypts. These cells lose their ability to undergo mitosis, and differentiate into goblet cells and absorptive enterocytes as they move from the crypt to the villus. In most species, they are shed from the tips of villi in 2-8 days; apoptosis is a minor contributor to physiological enterocyte loss. Generally cells are shed more quickly in the ileum than in the duodenum; this is perhaps related to reduced height of villi in the distal small intestine of most species.
The mass and topography of the mucosa are quite stable, the result of a dynamic equilibrium between the rate of movement of cells from crypts to villi, and the rate at which they are lost from villar tips. This steady state is influenced by interaction of the microflora with the epithelium, cell cycle regulators, and other mediators including transforming growth factor-β, glucagon-like peptide 2, and urokinase, which may facilitate cell shedding.
In young animals, the intestine grows by generation of new crypts followed by generation of new villi. As the bowel attains mature size, the number of villi and crypts apparently stabilizes; however, some adaptive variation in the ratio of crypts to villi may occur. Adaptive responses to a variety of factors alter the size and rate of turnover of the proliferative and functional epithelial cell populations and thus the microtopography of the gut. The appearance of the small intestinal mucosa is essentially a compromise achieved by equilibrium between the rates of cell production and loss. At one extreme is the intestine of germ-free animals characterized by short crypts containing a small proliferative compartment, and tall villi with a low rate of cell loss supporting a large functional compartment. At the other end of the spectrum is the intestine of an animal with severe intestinal helminthosis characterized by long crypts, shortened villi, few functional enterocytes, and a high rate of cell loss, reflecting an increased proliferative compartment.
Although quantitative description of epithelial kinetics is possible experimentally, in the diagnostic situation it is necessary to make a subjective or semiquantitative assessment of the status of the proliferative and functional compartments in tissue sections. The size of the proliferative compartment is reflected in the length and diameter of the crypts, and in the location of the uppermost mitotic cell. The prevalence of mitotic figures can be assessed subjectively; however, beyond calculating a mitotic index, no inferences can be drawn about from the cell into the lateral intercellular space. The concentration of solute, especially Na + , in the lateral intercellular space, causes water to follow from the intestinal lumen. Because cell membranes and junctional complexes are highly permeable to water, movement is rapid via both transcellular and paracellular routes, and differences in osmotic pressure between lumen and lateral intercellular space are small. Absorbed solute and water in isotonic proportions move into the interstitium of the villus, where, within a few micrometers, they encounter a subepithelial capillary or lacteal. The tight junctions also appear to become permeable during sodium ion and nutrient cotransport across the apical cell membrane, resulting in solvent drag of large nutrient molecules into the lateral intercellular space.
The colon of carnivores, the spiral colon of ruminants and swine, and the small colon of the horse play an important role in reducing the volume of electrolyte and water lost in the feces. In contrast to the small intestine, the colonic epithelium is relatively restrictive to the free movement of sodium and chloride, although not to potassium. Therefore it is capable of maintaining differences in osmotic pressure, ionic composition, and electrical potential between luminal and proprial surfaces, which make it more efficient than the small bowel in absorbing some electrolytes and water. Ultimately, fecal water may be hypotonic with respect to plasma. Absorption of volatile fatty acids also accounts for considerable water absorption from the colon. Potassium increases in concentration in colonic content as sodium concentration declines; this is due to an active secretory process and a passive response to transepithelial electrochemical gradients.
Under some conditions, the mucosa of the small and large intestine also secretes chloride, potassium, bicarbonate, and water. This process can be a function of both surface and crypt cells, and is important in some pathologic states; however, it is also physiologic and segmental, maintaining the fluidity and buffering capacity of the intestinal content.
Solute movement across the intestinal epithelium is regulated by a number of hormones and neurotransmitters, which act through intracellular second messengers. Activation of adenylate cyclase and guanylate cyclase as well as increased intracellular Ca 2+ all result in reduction of Na + absorption by enterocytes and promotion of Cl − secretion in crypt cells. Some products of intrinsic and extrinsic neurons, such as vasoactive intestinal polypeptide and acetylcholine, may stimulate secretion, whereas others, such as somatostatin and norepinephrine, are absorptive or antisecretory. Local paracrine effects are mediated by the products of enteroendocrine cells, such as somatostatin, neurotensin, and serotonin. Guanylin is a peptide secreted from epithelial cells that stimulates local fluid secretion. Mesenchymal elements in the lamina propria, including myofibroblasts, lymphocytes, mast cells, macrophages, and other inflammatory and connective tissue cells, also produce locally active substances with a direct or indirect effect on epithelial function. Circulating hormones also influence mucosal function: aldosterone and glucocorticoids enhance Na + absorption by the colon, and the latter may inhibit local production of eicosanoids.
Immunoinflammatory events are thus integrated with the systemic and local neural and hormonal regulation of intestinal absorption and secretion. Dysfunctions of absorption and secretion will be considered in the later section on the pathogenesis of diarrhea. time, although sparing the proliferative compartment in crypts. Villi contract and become shortened as the size of the functional compartment is diminished. If the animal survives the metabolic sequelae of malabsorption that results from the damage to surface cells, compensatory expansion of the proliferative compartment in crypts permits complete recovery. Epithelial cells emerging and differentiating from crypt stem cells result in recovery of normal mucosal topography and full function within a few days.
The microscopic appearance of the mucosa depends partly on the number of functional cells lost, which determines the initial degree of villus atrophy, and partly on the amount of regeneration that has occurred when the gut is examined. During early phases of injury, damaged epithelial cells exfoliate into the gut lumen and villi are shortened and blunted; alternatively, villi are more or less of normal length, but appear somewhat pointed. Atrophic villi are subsequently covered by poorly differentiated low columnar, cuboidal, or squamous cells and there may be fusion of the lateral surfaces or tips of villi in some areas. In severe atrophy there may be mild erosion if inadequate epithelium is available to cover the mucosal surface area. In the acute phase, crypts appear normal, but within 12-24 hours proliferative activity is noticeably increased and crypts enlarge in diameter and length to accommodate more mitotic cells. Mitotic cells are poorly differentiated and crowded, have increased basophilia, and sometimes mitotic figures are observed close to the mucosal surface. The lamina propria may appear hypercellular; perhaps this is due to contraction of the lamina propria or mild mononuclear cell infiltrate. As regeneration progresses, the length of villi and differentiation of lining epithelial cells increases, and proliferation gradually subsides.
Atrophy of villi and hypertrophy of crypts is also associated with chronic or persistent processes such as nematode parasitism; chronic coccidial infection; giardiasis in some species; response to some dietary components such as soybean protein in calves, kidney bean protein in pigs, and wheat in dogs; idiopathic or specific granulomatous enteritis such as Johne's disease and histoplasmosis; and chronic inflammatory bowel disease. Epithelial kinetics have not been thoroughly investigated in most of these situations in domestic animals; however, these have in common chronic antigenic exposure, parasitism, or a persistent infectious process, which are usually associated with significant infiltration of inflammatory cells. Where the cause can be eliminated, the lesion usually remits, implying that active host-pathogen interaction is required for its induction and maintenance. The situation is analogous to celiac disease in humans, which is a dietary gluten-specific T helper-1 lymphocyte immune-mediated response resulting in production of interferon-γ, among other cytokines. Some experimental evidence has implicated nitric oxide, interleukin-12, interferon-γ, and tumor necrosis factor-α in the pathogenesis of villus atrophy; however, the source and effect of these molecules remain uncertain.
Immune reactions in the gut are associated with increased epithelial cell proliferation; however, hypertrophy of the proliferative compartment in these conditions precedes the development of villus atrophy, and is not a response to it. Local stimulation of the proliferative compartment and perhaps the associated myofibroblast sheath is likely mediated by nitric oxide or cytokines produced by activated T lymphocytes in the mucosa. Epithelial cells leaving these crypts usually do not differentiate fully and often exfoliate prematurely, low on the the proportion of the crypt cell population that is replicating or the duration of the cell cycle.
The degree of differentiation, and hence functional status of enterocytes on villi, can be inferred from their appearance. Cytoplasmic basophilia; loss of regular basal nuclear polarity; low columnar, cuboidal, or squamous shape; and an ill-defined brush border all indicate a poorly differentiated population of surface enterocytes and suggest an increased rate of turnover. Fasting causes atrophy and reduction of mucosal epithelial mass caused by prolongation of the postmitotic phase of proliferative cells. Villi do not directly atrophy; however, surface enterocytes persist longer and are lost from the villus more slowly. Fasting-induced atrophy is immediately reversed by refeeding. Weaning has similar effects on the microtopography of the intestine, which is observed as marked reduction in height of villi in most species.
Restoration of epithelial integrity is dependent on a finely regulated balance of migration, proliferation, and differentiation of adjacent epithelial cells, which are ultimately mediated by local growth factors, cytokines, dietary factors, and especially by trefoil factors present in mucus.
Following minor loss of mucosal enterocytes, restitution occurs by lateral migration of adjacent intact epithelial cells within minutes. If epithelium on villi is obliterated, for instance by transient ischemia or by viral cytolysis, the villus core contracts because of myofibroblast activity mediated by the enteric nervous system, and stromal elements rapidly undergo apoptosis. Surviving epithelial cells become flattened and migrate across the denuded surface. Proliferation of epithelial cells then occurs and regeneration of the mucosa follows in hours to days after injury. Last, maturation and differentiation of cells occurs as the 3-dimensional architecture is restored within a few days. A bed of granulation tissue forms at the base of extensive mucosal ulcers, and with time (weeks to months) this may become covered by a neomucosa, with crypts and villi following immigration of epithelial cells from the periphery of the lesion. A similar process repairs the mucosal gap in healing intestinal anastomoses.
Atrophy of villi is a common pathologic change in the intestine of domestic animals. It results in malabsorption of nutrients, and can be associated with loss of plasma protein into the gut. Villus atrophy can be categorized histomorphologically into 2 broad types based on the appearance of the crypts, recognition of which has implications with respect to pathogenesis and prognosis. The first category includes intestine with apparently normal or hypertrophic crypts, and the second category is characterized by some evidence of damage to the proliferative compartment. Recognition, evolution, and interpretation of each category are considered later.
Villus atrophy with an intact or hypertrophic proliferative compartment takes 2 forms in domestic animals. A primary increase in rate of loss of epithelium from the surface of villi is one mechanism initiating such a lesion. This is the major mechanism involved in a number of important viral infections including coronavirus and rotavirus; of coccidial infections, which damage surface enterocytes predominantly; of some enteroinvasive bacteria; of transient ischemia, in which the effect is limited to the functional compartment; and, in some circumstances, of necrotizing toxins released by clostridia in the lumen of the bowel. The effect of these agents is increased loss of surface epithelium over a relatively short period of squamous epithelial cells derived from surviving crypts. The mucosa may eventually ulcerate, to be eventually lined by granulation tissue. Crypts that have not been severely damaged will undergo hypertrophy within several days of the original insult, as compensatory hyperplasia of the remnant crypt epithelial cells occurs. In viral diseases, the severity and histologic appearance of the lesion often vary considerably at different sites in the gut, and even within an individual tissue section. Lesions caused by ischemia tend to be uniform in severity but may be localized; acute or subacute lesions are often hemorrhagic, especially if there has been re-establishment of blood flow.
Extensive crypt cell necrosis, erosion, or ulceration lead to severe malabsorption and effusion of tissue fluid and hemorrhage. The mucosa is susceptible to invasion by the enteric flora, sometimes including fungi. Local ulceration may contribute further to persistent fluid and plasma loss, and if circumferential, to eventual stricture formation and stenosis. Small ulcers in areas where a few crypts have dropped out will heal as epithelial cells from adjacent crypts migrate to repair the denuded surface; however, crypts may take longer to regenerate, so local villus atrophy will persist.
Epithelial turnover in the cecum and colon is fundamentally similar to that in the small intestine, though villi are not present on the surface. Epithelial cells lose the ability to divide after leaving the proliferative compartment in the lower part of the gland. In the upper portion of the gland, they differentiate into goblet cells or columnar absorptive cells that emerge and migrate over the surface. Cells are subsequently lost into the lumen, probably within about 4-8 days of being produced, although no studies of colonic epithelial turnover have been made in domestic animals. Colonic epithelial cell proliferation is experimentally reduced by fasting and restored by refeeding. Physical colonic distention and certain types of dietary fiber also appear to induce colonic epithelial cell proliferation. Compared with conventional animals, the colon of gnotobiotic animals has fewer proliferative cells, mostly limited to the lower portion of the glands.
Following insult and exfoliation of surface epithelial cells, restitution of the epithelial integrity in the large bowel resembles that in the small bowel. Within a few minutes of injury, surviving surface epithelial cells and cells emerging from crypts become attenuated and migrate at a rate of several micrometers per minute to cover mucosal defects. Ulcers, surgical incisions, or anastomotic sites in the colon heal by immigration of a single layer of epithelium from the periphery of the defect, with gradual differentiation of crypts, and eventual restitution of normal mucosal architecture. Depending on the type of anastomosis in the horse, epithelial cells may take >2 weeks to bridge the granulation tissue in the mucosal gap, and full restoration of mucosal architecture may require ∼2 months.
Microscopic lesions in the large bowel associated with increased epithelial turnover can be induced by alterations in the replication rate of both surface and glandular epithelium. The number of goblet cells on the surface and in the upper portion of glands is often diminished. Epithelial cells in these areas appear poorly differentiated, have increased cytoplasmic basophilia and morphologically may be of low columnar, cuboidal, or squamous type. In severe diseases, erosion of the surface is present. The proliferative compartment in the gland may villus or near the crypt opening. Coupled with normal shedding of pre-existing enterocytes, this contributes further to atrophy of villi over a period of several days. Epithelial cells that reach the surface also do not differentiate fully, are rapidly lost into the gut lumen, or undergo mucous metaplasia.
Microscopically, hypertrophy of crypts is the early and outstanding change in this lesion, and is consistently present. In its milder forms, the lesion may be better characterized by elongate crypts than by obvious atrophy of villi. The proliferative compartment is expanded and active, mitotic figures are numerous, and goblet cell hyperplasia may also occur. Elongation of crypts may be so extensive that even with severe atrophy of villi the total mucosal thickness will not be much reduced from normal. Close observation may reveal poorly differentiated enterocytes exfoliating prematurely from intercrypt ridges on the mucosal surface, or from buttress-like folds around the base of stubby villi. The lamina propria has a prominent population of lymphocytes, plasma cells, and associated inflammatory cells; intraepithelial lymphocytes are common. The etiologic agent may be evident, removal of which, where possible, usually results in a return to "normal" within days or weeks.
However it is induced, atrophy of villi with hypertrophy of crypts results in local malabsorption of nutrients and water. Poorly differentiated surface epithelial cells may secrete electrolytes and water, and increased epithelial turnover may contribute to enteric loss of endogenous protein. Proprial inflammation and microerosion of the mucosa may also contribute to effusion of tissue fluid.
Villus atrophy associated with damage to the proliferative compartment is also commonly seen in domestic animals. This form is the sequel to insults that cause necrosis of cells in crypts, or impair their mitotic capacity. Agents that cause these lesions usually have a propensity for damaging actively proliferating cells in any tissue. Because ionizing radiation was recognized early as a cause of such lesions, they are generally often termed radiomimetic. Other agents inducing similar lesions include cytotoxic chemicals and mitotic poisons, such as chemotherapeutic agents, T-2 mycotoxin, and pyrrolizidine alkaloids in large doses; viruses that infect proliferating cells, particularly the parvoviruses, and bovine viral diarrhea virus. Ischemia of sufficient duration to cause necrosis of some or all cells lining the crypts also causes this lesion.
The microscopic appearance of affected mucosa depends on the severity and extent of the insult, and the interval since it occurred. The primary event is damage to the proliferative compartment, and, except in ischemia, lesions will be evident in crypts well before significant atrophy of villi occurs. Individual necrotic epithelial cells and neutrophils may be present in the dilated lumen of damaged crypts. With severe damage to crypts, remaining epithelial cells become extremely flattened in an attempt to maintain the integrity of the crypt lining. Following the radiomimetic injury, irregular epithelial cells with large nuclei and nucleoli may be observed within crypts and will migrate onto the surface.
Pre-existing surface epithelial cells are shed from villar tips at an apparently normal rate, even though few or no new cells emerge from crypts. Villi eventually become atrophic or collapse as the surface cell population shrinks. If the majority of crypt cells are damaged, crypts stripped of epithelium collapse or "drop out," perhaps leaving a few scattered cystic remnants, lined by attenuated epithelial cells in the deeper lamina propria. The overlying surface may be eroded, or covered by neuroendocrine, and systemic cytokine inputs impacting centrally on satiety. The potential for physical impairment of gastrointestinal function to affect appetite seems relatively obvious. Less apparent but highly significant are effects on appetite of chronic inflammatory or neoplastic diseases affecting the alimentary system or distant sites. Proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1 associated with chronic inflammation and neoplasia, are probably strategic mediators in the complex metabolic puzzle that is cachexia. Ghrelin is a stomach-derived hormone known to be an important mediator of cachexia, and although the mechanisms remain unclear, ghrelin may function directly by stimulating appetite centrally and indirectly by attenuating inflammation or altering lipid and muscle metabolism to limit cachexia.
Protein-energy malnutrition must be differentiated from the effects of endogenous conditions, resulting in malassimilation or protein-losing enteropathy, from cachexia induced by chronic inflammatory and neoplastic disease, and from other conditions resulting in recumbency.
In neonates, several factors predispose to death by starvation within the first few weeks of life. These include fetal malnutrition with poor fat depots at birth; increased energy demands caused by cold and exposure; and postpartum hyponutrition. Piglets are born with negligible fat reserves and die quickly of hypoglycemia if not fed adequately. Neonatal ruminants usually have fat depots sufficient to compensate for longer periods of inanition (2-4 days for lambs; 6-10 days for calves), if the quality and quantity of milk is sufficient, and cold stress is not severe.
In animals that die of inanition, muscle mass is reduced because of mobilization of amino acids for gluconeogenesis. Fat in the bone marrow, coronary groove, on the pericardial sac, and around the kidneys is completely depleted, and has the gelatinous clear pink appearance of serous atrophy. The liver may appear small, with sharp margins, presumably because of reduced trophic stimuli. A diagnosis of starvation is supported by a history of conditions compatible with reduced quantity or quality of feed, and by ruling out other conditions causing protein loss.
Digestion and assimilation of nutrients have an intraluminal phase mediated by biliary and pancreatic secretions, and an epithelial phase carried out by enzyme systems on the surface and in the cytoplasm of absorptive enterocytes. The final step is delivery of the nutrient by the enterocyte to the interstitial fluid, and its uptake into the blood or lymph.
Exocrine pancreatic insufficiency is the major cause of intraluminal maldigestion, and is usually the result of juvenile pancreatic atrophy in dogs, or of pancreatic fibrosis and atrophy following repeated episodes of pancreatic necrosis (see Vol. 2, Pancreas). It is occasionally seen in cats. This condition may be complicated by bacterial overgrowth of the small intestine. Bile salt deficiency is rarely seen as a cause of intraluminal maldigestion in domestic animals.
The epithelial phase of assimilation is impaired by loss of functional epithelial surface area. This occurs with villus atrophy, or less commonly in short-bowel syndrome following intestinal resection in which >75-85% of the small bowel has been removed. This phase of assimilation is dependent on enzyme systems, which vary in domestic animals. Neonates and ruminants have low levels of maltase; ruminants lack sucrase. In hypertrophy, causing glands to elongate and dilate. Mitotically active cells are increased in number and distributed over a greater proportion of the glands' length. In some acute or chronic inflammatory conditions of the lamina propria, gobletcell hyperplasia may occur. It is uncertain whether this is caused by primary damage to surface epithelium, or by local cell-mediated immune effects on the proliferative compartment, as occurs in the small intestine in celiac disease of humans.
The proliferative compartment in the cecal and colonic glands is damaged by the same insults that attack cells in crypts of the small bowel, although the lesions in large bowel tend to be comparatively less severe. This is perhaps because a lower proportion of the proliferative compartment in the colon is in mitosis at the time of maximum availability of drug or virus. Additional agents that damage the proliferative compartment in the colon include bovine and canine coronaviruses, and several species of coccidia in ruminants, which develop in the epithelial cells lining colonic glands.
The evolution and sequelae of lesions resulting from damage to proliferative epithelial cells in the colon are similar to those in small bowel: dilation of crypts, accumulation of necrotic debris within crypts, and/or attenuation of the lining epithelium. Severe lesions will lead to loss of glands, erosion, and ulceration of the mucosa; hemorrhage; stricture and stenosis may ensue. Following milder damage that spares some stem cells in each gland, the mucosa has the potential to recover fully after a period of reparative hyperplasia.
Pathophysiology of enteric disease Protein-energy malnutrition caused by inadequate intake of feed or deficiencies in quantity or quality of nutrients is a well-recognized co-morbidity factor in many diseases. In its most severe forms, this results in depletion of fat and muscle mass, emaciation, and ultimately death by starvation. Importantly, protein-energy malnutrition is a common cause of secondary immune deficiency and is thus associated with increased susceptibility to infections.
Inappetence or anorexia are commonly associated with gastrointestinal diseases. Appetite is modulated by a complex and incompletely understood meshwork of neurologic, Protein maldigestion occurs if pancreatic protease activity is decreased to ~10% of normal, as may occur with exocrine pancreatic insufficiency. Loss of gastric proteolytic activity is of little nutritional significance. In conditions with villus atrophy, reduced mucosal surface area and poor differentiation of enterocytes result in malabsorption of small peptides and particularly of amino acids by mechanisms similar to those involved in carbohydrate malabsorption. Argiles JM, et al. Cytokines
Diarrhea is the presence of water in feces in relative excess in proportion to fecal dry matter. Diarrhea usually reflects increased absolute fecal loss of water, but may not, if absolute fecal drymatter excretion is markedly reduced. Loss of solute and water in diarrhea may lead to severe electrolyte depletion, acidbase imbalance, and dehydration, which are life-threatening if not corrected. Large volumes of fluid derived from ingesta, and from gastric, pancreatic, biliary, and enteric secretions, enter the small bowel; in addition, considerable passive movement of water occurs into the upper small bowel from the circulation in response to osmotic effects. Overall, the bulk of the fluid entering the small intestine is absorbed by the enterocytes, so that the volume leaving the ileum and entering the colon is but a small fraction of the total fluid flux through the small bowel. The large size of this flux implies that relatively small perturbations in unidirectional movement of electrolyte and water in the small intestine may have significant effects on the net movement of fluid.
The colon, in addition to its fermentative function, has the ultimate responsibility to minimize fecal water loss by conserving electrolyte and water by absorption from the digesta. It has a finite capacity for absorption, and if this is exceeded by the rate at which content enters from the small bowel, diarrhea occurs. This is important in so-called smallbowel diarrhea, where the lesion is in the small intestine. Because the colon has reserve absorptive capacity, the excess volume entering from the ileum must be considerable for diarrhea to occur. The large capacity and fermentative function of the equine colon may mitigate to some extent the expression of small-bowel diarrhea in mature horses. Large-bowel diarrhea, on the other hand, reflects an intrinsically reduced capacity of the colon to handle even normal volumes of fluid and electrolyte presented to it by the small intestine. most species, lactase levels decline with age, and malabsorption in dogs has been attributed to low levels of lactase. The poorly differentiated surface epithelium present on atrophic villi may lack the full complement of enzymes on the brush border and in the cytoplasm necessary for nutrient digestion and assimilation. Lectins present in uncooked beans attach to and damage microvilli on enterocytes, which may explain the malabsorption and diarrhea associated with their use in feeds; lectins also promote bacterial adhesion and overgrowth in the small intestine. A heritable syndrome of gluten-sensitive enteropathy is reported in Irish Setter dogs, and is characterized by villus atrophy, increased intraepithelial lymphocytes, and abnormal levels of mucosal microvillar hydrolases. Cobalamin malabsorption has been described as a hereditary defect in Beagles, Australian Shepherd Dogs, Chinese Shar-Peis, Giant Schnauzers, and Border Collies, resulting in anemia and failure to thrive. Delivery of nutrients, especially lipid, to the circulation, may be impaired in lymphangiectasia. The pathogenesis of malabsorption of the major classes of nutrients will be considered briefly.
Assimilation of fat is susceptible to interference at all 3 phases of digestion and absorption. Lipolysis is impaired if insufficient lipase is available. Mostly this is a result of pancreatic atrophy or fibrosis; however, it also may be due to failure by atrophic intestinal mucosa to release the cholecystokinin necessary to stimulate pancreatic secretions. Reduced surface area for lipid uptake also may contribute to malabsorption of fat. The availability of bile salts is reduced in intrahepatic cholestasis, biliary obstruction, or by depletion resulting from reduced ileal absorption following resection or atrophy. Thus fatty acid and monoglyceride are not emulsified and are therefore not as accessible to absorptive enterocytes. Poorly differentiated enterocytes may be less able than normal epithelium to re-esterify long-chain fatty acids to triglyceride and to produce chylomicrons for export from the cell. Obstructed lymphatic drainage in lymphangiectasia, granulomatous enteritis, and intestinal lymphosarcoma contributes to reduced flow of chylomicrons to the systemic circulation.
Malabsorption of lipids may cause steatorrhea (excess fat in the feces), and this is seen in monogastric animals, especially dogs. Severe fat malabsorption may result in deficiencies of fat-soluble vitamins. Malabsorption of calcium, magnesium, and zinc occurs when these minerals are sequestered in soaps formed by combination with malabsorbed luminal fatty acids. Increased absorption of oxalate predisposing to nephrolithiasis may be a sequel to reduced concentrations of calcium in the lumen because of soap formation. Malabsorbed lipid may cause colonic diarrhea, by mechanisms that will be discussed subsequently.
Maldigestion of polysaccharides occurs if levels of pancreatic amylase are reduced; this is most commonly encountered in dogs with severe loss of functional exocrine pancreatic tissue. Ruminants normally lack significant amounts of pancreatic amylase and digest starch poorly in the small intestine. Mucosal oligosaccharidase deficiency occurs in villus atrophy, because poorly differentiated enterocytes have a reduced complement of oligosaccharidases. This results in impaired membrane digestion of disaccharide and malabsorption of carbohydrate. The osmotic effect of malabsorbed disaccharide in the small intestine is an important component of neonatal diarrhea caused by rotavirus and coronavirus, or other conditions in which there is extensive villus atrophy in the small intestine. movement via the paracellular route across the mucosa into the intestinal lumen, which is driven by alterations in the interstitial and vascular pressure gradients. Elevated hydrostatic pressure, or decreased plasma oncotic pressure in the villus, alters Starling forces, permitting leakage of interstitial fluid and large protein molecules. Portal hypertension, rightsided heart failure, hypoalbuminemia, and expansion of plasma volume establish such conditions. Effusion also may be associated with lymphangiectasia, inflammation or edema of the lamina propria, increased vascular permeability, and enteric plasma protein loss. Increased rate of epithelial loss and transient microerosions may provide further potential sites for effusion of interstitial fluid. Extensive necrosis of the epithelium and vascular damage in the mucosa cause more severe malabsorption and effusion of tissue fluid and blood, evident grossly as fibrin and hemorrhage in the lumen.
Large-bowel diarrhea is due to a reduction in the innate capability of the colon to absorb the solute and fluid presented by the more proximal bowel. A reduction in net absorption by the colon that is relatively small in absolute terms may be sufficient to cause diarrhea. Large-bowel diarrhea is characterized by frequent passage of small amounts of fluid feces, perhaps with mucus and blood. The colonic mucosa is not as leaky as the small intestinal mucosa because of the nature of the tight junctions between epithelial cells. As a result it is relatively resistant to alterations in permeability owing to increased hydrostatic pressure in the propria, in comparison with the small intestine.
When normal enterohepatic circulation of bile acids is interrupted by ileal damage or resection, excess dihydroxy bile acids enter the colon where they stimulate colonic epithelial cells to secrete fluid and electrolytes through calcium and cAMP-dependent mechanisms, resulting in diarrhea. Fatty acids enter the colon in increased quantities in steatorrhea resulting from bile salt depletion, where they cause diarrhea by altering mucosal permeability and stimulating fluid secretion from colonic epithelium. This is also the mode of action some laxatives such as castor oil, which contains the hydroxy fatty acid ricinoleic acid.
Although colonic secretion stimulated by bacterial enterotoxin is not clearly implicated in diarrhea, alterations in the flora of the large bowel may be detrimental to normal function. Short-chain fatty acids, especially butyric acid produced by bacterial fermentation in the lumen, regulate colonic epithelial cell growth and differentiation and are linked to electrolyte and fluid absorption in the colon. Reduced production or absorption of short chain fatty acids secondary to imbalance of the bacterial flora in the cecum and colon may explain some instances of wasting and diarrhea in horses in which no morphologic abnormality of the mucosa can be found.
Osmotic overload of the large bowel results from the delivery by the small bowel of a large volume of fermentable substrate. This is usually caused by malabsorption in the small intestine, but may result from excessive intake. Carbohydrate is the only nutrient of significance in initiating colonic osmotic overload, as bacterial fermentation of carbohydrate results in the generation of excess short-chain fatty acid. This is rapidly absorbed and buffered in the colon under normal circumstances; however, a heavy carbohydrate load may overwhelm the colonic buffering capacity, and cause reduced pH. The result is an altered gut flora in which there is overgrowth of organisms producing lactic acid, further contributing to acidification and increased mucosal permeability. Loss of water and Small-bowel diarrhea is classified as secretory, malabsorptive, or effusive; however, these mechanisms are not mutually exclusive and are often seen as overlapping syndromes. Smallbowel diarrhea is characterized by infrequent passage of large amounts of fluid feces. Secretory diarrhea is due to an excess of secretion over absorption of fluid, resulting from derangement of normal secretory and absorptive mechanisms. It is best exemplified by the effects of diarrheagenic bacterial enterotoxins. Vibrio cholerae and Escherichia coli are the most important sources of such toxins, though only the latter occurs in domestic animals; some Salmonella serotypes, Yersinia enterocolitica, and Shigella also produce enterotoxin. Cholera and heat-labile E. coli enterotoxin act through the mediation of cyclic adenosine monophosphate (cAMP). Toxin-stimulated cAMP shuts down sodium chloride cotransport at the luminal cell membrane of enterocytes, reducing passive water absorption. Meanwhile, cAMP-stimulated chloride secretion is promoted, and water follows. The resultant increase in secretion and decrease in absorption increase the solute and water load passing from the small bowel to the colon. Heat-stable E. coli and Y. enterocolitica enterotoxins stimulate cyclic guanosine monophosphatemediated secretion by the mucosa.
In addition to bacterial enterotoxins, other factors may cause or contribute to secretory diarrhea. Prostaglandins, other eicosanoids, histamine, kinins, and various other cytokines directly or indirectly stimulate secretion, often by local stimulation of enteric nervous reflexes, and they may contribute to diarrhea in inflammatory bowel disease. Vasoactive intestinal polypeptide secreted by pancreatic islet cell tumors causes severe diarrhea in humans with such tumors; this neurotransmitter causes active chloride and bicarbonate secretion, and is probably the final mediator in secretion stimulated by the enteric nervous system. Other circulating agents are directly or indirectly diarrheagenic: calcitonin secreted by thyroid C-cell tumors; serotonin, bradykinin or substance P secreted by carcinoids; histamine secreted by mast cell tumors; gastrin secreted by gastrinomas. Peptide YY is secreted by enteroendocrine cells of the gut and is known to inhibit intestinal secretion and promote absorption; altered peptide YY secretion has been observed in a variety of gastrointestinal diseases in humans and some domestic animal species.
Malabsorptive diarrhea commonly results from villus atrophy no matter what the cause, and is exemplified by osmotic retention of water in the gut lumen by poorly absorbed magnesium sulfate, used therapeutically as a laxative. Electrolyte and nutrient solute are malabsorbed as the result of reduced villus and microvillus surface area, and along with osmotically associated water are retained in the lumen of the bowel and then passed into the colon. A secretory component probably contributes to diarrhea caused by villus atrophy, at least in transmissible gastroenteritis in pigs. In this scenario the villus limb of the postulated crypt-villus fluid circuit is diminished or missing, so fluid secreted by the crypts may not be absorbed and poorly differentiated cells emerging on to the intestinal surface from crypts may also retain some secretory capacity. Malabsorptive diarrhea also occurs in short-bowel syndrome caused by reduced absorptive surface.
Increased permeability of the mucosa may contribute to diarrhea by permitting increased retrograde movement of solute and fluid from the lateral intercellular space to the lumen, or by facilitating transudation of tissue fluid. Filtration secretion is characterized by increased protein-rich fluid entering the intestine is derived mainly from effusion of plasma protein into the lumen of the bowel but can also be associated with increased turnover of cells lining the gut. Protein-losing enteropathies can be divided into 3 categories according to the mucosal alteration causing protein loss: mucosal ulcerations or erosions leading to secondary protein exudation; nonulcerated mucosa with abnormal permeability; and lymphatic disruption with leakage of protein-rich lymph (see later section on lymphangiectasia).
Plasma protein loss may result from the blood-sucking activity of nematodes such as Haemonchus, Ancylostoma, and Bunostomum, or hemorrhage from sites of trauma in the mucosa caused by the feeding activity of worms such as Oesophagostomum, Chabertia, and Strongylus. Considerable loss of erythrocytes and plasma protein leading to fibrinohemorrhagic enteritis can occur secondary to mucosal erosions or ulcerations caused by ischemia, epithelial cell necrosis, or inflammation associated with bacteria, viruses, and coccidia. Plasma protein can also be lost through transient gaps, or leaks in the mucosa that develop during increased exfoliation of enterocytes into the lumen. With an increased rate of enterocyte turnover seen in villus atrophy, temporary microerosions may develop when flattened enterocytes fail to maintain the integrity of the surface epithelium.
The permeability of tight junctions between epithelial cells may be sufficiently altered to permit transit of plasma protein molecules. Filtration secretion occurs when the hydrostatic pressure in the proprial interstitium is elevated in congestive heart failure and portal hypertension; by decreased plasma oncotic pressure; by increased vascular permeability in acute or chronic inflammation; and in lymphatic obstruction or lymphangiectasia. Proinflammatory cytokines such as tumor necrosis factor-α are often prevalent during acute or chronic inflammation and may cause increased paracellular epithelial permeability to large molecules entering the mucosa.
Plasma protein loss into the gut is generally considered nonselective, as albumin, immunoglobulins, clotting factors, and a variety of transport or carrier proteins, including transferrin, ceruloplasmin, and transcortin, are lost equally. The physiologic consequences of protein-losing enteropathy may be observed with increased loss of any of these molecules, but are most frequently related to albumin turnover. Loss of plasma protein into the gut expressed as a proportion of the total body pool will vary in absolute terms; this concept of fractional catabolic rate is essential to understanding the kinetics of plasma protein turnover.
In protein-losing enteropathy, albumin turnover may pass through 3 phases. During the first phase, the fractional catabolic rate increases along with the absolute amount of protein lost into the bowel. As the size of the circulating pool of albumin shrinks, so does the absolute rate of loss of protein, even though the fractional rate remains the same. During the second phase, the size of the circulating pool stabilizes as the rate of albumin synthesis by the liver increases to match in absolute terms the rate of loss into the gut lumen. The plasma albumin pool is then in a state of hyperkinetic equilibrium in which the total pool is smaller, but a higher than normal fractional catabolic rate is compensated by an increased rate of hepatic albumin synthesis. Provided that the amount of albumin lost does not exceed the synthetic capacity of the liver, this equilibrium may persist for a considerable period. In the third phase, hypoalbuminemia develops as the fractional catabolic rate exceeds in absolute terms the synthetic capacity solute into the lumen along the osmotic gradient generated by lactic acid in the lumen leads to diarrhea.
Increased intestinal motility probably does not have a primary role in the pathogenesis of diarrhea in domestic animals. Often the small intestine of animals with diarrhea is flaccid and fluid-filled, rather than hypermotile. Increased colonic motor activity is often segmental and antiperistaltic, and probably unrelated to increased transit. Hypermotility, if it does occur, may be in response to, rather than a cause of, increased volumes of fluid in the gut. Argenzio
Disorders of protein metabolism attributable to enteric disease are responsible for significant economic loss in the form of reduced weight gain, wool growth, and milk production. Severe derangement resulting in negative nitrogen balance in any species may lead to cachexia, hypoproteinemia, and death. Decreased protein intake is the most obvious threat to the nitrogen economy, and it is probably the most important in many chronic gastrointestinal diseases. Subclinical inefficiency in production, reduced growth, and emaciation may be the product of various degrees of inappetence, or difficulty in prehension, mastication, and swallowing, or recurrent regurgitation. Low feed quality compounds the effect of reduced feed intake.
Anorexia is a sharp decline in appetite, and a common sign of indigestion, obstruction, or systemic disease. In ruminants, loss of appetite to various degrees is an especially important component of the pathogenicity of gastrointestinal parasites, including those infecting the abomasum (Ostertagia), small intestine (Trichostrongylus), and large bowel (Oesophagostomum). Interactions among cholecystokinin, parasympathetic efferent and afferent reflexes, and systemic or gastric leptins appear to mediate satiety; however, their mechanisms in health and disease remain unclear.
Malabsorption of peptides and amino acids may occur locally in the small intestine as a result of significant villus atrophy. However, unless the lesion is widespread or low in the small bowel, net absorption of nitrogen over the length of the small intestine will not be reduced because of the compensatory capacity of more distal normal mucosa. Overall, the contribution of malabsorption to disordered nitrogen metabolism appears to be minor in most situations.
Protein-losing gastroenteropathy, increased catabolism and loss of endogenous nitrogen via the gastrointestinal tract, is important in many diseases. Excess endogenous protein less common source. Anemia and hypoproteinemia may be due to hemorrhage externally or into the gastrointestinal tract. Advanced liver disease may cause hypoalbuminemia, in which case concurrent signs of hepatic failure will likely be observed (see Vol. 2, Liver and biliary system). Inability or reluctance to eat, inadequate nutrition, or starvation also cause emaciation, usually without profound hypoalbuminemia. The cachexia of malignancy also must be differentiated.
When adequately hydrated, the hypoalbuminemic animal shows evidence of subcutaneous, mesenteric, or gastric submucosal edema, perhaps with hydrothorax or ascites. Wasting of muscle mass may be marked if the protein loss has been severe and chronic. Unlike starvation, protein-losing gastroenteropathy may be associated with the presence of internal fat depots because assimilation of energy is not necessarily severely impaired, especially in ruminants.
The development of anemia and the kinetics of the erythron following blood loss into the gastrointestinal tract are similar to those of albumin in plasma loss. Blood loss of any origin, including that caused by hematophagous parasites, may cause anemia. Erythroid hyperplasia in the marrow or in extramedullary sites may not compensate for the continued erythrocyte loss. Resolution of the hemorrhage results in eventual restoration of normal red cell numbers and an ultimate decline in erythrocyte production. Chronic blood loss may culminate in depletion of iron stores and development of a nonresponsive hypochromic microcytic anemia. Coop
Segmental anomalies of the intestine are commonly encountered. In early embryonal life the intestine consists of a simple tube, the lumen of which is lined by epithelial cells of endodermal origin surrounded and supported by an outer layer of connective tissue from the splanchnic ectoderm. As the intestines grow with the developing fetus, they form coiled loops that herniate temporarily through the umbilicus into a peritoneal-lined sac before they are later retracted back into the fetal abdomen. The most plausible cause of segmental defects in intestinal continuity is ischemia of a segment of gut during early fetal life, resulting in necrosis of the affected area.
The segmental anomalies of the intestine may vary in degree. Stenosis implies incomplete occlusion or narrowing of the lumen; complete occlusion is referred to as atresia. Atresia is further subdivided into membrane atresia, when the obstruction is formed by a simple membrane; cord atresia, in which the blind ends of the gut are joined by a cord of connective tissue; and blind-end atresia, in which a segment of gut and possibly the corresponding mesentery are missing, leaving two of the liver. Alternatively, hypoalbuminemia occurs in the third phase if the rate of synthesis declines because of deficiency in amino acids derived from the diet or by catabolism of other body protein. The hypoalbuminemia in enteric plasma loss may be accompanied by hyperglobulinemia, the mechanism of which is not completely clear, but has been associated with underlying or concurrent inflammatory disease stimulating hepatic globulin production in these patients.
The progression and clinical manifestations of proteinlosing enteropathy vary with the rate of onset of plasma loss and the fractional catabolic rate. A sudden onset of severe plasma protein loss may cause death during the first phase, before there is time for compensatory synthesis. If the fractional catabolic rate is gradually and only slightly increased, so that compensation occurs with the albumin pool in equilibrium at only a marginally reduced state (perhaps near or within the normal range), subclinical protein loss occurs. Although the fractional catabolic rate is only slightly elevated, the relatively large size of the albumin pool may mean that the absolute loss of protein exceeds that in a hypoalbuminemic animal with a higher fractional catabolic rate, but a smaller albumin pool.
Endogenous protein derived from exfoliated cells of the stomach or upper small intestine during villus atrophy may be digested and absorbed in the lower small intestine. This is dependent on luminal proteolysis by pancreatic enzymes, digestion and absorption that may compensate for any malabsorption caused by the more proximal lesions. The efficiency of protein digestion and absorption is not 100%, so a proportion of this increased endogenous protein is added to the protein escaping digestion in the small bowel, and enters the large intestine.
Here, most of this protein may be converted to ammonia by the colonic flora and absorbed. The loss of significant protein from stomach or small intestine may be accompanied by little or no increase in fecal nitrogen excretion, although much of the protein lost from lesions in the colon is ultimately lost in the feces. Ammonia nitrogen absorbed from the colon is converted in the liver mainly to urea, so animals with increased endogenous protein loss into the stomach or small intestine tend to have slightly raised levels of plasma urea, and an elevated rate of urinary urea excretion.
Elevated hepatic synthesis of albumin, resulting from increased turnover of the plasma albumin pool, and increased enteric protein synthesis in support of elevated epithelial turnover in conditions with chronic villus atrophy, is at the expense of anabolic processes elsewhere. Dietary amino acid is diverted preferentially to synthesis of plasma and enteric protein. If protein intake is poor due to inappetence or a low-quality ration, or if the rate of protein loss is high, the animal moves into negative nitrogen balance. Catabolism of peripheral protein then assumes an increasingly important role in maintaining the pool of amino acids available for plasma and intestinal protein synthesis. This explains in part the reduced growth rate, decreased muscle mass, and reduced bone matrix in sheep with subclinical or mild parasitism, and the cachexia and osteopenia associated with severe parasitism. These principles probably hold for all syndromes causing enteric loss of endogenous protein in any species.
Loss of enteric protein, and especially plasma, should be suspected in cachectic or hypoproteinemic animals, although diarrhea is not invariably present. The 2 major routes of occult plasma protein loss are glomerular disease, particularly amyloidosis, and gastrointestinal disease; exudative skin lesions are a Although several gene mutations can cause intestinal aganglionosis, loss of function mutation of the endothelin receptor type B gene are observed in horses, rodents, and humans with this condition. The pathogenesis is thought to involve improper migration of cells of the neural crest, from which cutaneous melanoblasts and the myenteric plexus neurons are derived. A similar condition of megacolon resulting from segmental colonic aganglionosis has been reported in pigs. Megacolon associated with few myenteric ganglion cells in Clydesdale foals is not clearly congenital, and is discussed with intestinal obstruction, as is megacolon in other species.
Intestinal diverticula occur rarely in dogs, cats, and horses. True diverticula, congenital lesions involving all layers of the intestinal wall, are distinguished from pseudodiverticula resulting from disruption or weakening of the tunica muscularis and not involving all layers of the intestinal wall. They may be incidental, but in horses have been associated with idiopathic muscular hypertrophy or other lesions of the small bowel, including neoplasia. Diverticula can cause impaction, obstruction, intussusception or fistula, and potentially diverticulitis, rupture, and peritonitis.
Persistent Meckel's diverticulum is an uncommon embryonic developmental anomaly occurring mostly along the antimesenteric border of the lower small bowel, mainly in swine and horses. It is derived from the omphalomesenteric (vitelline) duct, which is the stalk of the yolk sac. The vitelline membrane can also persist forming a fibrous ligament or mesodiverticular band between the distal small jejunum and the diverticulum or umbilicus. Multiple persistent vitelline duct cysts, distinct from Meckel's diverticulum, have been described on the ileal serosa in a dog.
Hypoplasia of the small intestinal mucosa has been reported in foals with failure of passive transfer, and this may represent defective fetal organogenesis.
Acute obstruction typically involves the upper or middle small intestine whereas chronic blockage usually involves the ileum and large bowel. Intestinal obstruction may be the sequel to a physical blockage of the lumen resulting from stenosis (narrowing, stricture) caused by an intrinsic lesion involving the intestinal wall, obturation (occlusion) by an intraluminal mass, or extrinsic compression. Failure of the intestinal circular smooth muscle to contract blocks the peristaltic wave, causing functional obstruction, a blind ends. All types of segmental anomaly can be produced experimentally by ischemia to a portion of the fetal intestine.
Atresia coli is the most common segmental anomaly of the intestine in domestic animals. It is seen particularly in the spiral colon of Holstein calves, and in the large and small colon of foals; it occurs rarely in cats. Atresia coli may be an autosomal recessive trait in Holsteins. A predisposition for male calves has been described, but this is not consistent among studies. An association has been postulated between pressure on the amniotic vesicle during palpation of the embryo for pregnancy diagnosis before 42 days of gestation, and the development of atresia coli in calves; however, the mechanism of this effect is uncertain. Atresia intestinalis is less common. Atresia ilei is most prevalent in calves, and rare in foals, lambs, piglets, and pups. These lesions prevent normal movement of gut content and meconium and therefore lead to dilation of the proximal segment and progressive abdominal distention, which may become so extensive in an affected fetus to cause dystocia. The bowel distal to the obstruction is small in diameter, and devoid of content other than mucus and exfoliated cells. Animals fail to pass feces after birth.
Atresia ani (imperforate anus) is the overall most common congenital defect of the lower gastrointestinal tract. It may be seen in all species, but is most often encountered in calves and pigs, in which it is considered to be hereditary. The defect may consist only of failure of perforation of the membrane separating the endodermal hindgut from the ectodermal anal membrane, or both anus and rectum may be atretic. Atresia ani may be an isolated abnormality, but is more commonly associated with other malformations, especially of the distal spinal column (spinal dysraphism, sacral or coccygeal vertebral agenesis), genitourinary tract (rectovaginal fistula, renal agenesis, horseshoe kidney, polycystic kidneys, cryptorchidism, duplication of scrotum or penis), and occasionally with intestinal atresia or agenesis of the colon. Vitamin A deficiency during pregnancy has been associated with increased risk of congenital ano-rectal malformations in several species; this is thought to be related to improper development of the enteric nervous system. Short colon has been reported in dogs and cats, and is probably the result of abnormal rotation of the midgut and failure to lengthen during fetal life. Clinical signs were subtle and possibly unrelated to the colonic lesion. Affected animals had a shortened colon with the cecum located on the left side of the abdomen. Concurrent anorectal or urogenital abnormalities were observed in some cases. Anomaly of the colonic mesenteric attachments has been described and associated with development of colic in a horse, because of distortion and convolution of the large colon.
Congenital colonic aganglionosis, somewhat analogous to Hirschsprung's disease in humans, occurs in white foals that are the offspring of "frame overo" spotted parents. The disease has not been convincingly demonstrated in other species of domestic animals. Clinically affected foals, which are predominantly white, develop colic and die generally within 48 hours of birth. Grossly, there is stenosis mainly of the small colon, but the entire colon and rectum may be patent but contracted; the proximal intestine is distended with gas and meconium. Microscopically, ganglia of the myenteric plexus are absent in the walls of the terminal ileum, cecum, and colon, although occasional nerve fibers are evident. Except for the few pigmented spots, melanocytes are absent in the skin. by ileus and accumulation of fluid contents and gas. The volume of distention and length of bowel involved is dependent on the location, degree, and duration of obstruction; this may be remarkable with distal lesions such as rectal stricture in pigs, which can cause profound abdominal distention. As distention increases, interference with venous return may develop and the mucosa and submucosa become congested. Devitalization of severely dilated gut or pressure necrosis of the mucosa at the site of lodgment of intraluminal foreign bodies may occur, leading to necrosis, perforation, and peritonitis. Distal to the point of obstruction, the bowel is collapsed and empty.
Congenital intrinsic obstruction caused by segmental atresia and imperforations is considered under the previous section on congenital anomalies of the intestine. The primary lesions involving the intestinal wall causing acquired stenosis include intramural abscesses or hematomas, neoplasms, and fibrosis secondary to ulceration. These lesions can result in partial or complete stenosis and may develop slowly with a course as described for simple chronic obstruction.
Foreign bodies of all kinds are commonly found. Small rounded foreign bodies and even some sharp-edged objects may pass through the intestines uneventfully, but for these and many large foreign bodies the course is unpredictable. Some may reside in the intestine for long periods and produce no disturbance until they act as a nidus for the development of an enterolith. Foreign bodies may cause partial or complete intestinal obstruction and compromise the blood supply by luminal distention, which may progress to edema, necrosis, and possibly perforation. Most obstructions occur in the jejunum, although any segment of bowel can be affected. Linear foreign bodies such as strips of cloth or string probably occur more commonly in cats compared with dogs, and once ingested may pass through the intestine. However, if they become immobilized they produce a characteristic lesion. One portion becomes fixed, most commonly around the base of the tongue or by impaction at the pylorus. The free end is then stretched taut distally because of peristalsis, which results in pleating of the distal gut onto the string ( Fig. 1-43A ). Peristalsis results in progressive mucosal damage ( Fig. 1-43B ) along the lesser curvature of intestinal loops that may lead eventually to perforation and peritonitis.
Enteroliths (mineral concretions) were historically common in the colon of horses, and are observed more frequently in some areas, such as California and Florida. Aged Arabians, Morgans, American Saddlebreds, and donkeys seem to be overrepresented. The concretions are comprised of magnesium ammonium phosphate, the source of which is probably grain, bran, alfalfa, or alkaline water. Colonic pH >6.6 seems to contribute to enterolith formation. The mechanism is not completely clear; however, mineral salts are deposited in concentric lamellae around a central nidus-a foreign body such as a nail, wire, stone, or particle of feed. They can vary greatly in size, some weighing as much as 10 kg. Enteroliths are usually smooth and spherical but can be flattened; irregular mineralized masses may also occur, usually centered on a fibrous nidus, such as twine, rope, or netting.
Fiber balls (phytobezoars or phytotrichobezoars), which consist largely of plant fibers intermixed with phosphate salts, may be found especially in the colon of horses. They are not as heavy as enteroliths, and are usually round, smooth, and clinical syndrome of pseudo-obstruction in which there is no physical occlusion of the lumen of the impacted intestine. Adynamic ileus, intestinal obstruction resulting from inhibition of bowel motility, is a common sequel to peritonitis and pain. Circulatory embarrassment of a segment of bowel via embolism or venous infarction also causes functional obstruction without a physical blockage. Many intestinal displacements that produce obstruction such as volvulus, strangulation, or intussusception may cause ischemia. The term strangulation obstruction refers to an event that simultaneously causes ischemia and physically blocks the intestine. Mucosal hypoxia may be a sequel to venous occlusion caused by physical distention of gut proximal to an obstruction; to local pressure caused by an adjacent mass; or to generalized circulatory failure. The pathogenesis and consequences of intestinal ischemia are dealt with later in this chapter.
Proximal to an obstruction there is accumulation of fluid derived from ingesta, gastric, biliary, pancreatic, and intrinsic intestinal secretion, and gas swallowed or originating from bacterial activity in the gut ( Fig. 1-42 ). Intestinal distention results in luminal sequestration of water and electrolytes and mucosal edema; further fluid secretion into the lumen may be associated with contractile stimuli, and potentially transudation from the peritoneal surface. Upper small-bowel obstruction progresses rapidly to vomiting in most species, with dehydration, hypochloremia, hypokalemia, and metabolic alkalosis caused by loss of acid in vomitus and of fluid sequestration in the stomach. If acute complications of ischemia including rupture do not occur, an animal with obstruction succumbs to the systemic effects of hypovolemia, electrolyte, and acid-base disturbance.
With obstruction of the lower small intestine or colon, there is usually less pronounced electrolyte and acid-base imbalance because vomition is less severe and absorption of fluid proximal to the obstruction may prevent or delay severe distension and additional fluid secretion. Metabolic acidosis eventually follows however, with dehydration and catabolism of fat and muscle once food consumption and assimilation ceases. In the horse, obstruction or impaction of the cecum or colon in particular often leads to local ischemia and rupture.
In obstruction, the outstanding gross alteration in the bowel is distention proximal to the point of blockage, caused the colon lumen narrows or changes direction, for example, at the pelvic flexure, and the transverse or small colon.
Small intestinal obstruction may be caused by parasites that can form rope-like tangled masses in the lumen. This occurs in pigs and foals infested with large numbers of ascarid nematodes. It also occurs rarely in sheep heavily infested with cestodes. Impaction of the ileum is the most common cause of small intestinal nonstrangulating obstruction in horses. Feeding of a high-fiber diet, such as coastal Bermuda grass hay, predisposes to this condition. Gravel and sand have been reported as causes of small intestinal obstruction in cattle and dogs, respectively.
Impaction of the colon is a common cause of simple intestinal obstruction. The impaction cause is often feces in dogs and cats. In horses the cause is digesta, fibrous foreign material, sand, or feces and can be complicated by intestinal tympany from fermentation if the obstruction is complete. Obstipation of the colon in dogs may result from voluntarily suppressed defecation caused by pain from inflammation or neoplasia involving the prostate gland or anal sacs. Impaction with foreign bodies, such as hair or fine bones in the colon or rectum, or the result of stenosis caused by tumors or strictures, is less common. Colonic obstipation also may be associated with trauma to the pelvic area or spinal cord; it is described in Manx cats because of sacral spinal cord anomalies. Megacolon ensues if the obstruction persists; however, in small animals megacolon is frequently idiopathic. Examination of the syndrome in cats reveals no histologic abnormalities and it is suggested that the underlying problem is a disturbance in the activation of smooth-muscle myofilaments. Impaction of the cecum or colon in horses occur mostly where the lumen narrows at the pelvic flexure and transverse or small colon. Impaction may be precipitated by water deprivation, a dietary change to rough hay or chaff, or poor dentition; recurrent impaction is seen in animals with dental problems. Abnormal motility resulting from altered colonic or cecal peristalsis may explain impaction in the absence of other predisposing causes and is discussed later with pseudoobstructions of the gut. Ingestion of indigestible synthetic fibers has been associated with colonic impaction. In horses grazing poorly covered sandy soils, sand may cause chronic colitis and diarrhea or it may sediment, accumulate, and cause impaction at any level of the large or small colon. Sand impaction in horses is often associated with concurrent displacement or torsion. Ingestion of large numbers of acorns and leaves may also cause impaction of the intestinal tract in ruminants. Rupture of the bowel may occur if impactions are not treated, and the bowel wall becomes ischemic and devitalized.
Cecal rupture in horses occurs as a complication of impaction, or of parturition in mares. Two distinct forms of cecal rupture are described. In type 1, the cecum is filled with firm dehydrated food, whereas in type 2, the cecum is distended with more normal digesta, often with increased amount of fluid. Type 2 is considered a rare complication of general anesthesia or administration of NSAIDs, and is thought to be due to dysfunctional motility.
Compression of intestine causing obstruction is rather common and is caused by tumors, abscesses, peritonitis, and fibrous adhesions. Neoplasms involve the intestine by extension from adjacent viscera, particularly the pancreas. Many abdominal tumors involve the craniodorsal part of the abdominal cavity moist with a velvety and occasionally convoluted surface. Response to medical therapy and dissolution of phytobezoars has been reported in horses. Hairballs (trichobezoars) sometimes occur in dogs, cats, and ruminants; in ruminants they occur mostly in the forestomachs ( Fig. 1-44 ) and abomasum but can also cause small intestinal obstruction. Enteroliths and bezoars in horses are often insignificant; apparently they are moved about by peristalsis and are passed in the feces. They may obstruct the gut if they become impacted, usually where season and the gastrointestinal tract is most affected. Grass sickness can occur acutely as colic, tympany, and drooling with rapid progression and is nearly always fatal, usually within 7 days. The condition can also occur as chronic colic of >7 days duration, usually characterized by weight loss or dysphagia. Horses with this form may survive with appropriate management. In acute cases, postmortem findings include gastric and small intestinal distention; often there is esophageal ulceration caused by reflux. In chronic cases gross lesions are often not present except for marked emaciation. There also may be impaction of the colon and cecum by dehydrated ingesta in cases of longer duration. Characteristic histologic lesions are present in the intestinal and extraintestinal autonomic ganglia and include chromatolysis, nuclear eccentricity, and karyorrhexis of nerve cell bodies of both peripheral and central neurons. Neuronophagia and the presence of smooth round eosinophilic bodies or spheroids within or adjacent to perikarya are also recognized. Significant inflammation is not evident. Lesions in several brainstem nuclei have been described, albeit inconsistently. The severity of lesions has been shown to correlate with decreased functional cholinergic responses. Diagnosis can be confirmed in live horses by histological evaluation of nerve cell bodies of the myenteric or submucosal plexus in surgically obtained ileal samples. Examination of the cranial celiaco-mesenteric ganglia, sympathetic thoracic chain, stellate and/or superior cervical ganglia provide confirmation of the diagnosis in dead horses. Clostridium botulinum has been suggested to play a role in equine dysautonomia, although this remains unconfirmed and it is not known if the presence of C botulinum type C and/or type C neurotoxin represents secondary bacterial overgrowth or the cause of this syndrome.
Feline dysautonomia, or Key-Gaskell syndrome, is an autonomic dysfunction of unknown etiology, most common in the United Kingdom and continental Europe, with sporadic cases reported elsewhere. A similar syndrome has also been reported in a few dogs and a llama. Cats <3 years of age seem to be preferentially affected. Signs include depression, anorexia, reduced lacrimation and salivation, bradycardia, mydriasis, delayed pupillary light reflex, megaesophagus, constipation, or ileal impaction. Diarrhea is reported in some dogs with dysautonomia. The gastrointestinal signs suggest disordered motility, and animals often succumb to the effects of regurgitation, inanition, or aspiration pneumonia, among other problems. Cases tend to occur in clusters, suggesting an environmental toxin or infectious agent. As for horses, exposure to Clostridium botulinum and type C neurotoxin has been hypothesized, although no conclusive etiologic associations have been made.
Involvement of functions of both sympathetic and parasympathetic divisions of the autonomic nervous system, and of some functions under voluntary control, is reflected in the distribution of neuronal lesions in autonomic ganglia. Cranial nerve nuclei III, V, VII, and XII, ventral horns of the spinal gray matter, and dorsal root ganglia may be involved. Chromatolysis-like lesions of affected neurons seen by light microscopy have a distinctive ultrastructural appearance in dysautonomia: autophagocytic vacuoles, dilated cisternae, and complex stacks of smooth endoplasmic membranes are in the cytoplasm of affected cells. Neuronal lesions including neuronal loss may be transient and difficult to confirm histologically.
Intrinsic disease of intestinal smooth muscle may produce a syndrome of intestinal sclerosis, resembling progressive and thus cause compression of the duodenum. Peritoneal adhesions are common, and fibrous bands may stretch from the wall of the bowel to some fixed point, or between two or more points along the bowel or mesentery. In these cases, obstruction develops gradually as fibrous tissue contracts and restricts or adheres the bowel to itself or other abdominal structures. Large firm masses of abdominal fat necrosis cause extrinsic obstruction of small intestine, spiral colon, or descending colon and rectum of cattle. Pedicles of some tumors, especially mesenteric lipomas in older horses, occasionally entrap loops of intestine causing obstruction and strangulation. Similarly, the ovarian suspensory ligaments may entrap the equine colon if the ovary is enlarged because of neoplasia or inflammation. Incarceration in hernias, discussed with other displacements of the bowel, is also a common cause of extrinsic obstruction of the gut.
Adynamic (paralytic) ileus is itself not of specific interest to the pathologist but is a rather common condition. It frequently follows abdominal surgery, especially when the intestines are handled roughly or traumatized. It also is associated with peritoneal irritation of any cause, especially peritonitis. It is the result of neurogenic reflexes that interfere with control of the inhibitory neurons of the myenteric plexus. Continual tonic discharge by these neurons inhibits contraction of circular smooth muscle and prevents peristalsis. Grossly, the intestines are distended with a mixture of gas and fluid, and the wall is flaccid. The defect may be segmental, involving short lengths of the intestinal tract, but many such segments may be involved, especially in diffuse peritonitis. Idiopathic gastric or intestinal ileus may be more common in horses during the postparturient period, and acute colic and gastric rupture may occur in this species as a complication.
Pseudo-obstruction, a clinical syndrome described mostly in dogs, in which there is no physical occlusion of the lumen of an impacted intestine, may result from segmental or diffuse neuromuscular dysfunction in the gut. In humans, pseudoobstruction is classified as failure of nervous or muscular components of the intestine. In dogs, fibrosis and cellular infiltration of the tunica muscularis are the most commonly described lesions leading to pseudo-obstruction. In addition to equine congenital aganglionosis discussed previously, pseudoobstruction associated with neuronal loss or ganglioneuritis involving autonomic ganglia in the gastrointestinal tract, systemic dysautonomia, and intrinsic disease of intestinal smooth muscle are recognized among domestic animals. A segment of contracted or thickened bowel may be noted as a cause of obstruction; in neurogenic disease, the affected bowel is often dilated, flaccid and unable to maintain tone.
Megacolon in Clydesdale foals associated with hypoganglionosis of the myenteric plexus has been reported in 4-9 month foals from the United States and Australia. The timing of clinical onset of these cases suggests an acquired condition; however, the common breed suggests a genetic basis for the syndrome. The pathogenesis of the condition remains unknown. Some variation in neuron density of the dorsal colonic myenteric plexus has been reported.
Grass sickness in horses, the prototypic dysautonomia in domestic animals, occurs chiefly in parts of the United Kingdom, western Europe, and southern South America where it is known as mal seco. The disease more commonly affects young horses with pasture access during the spring An increase in the concentration of dissociated volatile fatty acids, especially butyric acid, causes atony of the cecum, and dilation follows. Cecal dilation occurs more often in cattle that are not receiving mineral supplements and in one study hypocalcemia was found in 85% of cases of cecal dilation. Although it has been suggested that calcium deficiency may cause cecal dilation, this has not been proved and it is not clear whether hypocalcemia is the cause or a result of cecal dilation. Once the cecum is dilated and distended with watery digesta, various degrees of clockwise or counterclockwise rotation can occur, which may incorporate adjacent terminal ileum or proximal colon.
In horses, cecal and colonic tympany has a similar pathogenesis. Readily fermentable carbohydrate, following a sudden change in feed, results in an increase in volatile fatty acid production, which exceeds the buffering and absorptive capacity of the organ. As the pH drops, and fermentation shifts to production of the less well-absorbed butyric and lactic acids, water is drawn into the lumen by the osmotic effect. The large bowel dilates with fluid digesta and gas, and motility is reduced by the effects of the volatile fatty acids. Severe abdominal distention, compression of intra-abdominal organs, reduced cardiac return caused by postcaval compression, and reduced respiratory capacity resulting from compression of the diaphragm may follow, with attendant severe pain. Death caused by hypovolemia and acidosis may occur before the large bowel ruptures. In recovered horses, laminitis may occur because of absorption of endotoxin through the cecal mucosa, which becomes eroded and permeable as a result of local acidosis.
The large colon of the horse is comprised of a loop of capacious bowel joined along its length by the short mesocolon, and folded upon itself at the sternal, pelvic, and diaphragmatic flexures. The loop is only fixed at its base, by the cecum, the transverse colon, and mesenteric root. Its volume and lack of attachment make the large colon prone to displacement or torsion.
Right dorsal displacement of the colon involves displacement of the left segments of the large colon to the right of the cecum. This occurs when the large colon pelvic flexure moves under or around the cecum (clockwise in the standing animal viewed from above), ending up located between the cecum and the right abdominal wall. Consequently, when the carcass is opened from the right side of the body, the left colons are visible first. It presumably results from displacement and wedging of the large colon because of tympany. This displacement is usually preceded by impaction of the pelvic flexure, which then is bent to the left and migrates cranially in the abdomen coming to rest close to the sternum. This is termed right dorsal displacement with flexion. Alternatively, the left colon may move in the opposite direction, caudal and to the right of the base of the cecum, with the pelvic flexure again lying at the sternum. This is termed right dorsal displacement with medial flexion. Some degree of torsion may also occur, and obstruction, with mild to severe colic, ensues. Surgery is required to correct the displacement.
Left dorsal displacement of the colon, variously known as entrapment of the colon by the nephrosplenic, renosplenic, or phrenicosplenic ligament, or by the suspensory ligament of the spleen, is also encountered as a cause of obstruction and colic in horses ( Fig. 1-45) . The left dorsal and ventral large systemic sclerosis or scleroderma of humans. In dogs the lesions are restricted to the intestinal tract, where there is diffuse dilation of the small and large bowel. Histologically, mononuclear inflammatory cells infiltrate the smooth muscle of the bowel wall; also there is atrophy of myofibers and fibrosis. Fibrosis of the small intestinal submucosa has also been reported in horses, and in some cases there is arteriolosclerosis. The cause is unknown, although geographical clustering of cases is described.
Eventration is displacement of a portion of the gut, usually the small intestine, outside the abdominal cavity, and it has been described in most domestic animal species. This is commonly congenital or predisposed by a congenital anomaly, as in schistosomus reflexus, patent umbilicus, and congenital diaphragmatic hernia. Acquired eventrations result from trauma, and therefore are varied. The displaced intestine herniates into the abdominal muscle or subcutis, or it may be completely exteriorized. Vaginal eventration may occasionally occur in females following trauma. Diaphragmatic eventration may occur as a consequence of diaphragmatic rupture or malformation.
In ruminants, cecal dilation and torsion is an uncommon condition. It mainly occurs in animals fed high-concentrate rations, but it has been associated with late gestation and ileus from other causes. It usually occurs within 2 months postpartum in cattle. It is rare in other ruminants. About 30% of the carbohydrates in the ration are digested in the cecum of ruminants. Sudden change from a roughage to a grain-based ration results in an increase in the concentration of volatile fatty acids, with only a slight decrease in pH of the cecal contents.
Herniation through a natural foramen occurs mainly in horses. In incarceration in the epiploic foramen, a portion of small intestine, usually distal jejunum and ileum, may pass down into the omental bursa and become incarcerated, if the normally short and slit-like epiploic foramen of Winslow is dilated for any reason. In these circumstances, the wall of the omental bursa often ruptures.
Omental hernia occurs when a loop of intestine passes through a tear in the greater or lesser omentum. Mesenteric hernia is the result of passage of intestine through a tear in the mesentery. These are probably traumatic defects and usually involve the mesentery of the small intestine, but occasionally, that of the colon.
Pelvic hernia occurs in young ruminants, and rarely in other species, following castration. During the operation, excessive traction on the spermatic cord may tear the peritoneal fold of the ductus deferens, which fixes the duct to the pelvic wall. A hiatus is formed between the ductus deferens and the lateral abdominal or pelvic walls through which loops of intestine may become incarcerated.
Gut may also become incarcerated by passing through lacerations in the lateral ligament of the bladder, or through entrapment by the remnant of a persistent urachus, by the gastrosplenic ligament, and by mesodiverticular or vitelloumbilical bands in the horse.
External hernia typically consists of a hernial sac formed as a pouch of parietal peritoneum; a covering of skin and soft tissues; depending on the location of the hernia, a hernial ring; and the hernial contents. The hernial ring is an opening in the abdominal wall, and this may be acquired, or it may be natural as, for example, the vaginal ring at the inguinal canal. The hernia usually contains a portion of omentum, a colon move laterally and dorsally between the spleen and the left body wall, and become entrapped, with the spleen to the left and below, the suspensory ligament of the spleen below, the left kidney on the medial aspect, and the abdominal wall dorsolaterally. As the colon becomes entrapped it rotates along its axis with the result that the ventral colon lies dorsally and the dorsal colon lies ventrally. The colon caudal to the entrapment may become curved cranially, with the pelvic flexure rotated through 180 o because of tension on the taeniae. If the weight of the displaced colon is supported by the nephrosplenic ligament, the spleen may move away from the left body wall. The weight of the colon may also compress the splenic vein causing splenic congestion. Compression of the colon at the point of entrapment can cause impairment of the flow of ingesta, local bruising or edema and partial ischemia of the displaced organ, and results in partial or complete impaction. If the gut remains patent, clinical signs are intermittent. The cecum and small intestine may be distended as a result of the colonic obstruction. The cause of left dorsal displacement is unknown, but may be related to an anatomic predisposition resulting from a large cleft between the spleen and the left kidney.
Colonic volvulus is one of the most common and grave colic causes in horses. The loop of large colon, with or without the cecum, may rotate around itself at some point along its length, or around the root of the mesentery. The condition is lifethreatening because of severe vascular embarrassment, and is discussed further under the section Intestinal ischemia and infarction.
This is a displacement of intestine through normal or pathological foramina within the abdominal cavity without the formation of a hernial sac. It is uncommon.
inguinal ring and canal, through which the omentum and the uterus may pass. The herniated uterus may become incarcerated when pregnant, or if pyometra develops. In horses, indirect inguinal hernias may rupture through the inguinal canal, coming to rest in a subcutaneous location. These ruptured indirect hernias have a similar prognosis as the direct inguinal hernias described previously. Femoral hernias develop as an outpouching of peritoneum through the femoral triangle along the course of the femoral artery. They contain omentum and small intestine.
Perineal hernias occur principally in old male dogs in association with prostatic enlargement and obstipation. They are precipitated by abdominal straining and are probably predisposed to by weakening of perineal fascia and muscles from some unknown cause, possibly hormonal. They are very unusual in females. Retroperitoneal pelvic fat bulges through a defect between the coccygeus medialis muscle and the cranial border of the anal sphincter. Usually this is the only tissue to prolapse, and the lesion consists, essentially, of a loss of support on one side of the anal ring. Concomitant with the loss of pelvic support the rectum deviates, and the prostate and the bladder may move into the pelvis. Further displacement may occur occasionally and then the latter organs are forced through the ruptured perineal fascia, causing acute urethral obstruction. Perineal hernias are most commonly unilateral, but bilateral hernias may occur.
Diaphragmatic hernias are common. The defect in the diaphragm may be congenital, but most often it is acquired, generally as the result of increased abdominal pressure. Although abdominal viscera pass into the thoracic cavity, strangulation of displaced gut is rare. Acquired diaphragmatic hernias are considered more fully in the section Traumatic lesions of the abdomen and peritoneum.
Prepubic hernias occur in small animals, usually associated with severe trauma to the caudal abdomen that produces rupture of the prepubic tendon.
The sequelae of hernias depend largely on their location and content, but some generalities apply to all. As long as the hernial contents remain freely movable and reducible, there may be no untoward sequelae. Fixation of the hernial contents (incarceration) is a serious development. Incarceration may result from stenosis or tension of the hernial ring, adhesion between the contents and the sac, or distention of the herniated viscus. This distention may be due mainly to mural congestion and edema in any incarcerated viscus, accumulated gas or ingesta in the intestine, urine in a herniated bladder, and fetuses or pus in a herniated uterus. Incarcerated intestine may become obstructed, or undergo ischemic necrosis and perforate, causing peritonitis. Small intestine fixed by incarceration may be predisposed to volvulus. freely mobile portion of the intestine and occasionally, other viscera. Ventral hernia of the abdominal wall occurs uncommonly in horses, rarely in cattle, and exceptionally in other species, except perhaps following blunt trauma or biting injuries in small animals. These hernias through the abdominal musculature into the subcutaneous tissue, may be spontaneous in heavily pregnant females, especially older animals, or be a consequence of blunt trauma, bite wounds, horn injuries, surgical scars, or inflammations, which cause weakening or perforation of the muscle. In pregnant mares, they often occur in the lower flank lateral to the mammae, where there is only a single layer of muscle, the transverse abdominal. They may become very large in herbivores because of the weight of the alimentary viscera and pregnant uterus. The lesion must be differentiated from rupture of the prepubic tendon, and from postmortem rupture of abdominal muscle in bloated animals.
Umbilical hernia is common and is often present as a congenital and perhaps inherited defect. It is most frequent in pigs, foals, calves, and pups and depends on persistent patency of the umbilical ring. It is the most common congenital defect in cattle and has a hereditary component in the Holstein and probably other breeds. In calves it is also significantly predisposed by umbilical infection. The hernial sac is formed by peritoneum and skin; the contents depend on the size of the ring and of the sac. Incarceration of enclosed intestine is uncommon. Formation of an enterocutaneous fistula, a rare complication of umbilical hernia, is seen most frequently in the horse.
Inguinal hernia may evolve to scrotal hernia when the herniated viscera pass down the inguinal canal. The internal, or deep, inguinal ring remains patent in intact male animals, but its diameter and the tendency to herniation in the neonate may be inherited. Inguinal hernias are classified as direct or indirect.
In direct inguinal hernia, which is less common, abdominal contents pass through the internal inguinal ring and come to rest in a subcutaneous position, through a tear in either the peritoneum or the fascia around the deep inguinal ring. This is most commonly seen in foals and is thought to result from increased intra-abdominal pressure during passage through the birth canal. These direct inguinal hernias often cause necrosis of overlying skin, can become fixed by adhesions and strangulate. They are life threatening.
Indirect inguinal hernias, by contrast, consist of abdominal contents contained within the tunica vaginalis. These are by far the most common form, occurring as a congenital problem in the young of many species, and as an acquired problem in older animals. Although size of the inguinal rings may be a factor in neonates, there is usually no apparent cause in acquired cases. The herniated viscus passes through the inguinal and vaginal rings within the vaginal sheath, coming to lie in the scrotum inside the cavity of the tunica vaginalis. If the hernia is scrotal, there may be degeneration of the testicles. Routine castration of such animals can lead to eventration through the scrotal incision, and closed castration may cause infarction of the herniated loop of gut.
Congenital inguinal hernia is rare in dogs; West Highland Whites, Pekingese, and Basenjis may be predisposed, and it is more common in males than females. However, overall, inguinal hernia is much more common in female dogs. The bitch differs from females of other species in having a patent after 1 hour. However, by 3-4 hours, crypt epithelium is becoming necrotic, dissociating and exfoliating, and from that point events progress as in the small intestine.
Reperfusion injury, superimposed on the effects of ischemia alone, may enhance the severity of the lesion, if hypoxia is only partial or ischemia is transient, and reflow of blood raises the tissue oxygen tension. Reperfusion injury implies that the effects of the hypoxic episode have not progressed to complete necrosis of the mucosa, and that further damage is possible because of oxygen free radicals and/or cytokines. Hence, there is a relatively short duration of hypoxia, and a concomitant mild-to-intermediate degree of mucosal damage, permissive of this phenomenon. In cases of enteric ischemic disease encountered in veterinary medicine, this threshold may frequently have been crossed by the time that the animal is presented for therapy. In addition, there is evidence that in swine and in horses, where intestinal ischemic events are most common, reperfusion injury is less likely to occur than in other species. Because reperfusion injury may cause necrosis and/or apoptosis, it is almost impossible to differentiate morphologically the changes produced by ischemia from those of reperfusion injury.
Reperfusion injury is the result of the interplay among free-radical-mediated damage to the microvasculature and probably stromal elements and epithelium; neutrophil margination and diapedesis into tissue; complement activation; and release of proinflammatory proteins and cytokines, some of which may have systemic effects.
Free radicals in reperfusion injury are largely generated through xanthine oxidase mechanisms in the intestinal mucosa, and through NADPH oxidase mechanisms in leukocytes, mainly neutrophils, already resident in or recruited to the damaged tissue. Hypoxia stimulates the conversion of xanthine dehydrogenase to xanthine oxidase in epithelial cells.
In the presence of xanthine oxidase, hypoxanthine accumulating from adenosine triphosphate degradation in hypoxia is converted to xanthine, and molecular oxygen is reduced, generating hydrogen peroxide, superoxide radical and hydroxyl radical intermediates, which inhibit the accumulation of protective nitric oxide. The hydroxyl radical is likely most significant in damaging proteins and initiating a cascade of lipid peroxidation, resulting in metabolic and structural lesions and culminating in cell death.
The acute inflammatory response that accompanies reperfusion results in production of free radicals by the respiratory burst from neutrophils, release of proteolytic enzymes, and physical impairment of the microcirculation. Reduction in tissue nitric oxide permits dismutation of oxygen free radicals to H 2 O 2 , which promotes activation of phospholipase, accumulation of proinflammatory mediators, and production of cytokines (tumor necrosis factor-α and -β, interleukins) and adhesion molecules by endothelium. Complement activation is mediated by adhesion molecules, promoting inflammatory events and release of cytokines such as tumor necrosis factor-α and interleukin-1, as well as other cytokines that increase during reperfusion.
Sequelae of ischemia vary with duration and severity of insult. Short-term ischemia (maximally, ~3-4 hours), with preservation of at least the base of the crypts of Lieberkühn, will permit repair, as cells proliferating in the crypts re-epithelialize the mucosal surface within 1-3 days. Normal architecture is re-established after up to 1-2 weeks, although necrotic muscularis mucosae is not replaced. Effusion of tissue fluid and
Inadequate or interrupted circulation of blood to the gut is a common problem, particularly in the horse. Obstruction of the efferent veins, blockage of afferent arteries, and reduced flow through an open circulation cause hypoxic damage to the intestine. Whatever the initiating cause, the effect of hypoxia at the level of the mucosa is similar.
In the small intestine, within 5-10 minutes of the onset of ischemia, changes are observed at the tips of villi in tissue sections examined under the light microscope, and lesions are well advanced by 30 minutes. Separation of the epithelium from the basement membrane, beginning at the tip of the villus and progressing toward the base, causes the formation of the so-called Gruenhagen's space. Epithelial cells appear relatively normal, and may separate from the villus in sheets. The core of the villus contracts toward the base. Within 1-3 hours, the villus is almost completely denuded of epithelium, and the mesenchymal core is disintegrating or collapsed and stumpy, with hemorrhage from capillaries. Superficial epithelium may persist for several hours in the crypts of Lieberkühn.
That this lesion is largely a function of hypoxia is indicated by the mitigating effects of intraluminal perfusion of oxygenated saline demonstrated experimentally in dogs and cats. The putative countercurrent exchange of oxygen between the afferent arteriole and efferent venules in the villus, and an associated progressive decline in oxygen tension distally in the villus, may render the tip prone to early damage in hypoxia. Villus smooth-muscle contraction, exacerbating the epithelial exfoliation on the distal villus, may be mediated by sympathetic stimulation in ischemia.
Dissociation and necrosis of cells in the crypts of Lieberkühn begin ∼2-4 hours after the initiation of ischemia, and within 4-5 hours the epithelium appears completely necrotic or has sloughed, leaving a mesenchymal ghost of the mucosa. The muscularis mucosae may undergo necrosis, but the muscularis externa remains viable for 6-7 hours. During acute ischemia, there is initial hyperexcitability of muscle in affected areas, followed by progressive loss of contractility, which will fail to recover if ischemia persists beyond 4-6 hours. Mesothelial cells on the serosa undergo necrosis within 30-60 minutes of ischemia, and exfoliate; there is a local acute inflammatory response, which may predispose to the development of adhesions. The speed with which lesions develop in hypoxia emphasizes the significance of rapid fixation of intestinal mucosa if artifact is to be avoided. Differentiation between post mortem autolysis and necrosis can be particularly challenging in the intestine. A few useful hints to help determining autolysis versus necrosis include hemolysis of red blood cells, large numbers of rods within blood vessels and tissues not associated with inflammation, gas bubbles in the tissues and desquamation of slabs of epithelial cells.
The colon of the dog and horse seems less sensitive to short-term ischemia than the small intestine. Mild morphologic damage, characterized by mild edema, and separation and exfoliation of surface epithelium between crypts, is found lumen of the stagnant ischemic area, with accumulation of gas, and extreme distention of the closed loop in strangulation obstruction. Toxin production by anaerobes, particularly clostridia, plays a large part in gangrene and ultimate rupture of ischemic gut, as well as having systemic effects. Absorption of endotoxins and exotoxins from the lumen may occur through devitalized mucosa via the portal flow, lymphatic return, or peritoneum. Toxins have a severe detrimental effect on cardiovascular function, contributing to circulatory failure. If death from some other cause does not supervene, transmural invasion by enteric bacteria or perforation of the devitalized wall results in septic peritonitis that is ultimately fatal.
Obstruction of efferent veins is by far the most common cause of intestinal ischemia. This is a sequel to incarceration of herniated loops of bowel; strangulation by pedunculated masses, such as lipomas in older horses; torsion (twist about the long axis of the viscus); volvulus (twist of the intestine on its mesenteric axis ); and intussusception. In these circumstances, compression of thin-walled veins tends to occur before the influx of arterial blood is obstructed.
In venous infarction, the affected tissue field, often including involved mesentery, becomes intensely edematous, congested, and hemorrhagic, so that the hypoxic bowel wall is thickened and eventually assumes a deep red-black appearance ( Fig. 1-47 ). It has been estimated that 40 liters of fluid may accumulate in the wall of a horse colon that has undergone volvulus. Bloody fluid content and gas distend the lumen of the infarcted segment. As gangrene of the intestinal wall proceeds, the tissue becomes green-black, and septic peritonitis eventually ensues, with or without perforation of the bowel. Advanced venous infarction involves the full thickness of the intestinal wall, and the initiating intestinal accident is commonly evident, except in cases subjected to surgery. Even if a displacement has been reduced, the limits of the infarcted segment are usually relatively sharply demarcated, and the acute inflammatory cells prevails until epithelium extends to cover the eroded surface fully. Partial damage to the proliferative compartment initially results in dilation of crypts, which are lined by flattened epithelium resembling that seen after radiation injury. If the amplifier population of progenitor cells can be regenerated, hyperplastic basophilic cells will populate crypts until the mucosal architecture is reconstituted ( Fig. 1-46) .
Ischemic necrosis of the full thickness of the mucosa will be bounded by an acute inflammatory reaction in the submucosa, which, under favorable conditions, evolves into a granulating ulcerated surface. Focal ulcerative lesions may ultimately heal by epithelial migration over the bed of granulation tissue from surviving crypts within the lesion and around the periphery.
Extensive mucosal ulcers that form following severe ischemia have little chance of resolution, owing to their large surface area. Chronic ischemic ulcers in the small bowel tend to develop a depressed, fairly clean granulating surface, occasionally with some fibrinous exudate.
Ischemic ulcers in the large bowel, especially of horses, develop a dirty yellow-gray fibrinonecrotic surface. If the animal does not succumb to the effects of malabsorption and protein loss from the defect, or to transmural bacterial invasion, scarring and stricture may occur. The sequelae of ischemia with reflow are mainly seen in strangulated segments of gut that have been reduced without resection, or with inadequate resection, and in some cases of presumed thromboembolic infarction of the equine colon.
Persistent ischemia results in necrosis involving all mural elements. The full thickness of the gut wall ultimately becomes necrotic, green-brown or black, flaccid, and friable.
The consequences of ischemic lesions are partly a function of the species, and of the level of bowel affected. Strangulation, volvulus, and similar lesions cause physical obstruction at the site, and ileus proximal to it. Reduced arterial perfusion or thromboembolism causes functional obstruction and ileus. Loss of mucosal integrity results in cessation of electrolyte and water absorption, and ultimately in effusion of tissue fluid and blood into the lumen. Proliferation of anaerobes occurs in the and eventually endotoxemia. Part of the cecum may be incorporated in the volvulus. The equine cecum alone rarely undergoes torsion, and if so, it may be related to hypoplasia of the cecocolic fold. At surgery or autopsy, the usual signs of strangulation obstruction are evident, including dilation and devitalization of the infarcted segment and distension of the cecum if it is not twisted. Postmortem rupture of the diaphragm or abdominal wall may occur because of tympany.
Duodenal sigmoid flexure volvulus is a recently described and unusual lesion of adult dairy cattle. The sigmoid flexure of the duodenum is first displaced in a dorsolateral direction, and then rotates about its omental attachment causing obstruction of the proximal small intestine and the common bile duct. The cause is unknown but this condition has been associated with prior surgical correction of a displaced abomasum.
Intussusception involves the telescoping of one segment of bowel (the intussusceptum) into an outer sheath formed by another, usually distal, segment of gut (the intussuscipiens) ( Fig. 1-48 ). Any level of the gut with sufficient mesenteric mobility may be involved. The naming convention is that the intussusceptum is followed by the intussuscipiens; hence an ileocolic intussusception is a normograde intussusception in which the ileum has invaginated into the colon.
The cause is usually not apparent, although linear foreign bodies, heavy parasitism, previous intestinal surgery, enteritis, and intramural lesions such as abscesses and tumors may be associated. It also may be a terminal, agonal, or postmortem event. The history is that of partial or complete intestinal obstruction, perhaps with bloody feces, and it is most common in young animals.
Intussusception is common in dogs, in which most frequently it is ileocolic. It is much less common in cats. Intussusception is also moderately common in lambs, calves, and young horses, where it may involve small intestine, cecum, and colon.
The progressive invagination of the leading edge of the intussusceptum into the distal segment results in the wall of the intussusception being comprised of 3 layers: (1) the inner entering, (2) middle returning, segment of invaginated bowel, and (3) the outer wall of the receiving segment of gut. It is affected bowel remains edematous and hemorrhagic. Microscopically, severe transmural edema, congestion, distention of veins, sometimes venous thrombosis, and hemorrhage are present, initially most severe in the mucosa and submucosa. With time, the full thickness of the mucosa becomes necrotic, and the deeper layers of the muscular wall are also devitalized, with invading enteric flora present throughout. Lesions that have advanced to significant necrosis or effacement of the crypt epithelium are associated with failure of the animal to survive, resulting from either euthanasia on the grounds of the degree of damage, or systemic complications despite correction of the strangulation, or resection.
Displacements of intestine that may progress to incarceration or volvulus with strangulation and infarction have been discussed in the previous section. They are a common cause of colic and mortality in horses.
Mesenteric volvulus (often referred to as "mesenteric torsion") occurs commonly in suckling ruminants and in swine, uncommonly in horses, and rarely in cats and dogs. The abdomen is distended and, upon opening the cavity, tensely dilated deep red-to-black loops of bowel are usually immediately apparent.
In swine the mesentery of the small intestine and sometimes the large bowel is involved in a volvulus that is usually counterclockwise, when viewed from the ventrocaudal aspect. In volvulus involving the small and large intestines, the apex of the cecum may be pointing cranial in the cranial left quadrant of the abdomen, reflecting the rotation of ∼180 o . In swine, mesenteric volvulus may be due to gas production from a highly fermentable substrate in the colon, and its subsequent displacement, with progression to mesenteric volvulus. Mesenteric volvulus is a common cause of sporadic sudden death in swine but may occur as a recurrent problem in a herd. Many cases of intestinal hemorrhage syndrome in that species are probably misdiagnosed mesenteric volvulus.
Death caused by mesenteric volvulus is common in suckling or artificially reared calves and lambs. In these species, vigorous ingestion of large amounts of feed over a short period may predispose to gas formation in the gut, or perhaps hypermotility, which induces volvulus. Usually only the mucosa of the proximal duodenum and terminal ileum, cecum, and colon is spared from infarction, although occasionally volvulus is restricted to shorter segments of intestine. Similar lesions are occasionally encountered in other species.
In dogs, volvulus has been associated with ingestion of large quantities of food, and with exocrine pancreatic insufficiency in German Shepherds. It is occasionally accompanied by gastric volvulus.
Volvulus of various lengths of the small intestine may occur in any species, but is perhaps most prevalent in the horse, where it is a common cause of strangulation obstruction of the bowel.
The large colon of the horse is predisposed to volvulus by its lack of mesenteric anchorage, and potential mobility. Although frequently referred to as large colon torsion, this condition is a true volvulus, because the twist involves the mesentery between the ventral and dorsal colon at the level of the ceco-colic mesentery. The volvulus begins with the right ventral colon rotating medially and dorsally (clockwise as seen from behind); the severity of the rotation can vary between 270 o and 720 o . If the twist exceeds 360 o , there is obstruction of the lumen of the colon with subsequent accumulation of gas, ischemia of the majority of dorsal and ventral colon wall and occasionally transmural focal or segmental infarctive lesions are seen in Pasteurella septicemia in lambs and in Histophilus somni bacteremia in cattle. Most cases of embolic disease are associated with bacterial infections that cause softening and lysis of thrombi and facilitate formation of emboli. This is particularly true for the lesions associated with strongyle migrations in horses, in which lesions remain localized unless thrombi induced by the parasite become secondarily infected.
In horses it is associated with endoarteritis, mainly at the root of the cranial mesenteric circulation, caused by migrating larvae of Strongylus vulgaris (see Vol. 3, Cardiovascular system). Effective worm control programs have rendered this problem increasingly rare.
Candidates for a diagnosis of nonstrangulating infarction are animals in which the anatomic distribution of an ischemic lesion is incompatible with volvulus or other strangulation, or physical evidence for incarceration or strangulation obstruction is not present in the surgical history or at autopsy, and there is evidence of verminous arteritis. Careful consideration should be given to the fact that verminous arteritis can be present in horses without embolic intestinal lesions. Therefore the presence of the former does not definitely prove that intestinal infarction was produced by verminous arteritis. Typically, ischemic lesions of this type are limited to the "watersheds" at the periphery of the colic and cecal arterial circulatory fields-the pelvic flexure and the distal cecumbecause collateral circulation within these circulatory fields is extensive.
Lesions limited essentially to the mucosa usually appear to be subacute, the result of ischemia of relatively short duration, and are ulcerative or fibrinonecrotic, usually with a hyperemic margin. They may be tens to many hundreds of square centimeters in area.
Transmural lesions represent ischemia of longer duration. Devitalized gray-brown intestine of normal thickness is interpreted to represent arterial obstruction without significant reflow, except along the boundary with viable tissue. Large edematous, congested, or hemorrhagic, full-thickness lesions, physically or anatomically inconsistent with strangulation, are interpreted as severe arterial obstruction, with subsequent reflow either by relief of the obstruction or by way of collaterals. Ischemic damage to vessels of the mucosa, submucosa, and perhaps deeper structures results in hemorrhage and edema when blood flow returns ( Fig. 1-50A ). Ulcerative or fibrinonecrotic mucosal lesions are probably the result of transient ischemia with subsequent reflow (Fig. 1-50B ). Similar lesions may occur after relief of strangulation of short duration, and in NSAID drug toxicosis, salmonellosis, and infections by C. difficile or C. perfringens type C, all of which involve, in part, mucosal microthrombosis.
Ischemia caused by reduced perfusion of the intestinal vascular bed is a difficult and uncommon diagnosis. Circumstances in which it may be expected to occur include severe hypovolemic states, such as hemorrhagic shock in the dog, cat, and possibly other species; in animals, particularly dogs, with disseminated intravascular coagulation (DIC); in dogs with hepatic disease and portal hypertension; in hypotensive shock caused by heart failure; and in animals with reduced mesenteric arterial perfusion, mainly horses with severe verminous endoarteritis. limited in length by the increasing tension on the mesentery drawn into the lesion, to ∼10-12 cm in small animals, and ∼20-30 cm in large animals. This tension along one edge of the gut may cause the mass to become bowed or spiraled.
Tension and compression of mesenteric veins cause the intussusceptum, or a portion of it, to undergo venous infarction. It swells with edema and congestion, and the adjacent apposed serosal surfaces become adherent as fibrin and inflammatory cells effuse from the affected bowel. Adhesion quickly renders the intussusception irreducible. Necrosis and gangrene of the invaginated intestine usually develop, but sometimes the intussusceptum sloughs, and the remaining viable segments maintain continuity of the gut, or rarely, form two adjacent blind ends. Intestine cranial to the obstructing intussusception may be dilated, and that distal contracted and devoid of content. If obstruction is chronic or partial, there may be hypertrophy of the smooth muscle of proximal bowel. In horses, chronic ileocecal intussusception involves a relatively short (<10 cm) length of bowel. Incidental terminal, agonal, or postmortem intussusception is recognized by the relative absence of congestion, edema, and adhesion of the involuted segment of gut.
Cecal inversion, and cecocolic intussusception in the horse, with inversion of the cecum into itself, or into the right ventral colon ( Fig. 1-49) , may result in ischemia of the cecum and possibly part of the involved colon; if partial, ischemia usually involves the more distal cecum. Cecocolic intussusception in horses has been associated with typhlocolitis caused by Salmonella spp., cyathostomiasis, or Anoplocephala perfoliata.
Segmental ischemic necrosis of the small colon may occur in pregnant or postpartum mares, because of mesenteric tension from intussusception and rectal prolapse of the distal large bowel, or perhaps because of laceration of the mesocolon and associated vessels by the feet of the foal during parturition. Colic, and intestinal obstruction, necrosis, rupture, and peritonitis may follow.
Ischemia of the gut caused by arterial thrombosis and embolism is rare in domestic animals other than the horse. Mucosal endotoxemia may contribute to mucosal ischemia by obstructing capillaries in the villi, and mucosal and submucosal venules. Microthrombi in these vessels in association with hemorrhagic mucosal necrosis suggest the possibility of ischemia caused by "slow flow." Transient or incomplete reduction in perfusion caused by obstruction of the arterial blood supply has a similar effect on the mucosa. The obstruction may be due to arteriospasm, perhaps induced by vasoactive mediators such as thromboxane. Mucosa devitalized by hypoxia will become hemorrhagic with continued blood flow. Because the primary problem may not involve a systemic state as complicated as severe shock, the animal may survive long enough to develop an effusive ulcerated or pseudomembranous mucosa, with some prospect of stabilization or repair, if the lesion is not widespread. "Slow flow" caused by reduced arterial perfusion with inadequate collateral flow may be expected to affect the "watershed" of a circulatory field preferentially. In the horse this may be the explanation for mucosal lesions at the pelvic flexure and apex of the cecum in which thromboembolism cannot be implicated, but in which mural thrombi in the cranial mesenteric root could have caused significantly reduced perfusion or flushed vasoconstrictive thromboxane into circulation.
Transient or noninfarctive "slow flow" has been proposed as a cause of intermittent colic resulting from verminous arteritis. It may also play a role in the development of functional obstruction and volvulus in horses with cranial mesenteric arterial lesions.
Ischemia at the periphery of the circulatory field of the caudal mesenteric artery may possibly predispose to rectal perforation in horses. The precarious perfusion of the mucosa at this site may contribute to ischemic ulceration and the development of rectal stricture in swine. In many cases this condition appears to be associated with Salmonella infection, and it is discussed further with porcine salmonellosis.
Acute acorn poisoning in the horse may cause severe gastrointestinal edema and focal hemorrhage, with infarction and ulceration in the cecum and colon. Microscopic lesions in the small and large intestine are consistent with an ischemic pathogenesis, and microthrombi have been associated with mucosal infarcts in the large bowel as well as in other organs.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause ulceration of the upper small intestine and colon, as well as oral and gastric ulceration, which seem to be related to ischemia, in horses and dogs. In horses, phenylbutazone, even at therapeutic dosages, can result in ischemic damage to the intestinal mucosa. It may be that intercurrent stress or dehydration contributes to the pathogenesis. The right dorsal colon is affected preferentially, resulting in the term right dorsal colitis; lesions in other parts of the colon also occur occasionally. The NSAID-associated lesions are characterized by ischemia, often with marked edema and avascular necrosis. Lesions may be focal, linear, or extensive and segmental, involving the entire circumference of the bowel (Fig. 1-51) . Depending on the duration and severity of the lesion, the mucosa may be congested and edematous, with superficial necrosis and fibrin exudation, or extensively eroded and ulcerated, with fibrinonecrotic exudate. Early in the process, superficial epithelial necrosis and progressive mucosal necrosis and inflammation are evident.
Microvascular injury, with subsequent microthrombosis and ischemic ulceration, is considered by some to be the cause of the lesions in the stomach and intestine. This
In "shock gut" in dogs, and rarely other species, associated terminally with heart failure, hemorrhage, hypovolemia, and DIC, part or all of the mucosa of the small intestine is deeply congested, and the content is hemorrhagic. The pathogenesis of the lesion is related to reflex vasoconstriction in the mucosa and submucosa, shunting of blood away from the mucosa, dilation of mucosal capillaries, and reduction in rate of flow of blood through the villus. Countercurrent transfer of oxygen from the afferent to efferent vessels in the villus aggravates hypoxemia in the villus by increased shunting of oxygen to the efferent venule. Splanchnic pooling of blood, systemic arterial hypotension, and intestinal vasoconstriction occur in endotoxic shock in dogs, causing similar mucosal lesions. Microthrombosis associated with sluggish flow, DIC, and
absolute increase in small intestinal bacterial numbers. SIBO is a recognized entity in humans occurring secondary to a number of underlying disorders including hypochlorhydria, exocrine pancreatic insufficiency, hypomotility, partial smallbowel obstruction, radiation injury, or impairment of systemic and local immunity. The existence of genuine bacterial overgrowth in animals remains controversial. Though cases of "idiopathic SIBO" have been described in young large-breed dogs, many of these have been responsive to antibiotic therapy, which supports a diagnosis of a similar condition antibioticresponsive diarrhea (ARD). This term is more appropriate in cases that respond clinically to antibiotics and where other conditions have been ruled out. Secondary SIBO, however, likely exists in dogs, and this term is best used in cases where such an initiating cause is documented. For SIBO and ARD, histologic examination of intestinal biopsies is often normal, other than the presence of bacterial colonies in mucus on the mucosal surface in some cases.
Intestinal lipofuscinosis (brown gut) in dogs is characterized grossly by tan-brown discoloration of the tunica muscularis ( Fig. 1-52) . It may involve any segment of gut, but is most commonly observed in the lower small intestine; the bladder and mesenteric or peripheral lymph nodes also may be affected. Although the lesion may be incidental, it is usually associated with chronic enteric and/or pancreatic disease. may be the result of direct phenylbutazone toxicity to the microvasculature.
Vasoconstriction or depression of other cytoprotective effects, mediated by phenylbutazone inhibition of prostaglandin synthesis, could be the cause of the lesions. Animals may develop diarrhea and hypoproteinemia as a result of the extensive mucosal defects. Minor mucosal lesions may resolve; a sequel to severe colonic damage in horses is colonic stricture.
Lesions in the oral cavity associated with NSAID administration are deep crateriform ulcers, with a clean granulating base. Concurrent with punched-out ulcers in the glandular mucosa, there may be chronic gastritis and atrophy of the mucosa with loss of differentiation of the cells in the fundus.
In the upper small intestine, ulcers may be focal, linear, or segmental and annular. Microscopic lesions that may precede ulceration of the small intestine include mild to severe atrophy of villi, epithelial necrosis, mucosal inflammation, and fibrin exudation. Renal papillary necrosis is often concurrent, if animals are dehydrated. intestinal wall, and they tend to follow the pathway of blood vessels and are mainly located adjacent to the mesenteric attachment.
Intestinal emphysema, or pneumatosis cystoides intestinalis, is a rare condition found mainly in weaned pigs, in which it is usually an incidental finding in slaughtered animals ( Fig. 1-54 ). It is characterized by numerous thin-walled, gas-filled cystic structures, a few millimeters to several centimeters in diameter, within the gut wall and on the serosal surface. These are mainly located in the small intestine, although the large intestine, mesentery, and mesenteric lymph nodes may be involved. Microscopically, the cystic structures appear to be dilated lymphatics that are located in the lamina propria, submucosa, muscularis, subserosa, mesentery, and mesenteric lymph nodes. A mixed cellular inflammatory reaction may be evident in the walls of the cysts. Although production of gas by bacteria has been implicated, the cause remains obscure.
Lipofuscinosis is reported in Boxer dogs with histiocytic ulcerative colitis, but a definitive correlation between the two conditions has not been established. Increased prevalence of lipofuscinosis has also been reported in dogs consuming high levels of polyunsaturated fats with a relative deficiency of vitamin E, and the condition is prevented by vitamin E supplementation. Any condition, such as exocrine pancreatic insufficiency, causing a reduction in the absorption of fats and fat-soluble vitamins, especially in the presence of polyunsaturated fatty acids in the diet, may predispose to lipofuscinosis.
The microscopic lesions of intestinal lipofuscinosis are gray-to-brown granules in the cytoplasm of smooth-muscle cells in the tunica muscularis; the reason they tend to accumulate here is unknown. The granules stain positive by periodic acid-Schiff and Sudan, are weakly acid-fast with Ziehl-Neelsen, and are mildly fluorescent in paraffin section. The granules, termed leiomyometaplasts, are oxidized polymerized phospholipids derived from cell membrane lipid peroxidation, and are highly resistant to further endophagocytic degradation. In Cocker Spaniel dogs affected with the inherited storage disease generalized ceroid-lipofuscinosis, intestinal lipofuscinosis is also observed, and is often accompanied by progressive hindlimb paresis and incoordination.
Muscular hypertrophy of the intestine was formerly a common finding in swine, but it appears to have diminished in prevalence in most areas. It may be found in apparently healthy animals at slaughter as a uniform thickening of the muscular coats of the terminal ileum. The most caudal ileal segment is involved, but it may extend a variable distance forward, usually 25-50 cm. The ileum is thickened and turgid; the lumen is small, the tunica muscularis is markedly thickened and the mucosa is folded. This condition must be differentiated from manifestations of enteropathy associated with Lawsonia in swine. Perforation or rupture of the intestine may occur in association with feed impaction in the hypertrophic segment; this may be a secondary to formation of pseudodiverticula, or as the result of violent peristalsis through the affected segment. Although the underlying basis remains obscure, it is likely that the muscular hypertrophy is secondary to a functional obstruction of the ileocecal orifice.
Idiopathic muscular hypertrophy of the small intestine also occurs in horses ( Fig. 1-53) . A similar lesion has been associated with Anoplocephala sp. tapeworms at the ileocecal orifice; however, this remains uncertain because many cases also show muscular hypertrophy of the terminal esophagus. The lesions are similar to those described in swine and the ileum is the most common site; however, any segment of the small intestine, and occasionally the large intestine can be affected. Horses with this condition may have chronic mild colic and anorexia or intermittent diarrhea with progressive loss of weight. Diverticula, and perforation or laceration of the thickened intestinal wall, also may occur.
Intestinal smooth-muscle hyperplasia has been described in a goat and, unlike the condition in horses and swine, only the jejunum was affected.
Pseudodiverticulosis of the small intestine is a rare lesion that is sometimes associated with muscular hypertrophy in pigs and horses. Single or multiple saccular dilations lined by intestinal mucosal epithelium are formed secondary to defects in the tunica muscularis and subserosa of the small intestine. Pseudodiverticula are distinguished from true diverticula, which are congenital defects involving all layers of the A study of a large number of cases of jejunal hematoma and normal cows did not find a statistically significant relationship between the isolation of C. perfringens, C. perfringens type A or the cpb2 gene and jejunal hematoma, strongly suggesting that C. perfringens is not associated with this condition. No association was found between jejunal hematoma and bovine viral diarrhea virus, Salmonella sp., or copper levels.
Intestinal encephalopathy with clinical signs and lesions similar to those traditionally seen in hepatic encephalopathy, has been described in horses without liver disease, but with colic and/or diarrhea preceding neurological signs. Because those horses had hyperammonemia, it was speculated that this was consequence of excessive production and absorption of ammonia in the intestine because of intestinal disease. Intestinal overgrowth of ammonia-producing bacteria may be responsible. An investigation of 13 documented cases of this syndrome did not find any breed, age or sex predisposition, and no specific diet could be found to be associated with these cases. As in cases of hepatic encephalopathy, the most common microscopic finding in the brain of horses with the disease is the presence of Alzheimer type II cells. Laboratory findings include hyperammonemia, metabolic acidosis, and hyperglycemia.
Rectal prolapse most commonly occurs in swine, sheep, and cattle. It may occur in any animal that has prolonged episodes of tenesmus or excessive coughing increasing abdominal pressure, and is often associated with colitis or urinary infection or obstruction. In pigs, rectal prolapse occurs as a herd problem when the ration contains zearalenone, an estrogenic mycotoxin produced by fungi of the genus Fusarium. The toxin causes marked swelling and congestion of the vulva and vaginal mucosa, straining, and eventually vaginal and/or rectal prolapse. Rectal prolapse in sheep may be the consequence of ingestion of estrogenic pastures, and is accompanied by other signs of hyperestrogenism (see Vol. 3, Female genital system).
The prolapsed rectum is edematous, congested, and there may be necrosis and ulceration of the everted mucosa. These lesions are ischemic in origin owing to interference with venous blood flow from the prolapsed section. Only the mucosa, or all layers of the bowel, may be involved in the prolapse. In swine surviving slough or amputation of the prolapsed tissue, rectal stricture may ensue. Rectal stricture is discussed further in the section on salmonellosis.
Jejunal hematoma (hemorrhagic bowel syndrome, intestinal hematoma) has been described mainly in adult dairy cattle in North America, with occasional reports from Europe, the Middle East, and South America. The syndrome is usually characterized clinically by sudden death, although a few affected animals may have blood in their feces, bloat and acute abdominal pain for a short time before death. At postmortem examination, there are one or more short jejunal loops with intramural hemorrhage (Fig. 1-55A ). The latter usually distends the intestinal mucosa to the point of complete or partial obstruction of the intestinal lumen ( Fig. 1-55B) . Intraluminal hemorrhage is also present in some cases. Determination of the primary location of the hemorrhage (intramural versus intraluminal) requires careful dissection, as in the cases of intramural hemorrhage, the compressed and thin intestinal mucosa frequently tears when the intestine is opened, giving the false impression that the blood is intraluminal rather than intramural. Microscopically, the interface between the hematoma and nonhematoma portions of the jejunum has an abrupt elevation of the mucosa, and the muscularis mucosa is often split by severe hemorrhage, with one portion adherent to the submucosa and the other to the lamina propria. The elevated mucosa may be completely necrotic or have only necrosis of the surface epithelium. Often, the affected mucosa has moderate to large numbers of large, gram-positive rods on the luminal surface. Because the percentage of gram-positive rods was found to increase with the degree of autolysis, it has been postulated that this bacterial population is a consequence rather than a cause of the condition. The affected mucosa, but also the more normal looking adjacent mucosa, has dilated villus lacteals that are either empty or contain abundant erythrocytes and/or pale eosinophilic, hyalinized material. Occasionally there are small numbers of hemosiderophages in the lamina propria of the affected mucosa. In a few cases, the mucosa may show mild to moderate edema, mild neutrophilic infiltration and small foci of submucosal hemorrhage. Submucosal blood vessels in these areas are usually within normal limits but a small percentage of cases may have mild to moderate vasculopathy with hyaline change of the vessel wall, mild pleocellular perivascular and subintimal inflammatory infiltrates and plump lining endothelium. Focal suppurative peritonitis can rarely be seen in affected areas of the jejunum. The cause of this entity is not known. A B factor for these changes. In a study of 30 equids referred to a medical teaching hospital with a diagnosis of oleander intoxication, 85% had gastrointestinal signs included colic, diarrhea, gastric reflux, intestinal hyper- or hypo-motility, and abdominal distention. Gross changes in the alimentary tract of horses and ruminants with oleander intoxication include hemorrhage ( Fig. 1-56 ), edema and, occasionally, the presence of pseudomembranes in the small intestine. Histologically, the most significant changes are hyperemia and hemorrhage of the mucosa in the small and/or large intestine, although neutrophilic and/ or pseudomembranous enteritis can be seen in more advanced cases.
In dogs, and to a lesser extent in horses, cats, and other species, usually idiopathic syndromes occur, variably signaled by chronic diarrhea, weight loss, hypoproteinemia, and malabsorption. Endoscopic or full-thickness intestinal biopsy, where feasible, is usually necessary to make a diagnosis and establish a prognosis. These syndromes are typically characterized by abnormal lamina proprial inflammatory infiltrates (eosinophils, lymphocytes, and plasma cells, or granulomatous inflammation), neoplasia, especially lymphosarcoma, or amyloid, and structural alterations, including hyperplasia of the crypts and villus atrophy. Lymphangiectasia may also produce a similar syndrome. Infectious causes of erosion or ulceration need to be considered, but are less common. In dogs, histoplasmosis, protozoal infections (giardiasis, cryptosporidiosis), and sequelae to severe parvoviral infections in animals recovered from the acute phase may cause such a syndrome. Inflammatory bowel disease in dogs and cats can be associated with protein-losing enteropathies where clear evidence of lymphangiectasis is absent. This may be due to alterations in epithelial permeability secondary to chronic mucosal inflammation. In horses, chronic salmonellosis and Lawsonia are potential infectious causes of malassimilation and protein loss.
The limitations on the interpretation of biopsies noted in the section on normal form and function of the intestine must be borne in mind. Neoplasia needs to be differentiated from inflammation, amyloidosis, and lymphangiectasia. Rarely, characteristic lesions or an agent may be recognized, implicating an infectious process. If inflammatory bowel disease is recognized, associated or complicating problems, such as Baccharis cordifolia and B. megapotamica are found in several South American countries, but most cases of intoxication have been reported in Brazil and Argentina. Baccharis pteronioides has been implicated in similar livestock poisoning in the southwestern United States. The numerous toxic principles of these plants include the macrocyclic trichothecene complex of antibiotics. Spontaneous intoxication by B. cordifolia causes acute disease in cattle, sheep, and horses; intoxication by B. megapotamica has been reported in cattle, buffalo, and sheep. The syndrome produced by both plants is similar and it is characterized clinically by ocular discharge, incoordination, mild bloat, and muscle trembling. Gross findings include dehydration, abundant liquid rumen content, reddening of the mucosa of forestomachs, abomasum and intestine, and edema of the ruminal wall. The main histologic lesions are superficial to full-thickness degeneration and necrosis of the stratified epithelium lining the forestomachs, necrosis of the small intestinal mucosa, hemorrhagic gastroenteritis, and widespread lymphoid necrosis.
Chinaberry tree (Melia azedarach) is cultivated worldwide as an ornamental plant which has caused intoxication in pigs, cattle, sheep, goats, and dogs. The toxic principles (melia toxins A1, A2, B1, and B2) are concentrated in the fruit. Pigs seem to be most susceptible. Neurological and/or gastrointestinal clinical signs develop within a few hours of ingestion of the fruits. The former include excitement or depression, convulsions, ataxia, paresis, and coma. Gastrointestinal signs include anorexia, vomiting, constipation or diarrhea, frequently bloody, and colic. Grossly, the changes observed in different animal species are similar and include intestinal congestion, yellow discoloration of the liver, and brain congestion.
Microscopically there is individual cell necrosis randomly distributed throughout the parenchyma or concentrated in the centrilobular zone of the liver, degenerative and necrotic changes in the epithelium of the forestomachs, necrosis of lymphoid tissue and hyaline degeneration and fiber necrosis.
Oleander toxicosis occurs in several mammalian species, including sheep, goats, cattle, camelids, monkeys, equids, and humans. In addition to the main cardiac lesion produced by intoxication with Nerium oleander, intestinal changes are frequently observed in several animal species. In horses and ruminants, it is thought that the changes in the alimentary tract are primarily caused by the highly irritant effect of oleandrin, the main glycoside present in oleander. However, it is possible that hypoperfusion caused by cardiac failure is a contributing
Further reading Berghaus RD, et al mesenteric lymphatics may be prominent, white, and dilated. Nodular white masses up to 5-10 mm in size may be present on the serosa at the mesenteric border and along lymphatics; rarely, they are found on the liver, diaphragm, other abdominal organs, and pleura. In section, villi may be of normal length or somewhat blunt or stubby, with some hypertrophy of crypts. The surface epithelium may appear normal or perhaps slightly attenuated, and lateral interepithelial spaces are often dilated. The lacteals in many villi are distended, and lymphatics in deeper portions of the mucosa, submucosa, and muscularis usually are as well. Occasional lipid-laden macrophages are present in and around lacteals and lymphatics; large focal accumulations of lipophages around lymphatics, sometimes with a local granulomatous response to lipid or saponified fat, form the white masses that may be seen grossly. A similar reaction may be present in the draining lymph nodes. The lamina propria is edematous, as are the submucosa and deeper portions of the gut wall. The proprial inflammatory cell population may be normal, or the numbers of lymphocytes, plasma cells, and eosinophils may be increased, as in chronic inflammatory bowel disease. Multiple dilated crypts that are filled with cellular debris (crypt abscesses) can be a microscopic finding associated with lymphangiectasia; however, this is a fairly nonspecific finding. Because dilation of lymphatics may be present in the submucosa and muscularis, multiple full-thickness intestinal biopsies that include duodenal and ileal samples may be more sensitive than endoscopic biopsies for diagnosis of lymphangiectasia.
The cause of lymphangiectasia may be lymphatic obstruction with increased lymphatic pressure that can be primary or acquired. Many cases appear to be acquired and common causes include lamina proprial inflammatory cell infiltrates, intestinal neoplasia (lymphosarcoma), and granulomatous infiltrates obstructing flow in mesenteric lymph nodes. Lesions may be multifocal or diffuse in the intestinal tract. Lipogranulomas along the lymphatic drainage are inconsistent features of lymphangiectasia, and are probably in response to chronic leakage of lipid-laden chyle, rather than a cause of lymphatic obstruction. Usually, no congenital or acquired obstruction of the lymphatic system is obvious, although several dogs with lymphangiectasia have had chylothorax associated with thoracic duct obstruction. Experimental obstruction of mesenteric lymphatics produces hypoproteinemia and lymphangiectasia, but not diarrhea and weight loss, suggesting that the etiology of the clinical syndrome may be more complex than simple lymphatic obstruction. Increased vascular permeability associated with chronic inflammatory bowel disease may also contribute to mucosal edema and lymphatic dilation.
Moderate malabsorption of lipid, and plasma protein loss into the gut, causes the signs associated with lymphangiectasia. Malabsorbed lipid may contribute to diarrhea via the effects of fatty acids on colonic secretion. Mucosal permeability associated with increased proprial hydrostatic pressure may cause filtration secretion and contribute to plasma protein loss. It has been proposed that dilated lacteals may rupture, releasing lymph into the lumen of the intestine. Hypocalcemia may be related to loss of the mineral bound to plasma albumin, and perhaps to vitamin D malabsorption, or formation of soaps with malabsorbed lipid in the gut lumen. Hypocholesterolemia is due to lipid malabsorption and effusion of plasma. Lymphopenia is thought to be the result of the loss of lymphocyte-rich lymph into the gut.
Associations with the dietary habits and history of the animal also should be investigated because some cases may be associated with inappropriate responses to dietary antigen.
Lymphangiectasia has been described most commonly in the dog, where it is among the most common causes of malabsorption/ protein-losing enteropathy; it has not been reported in cats. Breed predisposition seems limited to Yorkshire Terriers and the Norwegian Lundehund, in which lymphangiectasia is part of a syndrome of protein-losing enteropathy with inflammatory bowel disease and in which gastritis and gastric neoplasia may co-exist. The disorder has also been reported in the horse. Lymphangiectasia is associated with a syndrome variably characterized by chronic diarrhea, wasting, hypoproteinemia, lymphopenia, hypocalcemia, and hypocholesterolemia. Peripheral edema, ascites, and hydrothorax result from hypoalbuminemia.
The lesion in the small intestine is dilation of the lacteals, and often lymphatics of the submucosa, muscularis, serosa, and mesentery ( Fig. 1-57 ). Villi containing dilated chyle-filled lacteals may stand out grossly as white papillate foci in a thickened, transversely folded edematous mucosa. Serosal and A B impaired movement of interstitial fluid into lacteals or perhaps increased permeability of capillaries, possibly explaining protein loss into the lumen. Kim DY, et
Some animals, mainly dogs and cats, but less commonly cattle and horses, showing signs consistent with malabsorption and/ or plasma loss into the gut, have microscopic lesions in the mucosa of the small intestine described as chronic inflammatory bowel disease, lymphocytic-plasmacytic enteritis, filled-villi syndrome, or eosinophilic gastroenteritis. Eosinophilic gastroenteritis in cats and horses is often part of systemic eosinophilic syndromes affecting those species, considered separately in a later section. In dogs, there is no proof that differentiation of eosinophilic gastroenteritis from chronic inflammatory bowel disease is clinically relevant, nor are there clear criteria for such differentiation, so the two will be considered together.
In both dogs and cats, idiopathic mucosal colitis and gastritis may be present as components of chronic inflammatory bowel disease, perhaps with predominant signs reflecting gastric or colonic dysfunction; both are considered here. In contrast to the mucosal pattern of inflammation evident in these entities, inflammatory lesions of the large and small intestine of any species that include a significant population of macrophages usually adopt a transmural pattern, and may be associated with a specific etiology (e.g., Mycobacterium, Histoplasma) or represent a distinct syndrome (histiocytic ulcerative colitis of Boxers). They are described with transmural granulomatous enteritis and with typhlocolitis. Inflammatory bowel disease is a clinical syndrome for which it is difficult to develop a valid, objective histologic counterpart, and it should be considered by the clinician after alternatives such as food intolerance, motility disorders, and infectious disease have been ruled out. However, the thoroughness of the clinical and laboratory investigation before the use of endoscopic biopsy is influenced by the amount of time and money available to evaluate what are often elusive functional entities. Endoscopic biopsies are often done early, after symptomatic medical therapy has failed to control clinical signs. The microscopic findings commonly associated with inflammatory bowel disease are not specific, and reflect chronic mucosal inflammation resulting from a number of potential etiologies. It is probably not appropriate for a pathologist to issue a diagnosis of inflammatory bowel disease; it is more appropriate simply to list the histologic findings and to indicate that the changes could be compatible with a clinical diagnosis of that syndrome.
Regardless of the portion of the gastrointestinal tract under consideration, the histologic abnormalities are grouped under 3 broad headings: (1) changes in mucosal architecture reflecting active or recent epithelial abnormality; (2)
Amyloid deposition in the small intestine and stomach occasionally may be encountered in animals with systemic amyloidosis. Sometimes the gastrointestinal lesions predominate and contribute to the clinical syndrome. Significant intestinal amyloidosis leads to signs consistent with malabsorption and enteric protein loss. Usually there is no gross indication of the deposition of amyloid in the intestine. However, occasionally focal ulceration or hemorrhage may be noted. In geriatric dogs, amyloid deposits may occur in the intestine, often around blood vessels. Rarely, intestinal amyloid is associated with neoplasia, including intestinal extramedullary plasmacytomas. Microscopically, amyloid is seen beneath the epithelium or throughout the propria in villi, and perhaps around or within vessels in the submucosa ( Fig. 1-58 ). It must not be mistaken for collagen deposition, which is most unusual in these locations, although a band of collagenous material is sometimes present at the base of the mucosa in cats. The pathogenic effects of amyloid in the intestine seem to involve either
Further reading Hayden DW, et enteropathy; it is merely a severe variant of lymphocyticplasmacytic enteritis, and we see no benefit in expanding the nomenclature in an already-confused area. Occasionally, rupture of such crypts will be seen; lakes of mucus, reactive histiocytes, and occasional giant cells are present in the lamina propria ( Fig. 1-61 ). Other distended crypts may contain casts of eosinophilic glycoprotein. Care should be taken to differentiate chronic inflammatory bowel disease from early intestinal lymphoma (see discussion of Malignant lymphomas). Some suggest that, in the Basenji at least, the former can evolve into the latter. In cats this also can be problematic, where differentiation of lymphocytic enteritis from low-grade lymphoma is a diagnostic challenge.
Idiopathic mucosal colitis is the colonic manifestation of chronic inflammatory bowel disease, and the commonest form proprial leukocytes; and (3) fibrosis within the lamina propria. Of these, the epithelial changes are the most reliable, yet the least prevalent. Although severe inflammatory changes can be quickly identified, it is often more difficult to objectively identify moderate or mild mucosal inflammation. Subjective impressions of increased numbers of leukocytes within the lamina propria are the least reliable, but are the most widely used criterion for a diagnosis, simply because most biopsy samples do not have any other mucosal abnormalities. The pathologist, faced with substantial pressure to make some kind of diagnosis, may reach for the one observation that cannot be disproved (or proved): too many leukocytes.
In the small intestine, the cardinal finding is abnormally intense infiltrates of well-differentiated lymphocytes and plasma cells, and sometimes eosinophils, in the lamina propria of villi, between crypts and perhaps in the submucosa. However, normal intestine contains these types of cells and the distinction between normal and abnormal infiltrates is subjective, based on the position and number of cells in the villus. A layer of lymphocytes, plasma cells, and perhaps neutrophils or eosinophils more than about 4 cells thick, in the deep mucosa, below the crypts and above the muscularis mucosae, is abnormal ( Fig. 1-59) .
Villi may be normal, blunted, or moderately to severely atrophic, and occasionally fusion of villi may be prevalent ( Fig. 1-60A ). The surface epithelium may appear relatively normal, mucous metaplastic, or low columnar to cuboidal with an indistinct brush border. Intraepithelial lymphocytes may be increased. Detection of increased intraepithelial lymphocytes may aid in diagnosis of chronic mucosal inflammation associated with inflammatory bowel disease. Crypts may be hypertrophic and lined by numerous goblet cells; in other cases goblet cells are less obvious. There may be edema of the lamina propria and dilation of lacteals, suggesting concurrent lymphangiectasia, but usually the edema is not as severe as occurs with that lesion. In this and other conditions with increased inflammatory infiltrates ( Fig. 1-60B ) or edema in the lamina propria, including lymphangiectasia, crypts may be obstructed and dilated, and contain mucus and a few exfoliated epithelial cells. This has been termed cystic mucinous glands dilate and fill with mucus or cell debris. Hyperplastic glands are lined by basophilic enterocytes and goblet cells may be decreased. In some cases, goblet cells may be increased. Inflammatory cells, mainly neutrophils, but perhaps lymphocytes, plasma cells, and eosinophils, may accumulate excessively along the mucosal side of the muscularis mucosae, as in inflammatory disease involving the small intestine. The lesions in mild acute colitis often seem mild in proportion to the severity of the clinical syndrome.
The spectrum of inflammation in colitis grades from acute toward an increasingly chronic infiltrate, which, along with edema, separates colonic glands and may accumulate deep in the mucosa between glands and muscularis mucosae ( Fig. 1-63 ). Neutrophils and eosinophils may be scattered among round cells in the propria, and transmigrating surface and glandular epithelium. Globule leukocytes may be prevalent. Accumulation of granulocytes and necrotic debris in the lumen of glands forms so-called crypt abscesses.
Greater severity of the lesion is reflected in attenuation and exfoliation of surface epithelium, and the development of microerosions on the mucosal surface. Inflammatory cells, mainly neutrophils, and tissue fluid effuse into the lumen through defects in the epithelium. Persistent erosion, or previous erosion in a healed mucosa, is marked by the development of a thin, horizontally arrayed layer of connective tissue in the superficial lamina propria. With increasing chronicity in colitis of mild or moderate degree, there may be deposition within the lamina propria of a collagenous stroma, throughout which inflammatory cells are interspersed, which separates glands abnormally throughout the mucosa. Downgrowth of glands into often-involuted submucosal lymphoid follicles may occur in chronic colitis.
Severe erosion and ulceration are usually associated with local acute inflammation and with a heavy, mainly of colitis recognized in dogs. It is etiologically nonspecific, occurring as chronic or chronic-active lymphocytic-plasmacytic or eosinophilic mucosal inflammation. Histiocytic ulcerative colitis is the distinctive pattern differentiated from it on microscopic grounds, along with rare cases of Histoplasma or protothecal colitis.
Mild acute mucosal colitis, reflecting a grossly reddened friable surface visible on endoscopy, is characterized by congestion of superficial capillaries and venules, and proprial edema. Neutrophils infiltrate the superficial lamina propria around vessels, and transmigrate or pass between surface epithelial cells into the lumen. The population of lymphocytes and plasma cells in the lamina propria may not differ from normal, but there is generally a moderate increase in mononuclear cells, and perhaps eosinophils, which are usually rare in the superficial colonic mucosa, between glands ( Fig. 1-62 ).
There are often few goblets on the surface and in glands, probably owing to mucous discharge, rather than cell loss. Surface epithelium may be basophilic, low columnar, or cuboidal. Hyperplasia of epithelium in glands may be evident, and proof) that such fibrosis and glandular atrophy are sequelae to previous inflammation or necrosis, such changes have not been correlated with gastric dysfunction or clinical illness.
Unlike the situation in the intestinal and colonic mucosa, epithelial injury is not as prominent in gastritis in dogs or cats. It is uncommon to encounter erosion or ulceration as part of gastritis, and acute ulceration associated with chemical or mechanical injury to the stomach has little mucosal cellular infiltrate. It is therefore prudent to distinguish gastric ulceration from gastritis. Lesions compatible with a diagnosis of gastritis include leukocytic infiltrates in the superficial third of the mucosa, mucous metaplasia and hyperplasia in fundic glands, extensive lymphoplasmacytic and/or eosinophilic infiltrates deep in the mucosa, interstitial fibrosis, and associated atrophy of glands. The diagnosis of gastric mucosal atrophy must be made with great care because there is substantial difference in mucosal thickness between various portions of the stomach, and even within the same anatomic region.
Most discussions of inflammatory bowel disease assume that the change in mucosal cellularity is primary and that characterization of that cellularity should provide the greatest insight into pathogenesis and therapy. However, assessment of mucosal cellularity is almost entirely subjective and has exceedingly poor interobserver agreement. There are no useful objective reference intervals for small intestinal mucosal cellularity because the range is so broad, and accurate identification of the different cell types is problematic. Characterization of the immunophenotype of lymphocytes in the small intestine has produced variable results that have yet to be usefully associated with the presence or absence of clinical signs.
Attempts to create more objective grading systems for the histologic assessment of inflammatory bowel disease have stressed the significance of architectural changes within the surface epithelium and lamina propria rather than relying exclusively on shifts in total or relative leukocyte populations. Such grading criteria include detection of villus or cryptal enterocyte injury (villus fusion, superficial ulceration, enterocyte flattening and basophilia, cryptal hyperplasia), as well as remodeling of mucosal architecture (separation of the crypts from one another or from the muscularis mucosae by edema, fibrosis, and/or leukocytes). However, these schemes still fail to resolve the dilemma of substantial overlap between "normal" and subjectively increased leukocyte numbers in mild inflammatory bowel disease in which there is no epithelial injury or architectural change. The World Small Animal Veterinary Association Gastrointestinal Standardization Group has developed a standardized grading scheme that works toward distinguishing normal from mucosal lesions in each grading criterion.
Skepticism about the utility of estimating leukocyte numbers or identifying shifts in phenotype among mucosal leukocytes may not be so appropriate when looking at colonic and gastric inflammatory disease. Perhaps because of its lesser overall proprial cellularity in comparison with small intestine, or perhaps because of its greater accessibility to biopsy, the colonic mucosa was the first part of the canine intestinal tract to be subjected to morphometric grading of architectural changes and objective leukocyte counting, although application of such data is difficult. In comparison with small intestine, the normal range in leukocyte numbers is narrower and the overall population much smaller in both colon and stomach. This is particularly true of the granulocytes. The presence of neutrophils within the lamina propria of any part of mononuclear cell infiltrate in the lamina propria, and often in the submucosa. The ulcerated areas extend usually no further than the muscularis mucosae, and have a base of granulation tissue heavily infiltrated by neutrophils that effuse into the lumen of the bowel. The margin of surviving mucosa may overhang the ulcer. Crypt abscesses may be present in remaining mucosa, and all degrees of erosion and partial ulceration may be present. Idiopathic ulcerative colitis is uncommon, and does not seem as severe as histiocytic ulcerative colitis of Boxers; it rarely comes to autopsy. Severely affected dogs may be cachectic, probably owing in part to enteric loss of plasma protein. The mucosa in ulcerative colitis is usually deep red, swollen, folded, and granular because of edema and cellular infiltrates; the depressions may be punctate or up to several centimeters across, roughly round or oval, irregular or elongate. Their margins may be tattered or puckered. Colonic lymph nodes may be enlarged and edematous.
In canine colitis, there is a broad 3-dimensional spectrum: (1) in relative chronicity and density of the inflammatory infiltrate; (2) in the distribution of the infiltrate within the wall of the bowel; and (3) in the severity of the epithelial and mucosal change. Generally, milder lesions of superficial epithelium are associated with mild or moderate mucosal inflammation, which may be acute or chronic. In many cases of mild chronic mucosal colitis, the glands do not appear particularly hyperplastic. However, defective repair in the face of severe or ongoing injury may result in crypts that are tortuous or even nearly horizontal, and papillary hyperplasia of the epithelial surface. Severe erosion and ulceration are usually related to a more intense or heavy chronic inflammatory process, which may be limited to the mucosa, but which can extend into the submucosa. Truly granulomatous colitis is not common; when fully developed, perhaps as a component of regional enteritis involving the ileocecocolic area, or in histiocytic colitis of Boxer dogs considered later, it is ulcerative and transmural. Occasionally, a granulomatous response to barium, or to other foreign material breaching the epithelium, may be observed in the mucosa and submucosa. Atrophic colitis, in which the mucosa is markedly thinned, with relatively inactive crypts and modest chronic or chronic-active interstitial inflammation, perhaps with notable interstitial fibrosis, is occasionally encountered.
Gastric changes in dogs or cats with clinically suspected inflammatory bowel disease are challenging to interpret, because of variation in normal microscopic anatomy within the stomach, and because gastric lesions are often patchy. As well, ingestion of chemicals and foreign bodies can create gastric lesions misinterpreted as being those of inflammatory bowel disease.
The stomach has a variety of normal anatomic features and common background lesions that have not been proved to have any functional significance. These include a dense band of hyalinized fibrous tissue (lamina densa) between the muscularis mucosae and the base of the crypts in cats, lymphoid nodules within the deep lamina propria of both dogs and cats, and a substantial amount of fibrous tissue within the lamina propria of the pyloric antrum. It is not clear whether some of these have any significance as signposts of previous disease. Background lesions that may or may not be correlated with some previous specific stimulus include globule leukocytes in the gastric epithelium of cats, and a combination of gastric proprial fibrosis, glandular atrophy, and glandular nesting within the fundic mucosa. Although we assume (without invading enteric pathogens. Changes in mucosal dendritic cell phenotype and frequency have been detected in dogs with inflammatory bowel disease, suggesting altered antigen sampling and subsequent adaptive immune responses. The common morphologic changes in the mucosa-cryptal hypertrophy, villus atrophy, and in severe cases, mucous metaplasia of surface enterocytes-may be side-effects of T-cell-mediated activity in the mucosa. Similar lesions occur in humans with celiac disease (gluten-sensitive enteropathy), which is T-cell mediated. Reduced numbers of T-regulatory cells has been identified in dogs which also may play a role in loss of tolerance to luminal antigens, recruitment of inflammatory T-cell populations, and progression of mucosal inflammation.
Lymphocytic-plasmacytic enteritis associated with familial sensitivity to wheat protein has been demonstrated in Irish Setters. An enteropathy in Basenji dogs has similarities to other forms of inflammatory bowel disease. In Basenjis and in the Lundehund, syndromes of hypoalbuminemia, chronic diarrhea, and wasting occur with high prevalence, primarily attributable to lymphocytic-plasmacytic enteritis, with lymphangiectasia in some dogs. In the Basenji chronic gastritis or hypertrophic gastritis may be associated, and malassimilation and plasma protein loss into the gut have been documented. Hypergammaglobulinemia commonly occurs in the late stages of the syndrome in Basenjis, and lymphosarcoma develops in some affected animals. In this sense, the syndrome resembles immunoproliferative small intestinal disease (α-heavy chain disease, or Mediterranean lymphoma), which is a disorder of IgA immunoblasts in humans. IgA plasmacytes do not dominate in the Basenji intestinal mucosa; though high circulating levels of IgA are present, it is not known if they are associated with abnormal α-heavy-chain protein.
In cats, dogs, and horses, submucosal or transmural lymphoplasmacytic infiltrates may signal a precursor to lymphoma, and the infiltrating cell population must be carefully evaluated; a monomorphic population of lymphocytes, blurring of the proprial-epithelial interface by lymphocytic infiltrates, and mitotic activity suggest lymphosarcoma.
Animals with the gray Collie syndrome (cyclic neutropenia) also may have lymphocytic-plasmacytic enteritis (see Vol. 3, Hematopoietic system).
Malabsorptive and syndromes with weight loss have been described in the horse with some similarities to inflammatory bowel disease. The etiologies in the horse are unknown, but it is possible that similar mechanisms described earlier are involved. Multiple forms are described that include lymphoplasmacytic, granulomatous, and eosinophilic. Day M, et al the intestine is probably abnormal, and is probably a reliable marker for recent epithelial damage or permeability. Eosinophils have more variation, and often are present in very large numbers throughout the small intestinal mucosa. However, they are very sparse within the superficial half of the canine colonic mucosa, and are infrequent within the gastric mucosa. Because the normal stomach has relatively few mucosal leukocytes, the pursuit of a diagnosis of gastritis based upon objective assessment of leukocyte numbers may be a credible goal. Although it has been possible, by counting different types of leukocytes identified by routine histology and immunohistochemistry, to establish reference intervals for eosinophils, plasma cells, B cells, and T cells within various parts of the gastric lamina propria of healthy dogs, more than half of the round cells in the normal canine gastric lamina propria could not be precisely identified. Healthy dogs had an 8-fold range in total mucosal cellularity, and the pyloric antrum was 3 times more cellular than the fundic mucosa. Although dogs with clinical signs of gastritis had an objective increase in eosinophils, plasma cells, and/or intraepithelial lymphocytes in many different combinations, it was difficult to correlate clinical severity or response to therapy with cellular or other parameters of gastric mucosal abnormality. There was no significance to whether the inflammation was limited to the superficial third of the mucosa or was found throughout, although the former was more common than the latter. In a second study of idiopathic gastritis, all cases were classified as lymphocytic, and T cells predominated. Eosinophils were not a significant component, and there was no observed regional variation in severity.
The etiopathogenesis of idiopathic inflammatory bowel disease is not understood in any animal species. Similar to humans with IBD, it is likely that multiple factors, including genetics, mucosal immunity, intestinal microbiota, diet, and environment, play a role in pathogenesis. A familial role in dogs is established with enteropathies documented in multiple breeds including Boxers, Basenjis, German Shepherds, and Irish Setters. As molecular techniques to detect intestinal microbes improve, alterations in the intestinal microbial communities in dogs and cats have been detected. Shifts in the major microbial constituents, from gram-positive Firmicutes species to gram-negative proteobacteria in the gut have been noted in healthy animals versus those with intestinal inflammation. These alterations in the composition of the intestinal microbiota have been termed dysbiosis. Dysbiosis correlates with mucosal inflammation and may be a driver of persistent inflammation. Potential pathogens, such as invasive species of E. coli in Boxer dogs and French Bulldogs with granulomatous colitis, have been identified. Diet also appears to be important with a significant percentage of dogs and cats with chronic enteropathy responding favorably to dietary changes. An immunologic basis for this sensitivity is not always determined and adverse food reaction may be better terms than food allergy. In addition to food allergy, adverse food reactions would include food intolerance and intoxications.
The nature of the inflammatory infiltrate suggests that loss of tolerance to dietary antigen or antigens produced by the enteric microflora may be implicated. Similar to humans' defects in regulation of innate immune responses may be an initial component of loss of mucosal tolerance in dog and cats. In dogs with inflammatory bowel disease, innate recognition of commensal bacteria through toll-like receptors has been shown to generate a proinflammatory response typical of syndrome, associated with eosinophilic granulomatous pancreatitis and eosinophilic dermatitis, among other lesions. Affected animals have weight loss, and diarrhea or unformed feces, associated with hypoalbuminemia, suggesting enteric loss of plasma protein. Reduced absorption of glucose occurs, but peripheral eosinophilia is absent. At autopsy, mucosal and sometimes transmural thickening may occur at any level of the alimentary tract from esophagus to rectum. Esophageal and gastric squamous mucosa is hyperkeratotic. Thickened mucosa is thrown into turgid transverse folds, or occasionally is fissured and roughened. Focal or diffuse ulcers may be present on the small and large intestine and focal caseous lesions up to 1.5 cm in diameter may be in the submucosa of the gut and common bile duct, as well as in an enlarged fibrotic pancreas.
Microscopically there is diffuse infiltration of the mucosa, submucosa, and often deeper layers of the enteric wall by eosinophils, mast cells, macrophages, lymphocytes, and some plasma cells. Moderate to severe villus atrophy, fibroplasia in the lamina propria, and hypertrophy of the muscularis mucosae occur. Caseous foci in the mucosa and submucosa consist of central masses of eosinophils, sometimes surrounded by macrophages, giant cells, and occasionally fibrous tissue. Eosinophilic interstitial infiltrates and granulomas are described in the biliary and pancreatic ducts, pancreas, salivary glands, capsule, and outer cortex of enlarged firm mesenteric lymph nodes, and near portal tracts in the liver. The skin may be thickened and hyperkeratotic and the limbus of the hoof thickened and ulcerated. The eosinophilic dermatitis is described in Vol. 1, Integumentary system. Villus atrophy is common, but if large-bowel lesions are absent, there is no diarrhea. Chronic inflammation in the mucosa may explain protein loss and hypoalbuminemia. The cause of this syndrome is unknown. A hypersensitivity response to migrating parasitic larvae has been suggested, as has the possibility that undetected T-cell lymphoma secreting interleukin-5 may be responsible.
Eosinophilic gastroenteritis also occurs in horses apart from the multisystemic eosinophilic syndrome. In addition to eosinophilic inflammation associated with enteric parasitism, idiopathic eosinophilic enteritis has been described as a part of the equine inflammatory bowel disease complex. An uncommon focal form of eosinophilic inflammation of the equine small intestine also has been described. This lesion is characterized by focal infiltration of large numbers of eosinophils and macrophages that are focused on the submucosa and the tunica muscularis. In the lamina propria there is often increased density of lymphocytes, plasma cells, and macrophages with fewer eosinophils. This lesion has been associated with obstruction and colic.
Eosinophilic enteritis in cats is rare, and appears to be one manifestation of a hypereosinophilic syndrome that may involve many organs in middle-aged or older cats. It is much more severe than eosinophilic gastroenteritis in dogs. Diarrhea, sometimes bloody, vomition, loss of appetite, and loss of condition may occur. Clinically, intestinal thickening, hepatomegaly and splenomegaly, and enlarged mesenteric lymph nodes may be present, in association with circulating eosinophilia and hyperplasia of the eosinophil series in the marrow. The postmortem picture reflects the clinical findings. Enlargement of the various organs, including liver, spleen, lymph nodes in many locations, and tan nodularities on the kidneys, is associated with heavy infiltrates of usually welldifferentiated eosinophils. In the small intestine, the eosinophilic infiltrate may be transmural and is accompanied by grossly visible hypertrophy of the muscle layers ( Fig. 1-64) . Eosinophilic colitis may occur in some cases. Lymph nodes may have hyperplastic follicles and many mature eosinophils in sinusoids. Alternatively they may vary through eosinophilic lymphadenitis with fibrosis to complete obliteration of normal architecture and replacement by eosinophils in a fibrillar stroma extending through the capsule into surrounding tissue.
Chronic eosinophilic enteritis in horses has been described as part of a distinct multisystemic epitheliotropic
For general reactions to injury of the cecal and colonic epithelium, see the earlier section, Epithelial renewal in health and disease.
Ischemia, obliteration of the proliferative epithelium by etiologic agents, severe inflammation, and some luminal toxins are responsible for the development of focal or diffuse ulceration of the large intestine. Inflammatory infiltrates in the lamina propria are classified based on the inflammatory cell phenotype, and may be limited in distribution to the mucosa or be transmural involving all layers of the intestinal wall and frequently the draining lymph nodes. Typhlitis and colitis may be manifestations of a generalized disease; they may be part of enterocolitis involving both small and large intestine, or they may be regional and limited to any specific segment or segments of the intestine. Damaged colonic mucosa may provide the portal of entry for cross-mucosal translocation of bacteria or toxins. Increased mucosal permeability in the colon may permit enteric loss of plasma protein or blood. Intestinal flora dysbacteriosis in hindgut fermenters may compromise uptake of volatile fatty acids and water. In any species, damage to the colonic mucosa may result in malabsorption of electrolytes and water, or altered secretion. Colitis in each of the species is considered in turn.
Colitis cystica profunda, the presence of dilated mucusfilled colonic glands protruding through the muscularis mucosae into the submucosa or tunica muscularis, is uncommon in domestic animals and has been described in pigs, dogs, and goats; the cause is unknown. The lesion may be a sequel to colitis and local damage to the muscularis mucosae, or it may represent herniation into the space left by an involuted submucosal lymphoid follicle. The lesion may be associated with colitis, especially swine dysentery, or it also may be found incidentally.
Inflammation of the large bowel in dogs is usually associated with frequent diarrhea, which is small in volume, mucoid or bloody, and often accompanied by tenesmus. By far the most common form encountered in dogs is idiopathic mucosal colitis, considered in the earlier section, Idiopathic inflammatory bowel disease.
Histiocytic ulcerative colitis, or granulomatous colitis, is a distinctive histologic syndrome described mostly in young Boxers and French Bulldogs. This is a chronic transmural ulcerative colitis with nonspecific gross and characteristic histologic lesions. Clinically, there is frequent bloody mucoid diarrhea, anemia, hypoalbuminemia, weight loss, and chronic cachexia. Grossly, the colon of dogs with advanced disease is ulcerated, variably thickened, folded, and perhaps dilated and shortened with some segmental or focal areas of scarring and stricture. Lesions on the mucosa vary from patchy punctate red ulcers to more extensive irregular circular or linear coalescing ulcers, with islands of remnant surface mucosa. Histologic lesions are unique and include severe mucosal ulceration, goblet cell loss and infiltration of the lamina propria and submucosal layers by many granulocytes and macrophages ( Fig. 1-65) containing periodic acid-Schiff positive material. These cells are also found within and surrounding lymphatics of the tunica muscularis and serosal surface. Their presence in draining lymph nodes, along with lymphoid hyperplasia, explains the localized or generalized lymphadenopathy that often accompanies this syndrome. The cecum is
The presence of chronic inflammatory infiltrates, including aggregates of histiocytes, and perhaps giant cells, in the lamina propria is the criterion for a diagnosis of granulomatous enteritis. With time, the inflammatory reaction typically follows lymphatics transmurally into the submucosa and through the muscularis to the serosa. The submucosa is usually edematous, and lymphatics are prominent. Granulomas may be present in the submucosa or at intervals along lymphatics. The affected lymph nodes are hyperplastic, usually with prominent sinus histiocytosis. Giant cells may be present in sinusoids, or granulomatous foci of various sizes may be evident. Sinusoids contain numerous neutrophils and perhaps eosinophils, and neutrophils may accumulate in the center of granulomas.
Granulomatous enteritis can potentially occur in all species. Johne's disease, other intestinal mycobacterioses, and Histoplasma enteritis are specific examples (see later section on Infectious and parasitic diseases of the alimentary tract). Often the cause is not identified.
Transmural granulomatous enteritis is occasionally seen in dogs and cats. It is generally segmental and perhaps discontinuous in distribution, usually affecting the lower ileum, colon, and draining lymph nodes. Because of the extent of the attendant fibrosis, these lesions may be stenotic, and must be differentiated from invasive carcinoma. In dogs, there may be marked necrosis in the centers of granulomas and considerable fibrosis.
Idiopathic granulomatous enteritis as a cause of wasting and protein-losing enteropathy is most commonly seen as a sporadic problem in horses. Depending on the duration of the disease, animals may be markedly cachectic, have subcutaneous edema, especially of dependent areas, and there may be hydrothorax, hydropericardium, and ascites. Lesions in the horse usually affect the small intestine; stomach and large bowel are occasionally also involved. Mesenteric lymph nodes are usually enlarged, edematous, with mottled firm gray areas, fibrotic nodules, or, rarely, caseous or mineralized foci on the cut surface. Granulomatous pale, caseous, or calcified foci may be scattered in the liver.
The microscopic lesion may be patchy, regional, or diffuse, and it may be mucosal, or transmural, ultimately gaining the draining lymph nodes. Transmural inflammation is characteristically granulomatous. Villi are mildly to markedly atrophic with hypertrophy of crypts. The epithelium may vary from apparently normal to low columnar or cuboidal with an indistinct brush border. There may be leaks between cells on the surface, or microerosions may be present through which neutrophils and proteinaceous exudate pass into the lumen. The lamina propria is edematous and contains scattered aggregates of histiocytes and perhaps giant cells, or less commonly, more organized granulomatous foci. Neutrophils and eosinophils are distributed diffusely throughout the lamina propria, and may be concentrated in or near granulomatous foci. A heavy population of lymphocytes and plasma cells inhabits the lamina propria, and the infiltrate and edema may separate crypts abnormally from each other.
Further reading Cline JM, et occur in the antimesenteric border of the left colonic flexure or proximal descending colon. The pathogenesis of these lesions remains unclear. Ulcerative colitis with perforation has been reported in dogs with uremia, but the mechanism is uncertain. Given the frequency of concurrent vascular lesions including arteritis, fibrinoid necrosis, and mineralization, colonic mucosal damage may be related to mucosal ischemia or a variety of toxins, including increased ammonia formed by bacterial urease in the colon. Trichuris vulpis, the canine whipworm, causes acute or chronic mucosal colitis or typhlitis; in heavy infestations, there may be significant blood loss because of mucosal damage inflicted by the nematodes. Clinical trichuriasis is generally associated with adult trichurid nematodes extending from the cecum and proximal ascending colon into more distal parts of the large intestine. Ulcerative colitis in dogs is also rarely caused by Entamoeba histolytica. Ulcerative granulomatous transmural colitis is common as an enteric manifestation of infection with Histoplasma capsulatum. The alga Prototheca is a rare cause of enterocolitis as part of systemic disease in dogs. Leishmaniasis in dogs is often a multisystemic disease, but chronic mixed-cell inflammatory infiltration of the colon along with numerous L. infantum amastigotes is usually observed. Canine parvovirus 2 causes colonic damage, but in virtually all cases, there are more severe lesions elsewhere, notably in the small intestine. Canine coronavirus has also been implicated as a cause of colonic and small intestinal lesions. Brachyspira spp. may be present in the canine colon and may be associated with diarrheal disease; however, their role in disease remains controversial. Campylobacter spp. can be isolated from dogs with and without diarrhea, but has been implicated as a cause of enterocolitis outbreaks in some dog colonies. These conditions are discussed fully in the later section, Infectious and parasitic diseases of the alimentary tract. Craven M, et
Colitis in cats is less common compared with dogs. Idiopathic mucosal colitis, similar to that described in dogs, also occurs in cats, and is discussed with the previous section on idiopathic inflammatory bowel disease. Tritrichomonas foetus is associated with persistent large-bowel diarrhea and idiopathic mucosal colitis in cats <1 year of age, and is considered later in this chapter in the section Infectious and parasitic diseases of the alimentary tract. Feline panleukopenia virus (FPLV) causes colonic lesions in about half of the cases; typical lesions are less widespread or severe compared with small intestinal lesions. also involved with similar lesions, although often to a lesser degree.
This condition was long regarded as an idiopathic immunemediated disease with variable response to empirical therapeutic support. Recent work, however, has elegantly demonstrated the presence of selective intramucosal colonization by invasive strains of Escherichia coli. Furthermore, longterm clinical remission has been demonstrated in cases of ulcerative histiocytic colitis of Boxer dogs, with eradication of invasive E. coli using appropriate antibacterial therapy. Antibiotic resistance, especially to enrofloxacin, has been correlated with invasive E. coli isolated from Boxer dogs with nonresponsive or refractory disease.
Severe acute necrotizing colitis and, less commonly typhlitis leading to ulceration and perforation has been associated with functional adrenal cortical tumors or glucocorticoid administration, especially following trauma or surgery involving the spinal cord; gastric ulceration may occur concurrently. The perforations can occur anywhere in the colon, but usually A B sign, with sudden death the only sign in a few foals. C. difficile occurs in horses of any age and it almost invariably produces diarrhea regardless of the age of the affected animal.
Potomac horse fever usually results in diarrhea that does not exceed 10 days in duration; at autopsy there is congestion and ulceration of the mucosa of the large bowel, and enlargement of mesenteric lymph nodes.
Suppurative ulcers involving lymphoid tissue in the cecocolic mucosa, and cecal and colic lymphadenitis, characterize enteric infection with Rhodococcus equi in foals.
Other bacterial agents, including Clostridium sordellii, Actinobacillus equuli, and others, have been associated with acute colitis in horses, but definitive evidence of their role in these infections is lacking.
Subacute and chronic diarrhea in horses almost always involves the large intestine, with or without concomitant small-bowel involvement. Salmonella and C. difficile typhlocolitis must be suspected in such cases. Salmonellosis in horses may have an extremely variable course and pathologic manifestations (see section on Infectious and parasitic diseases of the alimentary tract). Histoplasmosis has been reported once in a horse with salmonellosis and ulcerative colitis. Extensive mucosal involvement by larval cyathostomes and strongyles and, rarely, ulcerative typhlitis resulting from anoplocephalid tapeworms, may also cause chronic diarrhea and wasting; these topics are discussed under specific parasitisms. Co-infection by Listeria monocytogenes, Salmonella enterica sv Typhimurium, and cyathostomes probably led to granulomatous typhlocolitis in a horse.
Ciliate protozoa may be seen over the colonic mucosa of horses dead of a variety of enteric and nonenteric problems; the protozoa are usually not associated with tissue inflammatory changes and are considered normal inhabitants of the intestine with no proven pathogenic role in enteric disease. Intralesional protozoa, however, have been reported in a horse with diffuse eosinophilic colitis.
Chronic diarrhea and possibly cachexia may also result from persistent ulceration of the cecum or colon caused by ischemic mucosal lesions. These may be the product of arterial thromboembolism and slow flow, or less likely, corrected strangulation with reflow. Use of NSAIDs also has been associated with cecal and colonic ulceration and plasma protein loss. Right dorsal colitis, in which ulcerative lesions are mostly limited primarily to the right dorsal colon, may be associated Panleukopenia is considered in the section on Infectious and parasitic diseases of the alimentary tract. Mycotic colitis has been reported in cats as a hemorrhagic ulcerative colitis with microvascular thrombosis and mucosal invasion by Candida, zygomycetes, or Aspergillus; these are probably secondary to colonic damage and leukopenia caused by FPLV. Clostridium piliforme is reported as a cause of mild mucosal colitis in kittens, also probably occurring primarily in kittens immunocompromised by FPLV infection. The lesions include focal necrosis, dilation of crypts, exfoliation of epithelial cells, and neutrophilic inflammation. C. piliforme was recognized by histology, immunohistochemistry, and ultrastructure.
Necrotic colitis caused by Entamoeba histolytica and characterized by severe necrosis of the colon and cecum is described in cats; a similar condition in older cats with no apparent etiologic agent has been described, and is hypothesized to be secondary to ischemia. Transmural acute ulcerative colitis with heavy infiltration of neutrophils is the hallmark of Salmonella enterica sv. Typhimurium infection in cats; this is discussed with salmonellosis in the section on Infectious and parasitic diseases of the alimentary tract. Anaerobiospirillum sp. is also associated with ileocolitis in cats, is discussed later in the section on Bacterial diseases of the alimentary tract. Ulcerative colitis as seen in dogs is apparently very rare in cats. Granulomatous or pyogranulomatous foci in the wall of the colon or ileocecocolic junction associated with feline infections peritonitis virus may mimic a neoplasm. De Cock HE, et
The diagnosis of acute colitis/typhlocolitis in horses resolves mainly into the differentiation of salmonellosis, intestinal clostridial diseases, and Potomac horse fever (equine monocytic ehrlichiosis). Although acute colitis can be produced in horses by other agents, they are less common and the role of many of them remains not fully understood. Infectious colitis must also be differentiated from the sequelae of intestinal accidents, NSAID intoxication, and thromboembolism involving the large bowel. Salmonellosis in horses is most frequently associated with Salmonella enterica ssp. enterica serovar Typhimurium, although other serovars may be associated with sporadic cases of disease. Diarrhea is the main clinical sign of equine salmonellosis.
Equine intestinal clostridial diseases are increasingly well defined. In the past, many of these cases were lumped together in an umbrella category, colitis X, a term that was used to refer to severe acute colitis in which all known etiologic agents had been ruled out. This term should no longer be used as it does not describe a specific syndrome but rather a group of diseases in which a final diagnosis cannot be established. Clostridium perfringens type C and Clostridium difficile (Fig. 1-66) are the most common clostridial species responsible for equine clostridial enteric disease. C. perfringens type C occurs most commonly in neonates although disease in older horses occasionally can be seen; diarrhea is a frequent but not consistent clinical
Further reading Harvey CJ, et al. An uncommon intestinal manifestation of feline infectious peritonitis: 26 cases (1986) (1987) (1988) (1989) (1990) (1991) (1992) (1993) acute stages of C. difficile infection being suppurative and marked by characteristic mesocolonic edema. Details of these conditions are discussed in the section on Infectious and parasitic diseases of the alimentary tract.
Diagnostic considerations in cattle >2-3 months of age with acute to subacute fibrinohemorrhagic typhlocolitis include salmonellosis, bovine viral diarrhea, coccidiosis, adenoviral infection, and winter dysentery (coronavirus). Lesions of the oral cavity and upper alimentary tract may be expected, but are not necessarily present, in bovine viral diarrhea and rinderpest. Bovine coronavirus causes microscopic lesions in colonic crypts in cattle with winter dysentery; mild fibrinous typhlocolitis may be seen grossly. Salmonellosis affects all age groups from neonate to adult and may frequently involve both small and large intestine in catarrhal to fibrinohemorrhagic enteritis; mesenteric lymph nodes usually are enlarged. Coccidiosis may involve ileum and large intestine. Bovine adenovirus infection may cause severe hemorrhagic colitis, with few lesions elsewhere. Arsenic, other heavy metals, and oak or acorn poisoning also may cause hemorrhagic typhlocolitis and dysentery. Rarely, trichuriasis causes hemorrhagic mucosal typhlitis in calves.
Chronic fibrinous or ulcerative typhlocolitis may occur in salmonellosis, bovine viral diarrhea, and coccidiosis.
Granulomatous typhlocolitis associated with chronic diarrhea and wasting may occur in Johne's disease, concurrently with granulomatous ileitis and mesenteric lymphadenitis. The mucosa of the large bowel in these cases is thickened and rugose. Impressions of affected mucosa or ileocecal lymph node will contain acid-fast bacilli. Johne's disease in sheep and goats is usually associated with wasting, but often not diarrhea. The large bowel may be involved in a minority of cases; the ileum is consistently affected.
In sheep, hemorrhagic typhlocolitis may be present in animals with bluetongue and peste des petits ruminants; it is rarely the only lesion. Salmonellosis may cause fibrinohemorrhagic enteritis in lambs and pregnant ewes, and typhlitis caused by trichuriasis will occur rarely, although the presence of parasites in small numbers is common in weaners. Coccidiosis may be implicated in hemorrhagic ileotyphlocolitis in lambs and kids, although the small intestine is usually more commonly and severely involved. In goats, enterotoxemia caused by C. perfringens type D may cause moderate to severe fibrinonecrotic typhlocolitis, which occasionally extends to the terminal small intestine as well. Uremia may cause hemorrhagic lesions associated with vasculitis in the cecum and colon.
Tumors of the lower gastrointestinal tract are not common in domestic animals. However, they are relatively prevalent among surgical biopsy submissions from dogs and cats, in sharp contrast to their rarity in horses and food-producing animals. Malignant neoplasms are more common than benign tumors, and excepting lymphosarcoma, most are carcinomas. Polyps are generally hyperplastic rather than neoplastic. The exceptions are rectal polyps in dogs, which also can be adenomas or carcinomas. Highly malignant scirrhous adenocarcinomas of the stomach and intestine occur in all species. Lymphosarcoma is the most common malignant tumor of with colic, and acute or chronic diarrhea. This syndrome and others associated with the use of NSAIDs are considered with ischemia caused by reduced perfusion (see section on Intestinal ischemia and infarction). The specific cause of extensive ulceration may be difficult to determine. Smaller chronic ulcers and widespread subacute erosion and ulceration are most likely the result of salmonellosis, rather than ischemia. A history of administration of NSAIDs, and the presence of lesions in the renal papilla, mouth, and upper alimentary tract, suggests intoxication by those agents. Arroyo LG, et
The differential diagnosis of typhlocolitis in swine mainly revolves around identifying swine dysentery and other spirochetoses, Salmonella enterocolitis, and Lawsonia intracellularis infection. Swine dysentery, caused by Brachyspira hyodysenteriae, involves only the cecum and spiral colon. It is a catarrhal to mildly fibrinohemorrhagic erosive mucosal typhlocolitis. The colonic content is fluid and usually blood-tinged. A similar but milder disease, intestinal spirochetosis, is associated with B. pilosicoli, which causes distinctive microscopic lesions as it colonizes the apex of surface epithelium. Salmonella enterocolitis, mainly resulting from Salmonella Typhimurium, is a fibrinous, erosive to focally ulcerative condition, mainly of the cecum and colon, but occasionally involving the small intestine, especially terminal ileum. The intestinal content is fluid but usually not bloody. Mesenteric lymph nodes are prominent. L. intracellularis infection is readily recognized by the consistent involvement of the terminal ileum by adenomatosis, with or without hemorrhage, or by necrotic ileitis.
Postweaning colibacillosis is characterized by catarrhal to mild fibrinohemorrhagic enterocolitis in piglets after weaning.
Fibrinohemorrhagic typhlitis is caused by heavy infestations with Trichuris suis, especially in weaned pigs with access to pastures and yards. Under similar circumstances, Eimeria infection may rarely cause ileotyphlocolitis.
Rectal stricture appears to be a product of ischemic proctitis, probably related in many cases to infection with Salmonella Typhimurium.
Clostridium perfringens type C and C. difficile are also increasingly important causes of enteritis with occasional typhlocolitis in neonatal piglets. They are both characterized by necrotizing or pseudomembranous inflammation, with • Based on easily observed and objective features to allow a high degree of interobserver agreement when in use; and • Easily adaptable in response to new information about significant differences in behavior or response to therapy. There appears to be no significant difference in the histologic appearance or the biological behavior of the various neoplasms based on their site of origin in the lower gastrointestinal tract, that is, there is no reason to consider colonic adenocarcinomas (or lymphomas) separately from small intestinal or gastric adenocarcinomas. Prefixes such as "gastric" or "colonic" are used as descriptive anatomic terms only to aid in communication of results. Head KW, et
The prevalence and distribution of gastrointestinal adenocarcinomas vary among species. In dogs, gastric carcinomas predominate; small intestinal and colonic carcinomas are relatively uncommon. In contrast, gastric carcinoma is rare in cats, but small intestinal and colonic adenocarcinomas are relatively common. In other species, where they are generally rare, gastrointestinal adenocarcinomas also involve mainly small intestine.
The microscopic appearance is similar, regardless of species or location. A few develop as tubular and papillary proliferations of differentiated columnar epithelial cells projecting into the intestinal lumen. This is perhaps most commonly seen with colonic carcinomas in cats. Such lesions are distinguished from rare papillary adenomatous hyperplasia because they have at least some invasion into the lamina propria, submucosa, or tunica muscularis. Such invasion cannot be appreciated with endoscopic biopsies, and these papillary carcinomas sometimes cannot be distinguished from benign adenomatous hyperplasia or papillary adenomas without full-thickness surgical biopsies. This becomes particularly relevant when trying to distinguish the very common rectal papillary adenoma from the occasional, truly malignant, papillary carcinoma arising in the distal colon or rectum of dogs.
The earliest recognizable histologic lesion of gastrointestinal carcinomas, regardless of the location, is local effacement or obliteration of glandular mucosal architecture at the site of origin by proliferating polygonal mucus-producing epithelial cells. These cells infiltrate the lamina propria, and then invade sequentially through the submucosa and tunica muscularis, infiltrating into lymphatics, and sometimes veins. They penetrate the serosa and exfoliate into the peritoneal cavity to establish neoplastic implants on omentum and mesentery. The tumor also spreads early via lymphatic and venous routes, so that even surgical excision on discovery is rarely curative, because it is too late to prevent metastasis.
The microscopic appearance of the invading tumor can be quite variable, and usually more than one histologic subtype mesenchymal origin in most species. It may arise in the gut, although involvement of this area is often part of multicentric disease (see Vol. 3, Hematopoietic system). The third major category of gastrointestinal tumors is stromal, mainly phenotypically smooth muscle or undifferentiated.
Elaborate classification schemes have been proposed based on histologic or immunophenotypic characterization with, in many cases, little evidence that they are relevant to the biological behavior of the tumor or its response to therapy. Furthermore, there is often so much variation within these lesions that it is difficult to make them conform to arbitrary categories. However, it is important to recognize the range in appearance inherent in the various neoplasms, so that they may be diagnosed correctly, in a clinically meaningful way.
The 2003 Table 1 -1 is considerably simpler. This classification, and the discussion arising from it, is based upon several fundamental principles:
Any classification of neoplasms should be: • The simplest that is compatible with our current understanding of tumor biology, including therapeutic and prognostic information; particularly lung, liver, and adrenal, by the time they are diagnosed.
Rare cases of gastric adenocarcinoma are described in cats. They adopt tubular and diffuse patterns, and behave typically, but are so rare that a diagnosis of carcinoma should be made only on a full-thickness surgical biopsy or autopsy specimen. Endoscopic samples suggestive of gastric carcinoma in cats are almost always foci of adenomatous hyperplasia upon further investigation.
Gastric adenocarcinoma in cattle is exceptionally uncommon, but when it occurs it resembles similar tumors in other species.
Intestinal adenocarcinomas are uncommon in dogs; they occur most frequently in the proximal small intestine and large bowel of animals averaging 8-9 years old. Some investigators have reported a slightly higher prevalence of intestinal carcinomas in males, with a breed predisposition in Boxers, Collies, Poodles, and German Shepherds. Weight loss, persistent vomiting, anorexia, emaciation, and abdominal distention are the most common signs when the tumor is located in the small intestine. Dogs with colorectal tumors have large-bowel diarrhea, tenesmus, hematochezia, and dyschezia. Many dogs with intestinal carcinomas are anemic on account of hemorrhage from ulcerating tumors.
Macroscopically, the tumors appear as gray-white, firm, sometimes annular, stenotic areas that commonly affect the entire thickness of the intestinal wall. These tumors often do not ulcerate, and they usually do not project into the lumen of the gut. Papillary or polypoid intestinal adenocarcinomas do form intraluminal masses, which tend to involve larger segments of the intestine, suggesting horizontal spread. There is dilation of the gut proximal to stenotic and obstructive tumors and there may be hypertrophy of the intestinal muscularis proximal to such neoplasms.
These tumors metastasize widely, mainly via the lymphatics ( Fig. 1-68) . Involvement of the small intestine leads to metastases mainly in the mesenteric lymph nodes, less commonly to other abdominal nodes, liver, spleen, and lungs. Histologic evidence of metastasis at the time of resection of small intestinal tumors predicts a markedly reduced postsurgical survival time, but even dogs without such evidence may succumb to metastatic disease, albeit with longer survival.
Colonic adenocarcinomas metastasize to colonic, iliac, and other pelvic and abdominal nodes. Metastases also may occur occurs within the same neoplasm. There is no proven prognostic or therapeutic significance to the different histologic patterns. Most are scirrhous, mucus-producing carcinomas that can create mucus-filled epithelial lakes throughout the intestinal wall, accompanied by what is often a great deal of fibrous stromal proliferation. The degree of cytologic maturation may be high, yet the diagnosis of carcinoma is obvious, given the transmural invasive behavior. Less commonly, the tumor cells invade in a tubular or acinar pattern, which tends to be less scirrhous, or as scattered individual anaplastic epithelial cells, accompanied by a great deal of desmoplastic fibrous tissue, so that recognizing carcinoma (in contrast to stromal malignancy or postinflammatory reactive fibrosis) may be challenging. In almost all cases, however, the tumor cells produce mucus, which may be revealed by periodic acid-Schiff staining. Formation of signet ring cells (an epithelial cell with the nucleus displaced to the periphery by a single large clear cytoplasmic vacuole) is relatively common.
The histologic diagnosis is best made with a full-thickness biopsy. The submucosal and transmural portions of the tumor are routinely larger and more readily identified as malignancy than the mucosal portion of the tumor, which endoscopic biopsies may not capture.
Alternatively, especially when large deep ulcerative lesions are biopsied endoscopically, only the necrosis, inflammation, and fibrosis that accompany neoplastic cells may be captured. On the other hand, a false-positive diagnosis may be made when attempting to distinguish early carcinoma (especially gastric carcinoma) from dysplastic repair of recent ulceration; in such cases, a full-thickness biopsy to detect invasion is more reliable than the best endoscopic sample.
Adenocarcinoma of the stomach is most frequently reported in dogs, usually in animals <10 years of age. It is the most common gastrointestinal adenocarcinoma in dogs, and the most common gastric neoplasm in that species. Males predominate in the population with gastric cancer, and more than half of gastric adenocarcinomas in dogs occur in the pyloric region. Breed predisposition has been reported in multiple breeds including the Tervuren, Bouvier des Flandres, Groenendael, Collie, Standard Poodle, and Norwegian Elkhound. In the Lundehund, there may be a relationship to the chronic gastritis common in that breed, but otherwise no causal association is recognized in dogs.
The antrum and pylorus are common sites for development of gastric adenocarcinoma in the dog. Grossly, some gastric neoplasms appear as nonulcerating, firm thickenings involving most of the gastric wall and causing loss of the normal rugal pattern on the mucosal surface ( Fig. 1-67) . Others are more localized plaque-like thickenings that tend to obliterate rugae and ulcerate centrally. Ulceration occurs in more than half of canine gastric adenocarcinomas. Surface proliferation or irregularity other than ulceration is very uncommon in gastric carcinoma in dogs. Cut sections through the stomach wall invaded by carcinoma reveal edema and pale, firm fibrous tissue. Induration or plaque-like pale masses may be evident on the serosa, where the pale outline of infiltrated lymphatics may be prominent. Widespread gastric mural fibrosis and thickening, the result of desmoplasia induced by the malignant epithelium, cause linitis plastica, the so-called "leather bottle" appearance.
Gastric carcinomas in dogs infiltrate the stomach wall aggressively, invading lymphatics, and usually they have metastasized to the local lymph nodes, and often to distant organs, certain fertilizers, and pastures with the weed Cynosaurus cristatus, have been reported from New Zealand. Tumors occur mainly in animals ≥5 years of age. Clinically affected sheep lose weight and have abdominal distention caused by ascites, but most cases are incidental findings at slaughter.
The tumors are usually located in the middle or lower small intestine (Fig. 1-70) , rarely in the colon. They are dense, firm, white masses, 0.5 to several centimeters long and up to 1 cm thick, which may form annular constrictive bands at the in most abdominal organs and the lungs. Implantation on serosal surfaces may result in obstruction of omental and diaphragmatic lymphatics, leading to ascites. In a few cases malignant cells may spread retrograde in the lymphatics of the abdomen and pelvic limbs, causing edema of the abdominal wall and legs. Dogs with annular colorectal carcinomas have a much shorter survival period compared to dogs that have a single, pedunculated polypoid tumor in this location. The etiopathogenesis of colonic carcinomas in dogs is uncertain, but there appears to be progression to malignancy from benign adenomatous lesions in at least some instances. Colorectal adenocarcinoma in the dog has been used as a model of human colon cancer with common features in tumorigenesis being identified. β-Catenin and cyclooxygenase-2 are overexpressed in malignant colonic epithelial cells in some cases, as they are in humans. In addition, adenomatous polyposis coli (APC), a protein encoded by the tumor suppressor gene APC, is frequently altered in sporadic canine colon adenomas and adenocarcinoma as it is in human colon tumors and changes in this gene may be an early event in tumor development.
In cats, intestinal adenocarcinoma is less prevalent than lymphosarcoma, but it is relatively more prevalent in cats than in dogs. Carcinomas of the intestine are more prevalent in Siamese cats than in other breeds. As in dogs, a higher prevalence of this tumor has been reported in males than females. The mean age of cats with intestinal carcinomas is 10-11 years.
The ileum is the most common site affected, followed by the jejunum. Carcinomas occasionally arise in the large intestine, and when the tumor is located at the ileocecal junction, both the large and small intestine usually are involved. The clinical signs and gross appearance are similar to those in dogs.
The microscopic appearance of intestinal carcinomas in cats is typical (Fig. 1-69) , except that osteochondroid metaplasia of the stroma may be a feature. The rare carcinomas involving the large intestine have tended to be papillary, better differentiated, and less scirrhous than carcinomas involving the small intestine.
Intestinal adenocarcinoma is relatively common in sheep in New Zealand, the United Kingdom, Scotland, Iceland, Norway, and southeastern Australia; in New Zealand and Australia there is a high prevalence in breeds used for fat lamb production. The cause of the high prevalence is unknown, but may be related to exposure to bracken fern or other unidentified carcinogens. Other associations, such as heavy use of
Hematogenous spread to the liver, lung, kidney, uterus, and ovaries may occur in cattle.
Adenomatous hyperplasia occurs as focal papillary or papillotubular proliferation of surface epithelium anywhere in the gastrointestinal tract. In the stomach (Fig. 1-72) , it is to be distinguished from chronic hypertrophic pyloric gastropathy, discussed with pyloric obstruction. The most common site is the distal rectum of middle-aged dogs, within 10 cm of the anal-rectal margin. Given a variety of names, such as adenomatous hyperplasia, papillotubular adenoma, colorectal polyp or adenoma, and polypoid carcinoma in situ, we refer to it as rectal papillary adenoma. It occurs in dogs of almost any age, and is usually a single nodule easily managed by adequate surgical excision. Tenesmus, prolapse of the polyp, rectal bleeding following defecation, chronic dyschezia, and diarrhea are the most common signs. Some, but not all, surveys indicate that this tumor is more common in males.
Macroscopically, the tumor is usually sessile or slightly pedunculated, varying from 1 cm to several centimeters in affected site. Cauliflower-like growths may be evident on the serosal surface. Polyps or plaques may protrude into the lumen, but ulceration of the mucosa is uncommon. The distal edge of the tumor is generally well demarcated. There is dilation of the intestine proximal to the lesion. Metastatic implantations on serosal surfaces are common and these appear as opaque to white plaques or diffusely thickened areas, which must be differentiated from mesothelioma. Obstruction of serosal lymphatics by tumor emboli may lead to ascites. Lung and liver metastases are rare.
Microscopically, the tumor is characterized by solid sheets or nests of well-differentiated to highly anaplastic polyhedral, cuboidal, or columnar epithelial cells that may form irregular acinar structures. They may be distributed singly, or in small aggregates, and are often difficult to detect in the heavy fibrous desmoplastic response. The neoplastic cells infiltrate the bowel wall along lymphatics, vessels, and nerve trunks, through to the serosal surface, whence they spread to the mesenteric lymph nodes. This is apparently followed by retrograde lymphogenous metastasis to the gut wall proximal to the primary tumor. These secondary tumors are particularly responsible for constriction of the gut lumen. Sclerotic masses with anaplastic epithelial cells, many of which are periodic acid-Schiff-positive, are located on the serosal surfaces of the abdominal organs but rarely infiltrate the parenchyma. Argentaffin cells may form part of some intestinal carcinomas, especially in lymph node metastases. Mineralization and osseous metaplasia may develop in the stroma.
Intestinal carcinomas are generally rare in cattle ( Fig. 1-71) , goats, horses, and swine. In horses, intestinal adenocarcinomas represent <1% of equine neoplasms and are found less frequently than intestinal lymphoma. In cattle, intestinal adenocarcinoma is associated with bracken fern, papillomavirus, and upper alimentary cancer (see section on Neoplasia of the esophagus and forestomachs). Most of these tumors in cattle are adenomas and three types are recognized: (1) a sessile plaque; (2) an adenomatous polyp; and (3) a more proliferative adenoma of the ampullae in which the bile and pancreatic ducts open into the duodenum. Intestinal carcinomas are usually an incidental finding at meat inspection. The location, morphology, and routes of metastasis are similar to those described for sheep, except that serosal lesions are less obvious. In cattle, intestinal polyps are usually an incidental finding, except in those cases in which they are large enough to cause partial obstruction. The tumors are raised, often pedunculated, gray-to-brown masses on the mucosal surface. They may occur singly, in grape-like clusters, or they may be scattered. Microscopically they resemble benign rectal polyps in the dog, but they may be capable of malignant transformation (see earlier in this chapter).
Adenomatous polyps frequently occur in sheep with intestinal carcinoma. Hyperplastic polyps occur in the small intestines of lambs and goats with chronic coccidiosis (see section on Infectious and parasitic diseases of the alimentary tract).
The proliferative lesions caused by Lawsonia intracellularis in horses and swine may impart a polypoid appearance to the intestinal mucosa grossly, and microscopically should not be mistaken for adenomatous neoplasia.
Carcinoids arise from neuroendocrine cells that are scattered in the mucosa of a wide variety of organs, including the stomach and the intestine. These cells secrete low-molecularweight polypeptide hormones, such as secretin, somatostatin, diameter. It may be firm or friable and hemorrhagic; the mucosal surface is often ulcerated. Microscopically, the polyp may have a predominantly tubular or papillary growth pattern ( Fig. 1-73) . In welloriented specimens the tubular pattern is characterized by branching crypts that are lined by generally well-differentiated columnar-to-cuboidal pseudostratified epithelial cells. The papillary type consists of villus-like projections of proprial connective tissue that are covered by a layer of pseudostratified columnar epithelial cells. There may be cytoplasmic basophilia, loss of nuclear polarity, and prominent nucleoli in epithelium in both types of polyps. The number of mitotic figures varies, often within the same polyp. These tumors often appear to originate in the superficial portion of the crypts, deeper portions of which may remain normal, with tubules or slender papillae of hyperchromatic tumor cells above them. The stalk of the tumor is highly vascular and is continuous with the lamina propria or submucosa of the rectum. The tumors are generally well demarcated from the adjacent normal mucosa. The amount of mucin in the epithelium varies considerably, and it is often absent, especially in more dysplastic cells. Some polyps have a malignant appearance histologically. These are characterized by the presence of anaplastic epithelial cells in situ in the mucosa, and, in some cases, invading the propria and adjacent submucosa ( Fig. 1-74 ).
There is limited information on the biological behavior of these tumors. In dogs, adequate surgical removal usually results in complete recovery. Some are interpreted at presentation as carcinoma in situ, based on cytologic characteristics, and deep biopsies and/or complete excision of these polyps are essential to rule out local invasion or infiltration of lymphatics, which should be sought in specimens with epithelial morphology suggesting malignancy. Polyps that are >1 cm in diameter tend to have cells with a more anaplastic appearance, and recurrence is most probable in cases interpreted as carcinoma in situ, those with multiple masses, or those with more diffuse colonic involvement.
In other species, polypoid and adenomatous tumors are uncommon. Benign adenomatous polyps are reported in the stomach and duodenum of cats, predominantly middle-aged males of Asian breeds. They are presented with vomition,
Squamous cell carcinomas derived from the mucosa of the pars esophagea are the most common gastric tumor in horses. They occur predominantly in middle-aged or older animals, which are usually presented in an advanced state, with unexplained anorexia, occasionally dysphagia, and weight loss sometimes progressing rapidly to emaciation. At autopsy there may be peritoneal effusion, and there is usually evidence of the neoplasm as plaques of proliferative or scirrhous tissue on the serosa of the stomach. There also may be peritoneal implants, especially on intestine, testes, omentum, parietal abdominal surfaces, and diaphragm; direct extension to adjacent organs, including liver, spleen, and diaphragm, with progression to the pleural space; and sometimes distant metastases, usually in liver and lung. The appearance of the tumor on serosal surfaces resembles mesothelioma, with smooth creamy plaques or nodules up to 2-4 cm in diameter.
The origin of these lesions is usually a fungating cauliflowerlike mass 10-40 cm in diameter, with superficial fissures, projecting above the surface of the pars esophagea ( Fig. 1-75 ). Sometimes these lesions are superficially more ulcerative than proliferative. Necrosis and hemorrhage are evident in the tumor mass, which is usually well demarcated from adjacent normal squamous mucosa. Occasionally the tumor extends into the distal esophagus, and may obstruct it. Microscopically, these neoplasms are typical squamous cell carcinomas, invading in cords or nests of cells through the gastric wall. They and cholecystokinin, or they are part of the amine precursor uptake decarboxylation (APUD) group, producing compounds such as serotonin (5-hydroxytryptamine).
Carcinoid tumors of the gastrointestinal tract are rare in domestic animals. They have been reported mainly in aged dogs and very rarely in the cat, cow, and horse. In dogs, most carcinoids are located in the duodenum, colon, and rectum, and only rarely in the stomach and lower small intestine. Clinically, they may cause intestinal obstruction, and anemia resulting from ulceration and hemorrhage. Associated diarrhea in some cases can speculatively be attributed to hypersecretion of functional polypeptide hormones. Rectal carcinoids may protrude from the anus and resemble adenomatous polyps.
Macroscopically, carcinoids are usually lobulated, firm, dark-red to cream-colored masses a few millimeters to perhaps 2 cm in diameter. They seem to arise deep in the mucosa, often forming submucosal or subserosal nodules, perhaps with ulceration of overlying mucosa, and infiltrating transmurally and into the mesentery.
Microscopically, carcinoids have a distinct endocrine appearance. Round or oval to polyhedral cells have abundant finely granular eosinophilic or vacuolated cytoplasm and vesiculate nuclei with prominent nucleoli. They form nests, ribbons, rosettes, or diffuse sheets in the mucosa, submucosa, and muscularis. A fine vascularized fibrous stroma often divides the tumor masses into pseudoalveolar arrays. Amyloid may be present in intercellular and perivascular spaces. Uninuclear megalocytes and multinucleated giant cells are present occasionally.
A diagnosis of carcinoid is based on the endocrine histologic pattern, cytoplasmic argentaffinic and argyrophilic granularity, immunohistochemical identification of specific secretory products, and the typical ultrastructural appearance. The histochemical reactions may be negative, especially in rectal carcinoids, and they also may be lost during fixation in formalin or by autolysis prior to fixation, as may immunohistochemical reactivity. These cells are routinely positive with immunohistochemical staining for neuron-specific enolase and chromogranin, as are most neuroendocrine tumors, and then with one or more of the specific immune probes related to the peptides being produced. An increased concentration of specific secretory products may be detected in circulation.
Electron microscopic examination helps to differentiate carcinoids from intestinal mast cell tumors. Carcinoid cells have dense, round-to-oval, membrane-bound secretory granules in the cytoplasm, which vary in diameter from 75 to 300 nm. They have abundant rough endoplasmic reticulum and the plasma membrane forms interdigitating processes. Carcinoid cells are Schiff-negative and do not show metachromasia with Giemsa stains.
Data on biological behavior of intestinal carcinoids in dogs are limited. Most cases reported have been malignant. There may be extensive invasion of the gut wall and veins, with metastasis, especially to the liver. The few cases that have been described in other species have features similar to those described in dogs.
Goblet cell carcinoids (adenocarcinoids, mucinous carcinoids) are tumors that are most commonly found in the appendix of humans, with features of both carcinoids and adenocarcinomas. There is a single report of such a tumor in the rectum of a dog. Microscopically goblet cell carcinoids have distinct areas of mucinous adenocarcinoma and carcinoid The tumors are located in the small intestine, stomach, and colon in that order of frequency. They are soft-to-firm, creamcolored masses located in the submucosa that may protrude into the gut lumen. The overlying mucosa may be ulcerated. The masses can be nodular to diffuse and several sections of the gut are usually affected. The mesenteric nodes are often enlarged and the liver is frequently involved at the time of presentation.
The majority of primary gastrointestinal lymphomas in dogs are epitheliotropic T-cell tumors based on immunohistochemical reactions, the remainder being mixed, B-cell, or indeterminate. Microscopically, in typical cases of epitheliotropic intestinal lymphoma, the mucosal, submucosal, and muscular architecture is effaced by a population of monotypic large lymphocytes with variable nuclear morphology and obvious mitotic activity. The crypts are effaced as they become infiltrated by neoplastic cells. In contrast to cats, alimentary lymphoma in dogs is usually large lymphoblastic type with small cell neoplastic infiltrates being uncommon.
The lesions of very early lymphoma are more challenging. They are distinguished from chronic inflammatory bowel disease by the relatively monotypic lymphocyte population and the intraepithelial infiltration of lymphocytes that obscures the distinction between lamina propria and epithelium. Even with these criteria, differentiation of early neoplastic from inflammatory disease can be problematic because residual plasma cells, eosinophils, and benign lymphocytes of the normal lamina propria persist among the neoplastic lymphocyte population. Similarly, not all cases of intestinal lymphoma exhibit epitheliotropic growth, and there is overlap between neoplastic epithelial invasion and the increase in intraepithelial lymphocytes that is commonly seen with inflammatory disease.
The key is not just the presence of the lymphocytes, but the obliteration of the proprial:epithelial boundary. Once the lymphoma effaces crypts or invades submucosa, diagnosis should not be problematic, but full-thickness biopsies from several areas of the intestine may help differentiate chronic inflammatory bowel disease from intestinal lymphoma.
Lymphoplasmacytic enteritis in the dog, particularly the Basenji, may represent a prelymphomatous stage similar to immunoproliferative small intestinal disease in humans. The latter is characterized by diffuse lymphoplasmacytic infiltration of the small intestinal mucosa that results in malabsorption, and predisposes to the development of primary enteromesenteric lymphoma.
In cats, the situation is substantially more complicated. There are at least three histologic categories of gastrointestinal lymphoma, small cell lymphocytic villus lymphoma, large cell lymphoblastic lymphoma, and large granular cell lymphoma. The small cell lymphomas tend to have a longer clinical course, whereas the lymphoblastic (T-and B-cell) and large granular cell lymphomas are associated with more rapidly progressive disease. The jejunum may be the site of highest incidence of T-cell lymphoma in the cat.
Small cell lymphocytic villus lymphoma is a T-cell lymphoma that typically begins at the base of the villi within the small intestine of old cats, and is the most frequent type of intestinal lymphoma in geriatric cats. Clustering of suspiciously monotypic small hyperchromatic lymphocytes within the lamina propria just at the base of villi is an exceedingly common observation in cats 15 years of age and older. It is not clear whether this is incipient lymphoma or a normal finding. The number of such cells may vary substantially from induce desmoplasia, imparting a scirrhous, firm texture and appearance to the thickened gastric wall and to the peritoneal and pleural implants. One such tumor has been reported as a cause of pseudohyperparathyroidism in a horse.
A squamous cell carcinoma is reported arising from the pyloric gland mucosa in a dog. Patnaik
Gastrointestinal lymphomas occur in most species and are common in cats. These neoplasms may be primary or part of the systemic or multicentric form of the neoplasm (see Vol. 3, Hematopoietic system). Primary lymphoma of the intestine includes cases having malignant lymphocytic infiltrates in the intestine, with or without involvement of the abdominal organs or bone marrow, but with no lesions in the thorax or peripheral sites. Lymphoma is the most common gastrointestinal neoplasm in companion animals, more prevalent in cats than dogs. It can be segmental within any portion of the gastrointestinal tract, or diffuse. Although the gastrointestinal tract may be involved in advanced multicentric lymphoma in dogs, such cases are rarely submitted for biopsy because the diagnosis has already been made based on lesions elsewhere. Most samples submitted for histologic assessment are from cases suspected of having primary gastrointestinal lymphoma. In cats, almost all cases examined at biopsy are primary within the stomach or intestine.
In both species, spread outside intestine is usually to mesenteric lymph nodes and to liver, and less commonly beyond. In liver, the neoplasm infiltrates in a characteristic portal pattern that should not be mistaken for chronic portal hepatitis or lymphocytic cholangiohepatitis. In lymphoma, the tumor cells often form layers 10-20 deep in the portal tract, and cholangiolar proliferation, fibrosis, and hepatocellular atrophy are absent. In advanced hepatic disease, the cells also surround central veins. Although scattered tumor cells may occur within the sinusoids, a primarily sinusoidal distribution of lymphocytes signals lymphocytic leukemia rather than intestinal lymphoma.
The classification of lymphomas in animals is complex, integrating distribution, histologic and cytologic appearance, and immunophenotype. Most categories are based on lymphomas discovered in lymph nodes or skin; as a group, intestinal lymphomas have received little detailed investigation in this context. Most of the controversy about intestinal lymphoma is related not to its diagnosis, but rather to the relationship (if any) between its classification and subsequent behavior, including response to therapy; currently no clear association is evident.
In dogs, intestinal lymphoma can affect animals from adolescence to old age, with a male sex bias. Nonspecific signs of enteric disease and weight loss may be acute or occur over a period of weeks to months. Hypoproteinemia, probably associated with enteric protein loss, occurs in ~30% of affected dogs.
Further reading McKenzie EC, et al. Gastric In the horse, alimentary lymphoma is a relatively common tumor; most are attributed to B lymphocytes. It occurs mainly in young adults. Affected horses lose condition, likely because of malabsorption and protein loss; in addition they may be anemic, icteric, and have mild intermittent bouts of colic. Diarrhea is inconsistent. Serum albumin often can be decreased, but they are frequently hypergammaglobulinemic. Alimentary lymphoma in horses needs to be differentiated from inflammatory bowel disease.
Macroscopic lesions in horses are usually located in the small intestine, and these are characterized by local to diffuse thickening of the gut wall with prominent rugae on the mucosa. Nodules or plaques with fibrous adhesions may be evident on the serosa. The mesenteric nodes are markedly enlarged. Other nodes may be enlarged, but to a lesser extent. Microscopically, there is diffuse lymphoid infiltration of the lamina propria and submucosa, usually extending transmurally to the serosa. There is marked villus atrophy to the point of complete loss of villi and crypts. Plasmacytoid cells are regularly present in the lamina propria but less numerous in the submucosa. Similar lymphoid cell infiltration involves the mesenteric nodes and the perinodal connective tissue. Other lymph nodes are involved in about half the cases. A plasmacytoid or plasmacytic reaction and occasional giant cells are also present in the nodes. The neoplastic lymphoid cells are probably of B-cell origin and home into the gut-associated lymphoid tissue and the lamina propria of the small intestine.
Epitheliotropic T-cell lymphomas resembling those in dogs, and ulcerating large granular lymphomas caused by T cells, somewhat resembling those described in cats, also occur infrequently in horses. A T-cell lymphoma occurred concurrently with multisystemic eosinophilic epitheliotropic disease in a horse, prompting the suggestion that undetected T-cell lymphoma secreting interleukin-5 may underlie that syndrome. Paraneoplastic eosinophilia has also been associated with intestinal lymphosarcoma in the horse.
In cattle and sheep, alimentary lymphomas are generally part of the adult multicentric form of the disease, and the intestinal lesions resemble the effacing tumors described in other species. More important in cattle is lymphosarcoma of the abomasum, which is common in adult cattle. Diffuse mucosal and submucosal lymphocytic infiltrates or nodular proliferations may occur. Strategically placed pyloric tumor may cause obstruction. Diffuse lesions, thickening the gastric wall, frequently ulcerate, and hemorrhage from such ulcers, as melena, is a common sign. The lymphoid infiltrates are recognizable as firm gray-white tissue in the submucosa and mucosa. Involvement of abomasal lymph nodes is disproportionately slight.
In swine, diffuse gastric lymphosarcoma occurs. The wall of the stomach is thickened by submucosal lymphocytic infiltrates, which sometimes invade the mucosa locally in many areas, producing nodular elevations that may ulcerate. B-cell lymphomas involving the Peyer's patches also have been detected at meat inspection in swine. villus to villus. As these clusters seem to expand, the lymphocytes infiltrate into the overlying epithelium, obliterating the distinction between lamina propria and epithelium. Unlike inflammatory bowel disease, such lesions may be very patchy, and there is no concurrent increase in plasma cells or eosinophils. With time, the lymphocyte population appears to expand throughout the lamina propria and then transmurally. Sixty percent of intestinal T-cell lymphomas have been reported to be epitheliotropic. Microscopically this is demonstrated by increased numbers of intraepithelial lymphocytes within villus and crypt epithelium. The syndrome shares substantial clinical overlap with inflammatory bowel disease in that it is often slowly progressive and it is usually not accompanied by clinical signs related to neoplastic infiltration of liver, spleen, or lymph node, even though there is often microscopic tumor within those organs. The extent of microscopic disease within the intestine is usually much greater than the macroscopic impression at the time of surgery. Determination of T-cell receptor (TCR) rearrangement clonality using PCR has been shown to be an accurate method of diagnosis of small cell lymphoma in cats. Large cell/lymphoblastic lymphoma, in contrast, is characterized by a rapidly progressing transmural lesion that is usually accompanied by clinically palpable intestinal masses and by markedly enlarged mesenteric lymph nodes. Cats of any age may be affected. Most of these are reported as B-cell tumors, although not all investigators concur, and the majority of these high-grade lymphomas have not been subjected to immunophenotyping. It is likely that the incidence of T-cell lymphoma has been underestimated. B-cell lymphomas have been shown to be most common in the stomach and ileocecocolic junction, whereas T-cell lymphomas are most common in the proximal small intestine, especially the jejunum. The tumor resembles canine lymphomas, in that there is usually transmural effacement of intestinal architecture, and obliteration of the structure of affected mesenteric lymph nodes. Many cases differ from canine lymphomas, however, in having marked cellular pleomorphism. The tumor cells may have fairly abundant cytoplasm, nuclear cleavage, and up to 2-fold anisokaryosis. Descriptive names such as "histiocytic lymphoma" for some of these more anaplastic variants are no longer appropriate because immunophenotyping is available to identify the cells more precisely. Lesions are often sharply segmental and the primary lesion can be completely excised. However, the high prevalence of metastatic disease makes surgical cures rare.
Large granular lymphoma is usually a rapidly progressive intestinal lymphoma of cats. The tumor cells are either T cells or natural killer cells. These are medium-to-large lymphocytes with pleomorphic nuclei with frequent clefting. The distinctive features are the large red cytoplasmic granules, and perforin immunoreactivity. In the presence of cleaved nuclei, the large granules may be mistaken for those of eosinophils, but they are larger, rounder, and are more intensely eosinophilic. The cytologic characteristics have also caused such tumors to be attributed to globule leukocytes in the past. The granular cells are not present as a pure population. They are often intermingled with other lymphocyte types and with macrophages, so these invasive and destructive transmural lesions are sometimes confused with transmural granulomatous disease or mast cell tumors. These tumors progress rapidly, with widespread dissemination and even leukemia, and they may perforate affected areas of intestine. c-KIT, but cytology and lack of metachromatic granules when stained with toluidine blue differentiate them.
Ultrastructurally the cytoplasm of gastrointestinal mucosal mast cell tumor cells contains many membrane-bound granules that appear as single or fused vesicles. Fine fibrillar material forms a loose network within these vesicles. A few tumor cells contain electron-dense fibrillar granules or intermediate forms. The crystalline electron-dense granules that are present in connective tissue mast cells, such as those from the skin, are rarely evident.
Metastases occur most often in the mesenteric lymph nodes, followed by the liver, spleen, and, rarely, the lungs. Ulceration of the gastrointestinal mucosa occurs commonly with systemic tissue mast cell tumors in cats and with large cutaneous mastocytomas in dogs, owing to histamine stimulation of acid production by gastric parietal cells. Gastrointestinal ulceration is not a feature of mucosal mast cell tumors of intestinal origin, except perhaps as a result of mucosal effacement by the tumor.
Plasmacytomas of the lower gastrointestinal tract are uncommon neoplasms in dogs, and rare in cats and other species. They are encountered most frequently in the submucosa of the distal colon and rectum of dogs, where they are associated with signs of large-bowel diarrhea and bleeding.
Histologically they resemble plasmacytomas of the skin, oral cavity, or larynx. The tumor is formed by solid packets of pleomorphic round cells with various degrees of plasmacytoid maturation, especially at the periphery of the tumor. There is frequent nuclear hyperchromasia and convolution. The cells are typically arranged in solid endocrine-like packets of 10-20 cells surrounded by a delicate fibrovascular stroma, and there may be AL amyloid deposition among the tumor cells. A few syncytial plasmacytoid or histiocytic cells may be evident. The majority of the tumor growth is submucosal, with a little bit of overflow into the deep half of the lamina propria. Most tumors have a discrete local growth habit amenable to surgical cure. A small proportion exhibit more aggressive behavior, including invasion of tunica muscularis, and some spread to regional lymph nodes and spleen, perhaps producing a monoclonal gammopathy. Platz SJ, et
These tumors are uncommon. They occur in aged dogs, and occasionally in cats, with signs such as vomition, diarrhea, and melena. They are seen in biopsies as invasive round cell tumors that can resemble carcinoids, lymphomas, and gastrointestinal stromal tumors; definitive diagnosis requires histochemical and possibly immunohistochemical investigations. Primary mast cell tumors of the gastrointestinal tract are comprised of mucosal mast cells, which differ from connective tissue mast cells, such as those found in skin, in having few granules, which usually do not stain well in formalin-fixed tissue. Abnormal mast cells do not appear in circulation in animals with these tumors. Mast cell tumors are most commonly seen in stomach, and least common in the colon. Affected areas in the mucosa are tan-colored, firm, thickened, possibly ulcerated, and may be 1 cm to several centimeters in size. The tissue architecture is effaced by a population of granular round cells accompanied by variable numbers of eosinophils. They generally grow in infiltrative cords, but occasionally form endocrine-like packets surrounded by a delicate fibrovascular stroma. There is a wide range in the cytologic appearance. Some tumors are populated by fairly mature mast cells with abundant cytoplasmic granularity easily demonstrated with toluidine blue. Others are populated by anaplastic and pleomorphic round cells or spindle-shaped cells, sometimes with giant nuclei or forming syncytia, in which cytoplasmic granules with metachromatic staining, while present, may be difficult to observe. Those with abundant metachromatic granules must be differentiated from connective tissue mast cell tumors metastatic to the gastrointestinal tract, in which case lesions should be sought in skin and elsewhere. There can be marked variation in the number of eosinophils in the tumor, and they are not definitive because eosinophils are also common in some intestinal lymphomas, and as part of the background cell population in normal lamina propria. In cats, a subset of intestinal mast cell tumors is associated with a significant collagen stroma.
Gastrointestinal mucosal mast cell tumors are differentiated using a suite of histochemical and immunohistochemical characteristics. They have at least a few metachromatic granules when stained with toluidine blue, and many tumors have at least some cells that stain with alcian blue. They stain immunohistochemically positive for mast cell tryptase and c-KIT (CD117), but negatively for CD3 (distinguishing them from most T-cell lymphomas), cytokeratin (distinguishing them from carcinomas), and chromogranin and synaptophysin (distinguishing them from carcinoids). However, only 33% of feline gastrointestinal mast cell tumors were positive for c-KIT. Gastrointestinal stromal tumors should be positive for
Further reading Howl figures are evident. Areas of coagulative necrosis may occur in the tumor mass. Leiomyosarcomas often resemble leiomyomas grossly, but they are invasive rather than circumscribed, and may ulcerate mucosa. The cells resemble those in leiomyomas in general cytology, but there is usually some degree of anisokaryosis, multiple nucleoli, scattered bizarre nuclei, and obvious mitotic activity. There may be necrosis in the mass and a mild lymphocytic or eosinophilic inflammatory infiltrate.
Gastrointestinal stromal tumors may be demarcated and grow by expansion, sometimes forming exophytic nodules on the serosal surface, or they may be transmural and invasive. Overlying mucosa, although usually intact, may ulcerate. They are usually comprised of spindle cells arranged as interlacing fascicles, or in a storiform (whorling or matted) pattern, with oval nuclei, and a somewhat basophilic cytoplasm with indistinct boundaries. A minority of cases may have somewhat epithelioid tumor cells arranged in trabeculae or solid sheets, perhaps with a somewhat myxoid intercellular matrix, often infiltrating between normal smooth-muscle fascicles. Epithelioid tumors are thought to reflect some degree of neural differentiation, whereas a storiform pattern is considered to reflect a poor degree of differentiation. There may be nuclear pleomorphism in all patterns of tumor, and mitotic figures are usually evident and may be common. Hemorrhage or necrosis may be present within the tumor, and lymphocytic and/or eosinophilic infiltrates can occur.
The difficulty in determining the prognosis of these tumors in dogs has not changed with the recognition that the great majority are gastrointestinal stromal tumors rather than leiomyosarcomas. No objective criteria or nomenclature differentiate benign from malignant gastrointestinal stromal tumors. In humans, larger tumor size and high mitotic activity are considered to be poor prognostic indicators, but there are no data substantiating these tendencies in animals.
Invasion into the mucosa causes ulceration and cavitation on the luminal surface ( Fig. 1-76) , which may lead to perforation of the bowel. Even in the absence of perforation, microorganisms from the gut lumen may cause local abscessation and secondary septic peritonitis in which there is intermingling of suppuration, granulation tissue, and tumor cells. Based on studies carried out before revision of the nomenclature,
The intestinal stromal tumors include leiomyoma, leiomyosarcoma, gastrointestinal stromal tumor, and very uncommon examples of almost every other type of stromal neoplasm, including hemangiosarcoma, nerve sheath tumors, fibroma and fibrosarcoma, osteosarcoma, and even lipoma. Ganglioneuromas have been described in dogs, a sow, horse, and a kitten. Other mesenchymal tumors include fibrous histiocytoma in a cow and histiocytic sarcoma in a dog.
Leiomyoma, leiomyosarcoma, and gastrointestinal stromal tumor are considered together, because recognition of the latter prompted re-evaluation of the criteria for diagnosis of leiomyosarcoma; older literature should be read with this in mind. Together, they are more common in dogs than other types of mesenchymal tumors except lymphosarcoma, and they also occur with some frequency in horses. Smoothmuscle tumors occur uncommonly in cats, equally prevalent in stomach, small intestine, and colon. They occur only rarely, if at all, in other species.
Leiomyoma and leiomyosarcoma represent the two extremes of a morphologic continuum, which included, toward the malignant end of the spectrum, tumors now classified as gastrointestinal stromal tumor. The latter are thought to be derived from interstitial cells of Cajal, or from a stem cell precursor to both those cells and smooth-muscle cells, and they are distinguished by expressing c-KIT (CD117) antigen. Although some may contain smooth-muscle actin, they rarely express desmin. Leiomyomas and leiomyosarcomas, on the other hand, do not express c-KIT, and should express smoothmuscle actin and desmin. Immunohistochemical reactivity is the definitive means of differentiating these tumors, but may be adversely affected by autolysis and duration of fixation, which must be considered in such studies. However, leiomyomas can be recognized based on their histology and cytology.
In dogs, as a group these tumors occur in older animals, in many of which they may be asymptomatic and incidental. Signs can include weight loss, lethargy, anorexia, anemia resulting from intestinal hemorrhage, abdominal pain, palpable abdominal masses, diarrhea, vomition, and dehydration or other signs of gastrointestinal obstruction. Based on limited studies in which the immunophenotype of stromal tumors of the gut has been determined, leiomyomas are most common and tend to occur in the esophagus and stomach of predominantly male dogs. Gastrointestinal stromal tumors are the next most common, and may occur in the stomach and intestine, with a tendency to predominate in the large bowel; sex distribution is equal. They have a spectrum of behavior from benign to malignant, and include tumors that were diagnosed as leiomyosarcomas before revision of terminology. Leiomyosarcomas are seemingly least common, and tend to occur in the intestine, with no apparent sex predisposition.
Most symptomatic tumors of this type are expansile nodules arising in the muscularis externa and can be cured by surgical excision, as is certainly the case with leiomyoma. However, a minority, perhaps up to 30%, of the other types have metastasized by the time that they are discovered.
Leiomyomas are sharply circumscribed masses of welldifferentiated smooth-muscle cells, and generally lie beneath an intact mucosa, although they may deform the serosal or mucosal profile, and ulceration, perhaps related to pressure necrosis, can occur. They are comprised of swirling bundles of uniform fusiform cells, with abundant eosinophilic cytoplasm, and a central nucleus with blunt ends; usually no mitotic conditions or the steps required at autopsy to confirm a diagnosis are discussed. The diseases causing gastritis, and those causing typhlocolitis in all species, have been discussed in previous sections. They are only briefly reiterated here; further information on the pathogenesis and diagnosis of most infectious and parasitic conditions is found in the next section.
Diarrhea causing dehydration, metabolic acidosis, and electrolyte depletion is an important cause of morbidity and mortality in neonatal piglets, calves, lambs, and kids, and to a lesser extent in foals. Several classes of agents occur in most species of large animals, and mixed infections often occur, such as Escherichia coli, coronavirus, rotavirus, and Cryptosporidium parvum. These and some other less common agents produce diarrhea in neonatal animals, the etiology of which cannot be readily differentiated on clinical grounds or on the basis of gross postmortem examination.
Undifferentiated diarrhea of neonatal animals requires etiologic diagnosis if appropriate advice is to be rendered regarding prevention and management of the disease. Many of the agents involved are either transiently present or produce lesions such as villus atrophy that is easily obscured by autolysis, which significantly hinders accurate diagnosis. To overcome these obstacles, one or more live untreated animals in the early phase of clinical disease and representative of the herd problem must be examined. They should be euthanized and examined immediately using an autopsy procedure modified so that specimens of small intestine are formalin-fixed within a few minutes of death, and so that appropriate samples of tissue and content are quickly collected to facilitate a complete etiologic investigation.
The prevalence of diarrhea and potentially associated agents in neonates is expected to vary considerably on the basis of locality, climate, season, and the management system, as well as by species. The presence of specific microscopic lesions and their distribution within the intestine may suggest an etiology. Bacterial culture or rapid immunologic methods using gut content, formalin-fixed or frozen tissues may identify a bacterial or viral agent. Some agents, such as cryptosporidia and coccidia, may be identified in Giemsa-stained mucosal scrapings or tissue sections. In each species, undifferentiated neonatal diarrhea may be caused by other less common agents; therefore care is required to establish an accurate diagnosis, and to distinguish from other potential diseases that may occur in each species.
In all species, neonates succumbing to the effects of undifferentiated diarrhea are overtly dehydrated. The eyes are sunken in the orbits, the skin lacks elasticity, and the subcutis and mucous membranes are tacky. There is usually fecal staining on the perineum, but rare acute cases may display signs of dehydration without significant diarrhea. Animals with diarrhea may continue to suckle during the early phase of their illness; therefore a milk clot or curd may be present in the stomach and internal fat depots may be adequate. Animals that lose interest in feed because of more chronic disease and those taken off nutrients may have serous atrophy of fat and appear cachectic. The small intestine is flaccid and dilated with thin walls, and increased fluid content is present throughout the full intestinal length. The content is usually watery and clear green-yellow and often separates into 2 phases, the more solid of which appears to consist of small masses of tumors in cecum and colon, where gastrointestinal stromal tumors predominate, were determined to have a relatively high metastatic risk. They may metastasize to the mesenteric nodes, mesentery, and liver, but in general, these tumors have a more favorable prognosis after complete resection than other malignant neoplasms of the lower gastrointestinal tract.
The large intestinal tumors may also cause paraneoplastic hypoglycemia, owing to the production of insulin-like growth factors that may precipitate the search for a neoplasm. Production of erythropoietin, resulting in erythrocytosis, also has been documented.
In old horses, tumors of the intestine have been described that in many cases meet morphologic or immunohistochemical criteria for gastrointestinal stromal tumor, as it has been described above. Most are encountered incidentally, at surgery, meat inspection, or autopsy, but tumors of this type, or previously diagnosed as leiomyomas, may cause intermittent bouts of colic that become more frequent with time. They occur in the stomach, small intestine, and most frequently in the cecum and colon, as encapsulated, moderately firm, multinodular, pale tan, or hemorrhagic masses in the muscularis or subserosa, protruding on the serosal surface, or rarely, as somewhat pedunculated tumors projecting from the serosa or into the lumen. They may vary from 1 to >10 cm in diameter, and are usually solitary, but occasionally may be multiple. Malignancy is not described.
The diagnosis of gastrointestinal disease is facilitated by knowledge of the entities that may be expected in a particular species and age group, and the clinicopathologic syndromes with which they are associated. In this section, etiologic entities associated with various syndromes in each domestic species are briefly summarized. The salient diagnostic features of some in hypogammaglobulinemic neonates. Enterohemorrhagic colibacillosis, caused by Shiga toxin (verotoxin) producing E. coli, seen as fibrinohemorrhagic enterocolitis, occurs in calves usually within the first 2 weeks of life.
Rotavirus and bovine coronavirus are common, and responsible for a significant proportion of neonatal calf diarrhea, alone, together, or in combination with other agents. Disease caused by these viruses may begin at any time in the first 1 or 2 weeks of life. Both viruses produce villus atrophy by causing lysis or exfoliation of surface enterocytes. Recent prevalence data suggest that bovine rotavirus group A plays a primary role in neonatal calf diarrhea. Bovine coronavirus also commonly causes microscopic and occasionally gross lesions in the colon. Both agents may be confirmed by demonstration of viral antigen or nucleic acids in feces or intestinal epithelial cells.
Cryptosporidium parvum, a minute apicomplexan protist, is very commonly associated with undifferentiated diarrhea and villus atrophy in calves often along with other pathogens, particularly viruses. It is most common in animals ∼4-20 days of age. Cryptosporidia organisms can be identified in their intracellular but extracytoplasmic location, along the brush border of epithelium on villi, and in mucosal smears, fecal smears, or flotations.
Beta toxin-producing Clostridium perfringens type C infection can occur in calves, and causes acute hemorrhagic and necrotizing enteritis with enterotoxemia. Confirmation is by detection of beta toxin in the intestinal contents or feces by ELISA. Clostridium perfringens type B may be a rare cause of hemorrhagic enteritis in neonatal calves. Clostridium perfringens type A also has been suggested to cause necrotizing and hemorrhagic enterocolitis in calves; however, it is a common inhabitant in normal calf intestine and its role as a primary pathogen remains unclear.
Salmonellosis, usually caused by Salmonella enterica serovar Typhimurium, or S. Dublin or S. Muenster in enzootic areas, occurs in calves as young as 4 or 5 days of age. Salmonellosis may mimic undifferentiated neonatal diarrhea, particularly in peracute cases; later there is often development of fibrinous and necrotizing enterocolitis, with septicemia in a proportion of cases.
Bovine herpesvirus 1 (infectious bovine rhinotracheitis virus) in calves <2 weeks of age causes multifocal necrotizing lesions throughout the gastrointestinal tract; these are often seen together with lesions in other organs because of systemic infection. Bovine viral diarrhea virus can be implicated in enteritis of calves as young as 1 week of age, on the basis of microscopic lesions in the small intestine and colon similar to those found in older animals, with confirmation by virus isolation or detection of viral antigen or nucleic acid.
Bovine torovirus (formerly Breda virus), in genus Torovirus and family Coronaviridae, has been documented as the sole pathogen from diarrheic calves, usually in calves <3 weeks of age. Although disease is uncommon, serologic surveys suggests that exposure is widespread. The pathogenesis and lesions caused by this virus are similar to other coronavirus infections, although epithelial cells from the lower half of the villi of small intestine and crypt cells of the ileum, colon, and cecum appear to be the first cells infected. Astrovirus infections usually appear to be subclinical, and their implication as a cause of diarrhea in calves is rare. Astrovirus infects dome enterocytes overlying the Peyer's patches causing mild transient villus atrophy. clotted milk or mucus ( Fig. 1-77) . Sometimes the content is more homogeneous and creamy in texture; however, in animals examined sometime after death, this appearance is due to postmortem autolysis of the epithelium. The large intestine also contains fluid, creamy or pasty content, usually white or yellow. The mucosa of the small intestine may appear glistening and mildly congested; that in the large intestine is usually unremarkable. The forestomachs in ruminants that have been tube fed or in which the ruminoreticular groove has apparently failed to close, may contain sour fermented milk or milk replacer and the mucosa may be mildly reddened. The abomasal mucosa of some calves may contain scattered focal stress-associated hemorrhages. In piglets, urates may precipitate in the renal medulla and pelvis as the result of dehydration. The spectrum of agents associated with diarrhea in neonates of each species is considered later in this chapter.
Several infectious agents have been associated with undifferentiated diarrhea in calves less than ∼3 weeks of age, some of which can be distinguished on the basis of gross lesions at postmortem examination. Frequently combinations of these agents occur together, or in sequence; compared with single agent infections, the consequences of combined infections often appear to be more severe. The diagnosis of these infectious problems in a herd can be complex, and examination of more than one untreated animal early in the course of disease is desirable. Causes of noninfectious diarrhea should be considered and eliminated; usually these involve nutritional or management problems.
Enterotoxigenic E. coli is probably the most common single cause of undifferentiated neonatal diarrhea in neonatal calves. Little or no morphologic change may be evident in tissue section, although bacteria are seen attached to the surface of enterocytes on villi. The disease usually occurs within the first 4 days of life, and is confirmed using culture along with molecular techniques to identify virulence factors and toxins. Enterotoxigenic colibacillosis is distinct from the less-common enteropathogenic colibacillosis, which occurs in older calves and is caused by attaching and effacing E. coli, and from septicemic colibacillosis or other gram-negative infections seen and possibly diarrhea. Enterotoxin-producing Bacteroides fragilis has been implicated as a cause of diarrhea in neonatal lambs. Astrovirus has been found in lambs and experimentally produces diarrhea. An adenovirus antigenically related to ovine adenovirus-2 is reported as a cause of enteritis in goat kids. Strongyloides may be associated with diarrhea in ruminants only a few weeks old.
Agents commonly implicated in undifferentiated diarrhea in piglets <3 weeks of age include enterotoxigenic E. coli, coronaviruses, rotavirus, and Cystoisospora suis.
Enterotoxigenic E. coli is a significant cause of diarrhea in piglets <1 week of age, and the organisms use F4 (formerly K88) fimbriae to adhere to the brush border of enterocytes, but induce no other specific gross or microscopic lesions. Rotavirus and transmissible gastroenteritis virus (TGEV, coronavirus) infections cause villus atrophy, in contrast with most types of E. coli. Cystoisospora suis tends to occur in piglets >5-6 days of age, and the severity of clinical signs wanes with increasing age. It also causes villus atrophy, and in heavy infections necrotic enteritis in the distal small intestine. Meronts or gamonts may be found in mucosal smears and histologically within epithelium.
A number of other agents are less commonly associated with undifferentiated neonatal diarrhea in pigs. Porcine epidemic diarrhea virus (PEDV, family Coronaviridae) infection is clinically and pathologically indistinguishable from epidemic transmissible gastroenteritis. PEDV, which is endemic in Europe and China, has emerged recently as a significant cause of diarrhea and mortality of suckling piglets in North America. Porcine deltacoronavirus (PDCoV, SDCV) also has emerged as a cause of neonatal piglet diarrhea in North America. Non-group A rotaviruses may be more prevalent than once thought in pigs. They may act as primary pathogen or co-pathogen and cause lesions similar to group A rotavirus. Adenovirus infection can be seen as intranuclear inclusion bodies in epithelium on the dome over Peyer's patch in tissue sections, and is a rare cause of villus atrophy. Enteroviruses, astroviruses, and calicivirus have poorly defined significance as pathogens in piglets, though a calici-like virus causes villus atrophy in gnotobiotic pigs. Cryptosporidium and Giardia are described in pigs of all ages; these seem to play minor role as enteric pathogens. Salmonella and Klebsiella, Bacteroides fragilis, and some strains of E. coli can cause villus atrophy and diarrhea in neonatal pigs, although these are rare. Strongyloides ransomi is transmitted in the milk and may infect young piglets, causing villus atrophy, malabsorption, protein loss, and diarrhea.
Hemorrhagic and necrotizing enteritis caused by beta toxin-producing Clostridium perfringens type C in piglets in the first week of life is readily recognized at autopsy. Clostridium perfringens type A has been associated with nonhemorrhagic mucoid diarrhea with mucosal necrosis in suckling piglets, although the role of this microorganism in the disease remains controversial. C. difficile also causes diarrhea in 1-7-day old piglets; lesions include edema of the mesocolon and fibrinonecrotizing colitis.
In the young foal, nonspecific diarrhea may be associated with rotavirus, Cryptosporidium, and Strongyloides. Enterotoxigenic E. coli and coronaviruses are not proven pathogens in Several caliciviruses (family Caliciviridae, genus Norovirus; formerly Norwalk-like viruses, and genus Nebovirus) are considered emerging pathogens in calf neonatal diarrhea. Both viruses have been significantly associated with diarrhea in neonatal calves; however, their role in disease remains unclear as they also have been detected in clinically healthy calves. Enteroviruses are commonly isolated from the feces of clinically normal animals with highest prevalence on high-density farms. They have been thought to be not associated with significant disease; however, bovine enterovirus 1 has been correlated with enteritis and typhlocolitis in naturally and experimentally infected calves. Birnavirus also has been isolated from the feces of diarrheic calves, but with no proof of pathogenicity.
A bovine enteric group B rotavirus, or bovine enteric syncytial virus, was identified as a cause of diarrhea in beef calves. Experimentally, this virus causes diarrhea and syncytia of enterocytes on small intestinal villi. Bovine parvovirus (family Parvoviridae, genus Bocavirus) is associated with gastrointestinal, respiratory and reproductive disease in cattle. In neonatal calves, lesions include small intestinal crypt cell necrosis, villus atrophy, and fusion and lymphoid necrosis.
Chlamydophila infection is described as a cause of acute enteritis in young calves; however, current epidemiologic data suggest widespread distribution and a limited role as a primary pathogen. Chlamydiae are more likely significant as causes of economic loss caused by chronic low-grade infections, but the pathogenesis remains poorly understood.
Heavy infestation of Strongyloides papillosus may result in villus atrophy, diarrhea and sudden death in calves as young as 2-3 weeks of age. Enterotoxigenic Bacillus fragilis has been suggested as a cause of diarrhea in neonatal calves, but its role is unproved. Giardia, a flagellate protist, has been implicated in diarrhea of calves and other young ruminants; however, its role as a primary etiologic agent of calf diarrhea is controversial. Probably in some circumstances, Giardia may cause intestinal lesions and lead to diarrhea.
Undifferentiated diarrhea in neonatal lambs and goats is mainly associated with enterotoxigenic E. coli, rotavirus, and Cryptosporidium parvum. Lamb dysentery is due to Clostridium perfringens type B in lambs and kids <8-10 days of age is usually recognized at autopsy as severe hemorrhagic and necrotizing enteritis. Clostridium perfringens type A has been identified as a significant cause of ovine and caprine enterotoxemia in some parts of the world; however, this type is commonly isolated from the intestine of healthy goats and sheep, so its role as a primary pathogen is unproved. Beta 2 toxin-producing Clostridium perfringens type D has been reported to cause fibrinonecrotic enterocolitis and enterotoxemia in a goat kid. Coccidiosis caused by Eimeria spp. in lambs and kids may occur in animals as young as 3 weeks of age. Raised white plaques of coccidia-infected proliferative epithelial cells are found in the terminal ileum; there may be some degree of hemorrhage in severe cases.
A variety of other pathogens have been associated with diarrhea in neonatal small ruminants. Giardia is prevalent on some farms and in certain conditions may contribute to clinical disease; its significance is poorly defined. Salmonellosis may occur rarely in young lambs. Certain serotypes of E. coli or other bacterial species may be the cause of watery mouth disease in lambs, which is characterized by drooling, sepsis, Stevenson GW, et al Gastrointestinal parasitism may be associated with acute or chronic diarrhea and wasting in calves and young cattle at pasture. Coccidiosis in calves >3 weeks of age and older cattle usually causes dysentery and fibrinohemorrhagic typhlocolitis. The nematode fauna is usually mixed, but certain genera of helminths may dominate in particular epidemiologic circumstances. Most important is Ostertagia, which causes abomasitis with mucous metaplasia and hyperplasia. Intestinal nematodes such as Strongyloides and Nematodirus may cause diarrhea in calves at pasture or in semiconfinement. Trichostrongylus and Cooperia in adequate numbers are commonly pathogenic for pastured animals. Toxocara vitulorum may have some significance in warm climates.
Enteritis is often not grossly recognized in the small bowel at necropsy of animals with intestinal helminthosis. Therefore the pathologist needs a high index of suspicion to come to a diagnosis in some cases. To make a firm diagnosis of intestinal helminthosis, it is necessary to demonstrate substantial populations of nematodes by worm count in intestinal content or digests, and ideally to observe villus atrophy in tissue sections of infected intestine. These findings should be associated with a compatible syndrome-in the case of Ostertagia, Strongyloides, and the intestinal trichostrongyles, inefficient weight gain or wasting, and usually diarrhea. The hematophagous genera Haemonchus and Bunostomum cause anemia and hypoproteinemia, and associated poor growth but without diarrhea. Oesophagostomum radiatum, in the colon, may result in foals, although their role in diarrhea of foals has not been ruled out yet. Actinobacillus equuli may cause severe diarrhea and hemorrhagic enteritis, with lesions of bacteremia evident in other organs at autopsy. Salmonellosis in foals may be seen as fatal diarrhea with few gross lesions, or as fibrinous enterocolitis and septicemia, similar to that seen in older horses. Escherichia coli and Klebsiella pneumoniae, with occasional gram-positive infections, are common causes of neonatal septicemia and possibly diarrhea, predisposed by failure of passive transfer of immunoglobulin. Fibrinonecrotic enterocolitis in foals <1 week of age may be due to C. perfringens type C, C. difficile, or co-infection by both microorganisms. C. perfringens type B infection has been reported rarely in foals; the disease has not been diagnosed in North America. Rhodococcus equi may cause chronic diarrhea and wasting in foals. Pyogranulomatous ulcerative lesions of the large bowel, and purulent mesenteric lymphadenitis, often associated with chronic purulent bronchopneumonia, are characteristically found in R. equi infection. Enterococcus (Streptococcus) durans, an enteroadherent coccus, has been associated with diarrhea in a foal. Moderate atrophy of villi covered with adherent gram-positive cocci was characteristic; the large bowel not being colonized. Strongyloides westeri is capable of causing diarrhea in young foals occasionally. Tyzzer's disease-caused by Clostridium piliforme (formerly Bacillus piliformis)-which is restricted to foals less than ∼6 weeks of age, may be associated with diarrhea. However, the liver lesion dominates the pathologic picture.
diarrhea. Intestinal lesions and/or diarrhea are uncommonly observed in type D enterotoxemia of sheep. Where it occurs,
Johne's disease causes a syndrome of wasting, usually without diarrhea, in sheep and goats; in goats, caseous mesenteric lymphadenitis may occur. Schistosomiasis may cause ill-thrift in sheep in enzootic areas. Terminal (regional) ileitis of lambs is a syndrome of unknown etiology characterized by reduced weight gain, diarrhea, and apparent abdominal pain, usually in 1-4 month-old animals. It is reported from the United Kingdom, continental Europe, and North America. At autopsy, animals are typically in poor body condition, with evidence of diarrhea. There is marked enlargement of the caudal small intestinal mesenteric lymph node. The terminal small intestine is thickened, with transmural edema, and a corrugated appearance on the serosal aspect. The mucosa is reddened, and thrown into thick transverse nodular folds. There may be superficial erosion and fibrin exudation. The mucosa of the cecum and spiral colon also may be grossly thickened.
Microscopic lesions are always evident in the ileum, and consist of moderate to severe villus atrophy, hypertrophy of crypts, hyperplasia of crypt epithelium, and a heavy mixed inflammatory cell infiltrate in the lamina propria. Microerosions or ulcers may be present, through which neutrophils exude. In the large intestine, the crypt epithelium is hyperplastic, causing thickening of the mucosa, which is infiltrated by a mixed, mainly mononuclear, inflammatory cell population, and is thrown into folds superficially. Peyer's patches and submucosal lymphoid aggregates are hypertrophic, with lymphoid hyperplasia.
Rotavirus and coronaviruses (transmissible gastroenteritis virus and porcine epidemic diarrhea virus) may be responsible for villus atrophy and diarrhea in susceptible pigs of any age, although significant mortality is generally restricted to neonates and nursing pigs. Considerable morbidity but low mortality occurs in the later suckling, weanling, and feeder age groups. Postweaning diarrhea is associated with villus atrophy of uncertain etiology; it is discussed with villus atrophy in the section on epithelial renewal in health and disease. Escherichia coli causes postweaning enterocolitis, and Shiga toxinproducing strains of E. coli produce gut edema, as part of edema disease, causing sudden death or nervous signs in weaner and feeder pigs. No mucosal lesions are evident, but edema of the gastric submucosa and mesocolon may be found, among other lesions. Enterocolitis resulting from Salmonella, Lawsonia intracellularis, Brachyspira hyodysenteriae, and intestinal spirochetosis generally occurs in weaner and feeder swine, although proliferative hemorrhagic enteropathy, swine dysentery, and anemia, hypoproteinemia, and diarrhea as well as causing nodule formation in the gut wall. Trichuris may also cause occasional significant hemorrhagic typhlitis, wasting, and diarrhea.
Subacute-to-chronic diarrhea and poor growth or emaciation in cattle also may result from copper deficiency, chronic bovine viral diarrhea, salmonellosis, yersiniosis, chronic coccidiosis, and, in cattle >2 years of age, Johne's disease (paratuberculosis). Congestive heart failure and other causes of portal hypertension may also cause chronic diarrhea associated with alimentary tract congestion in individual animals.
The major causes of diarrhea and ill-thrift in sheep and goats at pasture are parasitic. The main helminth species causing this syndrome are Ostertagia, Nematodirus, and Trichostrongylus. The genera and species involved vary with the geographic area and climate, and perhaps seasonally, as well as with the age group and other local epidemiologic factors. Larval paramphistomes will also cause enteritis in lambs in enzootic areas. Strongyloides may affect lambs up to several months of age, even those held in confinement. Where it occurs, Nematodirus is usually a disease of lambs 1-3 months of age. Trichostrongylosis usually affects lambs 3 months to yearling age. Oesophagostomum columbianum may cause significant disease in sheep, as well as causing nodule formation in the intestinal submucosa. Trichuris typhlitis is an uncommon problem in sheep, as is Chabertia infection of the colon. Bunostomum and especially Haemonchus cause marked anemia and hypoproteinemia without diarrhea. Hemonchosis is a particular problem in lambs and kids at pasture or held in semiconfinement in warm humid climates. It is also important in ewes and does during the postparturient period, or spring, when retarded larvae emerge synchronously from the abomasal mucosa, and mature. Coccidiosis is a problem mainly in lambs and kids reared in confinement, on feedlot or heavily stocked on pasture. The disease is most severe between 2 and 8 weeks of age. Villus atrophy caused by mixed-species infections may be responsible for ill-thrift and diarrhea in older animals, whereas Eimeria arloingi and E. christenseni or E. ovina and E. ahsata may be responsible for mortality in very young kids and lambs, respectively.
Acute enterocolitis and septicemia caused by Salmonella Arizonae infection may occur in lambs and sheep. Yersiniosis causes fibrinous enterocolitis and caseous mesenteric lymphadenitis in both species. Grain overload may cause acute diarrhea in feedlot lambs and in sheep offered supplemental feed. Diarrhea and enterocolitis also may be associated with C. perfringens type D enterotoxemia in goats, although animals may die very acutely without the opportunity to show
Further reading Kasari TR, et
Ulvund MJ, Teige J. Regional ileitis in lambs. Res Vet Sci 1990;48:338-343.
We do so here, on the grounds of similar lesions in advanced cases. At surgery or autopsy, there is fibrinous enteritis or ulceration involving the duodenum, and a variable amount of more distal small bowel. The lesions may be segmental and circumferential, only a few centimeters long, or more diffuse, involving much of the small intestine, but sparing the ileum. The affected segment of bowel may be thickened, congested, or hemorrhagic on the serosal aspect, and there may be fibrinous peritonitis with adhesions, and pancreatitis. Perforation may occur. If the lesion is of some standing, there may be significant stricture at the site. Affected animals often have a distended stomach, with abnormally fluid content, and gastric ulcers, particularly of the pars esophagea. Perforation or rupture of the stomach may occur. Duodenal lesions always should be sought in foals with gastroesophageal ulceration.
Microscopically, there is edema and congestion, with progressive necrosis from the tips of villi in early lesions, advancing to mucosal or transmural acute fibrinonecrotic enteritis, grading to the development of granulation tissue and fibrosis in the bed of more chronic ulcerative lesions.
The etiology is undetermined. Clostridium difficile, Salmonella, mycotoxicosis, and ischemia associated with the use of NSAIDs have been proposed, but not firmly implicated. The segmental, often circumferential, nature of the lesions is compatible with ischemia, perhaps complicated by secondary bacteria.
Fibrinous enteritis in the small bowel may also occur in blister beetle intoxication. Enterocolitis associated with use of NSAIDs is discussed in the section Intestinal ischemia and infarction. Arroyo LG, et
Rotavirus and canine coronavirus infection appear to be causes of uncommon, generally nonfatal, diarrhea in young dogs. Various other viral agents have been associated with diarrhea in dogs, usually on the basis of electron microscopic observations or virus isolation from feces. These include astroviruses, adenovirus, and paramyxovirus, as well as calicivirus and herpesvirus antigenically related to feline calicivirus and feline herpesvirus. The pathogenic significance of these agents is unclear. Circoviruses have been incriminated recently as being involved in canine gastroenteritis, and may be a co-factor with other etiologies. Canine parvovirus 2 is by far the most significant cause of gastroenteritis in the dog. It is distinguished by severe fibrinohemorrhagic enteritis usually evident at autopsy, and the radiomimetic microscopic lesions in the gastrointestinal mucosa, lymphoid, and hematopoietic tissues. Dogs with canine distemper often develop diarrhea; canine distemper virus apparently does infect the intestinal cryptal epithelium.
intestinal spirochetosis occasionally involve suckling animals older than ∼3 weeks of age. The differential diagnosis of these conditions and trichuriasis was discussed in the section on typhlocolitis in swine. Coccidiosis, other than that in neonates caused by Cystoisospora suis, is rare in swine. Occasional ileitis or, less commonly, typhlitis is caused by infection with several species of Eimeria.
Porcine circovirus 2 (PCV-2) has been associated with watery diarrhea and weight loss, often accompanied by pneumonia, and occasionally inflammatory changes in liver, kidney, pancreas, and/or myocardium in weaned pigs. Grossly, the mucosa of the distal small intestine and colon is thickened and mesocolonic edema may be present. Microscopically, a prominent lymphoplasmacytic/histiocytic infiltrate is evident in the lamina propria and submucosa of these intestinal segments. There is lymphocytolysis and atrophy of follicles in gutassociated lymphoid tissue, and irregular basophilic intracytoplasmic inclusions characteristic of PCV-2 infection are evident in macrophages in lamina propria and lymphoid tissue. Immunohistochemical staining for circoviral antigen stains these inclusions, which are presumably phagocytosed viral inclusions from lytic/infected lymphocytes. Similar inclusions are evident in bronchiolar epithelium and alveolar macrophages in lungs affected with bronchointerstitial pneumonia. Other lesions characteristic of PCV2 infection, including lymphadenopathy, hepatitis, and interstitial nephritis, are also present.
Hemorrhage into the intestine may occur in proliferative hemorrhagic enteropathy and volvulus, and should be differentiated from the melenic content found in animals with esophagogastric ulcer.
Ascaris suum may contribute to diarrhea and ill-thrift in weaner and feeder pigs. The thorny-headed worm Macracanthorhynchus hirudinaceus may, under rare circumstances, cause ill-thrift or intestinal perforation. Submucosal nodules in the intestinal wall may be caused by Oesophagostomum infections, which are otherwise usually relatively inconsequential in swine. Thin-sow syndrome has been attributed to gastric hyostrongylosis.
Most of the significant gastrointestinal diseases of horses are discussed elsewhere, including salmonellosis, Lawsoniaassociated proliferative enteropathy, clostridial enterocolitis, antibiotic-associated diarrhea, Potomac horse fever, granulomatous enteritis, and parasitism. The reader should consult portions of the chapter dealing with displacements, obstruction, ischemic disease of the bowel, syndromes associated with malassimilation and protein-losing enteropathy, and typhlocolitis for discussions putting these conditions into a diagnostic context. The capacity of the equine large intestine probably compensates for the additional fluid load posed by diseases of the small intestine that in other species might be expected to produce diarrhea. Horses presented with a syndrome reflecting hypoproteinemia, usually without diarrhea, may have Lawsonia infection, chronic salmonellosis, chronic inflammatory bowel disease, granulomatous enteritis, or enteric lymphosarcoma.
Duodenitis-proximal jejunitis, also known as proximal enteritis or ulcerative duodenitis, is characterized by signs of upper small intestinal ileus, including depression and nasogastric reflux. There is debate about including ulcerative duodenitis of foals, associated with gastric ulcers, in the syndrome. but without lymphoid or bone marrow depletion. Astrovirus, enteric coronavirus, calicivirus, rotavirus, and other viruses are reported from the feces of cats, but are only rarely associated with diarrhea, and even less frequently associated with mortality. A torovirus has a questionable association with a syndrome of diarrhea and bilateral protrusion of the nictitating membranes. Diarrhea is a common sign in cats with feline immunodeficiency virus infection, and may occur in cats with feline leukemia virus infection. Bacterial infections such as salmonellosis, shigellosis, yersiniosis, helicobacteriosis, and Tyzzer's disease are unusual, as is significant parasitic enteritis resulting from helminths, Cystoisospora, Toxoplasma, Giardia, or Cryptosporidium. Chronic inflammatory small bowel disease and the forms of colitis occasionally encountered in cats are considered in previous sections. Hoskins JD
Foot-and-mouth disease (FMD) is a highly contagious viral infection of all cloven-hoofed animals. It is a problem of worldwide concern, being enzootic in large areas of Africa, Asia, and parts of Europe and South America. The presence of the virus imposes serious trade restrictions that effectively thwart the development of a healthy agricultural economy. FMD is an acute febrile condition characterized by the formation of vesicles in and around the mouth, on the feet, teats, and mammary glands. The disease is not notable for high mortality, except in sucklings, but morbidity is very high, with a concomitant loss of productive efficiency.
Species FMD virus (FMDV) belongs to genus Aphthovirus (aphtha = ulcer) in family Picornaviridae. The virus is highly resistant under many circumstances, but is inactivated by direct sunlight, because of drying and increase in temperature, and by moderate acidity (pH <5.0). The acid production that accompanies rigor mortis in carcasses and meat inactivates the virus. However, the alteration in pH is not dependable and the virus survives in viscera, lymph nodes, and bone marrow for an indefinite period under refrigeration. Next to the movement of infected animals, contaminated animal products are likely the most common mechanism of spread. FMDV may survive on hay and other fomites for several weeks.
The resistance of FMDV is of epidemiologic significance, especially where control policies involve slaughter rather than vaccination. The importance of a carrier state in the epidemiology of FMD is uncertain. The carrier state has been observed However, the enteric lesions of canine distemper have not been well described.
Salmonella infection occurs, especially in dogs that eat raw food diets. However, salmonellosis and enteritis caused by other gram-negative bacteria such as Yersinia is rare in dogs. Likewise, Campylobacter infection has been detected in both healthy dogs and those with diarrheal disease, and the role of Campylobacter in causing disease remains to be established. Histiocytic colitis in Boxer dogs and French bulldogs may have a bacterial etiology, with E. coli suspected. These dogs have been shown to improve with appropriate antimicrobial therapy, which supports an underlying infectious cause. Enterococcus durans has been associated with diarrhea in dogs. "Salmon poisoning" in the Pacific Northwest of the United States is due to Neorickettsia helminthoeca infection transmitted by the fluke Nanophyetus.
Hemorrhagic enteritis is associated with clostridial overgrowth, and also may be due to reduced perfusion, and coagulation defects, which may be congenital, part of disseminated intravascular coagulation, or caused by anticoagulant rodenticide intoxication. Castor beans (Ricinus communis) contain ricin, a glycoprotein known to cause gastroenteritis, vomiting, diarrhea, and occasionally death.
Ascarid infection in puppies may be associated with illthrift, diarrhea, and, in heavy infestations, occasionally with death. Hookworms may cause anemia, hypoproteinemia, and ill-thrift, or, in neonatal puppies, occasional acutely fatal infection. Isospora infection may cause diarrhea in puppies, and occasional mortality. Giardiasis is associated with chronic diarrhea in some dogs.
Syndromes of malabsorption and protein loss associated with granulomatous or eosinophilic enteritis, "filled villi," and lymphangiectasia have been discussed elsewhere. The differential diagnosis of colitis, including idiopathic colitis, parasitic colitis, protothecosis, histoplasmosis, Campylobacter, and spirochetal colitis, is discussed in the section on typhlocolitis in dogs. Ulcerating or widely infiltrating colonic neoplasms may be associated with diarrhea. Castro TX, et al. Clinical, hematological, and biochemical
Feline panleukopenia virus causes necrotizing enteritis in the small intestine with features similar to canine parvovirus. Feline leukemia virus has been associated with a syndrome of cryptal necrosis in the intestine, resembling panleukopenia, illness. It is believed that FMDV is localized in epithelial cells of the oropharynx during persistent infection of ruminants, so that virus may be found in esophagopharyngeal fluid for a considerable period of time.
Within a week of development of neutralizing antibody, the titer of virus in circulation declines. Ordinarily, serum antibody titers decline progressively and fairly rapidly. The duration of persistence of antibody is correlated with the initial titer. In general, animals are resistant to reinfection with homologous strains by natural exposure for ∼2-4 years; susceptibility increases as the antibody titer declines.
The characteristic lesions of FMD are only seen in those animals that are examined at the height of disease. As the infection progresses lesions heal or are obscured by secondary bacterial infection. Lesions develop mainly in areas subject to trauma: the oral mucosa, especially the tongue; the interdigital cleft; and the teats in lactating animals. In cattle, there is appreciable loss of weight and the buccal cavity may contain much saliva. In the living animal, there is diffuse buccal hyperemia and mild catarrhal stomatitis, but the hyperemia disappears at death. Vesicles form on the inner aspects of the lips and cheeks, the gums, hard palate, dental pad, and especially on the sides and rostral portion of the dorsum of the tongue. Sometimes they form on the muzzle and exterior nares. The primary vesicles are small, but coalesce to produce bullae which may be 5-6 cm across; these bullae rupture in 12-14 hours, leaving an intensely red, raw, and moist base to which shreds of epithelium may still adhere ( Fig. 1-78) . The eroded to ulcerated area may be replaced by regenerated epithelium in <2 weeks. Secondary infection may complicate this course.
Foot lesions occur in the majority of cases. There is inflammatory swelling with blanching of skin of the interdigital space in ruminants, coronet in swine, and heels in all species a day or so before vesicles form. The swellings persist until the vesicles rupture and the resultant erosions heal; healing may be considerably delayed on the feet. Vesicles may also occur in the other sites, but much less frequently.
in cattle, sheep, goats, and African buffalo (Syncerus caffer), but not in pigs, although the latter play a significant role in transmission because of the high number of viral particles that they produce. The carrier state may persist for up to 2 years post infection in cattle, even in animals with a significant level of serum-neutralizing antibody. Sheep and goats are considered to be a frequent inapparent source of dissemination of the virus because disease can be mild and lesions difficult to identify. Infection in wild ruminants is an obstacle to control. African buffalo can carry FMDV for at least 5 years. Field outbreaks have been associated with buffalo-cattle contact in Africa, but these appear to be rare. Although Asian water buffaloes (Bubalus arnee) may be affected in FMD outbreaks, it is not known whether they remain carriers.
Of equal importance to the persistence of the virus is its antigenic heterogeneity and instability. There are 7 principal antigenic serotypes, namely, the classical A, O, and C types, and SAT-1, SAT-2, SAT-3, and Asia-1. These can be distinguished by serologic tests. Six of the 7 serotypes (O, A, C, SAT-1, SAT-2, SAT-3) are known to occur in Africa, 4 (O, A, C, Asia 1) in Asia, and 3 (O, A, C) in Europe and South America, although recent pandemics are blurring these geographic distinctions. These serotypes are sufficiently different immunologically that infection with one type does not confer resistance to the other six. Within these 7 major types there are antigenic subtypes, each different, to variable degrees, from the parent type. Generally, the subtypes cross-immunize to a useful degree, but exceptions do arise and become recognizable, especially when vaccination fails. Antigenic drift also can be demonstrated experimentally; new subtypes can be produced by passing the virus in immune or partially immune animals, or by growing the virus in vitro in the presence of immune serum. There are presently >70 distinct antigenic strains of the virus of natural origin.
As well as differences and variability in antigenic characters, strains of the virus differ in virulence, and a given strain is probably able to vary in virulence. Certainly, comparing different outbreaks, there is considerable variation in the severity of the disease produced in a given host species. Virulence also varies among species. Although the vast majority of strains affect a wide range of species, there have been occasional viruses that show a distinct predilection for one species. An example is the porcinophilic strain that originated in China in the late 1990s and spread to Taiwan, destroying the swine industry there.
The main portal of entry and primary site of viral multiplication are the epithelia of the pharynx and lung. In the pharynx, this is often associated with mucosal-associated lymphoid tissue. Subsequent to the first round of replication, there is widespread viremic dissemination to surface epithelium, with subsequent development of lesions in sites of mechanical or physiologic stress, such as oral and pedal epithelium, or teats in lactating animals. FMDV probably gains entry to these areas via Langerhans cells, with replication in a contiguous group of cells in the stratum spinosum. The resulting cellular degeneration and lysis result in an epidermal vesicle, which is the hallmark of the disease.
Virus is present at high titer in the vesicular fluid, and is present in large amounts in expired air from acutely infected animals, which is the main source of spread-pigs in particular liberate large quantities of airborne virus. Virus persists in lesions for 3-8 days after the appearance of significant neutralizing titers in serum, but seldom beyond day 11 of clinical swine vesicular disease in susceptible species, and in the latter stages, from diseases producing erosive/ulcerative lesions of the oral cavity. Gross lesions alone cannot differentiate these entities. The disease must be considered in the differential diagnosis in cases of vesicular lesions in the oral cavity, teats, and feet, and sudden death among cloven-footed animals, especially the young. Definitive diagnosis requires virus isolation and characterization, demonstration of viral antigen by enzyme-linked immunosorbent assay, or detection of viral genome by polymerase chain reaction in lesional material. The regulatory status of FMD dictates that this must be carried out in accredited laboratories. In areas where vaccination is performed, vaccinated animals need to be differentiated from infected animals.
Vesicular stomatitis (VS) affects horses, cattle, and pigs, and may also affect wildlife species such as white-tailed deer, raccoons, feral swine, and some rodents. Experimentally, various rodent species are susceptible and persistence has been demonstrated in hamsters. Also, persistence of viral RNA has been shown in both experimentally and naturally infected cattle, but the reservoir of the virus is unknown. The disease is important because it causes a loss in production, especially in dairy herds, and it must be differentiated from foot-and-mouth disease in cattle and pigs. VS is the only vesicular disease naturally occurring in horses ( Fig. 1-80 ). Sheep and goats do not appear to be susceptible to the disease, but a severe, although nonfatal, influenza-like syndrome may occur in infected humans. Species Vesicular stomatitis virus (VSV) belongs to family Rhabdoviridae, genus Vesiculovirus (type species: VS Indiana virus (VSIV)). It is an enveloped single-stranded RNA virus, bullet-shaped and ∼80 × 120 nm. Apart from being inactivated by pasteurization temperatures, it shares qualities of resistance with the aphthoviruses. There are several serologically and immunologically distinct types of virus based on epitopes of the surface glycoproteins, including New Jersey, Indiana, Piry, Isfahan, and Chandipura. The 2 most common serotypes of VSV infecting domestic animals in the Americas are New Jersey and Indiana.
VS is enzootic in Central and South America and occurs sporadically elsewhere in the rest of the Americas. It has a seasonal occurrence; outbreaks occur in the warmer seasons A malignant form of the disease, without vesiculation, does occur in young animals and occasionally in adults. In these, death is common, as a result of myocarditis. Poorly defined pale foci of variable size are seen anywhere within the ventricular muscle. Although historically referred to as "tigerheart," these gross lesions are no different from those generated in any other syndrome of severe, acute myocardial damage, but necrosis of fibers may be striking. Animals that survive the acute phase of FMDV infection (or are not slaughtered during depopulation) can progress to develop a set of chronic lesions. Chronic lesions include myocardial necrosis and scarring, heat intolerance, pancreatitis with acinar necrosis, and regeneration. Diabetes mellitus occurs in experimental cases, as does hypophysitis, leading to a constellation of endocrinopathies because of a range of expressions of pituitary dysfunction.
In sheep, the infection runs a milder course, although there may be exceptions. Lesions may be subtle or not develop. When lesions do develop, the dental pad is the preferred site in the oral cavity. Lingual lesions tend to occur on the caudal dorsal portion as under-running necrotic erosions rather than vesicles. These are small and easily missed, and they heal within a few days. Lameness may be prominent in acute outbreaks. Typical vesicles develop in the interdigital cleft, on the coronet and bulb of the heel. Occasionally they may involve the entire coronet and lead to eventual shedding of the hoof. Vesicles also occasionally occur on the teats, vulva, prepuce, and on the pillars of the rumen. The peracute form with myocardial necrosis may occur in lambs.
The disease in goats is similar to that described for sheep. Both species may be inapparent carriers, and many outbreaks worldwide have been due to transport of inapparently infected small ruminants.
In pigs, lesions occur in the usual sites, although more commonly on the feet than in the mouth. Sloughing of the hooves leads to severe lameness. Lesions also may be present on the snout and behind its rim ( Fig. 1-79) , and on the teats of lactating sows. Abortion and stillbirth of infected piglets are recorded. The peracute form, with high mortality caused by myocarditis, occurs in sucklings, often before vesicle formation is noticed in sows.
FMD must be differentiated from other viral vesicular diseases such as vesicular stomatitis, vesicular exanthema, and Specific serum neutralizing antibodies persist for months in swine and years in cattle. There is no evidence that animals with persistent antibodies may act as a source of infection to herd mates. Animals are immune against the homologous but not the heterologous strains of the virus.
The lesions of VS are indistinguishable from those of footand-mouth disease. Initially, in cattle, there is a raised flattened pale pink to blanched papule a few millimeters in diameter in or near the mouth. These papules rapidly become inflamed and hyperemic. In the course of a day or so they develop into vesicles 2-3 cm in diameter and by coalescence may involve large areas. The shallow erosions that follow rupture of vesicles heal within 1-2 weeks unless secondary infections occur; in the mouth, the latter are common. Oral lesions heal rapidly in swine, but coronary band lesions often become secondarily infected to the point where the claw may separate and slough. Serous rhinitis, with the development of tags of necrotic mucosa, has been described in experimentally infected swine.
The first microscopic changes are seen in the deeper layers of the stratum spinosum, where the virus replicates. Increasing prominence of the intercellular spaces and stretching of the desmosomes are accompanied by a reduction in volume of the cell cytoplasm. This dissociation of cells proceeds to distinct intercellular edema (spongiosis) followed by further cytoplasmic retraction until the affected epithelial cells float freely in enlarging vacuoles, which in turn are loculated by strands of cytoplasmic debris. There is no hydropic degeneration of the epithelial cells and the nuclei until now remain normal. There are no inclusion bodies. With the onset of epithelial cell necrosis, there is a pleocellular inflammatory reaction in the mucosa and underlying lamina propria. Electron microscopic examination of epithelial cells adjacent to the vesicles confirms the intercellular edema and keratinocyte necrosis seen under the light microscope. The microscopic appearance of the lesions is not diagnostic.
In light of the similarity of VS to foot-and-mouth disease, laboratory confirmation of VS is essential. Vesicular fluid and mucosa from the tongue are good sources of the virus. Diagnosis is accomplished through virus isolation in tissue culture or embryonated eggs, fluorescent antibody techniques, complement fixation to identify viral antigen, polymerase chain reaction, and inoculation of suckling mice. Green
Vesicular exanthema (VE) of swine is an acute, febrile disease of swine that is characterized by formation of vesicles on the snout, mouth, nonhaired skin, and feet. The lesions are indistinguishable from those of foot-and-mouth disease, vesicular stomatitis, and swine vesicular disease. VE of swine was first and usually cease with the onset of cold weather. The seasonal nature of the disease suggests that it is transmitted by insects; however, insect transmission is not essential and contact transmission has been proved experimentally. VSV has been isolated from both biting and nonbiting insects and black flies have transmitted the virus to pigs. Biting insects most likely become infected from feeding on lesions rather than blood, because viremia is transient, if present. Nonbiting insects act as mechanical carriers of the virus. It is not known how the virus spreads from one geographic area to another. There is some indication that VSVs adapt to specific regions, developing distinct genotypes based on specific vectors or reservoirs in an ecologic area. The intact mucosa is resistant to infection, but abrasions in a susceptible site readily result in infection when contaminated with saliva or exudate from a lesion. Environmental factors that increase the chance of causing abrasions to the skin, teats, or oral mucosa may predispose to infection. Morbidity in lactating dairy cows may be as high as 100%, although only ∼60% of the affected animals drool or froth around the mouth. The lesions of VS occur mainly on the oral mucosa; occasionally they do occur elsewhere, including on the feet, and in swine, foot lesions are common. This is by no means a dependable feature, and outbreaks of the disease in cattle have been described in which the lesions were predominantly on the teats.
The incubation period following exposure by abrasion is 24-72 hours. Experimentally, VS New Jersey virus inoculation in cattle led to viral replication at the inoculation site from 24-48 hours and in the draining lymph nodes within the first 24 hours. In horses, experimental inoculation in the oral cavity and lips also led to local viral infection of the inoculation site, tonsil, and retropharyngeal lymph nodes. The viremic phase seems to be short-lived, because the virus cannot be cultured from blood. Secondary lesions are rare. In cattle, intramuscular injections will not initiate the disease, a distinguishing feature from foot-and-mouth disease. After experimental infection of swine, infectious viral particles can be recovered from a wide variety of tissues within 6 hours postinfection, including salivary gland, tonsils, snout, skin, and lymph nodes. However, infective virus, viral antigens, and nucleic acids cannot be demonstrated 6 days postinfection. is a porcine variant of human coxsackievirus B5, which is a serotype of human enterovirus B. SVDV is highly resistant to environmental factors. Unlike FMDV, it is not inactivated at the low pH in muscle commonly associated with rigor mortis.
Many outbreaks of SVD appear to originate by feeding raw garbage containing pork products. Transmission within and among affected herds is by direct contact, especially during the early stages of the disease, or by exposure to the virus in the environment, where it is very persistent. The portal of entry is most likely oral or by exposure of excoriated skin. Following contact with infected pigs, vesicles develop within 2 days and consistent virus isolation from tonsil is possible for 1-7 days. Viremia lasts for 2-3 days. SVDV has a strong affinity for the epithelial cells of the coronary band, tongue, snout, lips, lymphoid follicles of the tonsils, myocardial cells, and brain. Virus titers in tissue decrease with the appearance of circulating antibodies, which peak after 2-3 weeks and apparently persist for years. Secretions and excretions have high viral titers for a period of 12-14 days. Feces may contain virus for up to 3 months. There is some evidence that pigs may become carriers, with stress reactivating viral shedding several months postinfection.
Clinically, vesicles are most common on the feet. Oral lesions occur in only ∼10% of affected pigs. The foot lesions appear first at the junction between the heel and the coronary band. Initially, there is a 5-mm wide, pale, swollen area that encircles the digit. In later stages a 1-cm wide band of necrotic skin is located along the coronet. Vesicles on the mouth, lips, and tongue occur in clusters and they are small, ∼2 mm in diameter, white, and opaque. They coalesce and rupture within 36 hours and may be covered by a pseudodiphtheritic membrane resulting from secondary bacterial infections. Affected pigs usually recover in 2-3 weeks.
The development of vesicles tends to follow a similar course as that reported for FMD. The virus infects individual epithelial cells in the stratum spinosum, which leads to focal areas of keratinocyte degeneration and vesicle formation. There is an intense leukocytic reaction in the necrotic areas, which is mainly neutrophilic. As with the other vesicular diseases, after 1 week there are indications of epithelial regeneration.
Nervous signs and lesions of nonsuppurative meningoencephalomyelitis have been reported in field outbreaks and reproduced experimentally in SVD. Lesions involve most areas in the brain and sometimes spinal cord, and are centered on ganglia and spinal nerve roots. Clinically, the severe lameness tends to overshadow any nervous signs that might be present.
Laboratory diagnosis depends on demonstration of the agent by virus isolation, antigen capture enzyme-linked immunosorbent assay, or polymerase chain reaction, in accredited laboratories, on account of its regulatory status. diagnosed in California in the 1930s and eventually spread to most swine-producing states in the United States. An eradication campaign was undertaken and the last reported outbreak of VE was in New Jersey in 1956. Species Vesicular exanthema of swine virus (VESV) is the type species of the genus Vesivirus, family Caliciviridae. It has a single-stranded RNA genome and has only one major polypeptide. It is 35-40 nm in diameter and characteristic cupshaped structures (calyces) are evident in electron microscopic preparations. There are 13 immunologically distinct serotypes, which vary in virulence.
In 1973, a virus that is biophysically and morphologically similar to VESV was recovered from sea lions (Zalophus californianus) with vesicles on their flippers, off the coast of California near San Miguel Island. Several strains of this virus, called San Miguel sea lion virus (SMSV), produce milder but otherwise identical lesions to those of vesicular exanthema when inoculated into swine, and SMSV is classified as a serotype of VESV. The host range of SMSV is very broad. One serotype, SMSV-7, has been isolated from opaleye fish (Girella nigricans) and it produces lesions identical to VE when inoculated into swine, with horizontal transmission to contact swine. Evidence of SMSV infection continues to be identified in fish and marine mammals. It is thought that VE of swine arose through the feeding of ocean fish to swine, with some adaptation of the virus allowing for very efficient spread through swine.
Most outbreaks of VE were associated with feeding of raw garbage containing pork waste, indicating that the disease was transmitted by direct contact and fomites. VESV now exists only as viral stocks archived in freezers and should be considered a disease of historical significance only. The possibility of a recurrence remains, however, if swine are fed uncooked tissues from ocean-origin fish or marine mammals.
Swine vesicular disease (SVD) is a highly contagious viral disease of pigs that is characterized by formation of vesicles around the coronary bands and heels of the feet, and, to a lesser extent, on the mouth, lips, tongue, and teats. Clinically, the disease is indistinguishable from the other vesicular diseases of swine, including foot-and-mouth disease, vesicular stomatitis, and vesicular exanthema of swine.
The disease was first recognized in Italy in 1966 and it has since been reported from Hong Kong, the United Kingdom, continental Europe, and Asia. The economic importance of SVD is related less to the rather limited losses in production and more to the fact that it is difficult to differentiate from other vesicular diseases and hence restricts trade.
Species Swine vesicular disease virus (SVDV) is a small RNA virus in the family Picornaviridae, genus Enterovirus. It
Further reading Edwards JF, et BVDV infections. In a few situations, animals, mainly those >6 months of age, develop a more obvious clinical syndrome, with a high morbidity and low mortality-classical bovine viral diarrhea (BVD). The infecting agent is usually an NCP BVDV. After an incubation period of 5-7 days, the affected animals develop fever, leukopenia, and viremia that may persist up to 15 days. The virus is present in leukocytes (buffy coat), especially lymphocytes and monocytes, and in plasma.
There is a transient decrease in the number of B and T lymphocytes and a decline in responsiveness to mitogen stimulation. Clinically, the disease is characterized by lethargy, anorexia, mild oculonasal discharge, and occasional mild oral erosions and shallow ulcers. Diarrhea may occur. In dairy herds there is a transient drop in milk production. Affected animals develop neutralizing antibodies that peak in 10-12 weeks, and probably are immune for life. A syndrome of severe acute BVD, characterized by high morbidity and mortality in all age groups of susceptible animals, has been recognized since the early 1990s. Sometimes termed BVD type 2, because it is caused mainly, although not exclusively, by primary infections with BVDV-2, this syndrome usually has a peracute to acute course, with fever, sudden death, diarrhea, or pneumonia. It should be noted that not all BVDV-2 isolates are highly virulent. In some cases a thrombocytopenic syndrome, characterized clinically by epistaxis, hyphema, mucosal hemorrhages, bleeding at injection sites, and bloody diarrhea, is superimposed on the alimentary syndrome caused by BVDV-2, or occurs independently. The pathogenesis of BVD type 2 is most frequently linked to increased strain virulence. However, production of inflammatory cytokines, in response to widespread infection of mononuclear phagocytes, has also been postulated as a cause for the severe disease seen clinically. The mechanism of thrombocytopenia is not completely defined, although infected megakaryocytes in the bone marrow undergo necrosis.
Fetal infections may occur in pregnant immunocompetent seronegative acutely infected females, and in persistently infected counterparts. The outcome of fetal infection is primarily dependent on the stage of gestation. The most serious consequences occur if an NCP BVDV crosses the placental barrier during the first 4 months of gestation. It may result in fetal resorption, mummification, abortion, congenital anomalies, or, if the calf survives, a persistently infected (PI) calf. PI calves remain viremic for life, and are immunotolerant to homologous NCP BVD viruses because of failure of the immature fetal immune system to recognize the infecting viral antigens as foreign.
PI calves may be clinically normal, weak, or undersized at birth. They may appear normal, but are often unthrifty, and may have a rough or curly hair coat. The prevalence of these calves in a herd is usually <2%, but may be as high as 25-30% in herds in which a large number of naïve cows, early in pregnancy, have been exposed to NCP BVDV. Most PI calves succumb to mucosal disease (see later), usually between the ages of 6 months and 2 years. The offspring of the few animals that reach sexual maturity and become pregnant are also persistently infected, which can result in families of animals persistently infected with BVDV. PI animals are viremic, and lack antibody to the infecting virus (are antigen-positive but seronegative), which they shed constantly, acting as the most important source of infection in the population.
In PI animals, virus is present in a wide variety of tissues, and antigen can be demonstrated by immunohistochemistry
in genus Pestivirus, family Flaviviridae. Pestivirus is composed of 4 recognized species, BVDV-1 and BVDV-2 (previously referred to as genotypes 1 and 2), Classical swine fever virus, and Border disease virus. It is widespread in cattle populations and this or closely related viruses can infect most eventoed ungulates, including swine. Although evidence for BVDV infection has been found in farmed and free-ranging wildlife in North America, the risk of transmission of the disease from wildlife to cattle remains unknown. As an RNA virus, BVDV is highly mutable because of the error-prone nature of the RNA polymerases responsible for replication of viral RNA. As a result, "swarms" of viral mutants form "quasispecies" that circulate within an infected individual and among individuals in a population. Although most quasispecies lack a selective advantage, or suffer deleterious point mutations, preventing them from becoming dominant, the ability to generate mutants enables BVDV to adapt to host responses, and to establish chronic or persistent infections in some circumstances. Although low virulence would seem to promote prolonged viral shedding, there may be advantages in high virulence that favor the emergence of quasispecies capable of causing severe disease and high virus shedding.
Viral genotype may be linked to specific manifestations of BVDV infection; noncytopathic (NCP) BVDV-2 has been associated with thrombocytopenia, for instance. However, there is a range of virulence among both BVDV-1 and BVDV-2 isolates, varying from subclinical infections or mild clinical disease to severe fatal syndromes.
Recombination of RNA from homologous (BVDV) or heterologous (other viral or host) sources, usually involving the region encoding the nonstructural protein NS2-3 of noncytopathic virus, results in a shift in biotype of either genotype of virus, from the more common NCP biotype, in which inapparent persistent infection is produced in cultured cells, to a cytopathic (CP) biotype, capable of inducing cytoplasmic vacuolation and apoptotic death of cells in tissue culture. Recombination splits NS2-3, resulting in a small NS3 protein, which induces apoptosis, and is a marker for CP BVD viruses.
A new pestivirus species, tentatively called HoBi-like, BVDV-3, or atypical pestivirus, was recently identified in fetal bovine serum imported from Brazil into Europe. These viruses are genetically and antigenically related to BVDV and cause disease similar to that traditionally associated with BVDV infection. HoBi-like viruses may not be detected by conventional BVDV diagnostic techniques. Current BVDV vaccines confer limited protection cross-protection against HoBi-like viruses. These viruses have been identified in Brazil, Southeast Asia, and Europe.
BVDV gains access to the oropharyngeal mucosa by ingestion or inhalation, and primary replication is in oropharyngeal lymphoid tissues, including tonsils. The outcome of the ensuing viremia is a product of the genotype and virulence of the virus, the immune status of the host, whether or not the animal is pregnant, and if so, the stage of pregnancy.
Infection of immunocompetent, seronegative, nonpregnant animals usually results in subclinical infection or mild clinical disease. Affected animals develop slight fever, leukopenia, and specific neutralizing antibodies, the outcome in 70-90% of chronically affected animals, resulting in lameness. In these too, the skin is dry and scurfy, especially over the neck, withers, back, perineal and preputial areas, and vulva, whereas that on the medial aspect of the thighs and forelegs becomes moist and dirty yellow.
At autopsy, the gross lesions vary considerably, especially in acute cases, in which either upper alimentary or intestinal lesions rarely may be absent, and less so in the chronic disease, in which a broader pathologic picture often is present, perhaps partially obscured by healing or evolution of lesions.
Crusts, erosions, and shallow ulcers are present on the muzzle and nares of many affected cattle. There is loss of epithelium from much of the oral cavity. The most conspicuous oral erosions are on the palate, the tips of the buccal papillae ( Fig. 1-81B) , and the gingiva. Many, especially on the papillae, the hard palate, and in the pharynx, are sharp punched-out ulcers, and expose a denuded, intensely hyperemic lamina propria. In more chronic cases, ulcers may have a margin of thickened proliferative epithelium. The tongue is in skin biopsies-in keratinocytes, hair follicle epithelium, hair matrix cells of the hair bulb, and dermal papillae. Use of skin biopsies for diagnosis of persistent infections by immunohistochemistry or enzyme-linked immunosorbent assay has been exploited diagnostically, but it should be recognized that acutely infected animals may have virus in skin biopsies as well, and detection of BVDV antigen in skin is therefore not specific for PI animals. Lesions in PI animals are minimal and subclinical, in spite of the widespread infection of virtually all tissues.
Mucosal disease is a clinicopathologic syndrome occurring in PI animals that subsequently become infected with a closely related CP strain, or probably more commonly, when the virus causing persistent congenital infection spontaneously develops a recombination encoding NS3. The result is an overwhelming infection that destroys cells, and to which the animal is incapable of responding. Characterized by low morbidity but very high mortality, mucosal disease most commonly occurs in cattle that are 6 months to 2 years of age. Although deaths may occur within a few days of illness, and almost always within 2 weeks, some cases may survive for months. The incubation period after experimental infection with a CP strain in an animal persistently infected with an NCP BVDV is usually 7-14 days, but may be considerably longer. Mucosal disease occurred in yearling steers shortly after vaccination with a multivalent vaccine containing modified-live BVDV. Genetic studies of the BVDV isolate obtained from the affected animals, combined with the epidemiologic evidence, was considered as strong evidence that the BVDV vaccine was the cause of mucosal disease.
Basically, there are 2 forms of clinically severe BVDV infection: mucosal disease in persistently infected animals, and the more recently recognized severe acute form of BVD caused by primary infections with very virulent strains of virus. At autopsy, one cannot confidently differentiate spontaneous cases of severe acute BVD caused by BVDV-1 or BVDV-2 from each other, or from cases of mucosal disease, other than by the more hemorrhagic character of some cases of severe acute BVD caused by BVDV-2 isolates. Tentative differentiation of mucosal disease from severe acute BVD rests on the epidemiologic picture; antigenic or molecular characterization of the involved viruses is required for definitive diagnosis of the various syndromes.
Fulminant severe acute BVD or mucosal disease closely resembles rinderpest clinically and grossly. At the onset the animal is febrile, with serous to mucoid nasal discharge. Discrete oral lesions are preceded by acute stomatitis and pharyngitis, the mucosae being hyperemic and pink and covered by a thin gray film of catarrhal exudate. There is severe diarrhea and tenesmus with feces containing little or no blood or mucus. Affected animals become lethargic, anorexic, and dehydrated; they have ptyalism, polypnea, and tachycardia, and may die quickly.
In more chronic cases, the development of the oral lesions is like that found in acute cases; however, by the time they die there is usually some evidence of healing. The watery diarrhea of the early phase gradually gives way to feces that are passed frequently, are scant in volume, and contain a large proportion of mucus flecked with blood. Late in the clinical course, there is lethargy, emaciation, ruminal stasis, and frequent attempts at defecation accompanied by severe tenesmus. Interdigital dermatitis, dermatitis of pastern ( Fig. 1-81A) , coronitis, and laminitis affecting all 4 feet may be present in not always affected; when present, lesions may be evident on all surfaces (Fig. 1-82A) .
Esophageal lesions are usually present, most commonly in the upper third. In some acute cases, the lesions are shallow erosions, rather than ulcers. The erosions are more or less linear but otherwise irregular, have a dirty brown base, and little or no hyperemia, and may be covered by shreds of necrotic epithelium in animals that have not been swallowing ( Fig. 1-82B ). In more advanced cases, discrete ulcerations occur. In many chronically affected animals the ulcers are beginning to heal and have yellow-white slightly elevated plaques of proliferative epithelium at the periphery of the mucosal defect.
Lesions are found in the reticulorumen and omasum, but usually not in the esophageal groove. The ruminal content in chronically affected animals with prolonged anorexia is usually scant and dry. In most acute cases, the ruminal content is unusually liquid and putrid. The lesions on the wall of the rumen resemble those present elsewhere in the upper alimentary tract and, although they occur anywhere, they are best seen on the pillars and other smooth or nonvillus portions of the mucosa (Fig. 1-83) . The omasal lesions are most numerous along the edges of the leaves, sometimes causing a scalloped margin or perforation.
The morphogenesis of the lesions in the squamous mucosa of the upper alimentary tract begins with necrosis of the epithelium ( Fig. 1-84) . Individual cells and groups of cells deep in the epithelium are eosinophilic and swollen, with pyknotic nuclei. These foci enlarge progressively and form areas of necrosis that extend to, and may involve, the basal layer. In the early stages there is little or no inflammation of the lamina propria, but leukocytes infiltrate the necrotic epithelium. These necrotic foci enlarge progressively tending to coalesce, and may form small cleavage vesicles along the proprial-epithelial junction ( Fig. 1-85A ), leading to erosions or ulcers as necrotic epithelium is abraded away. The ulcerations of the squamous epithelium of the upper alimentary tract are accompanied by inflammation in the lamina propria, especially where this forms papillae ( Fig. 1-85B) .
Changes are regularly present in the abomasum. The sides of the rugae bear ulcers that may be punctate to 1 cm or more in diameter (Fig. 1-86) . The histologic changes in the glandular epithelium of the abomasum are characterized by epithelial necrosis, mainly in the depths of the glands, and accompanying interstitial inflammation.
The mucosa of the small intestine often appears normal over much of its length. However, in some cases the mucosa of the small intestine may have patchy or diffuse congestion. In rare cases, fibrin casts may be in the lumen of the small bowel.
In acute cases, it is usual to find coagulated blood and fibrin overlying and outlining Peyer's patches, the covering of which is eroded. This, when present, is a very distinctive lesion that is only paralleled in rinderpest. Severely affected Peyer's patches are often obvious through the serosa as red-black oval areas up to 10-12 cm long on the antimesenteric border of the gut (Fig. 1-87A ). Less acutely affected Peyer's patches may be overlain by a diphtheritic membrane, whereas in milder or more chronic cases the patches may be depressed and covered by tenacious mucus. Mesenteric lymph nodes may or may not be enlarged.
Lesions in the large bowel are highly variable. The mucosa may be congested, often in a "tiger-stripe" pattern following the colonic folds, a reflection of tenesmus. In acute cases there may be fibrinohemorrhagic typhlocolitis ( Fig. 1-87B) . In more chronic cases, fibrinous or fibrinonecrotic lesions and focal or extensive ulceration may be present at any level of the large bowel, but particularly in the cecum and rectum.
The characteristic microscopic lesion in the intestinal mucosa is destruction of the epithelial lining of the crypts of Lieberkühn. In the duodenum, only a few crypts are affected, but more crypts are affected more severely in the lower reaches of the small intestine and in the cecum and colon. Affected crypts are dilated and filled with mucus, epithelial debris, and leukocytes. Remaining crypt-lining cells are attenuated in an attempt to cover the basement membrane. Reparative hyperplasia of crypt lining is rarely encountered. Crypt drop-out may be evident microscopically. In the cecum and colon, extensive damage to crypts and associated collapse of An important microscopic lesion is hyaline degeneration and fibrinoid necrosis of submucosal and mesenteric arterioles ( Fig. 1-89) . A mild-to-moderate mononuclear inflammatory cell reaction is frequently present in the walls of the vessels and in perivascular areas. The vascular lesions also may be present in a variety of other organs, such as the heart, brain, and adrenal cortices, which may make it difficult to differentiate the disease from malignant catarrhal fever. The vascular lesions in acute mucosal disease are less consistently present and are usually milder, and there is involution of lymphoid tissue in BVD, in contrast with the lymphoproliferation characteristic of malignant catarrhal fever.
Coronitis may extend completely around the coronary band, with some separation of the skin-horn junction causing disturbance and overgrowth of the horn. Dermatitis may extend from the coronet up the back of the pastern. Milder dermatitis is generalized, with scurfiness, especially from the ears to the withers. In sections of the skin of animals with chronic mucosal disease, there is hyperkeratosis and parakeratosis with focal accumulations of necrotic epithelium with intense hyperemia of the adjacent superficial dermis. The epithelial lesions are basically similar to those in the squamous mucosa of the upper alimentary tract. Necrosis often extends deeply to or through the basal layers; it results in minute erosions or ulcerations. There is massive infiltration of macrophages and some lymphocytes in the underlying dermis. These deeper lesions occur in the inner aspects of the legs and the perineum, and there is exudation of serum in these areas. The overlying degenerate epithelium becomes disorderly and eventually is lifted off.
Some animals with chronic disease develop mycotic infections secondary to lesions in the forestomachs, abomasum, and Peyer's patches. The lesions are areas of hemorrhagic necrosis involving the mucosa, submucosa, and sometimes deeper layers of the wall. Fungal hyphae are found invading the stroma and causing thrombosis in venules.
Infection of oocytes and cumulus cells in the ovaries has been well-documented, causing speculation concerning the lamina propria are the probable cause of ulceration seen grossly ( Fig. 1-88A) . Congestion of mucosal capillaries, and in acute or ulcerated cases, effusion of fibrin and neutrophils from the mucosal surface may be evident.
The microscopic lesions of Peyer's patches are distinctive in BVD, comparable lesions being caused only by rinderpest. In the acute phase of the disease, severe acute inflammation in the mucosa over Peyer's patches accompanies almost complete destruction of the underlying glands, collapse of the lamina propria, and lysis of the follicular lymphoid tissues ( Fig. 1-88B) . Later in the course of the disease, dilated crypts, lined at least in part by cuboidal epithelium and filled with necrotic epithelial cells, mucus, and inflammatory cells, appear to herniate into the submucosal space previously occupied by involuted lymphoid follicles. Peyer's patches should be sought assiduously at autopsy because their gross and microscopic appearance may provide useful evidence for diagnosis. part the apparent susceptibility of such cattle to secondary bacterial infections.
Fetal infection with bovine viral diarrhea virus. In addition to the early embryonic death and abortions that can be ascribed to BVDV, infections of seronegative immunocompetent dams, usually between 90 and 120 days of gestation, may result in a wide spectrum of teratogenic lesions, including microencephaly, hypomyelinogenesis, cerebellar hypoplasia and dysgenesis, hydranencephaly, hydrocephalus, and defective myelination of the spinal cord. Ocular lesions, such as microphthalmia, cataracts, retinal degeneration, atrophy and dysplasia, and optic neuritis, have all been associated with fetal infections by BVDV (see Vol. 1, Nervous system; Vol.1, Special senses; Vol. 3, Female genital system). Infections of the immunocompetent fetus, usually after 135 days of gestation, result in antibody production that is detectable in precolostral serum samples of the newborn calf.
Fetal infection later in gestation may produce lesions unrelated to teratogenesis in the fetus, including alimentary tract lesions. Punctate hemorrhages with ulcers 1-3 mm in diameter may be profuse in the oral cavity, excepting the dorsum of the tongue, and in the esophagus, larynx, trachea, conjunctiva, and abomasum. The fetal lesions of squamous epithelium evolve in somewhat the same manner as those described earlier, with focal hemorrhages in the lamina propria and epithelial necrosis beginning in the basal layer.
The prevalence of naturally occurring antibodies to BVDV in swine has increased dramatically in the last several years with seroconversion in different countries varying between 2% and 43%. ovarian dysfunction and reduced fertility in animals surviving BVDV infection.
After experimental inoculation with virulent BVDV-2, animals are febrile by 7 days post infection. Prominent clinical signs are anorexia, depression, and episodes of profuse watery and bloody diarrhea that persist until the animal is moribund at 13-14 days post infection. Pregnant animals may abort. Leukopenia and thrombocytopenia are often marked. In cases with severe thrombocytopenia, hemorrhage may be evident clinically.
Lesions are found in the digestive and respiratory systems. There is mild tracheitis, bronchitis, and bronchiolitis, which can progress to secondary bacterial pneumonia. Strains may vary in their ability to infect the pulmonary tree and result in disease. Intestinal lesions strongly resemble those seen in mucosal disease, with severe lymphoid depletion and necrosis of epithelial cells. However, with these BVDV-2 infections, there is often also a significant amount of hemorrhage evident externally, as described previously, and there may be extensive subserosal hemorrhages in the thoracic and abdominal cavities ( Fig. 1-90) . Similarly, edema may be more noteworthy in this form than in mucosal disease. Severe necrotizing vasculitis, especially arteritis, is noted in multiple organs but is most readily identifiable in lymphoid tissue. Meningoencephalitis associated with neuronal infection by BVDV-2 has been reported.
By immunohistochemistry, there is widespread viral antigen within epithelial cells (including oral and esophageal epithelium), smooth-muscle cells, and mononuclear phagocytes in multiple organs, although lesions often do not correspond to sites of antigen staining.
Bovine viral diarrhea virus and secondary infections. BVDV infection suppresses interferon production and impairs lymphocyte function, monocyte proliferation and chemotaxis, humoral antibody production, neutrophil function, and bacterial clearance. These changes are fairly persistent in chronically infected animals and in those with mucosal disease. The failure of immunogenic response may be associated with immunotolerance, or destruction of immunocompetent cells, which is reflected in lymphopenia. In addition to a lack of humoral antibody response, there is also depression of cell-mediated immunity, as indicated by a poor response of cultured peripheral lymphocytes to various mitogens. The impairment of neutrophil function in cattle infected with BVDV may explain in BVDV should be considered as possible causes of that syndrome.
The pathogenesis of fetal infections, resultant border disease, and related enteric lesions in sheep appear to be similar to the multitude of conditions associated with NCP BVDV prenatal infections in cattle. Seronegative ewes infected before 80 days of gestation may produce persistently infected, immunotolerant, chronically viremic lambs. Braun U, et
Otherwise known as "cattle plague," rinderpest was an acute or subacute highly contagious disease of cattle, domestic buffalo, and some other species of even-toed ungulates, including buffaloes, large antelopes, deer, giraffes, wildebeests, and warthogs, characterized by erosive or hemorrhagic lesions of all mucous membranes. After a global eradication campaign, including limitations on animal movement and the use of highly efficacious vaccine, the disease was eradicated from the planet, with the virus last detected in 2001 in wild buffaloes in Meru National Park in Kenya, located on the edge of the Somali ecosystem, the last known remaining reservoir. For several years after that, studies in the region detected antibodies to the rinderpest virus in cattle, but it is thought that they came from old vaccinations. More recent surveillance confirmed the absence of the virus in the region. Vaccination against rinderpest is no longer used anywhere in the world. Before eradication, pandemics of rinderpest occurred in the Middle East and sub-Saharan and equatorial Africa.
Morbillivirus. It is a highly pleomorphic singlestranded RNA virus with a core diameter of 120-300 nm and a spiked envelope. The virus is highly fragile under ordinary environmental conditions; it is incapable of surviving more than a few hours outside the animal body under normal circumstances.
Probably all cloven-hoofed animals are naturally susceptible to infection, but the expression of infection varies considerably. Goats and sheep do respond, but inconsistently, to experimental inoculations of RPV. Infection in Asiatic pigs may be severe but it tends to be mild in European breeds, which are considered dead end hosts for rinderpest. Rinderpest strains that are responsible for mild disease in cattle might cause severe disease in susceptible wildlife species. Although different strains of RPV vary considerably in their pathogenicity, they are grouped in a single serotype and, when suitably modified, make effective vaccines. The infection impacted heavily on wildlife populations in close contact with cattle, and wildlife was important in virus spread.
The disease in cattle could be mild, especially in endemic areas, but it was acute or peracute and severe in new foci. The different degrees of severity were due in part to real The presence of antibodies to BVDV may complicate the diagnosis of classical swine fever, especially in those countries considered to be free of this disease. Cattle, and modified live virus vaccines containing contaminated fetal bovine serum, are considered to be common sources of infection for swine. Infection of pigs with BVDV usually occurs without clinical signs, allowing an opportunity for the virus to spread without detection. There are sporadic reports of disease in pigs associated with BVDV infection, including stillbirth, and poorly viable piglets, some showing tremors. A few 2-4-week-old pigs in infected herds are anemic, have a rough hair coat, growth retardation, wasting, and diarrhea. Affected pigs fail to develop neutralizing antibodies to the infecting homologous BVDV. Littermates that remain normal develop neutralizing antibodies. The suggestion is that the infections are congenital. In pigs infected postnatally with BVDV, usually no lesions, or very mild lesions, are observed. Experimental in utero BVDV infection of sows may result in prenatal and perinatal deaths, persistently infected immunotolerant or normal pigs. Many of these conditions resemble the effects of in utero infection with NCP BVDV in cattle. Tao Border disease. Border disease is a congenital infection of sheep and goats, usually with one of several NCP genotypes of border disease virus (BDV), a pestivirus antigenically related to BVDV and classical swine fever virus, but apparently also with some BVDV-2 strains. The disease was first reported in lambs from border areas between England and Wales. It is characterized by embryonic and fetal death, abortion, mummification, and birth of weak lambs or kids. The affected animals have an abnormal body conformation, long hairy fleece, clonic rhythmic tremors ("hairy shakers"), unthriftiness, and poor viability (see Vol. 1, Nervous system; Vol. 1, Integumentary system; Vol. 3, Female genital system).
A syndrome resembling mucosal disease has been reported in lambs that survived the initial border disease; they were persistently infected with an NCP BVDV. Immunohistochemical examination of tissues from persistently infected sheep reveals viral antigen in smooth muscle cells of hollow organs and blood vessels, epithelial cells in the gastrointestinal tract, lymphocytes, neurons, and glial cells. When cytopathic BDV is superimposed on persistent infection, affected sheep develop chronic diarrhea, wasting, nasal discharge, and polypnea. Macroscopic lesions are particularly present in the cecum and colon and in a few sheep also the terminal ileum. There is marked thickening of the gut wall caused by subserosal and mucosal edema and diffuse polypoid hyperplasia of the mucosa, which is hemorrhagic and focally ulcerated.
The microscopic lesions in the gut are similar to those described for mucosal disease in cattle. Lymphoid cell reactions are evident in the choroid plexus, portal triads of the liver, kidney, myocardium, thyroids, lungs, spleen, and lymph nodes. In addition, some lambs have marked hypertrophy and edema of the muscularis of the terminal ileum. The lesions in the terminal ileum resemble "terminal ileitis," and BDV and with lymphoid aggregates. Consequently, the caudal part of the oral cavity is affected preferentially. There is some strain variation with respect to presence of oral lesions. In nonfatal cases there is rapid regeneration of the oral mucosal lesions. Esophageal erosions are usually mild and affect the proximal portion. The forestomachs rarely exhibit any lesions. The histologic lesions of stratified squamous epithelium originate in the stratum spinosum. Entrance into the epithelium may be via infected Langerhans cells that then pass virus along to adjacent cells. Irregularly shaped rafts of acanthocytes are infected with virus as evidenced by immunohistochemistry. These same cells then undergo degeneration and necrosis. Multinucleated syncytia form in the epithelium (Fig. 1-92 ) and these may have cytoplasmic and nuclear inclusions. Abrasion causes the necrotic tissue to lift off and produce shallow erosions or ulcers. This occurs so readily that they are usually the first lesions observed. Their margins are sharp, and the bases are reddened by the underlying congested capillaries. The initial minute erosions enlarge and coalesce to form extensive defects.
The abomasum is often severely reddened, which may just be a reflection of generalized stress for, although immunohistochemically abomasal epithelium is infected with virus, the extent of infection and resulting necrosis is far less than that seen in intestinal mucosa. differences in virulence of strains, and largely because of differences in susceptibility of breeds or races of cattle. Rinderpest could also persist for prolonged periods as a very mild disease in endemically infected cattle and wild ungulate herds and it was thought to remain stable for years before the emergence of more pathogenic strains that induced the characteristic disease.
The nasopharyngeal mucosa appears to be the main portal of entry in rinderpest. The virus uses glycoproteins expressed on activate lymphocytes and monocytes and on dendritic cells as receptors, and destruction of such cells may be a means by which it causes immunocompromise. It localizes and replicates initially in the palatine tonsils and regional lymph nodes. This is followed after an 8-11 day incubation by a 2-3 day period of viremia that coincides with the fever seen clinically. In circulation, the virus is associated with mononuclear cells. After the viremic stage, the virus replicates in all lymphoid tissues, the bone marrow, and the mucosa of the upper respiratory tract and gastrointestinal tract. Nasal, oral, and ocular secretions, as well as feces, contain high titers of the virus. In general, excretion of virus ceases by about day 9 of the clinical disease, with the onset of neutralizing antibodies. Recovered animals do not appear to be carriers, although there are reports to the contrary.
Fever and its attendant signs usher in the clinical syndrome, with early leukopenia. Fever reaches its peak in ∼3 days and falls with the onset of diarrhea, which may be bloody. There is severe abdominal pain, anorexia, ocular and nasal discharge, tachypnea, fetid breath, occasional cough, lethargy, severe dehydration and emaciation, and prostration. Death occurs in 5-8 days. Explosive outbreaks with high morbidity and mortality were more likely to occur in naïve populations. Vaccinated or recovered animals usually had lifelong immunity. Secondary bacterial, viral, protozoal, and rickettsial infections were common.
The gross changes in rinderpest are characteristic but not pathognomonic. They are similar to bovine viral diarrhea and mucosal disease ( Fig. 1-91) , and they also bear some similarities with malignant catarrhal fever. The lesions in the upper alimentary tract are necrotizing and erosive-ulcerative.
RPV has an affinity for the alimentary epithelium. Most severely affected areas in the oral cavity are those contiguous
Multinucleated cells, similar to those in the oral mucosa, occasionally form in the lymph and hemolymph nodes. All or only some follicles may be involved and there is often an increase of other leukocytes in the sinuses. Similar lesions occur in the spleen, tonsils, and, as already noted, in the Peyer's patches.
Acute congestion and edema of the conjunctiva may be followed by purulent conjunctivitis and corneal ulceration. Petechiae are common in the mucosa of the upper respiratory tract, which is usually covered with mucopurulent exudate.
Although the gross lesions of rinderpest resemble those of severe acute bovine viral diarrhea, mucosal disease, and malignant catarrhal fever, rinderpest is distinguished microscopically most readily by the presence of syncytia and inclusion bodies.
Peste des petits ruminants is an acute viral disease of sheep and goats that closely resembles rinderpest and is also known as kata, stomatitis-pneumoenteritis complex, goat plague, ovine rinderpest, and pseudorinderpest. The disease was first recognized in West Africa, and is now distributed in north and sub-Saharan Africa, the Arabian Peninsula, Anatolia, the Indian subcontinent, including Nepal and Bangladesh, and China. Species Peste-des-petits-ruminants virus (PPRV), genus Morbillivirus, family Paramyxoviridae, is closely related to species Rinderpest virus, with which it shares common antigenic determinants. The virus cross-reacts with RPV in immunodiffusion and complement fixation tests. It may be differentiated from RPV using monoclonal antibody techniques and cDNA probes. Peste des petits ruminants is currently being considered for global eradication.
1-94 and 1-95), except that the disease is more acute in onset, especially in goats, and follows a more rapid course. Goats have been reported to be more susceptible than sheep in some outbreaks. West African goats appear to be more susceptible than European varieties, and, among the former, the dwarf varieties are most susceptible. Another difference is the marked involvement of the respiratory tract; affected animals have dyspnea, hyperpnea, and cough. There is also a marked serous to mucopurulent nasal and ocular discharge. Erosion/ ulceration of the oral and pharyngeal epithelium may be diffuse and pseudomembranes are characteristically observed in the oral cavity (see Fig. 1-95A) . The erosions can spread into the pharynx.
The pulmonary lesions of peste des petits ruminants are similar to pneumonia caused by canine distemper virus in dogs and measles virus infections in humans. The gross respiratory tract lesions include fibrinonecrotic tracheitis, and consolidation, atelectasis, and dark-red discoloration of the cranioventral lobes of the lungs. Some animals have fibrinous pleuritis Lesions in the intestine are severe and severity correlates with amount of lymphoid tissue in subjacent areas. Consequently, greatest mucosal damage is seen in ileum and the proximal colonic patch. Peyer's patches are almost universally involved. These areas become hemorrhagic and necrotic ( Fig. 1-93A) , and are associated with necrosis of the overlying mucosa, leaving deep ulcers.
There is replication of virus at all levels of intestine, with both crypt and villus epithelium involved. Replication is associated with formation of inclusion bodies, both nuclear and cytoplasmic, degeneration, necrosis, denuding of epithelium, formation of crypt abscesses and, if prolonged enough, villus atrophy. The formation of syncytia within gut epithelium is a rare event, in contrast with the oral cavity lesions, where it is seen with some regularity.
Receptor affinity dictates that RPV is trophic for lymphoid tissues. Infection and replication have been documented in both lymphocytes and macrophages. Necrosis of follicular lymphocytes is extreme (Fig. 1-93B) , and gross inspection, which reveals little abnormality of nodes, is misleading.
Further reading include diffuse colitis, multifocal hepatic necrosis, and severe lymphocytolysis in lymphoid tissues. Syncytial cells are conspicuous, particularly in the oral mucosa, pulmonary alveoli, liver, and lymphoid tissues.
Eosinophilic cytoplasmic and nuclear inclusions are present in the epithelial cells of the renal pelvis, abomasal mucosa, air passages, type II pneumocytes, and syncytial cells. Viral antigen may be demonstrated in the same cells and in brain, rumen, abomasum, heart, and myocytes of the tongue with appropriate immunohistochemical techniques. The primary viral lesions often are complicated by secondary bacterial infections.
Concurrent infection with PPRV and pestivirus was diagnosed in stillborn twin lambs that grossly showed several anomalies typical of border disease, including scoliosis, brachygnathism, prognathism, arthrogryposis, hydranencephaly, cerebellar hypoplasia, and hairy fleece. Microscopically these lambs had epidermal syncytial cells and necrotizing bronchitis/bronchiolitis with PPRV detected by immunohistochemistry in the skin, lungs, kidneys, rumen, and thymus.
Experimental inoculation of PPRV into cattle or pigs does not produce clinical disease, but these animals will resist subsequent challenge with rinderpest virus. These species are considered to be dead end hosts because they do not seem to spread the infection to other species. Natural infection or vaccination of sheep and goats with rinderpest virus protects them against PPRV.
A zoo outbreak of peste-des-petits-ruminants that involved several species of wild ungulates has been reported and Indian buffalo are also susceptible. The distribution of the virus in free-ranging wild ungulates has not been investigated. Baron MD, et
Malignant catarrhal fever (MCF) is an infectious disease primarily of ungulate species in the order Artiodactyla, principally in the families Bovidae, Cervidae, and Giraffidae. MCF is also known as malignant head catarrh, and snotsiekte. The disease is characterized by lymphoproliferation, vasculitis, and erosive-ulcerative mucosal and cutaneous lesions. MCF is distributed worldwide. It is generally sporadic, although severe herd outbreaks have been reported in feedlot, dairy, and range cattle, in farmed bison and deer, and in zoos. Among cervids, all species except fallow deer are probably susceptible. Other susceptible species of ruminants include banteng, Cape buffalo, and greater kudu. Lethality in susceptible species approaches 100%, although there are rare recorded cases of chronic infection and also of recovery from the disease, especially in infected goats, bison, cattle, and pigs. Although the agent is transmissible, the disease is apparently not contagious among cattle or bison by direct contact. (see Vol. 2, Respiratory system). Hemorrhagic colitis is almost always present (see Fig. 1-95B) . Microscopically, there is mild to severe tracheitis, bronchitis and necrotizing bronchiolitis, and diffuse proliferative interstitial pneumonia, with formation of alveolar syncytial cells. Other microscopic lesions hamsters, rats, and guinea pigs, in which it produces MCF-like lesions.
The etiologic agent of SA-MCF has never been isolated from sheep; however, polymerase chain reaction probes have permitted its differentiation. Most sheep have polymerase chain reaction-detectable specific OHV-2 sequences in cells, and identical sequences are detectable in spontaneous cases of SA-MCF. Experimental transmission of OHV-2 between sheep has been accomplished using an aerosol of virus-infected nasal secretions, and natural transmission from adults to offspring probably takes that route, producing very high rates of infection in the sheep population, where it can be considered ubiquitous. The other 2 gammaherpesviruses associated with MCF have also been identified and implicated by molecular diagnostic techniques.
MCF has been reproduced by infecting bison via intranasal nebulization with sheep nasal secretions containing OvHV-2. MCF-like disease can be induced in rabbits, hamsters, and guinea pigs by transfer of lymphocytes or T lymphoblast cell lines derived from MCF-affected cattle and deer. The domestic rabbit is the most commonly used model to study the pathogenesis of both forms of MCF. MCF caused by OHV-2 occurs spontaneously and experimentally in pigs, and the relative rarity of the disease in swine may be due to lack of exposure to ruminant gammaherpesviruses under most conditions of husbandry. Most sheep are presumed to be carriers of OHV-2 virus. However, spontaneous disease does not appear to occur in this species, although clinical signs and lesions resembling MCF were produced in sheep experimentally exposed to a high dose of aerosolized OvHV-2.
SA-MCF occurs where bovids and deer come in contact with sheep. There is considerable variation in the susceptibility of various ruminant species to SA-MCF. Domestic cattle (Bos taurus and B. indicus) appear to require high levels of exposure to induce disease. Bali cattle or banteng (B. javanicus), the domestic water buffalo (Bubalus bubalis), American bison (Bison bison) and most species of deer, with the exception of fallow deer (Dama dama), seem to be highly susceptible. MCF is one of the most serious diseases of farmed deer in New Zealand, Australia, and the United Kingdom. Multiple case outbreaks have also been reported in captive North American cervids.
The mucosa of the upper respiratory tract and/or the tonsil is the most likely natural route of entry for the agents of MCF. Both WA-MCF and SA-MCF can be transmitted to susceptible hosts with large volumes of whole blood or lymphoid tissues administered intravenously, but not by cell-free filtrates, indicating that the agents are cell-associated, probably with lymphocytes. The incubation period of MCF is usually 2-10 weeks, but may, on occasion, be very much longer than this.
Antibodies against the gammaherpesvirus involved can be detected in animals with MCF, and often in herdmates, implying subclinical infection. Development of antibodies does not prevent a fatal outcome.
The pathogenesis, clinical signs, and lesions are similar, whatever the agent inducing MCF. Viremia in WA-MCF usually starts ∼7 days before the onset of fever, and persists throughout the course of the disease. MCF is characterized by marked T-lymphocyte hyperplasia. A population of large granular lymphocytes appears to be infected and transformed by gammaherpesviral infection, and OHV-2 genome has been detected in CD8+ T cells, the predominant cell infiltrating MCF is caused by cross-species infections with members of the MCF virus group of ruminant gammaherpesviruses (genus Macavirus, subfamily Gammaherpesvirinae, family Herpesviridae). At least 10 members of the MCF virus group have been identified, 6 of which are associated with clinical MCF under natural conditions: (1) Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest (Connochaetes sp.); (2) Ovine herpesvirus 2 (OvHV-2), endemic in domestic sheep; (3)
(4) Caprine herpesvirus 3 (CpHV-3) causing MCF in whitetailed deer and red brocket deer; (5) Alcelaphine herpesvirus 2 (AlHV-2), carried by hartebeest (Alcelaphus sp.) and topi (Damaliscus sp.) and causing MCF in Barbary red deer and bison; and (6) Ibex MCF virus (Ibex-MCFV), carried by the Nubian ibex and producing MCF in bongo and anoa.
Related gammaherpesviruses, as yet unassociated with MCF, have been detected in a number of bovids. Gammaherpesviruses of ruminants are highly cell-associated lymphotropic herpesviruses, difficult or impossible to isolate, which are typically transmitted from adults to offspring within the first 2-3 months of life, probably via free virus shed in nasal secretions. In the natural host, infection is latent or inapparent, with intermittent virus shedding, although disease has been incited in sheep by experimental aerosol inoculation of a large dose of OvHV-2.
Most natural outbreaks of MCF are due to 2 agents originally incriminated in MCF outbreaks: AlHV-1 and OvHV-2. AlHV-1 is responsible for the "African" or wildebeestassociated (WA-MCF) form. OvHV-2 causes sheep-associated (SA-MCF). Each member of the MCFV group has an asymptomatic reservoir host species and, for those known to be pathogenic, one or more clinically susceptible host species that develop clinical disease. The division is not absolute and lesions and/or disease can be induced in some reservoir species when the challenge dose is sufficiently high. Nevertheless, as a general rule, reservoir species are well adapted to subclinical infection and efficiently shed cell-free virus, whereas MCFsusceptible species are poorly adapted and shed little or more commonly no cell-free virus. This absence of viral shedding accounts for end-stage hosts.
The classical form of MCF resulting from AlHV-1 and OvHV-2 are identical in clinical and pathological terms. However, the epidemiology of the 2 agents has important differences. The blue, brindled, or white-bearded wildebeest (Connochaetes taurinus) carries AlHV-1. Wildebeest calves become infected during the first 2-3 months of life, when they are also viremic and shed cell-free AlHV-1 in nasal and ocular secretions. Most wildebeest older than 7 months are serologically positive for AlHV-1. In utero infections have also been reported. Wildebeest are infected for life and transmit AlHV-1 to their calves without showing clinical signs. Wildebeest calves are considered to be the main source of infection for cattle in East Africa. They may shed virus in nasal and ocular secretions until they are 3-4 months old. Transmission to cattle may occur even without intimate contact, suggesting aerosol spread.
Viremia apparently ceases with the development of active neutralizing antibodies in animals >6 months old. It may be reactivated during late pregnancy or periods of stress, such as transportation. Although AlHV-1 produces MCF in many captive exotic species of ruminants, apparently most species that are exposed in their native habitat do not develop disease. AlHV-1 has been transmitted and adapted to domestic rabbits, generalized. In severe cases, the horns and hooves may slough. Caprine herpesvirus-2 has been associated with syndromes in deer that include dermatitis and alopecia, alone, or in combination with gastrointestinal or neurological disease.
The respiratory system may have minor or severe lesions ( Fig. 1-96) . When the course is short, the nasal mucosa may only have congestion and slight serous exudation. Later, there is a copious discharge. Lesions are most severe in the rostral third of the nasal cavity, corresponding to the zone of stratified squamous epithelium. In some cases, fibrinous tracheobronchitis may occur (see Fig. 1-96) .
The lower alimentary mucosae may have no significant lesions in the peracute disease, although oral lesions are present in most cases of MCF ( Fig. 1-97 ). Minor erosions are first observed on the lips adjacent to the mucocutaneous junction. Sometimes apparently normal epithelium on the surface of the tongue peels off in sheets. Later, erosive and ulcerative lesions may involve a large area of oral mucosa, frequently occurring on all surfaces of the tongue, the dental pad, the tips of the buccal papillae, gingivae, both areas of the palate, and the cheeks. In some areas the cheesy or tattered necrotic epithelium may not be sloughed at the time of inspection. Esophageal erosions or ulcers, similar to those that occur in the other diseases causing ulcerative stomatitis, occur in MCF, and, as in rinderpest, are most consistent in the cranial portion. Lesions of the same sort may be present in the forestomachs. Focal ulceration or generalized hyperemia may be evident in the abomasal mucosa. In deer, especially, hemorrhagic or fibrinohemorrhagic typhlocolitis may be a prominent finding.
The liver may be slightly enlarged. Close inspection will reveal, in some cases, diffuse mottling with white foci, which are periportal accumulations of mononuclear cells (Fig. 1-98 ). There may be numerous petechiae and a few erosions of the mucous membrane of the gallbladder.
Characteristic lesions may occur in the urinary system. Renal changes are not always present. They are infarcts or 2-4 mm foci of nonsuppurative interstitial nephritis ( Fig. 1-99) . They may be numerous enough to produce a mottled around vessels in the brains studied. These cells are probably cytotoxic T lymphocytes or T-suppressor cells, but the mechanism by which they mediate the lesions of MCF is unclear. Dysfunction of this cell population may result in de-repression of T-lymphocyte replication, permitting lymphoproliferation. Deranged cytotoxic T-cell activity may then create the epithelial and vascular lesions, through a type of graft-versus-host response, attacking epithelium of the respiratory and gastrointestinal systems, as well as medium-sized arteries throughout the body. This is a unifying, but unproved, hypothesis explaining the lymphadenopathy, mucosal epithelial lesions, and vasculitis characteristic of MCF. Vascular lesions may mediate infarction of some affected tissue fields, as well.
There is wide variation in the presenting clinical syndromes, which are potentially pansystemic. Quite consistently, affected animals have enlarged lymph nodes, although this may be less the case in bison, and there is usually some degree of ocular and oral disease, and exudative dermatitis. There is edema of the eyelids and palpebral conjunctivae and congestion of the nasal and buccal mucosae. Photophobia is accompanied by copious lacrimation. There is conjunctivitis and an increasing rim of corneal opacity, starting at the limbus and progressing centripetally. Corneal ulceration occurs in some cases, but in those that die quickly, the infiltration of the filtration angle may be all that is seen, and this is easily overlooked. Hypopyon may be seen. In some cases there are nervous signs, such as hyperesthesia, head pressing, trembling, nystagmus, incoordination, and behavioral changes. Other animals may have gastroenteritis with diarrhea, which may be bloody in acute cases. This is most commonly seen in deer. The disease may take an acute course of ∼1-3 days, particularly in animals with hemorrhagic enteritis. Those with less severe gastroenteritis, central nervous signs, or generalized disease may linger for as long as 9-10 days. Mortality in MCF has been considered to approach 100% of clinical cases, but recovery may occur, although chronic ocular lesions and vasculitis persist. Clinical signs in bison are more subtle than in cattle, with a high percentage of animals dying without clinical signs being observed or with animals dying very soon after onset of clinical disease.
Gross changes involve multiple organs and are the consequence of 3 basic microscopic lesions: widespread arteritisphlebitis of medium caliber vessels, lymphoid proliferation and production of atypical lymphoblastoid cells, and mucosal ulceration in digestive, urinary, and respiratory tracts. Gross changes may not be present in occasional animals that die of peracute MCF, and in these the diagnosis must rest on the detection of the characteristic histologic changes, and demonstration of the genome of an implicated gammaherpesvirus in tissue. The carcass is dehydrated, and may be emaciated if the course has been prolonged. Conjunctivitis may be evident. The muzzle and nares are heavily encrusted and, if wiped, often reveal irregular eroded or ulcerated surfaces, although in some cases there may be only a slight serous discharge. Cutaneous lesions, especially in SA-MCF, are common, but often overlooked. Affected areas include the thorax, abdomen, inguinal regions, perineum, udder, and occasionally the head. There may be, acutely, more or less generalized exanthema with sufficient exudation to wet and mat the hair, and to form detachable crusts; in unpigmented skin there is obvious hyperemia. The crusts may become several millimeters thick, and there is patchy loss of hair. Sometimes these cutaneous changes begin locally about the base of the hooves and horns, the loin, and perineum; they may remain localized or become and is one of the most consistent histologic lesions of the disease.
The histologic changes usually must be relied on for the diagnosis of MCF, and its differentiation from similar diseases, although access to molecular diagnosis of specific appearance, and may form slight rounded projections from the capsular surfaces. The pelvic and ureteral mucosa frequently has petechial and ecchymotic hemorrhages. Similar lesions are present on the mucosa of the urinary bladder, or there may be more severe hemorrhage associated with erosion and ulceration of the epithelium, and hematuria ( Fig. 1-100) . Superficial lesions may occur in the vagina and vulva, similar to those of the oral cavity and skin.
Enlargement of lymph nodes is a characteristic lesion of MCF in most species, perhaps except in bison, where lymphadenopathy has been found, in one large study, in only 62% of cases. This lesion is almost invariably present in cattle. All nodes may be involved, or some may appear grossly normal. Affected nodes may be many times the normal size, and some, including hemolymph nodes, which are usually too small to recognize, may become quite obvious. There is edema of the affected nodes and the pericapsular connective tissue. On microscopic examination it is apparent that the increase in size is due to lymphocytic hyperplasia. Some of the nodes are congested or hemorrhagic. The spleen is slightly enlarged, and the lymphoid follicles are prominent.
Most animals may have meningoencephalitis as a result of vasculitis that may be accompanied by meningeal edema cecum and colon in deer, may similarly be heavily infiltrated by lymphocytes, often with fibrin and blood exuding into the lumen where surface and glandular epithelium has undergone necrosis and collapsed, sometimes over wide areas (Fig. 1-102) . Submucosal arterioles in affected areas of abomasum and intestine are affected by the characteristic arteritis.
The mottling of liver and the focal nephritis seen grossly are due to the perivascular accumulation of mononuclear cells in the portal triads of the liver (see Fig. 1-98) and in the cortices of the kidney. In the liver, these cuffs may be very large and invest the branches of the hepatic artery, which may undergo fibrinoid necrosis. Microscopic lesions are frequently present gammaherpesvirus infections is increasing. The characteristic histologic changes are found in lymphoid tissues and in the adventitia and walls of medium-sized vessels, especially arteries in any organ, and these will be described before other lesions. They are characterized by perivascular accumulation of mainly mononuclear cells, and fibrinoid necrotizing vasculitis (see Fig. 1-99B) . These changes may be focal or segmental, and may involve the full thickness of the wall, or be confined more or less to one of the layers. When the intima is involved, there is often endothelial swelling. Thrombi are difficult to demonstrate in damaged vessels. The media may be selectively affected, or occasionally, the adventitia alone. Severely affected segments of vessel are replaced by a coagulum of homogeneous, eosinophilic material, in which fragmented nuclear remnants are seen. The perivascular accumulation of cells is particularly characteristic. They are mainly lymphoid cells with large open nuclei and prominent nucleoli; small lymphocytes and plasma cells may be present occasionally. The vascular lesions may be more subtle in other species (especially bison, deer and elk) than in cattle, and in bison this lesion tends to be less widely disseminated than that in cattle.
Cattle that recover from SA-MCF also have distinctive vascular lesions 90 days after clinical onset. Concentric fibrointimal plaques, disrupted inner elastic lamina, focally atrophic tunica media, and vasculitis of variable severity are evident in many organ systems.
In lymph nodes, there is active proliferation of lymphoblasts, which form extensive homogeneous populations of cells in the T-cell-dependent areas of the interfollicular cortical and paracortical zones. In bison, lymphoid hyperplasia is either absent or subtle in paracortical areas of lymph nodes. Focal areas of hemorrhage and necrosis associated with arteritis may be seen in all areas of the nodes. The lymphoid reaction in the spleen varies from marked lymphoid cell hyperplasia, in the periarteriolar sheaths, to atrophy and depletion of lymphocytes. In addition, there is marked proliferation and infiltration of lymphocytic and lymphoblastic cells, mainly perivascular in distribution, in a variety of organs. The lymphoreticular proliferation may become so severe in some organs that it is difficult to determine whether it is hyperplastic or neoplastic.
Microscopic arteritis similar to that present in other organs occurs in the nervous system of many cases. Necrotizing arteritis, plasma exudation into the meninges or Virchow-Robin space, and the predominantly adventitial lymphocytic response are, in the brain of cattle, unique to MCF, and allow it to be differentiated from other nonsuppurative encephalitides. Degenerative changes in nervous parenchyma can be explained on the basis of the vascular changes.
The lesions in skin and squamous mucosae of the alimentary tract consist of a lichenoid infiltrate, as the altered and proliferating lymphoid population moves into the upper dermis and then the epidermis (Fig. 1-101) . Often typical arteritis, involving small- and medium-sized vessels, is present in underlying tissue. Groups of epithelial cells become necrotic, with swollen, strongly acidophilic cytoplasm; ultimately the full thickness of epithelium in affected areas undergoes necrosis and ulcerates. Granulomatous mural folliculitis was the prominent microscopic finding in alopecic sika deer infected with CpHV-2.
The mucosa of the abomasum may be infiltrated by lymphocytes, and undergo mucous metaplasia or focal ulceration. The mucosa of the lower alimentary tract, especially the Sumatra, and Java. Jembrana disease is characterized by a severe lymphoproliferative response. Gross changes include lymphadenopathy, splenomegaly, and hemorrhages associated with vascular damage. Microscopically, lymphoid tissues of all organs show proliferating lymphoblastic cells. This is particularly marked in the enlarged peripheral lymph nodes and spleen, where proliferating lymphoblastic cells are present throughout the parafollicular T-cell areas; and B-cell follicles are atrophied. Proliferation of T lymphocytes and atrophy of follicles in lymph nodes and spleen, with lymphoid infiltrates in multiple organs in Jembrana disease, appear similar to lesions of MCF.
Bluetongue is caused by a reovirus-species Bluetongue virus (BTV), genus Orbivirus, family Reoviridae. There are at least 26 recognized serotypes of BTV, distinguished initially by serum neutralization tests and more recently by RT-PCR amplification of the serotype-specific genome segment 2. Immunity to one serotype does not confer resistance against another, and may cause sensitization, with a more severe syndrome following infection by a second type. Apparently not all serotypes are pathogenic. Epizootic hemorrhagic disease of deer and other ruminants, including cattle, is caused by a virus which represents another serogroup of genus Orbivirus. The virus causing Ibaraki disease, recognized in cattle in Japan, is a variant of Epizootic hemorrhage disease virus (EHDV); seropositive animals also have been found in Taiwan and Indonesia, and an identical virus has been isolated in Australia.
BTV, EHDV, and related viruses are spread by vectorcompetent Culicoides spp., also known as midges or gnats. The virus multiplies by a factor of 10 3 -10 4 in the Culicoides within a week of the infected blood meal being ingested, and transmission can occur after infection of the salivary glands, 10-15 days after the initial blood meal. Transovarial transmission of virus in Culicoides does not occur.
in the kidneys, even though gross lesions are not; they consist of vasculitis involving the smaller arteries and afferent arterioles (see Fig. 1-99B ). Extensive diffuse lymphocytic infiltrates disrupt the normal renal cortical architecture, and in some cases, infarcts appear to be associated with vasculitis involving arcuate arteries.
Ophthalmitis often occurs, and its presence is a useful differential criterion from other ulcerative diseases of the alimentary tract. Corneal edema, secondary to vasculitis, is responsible initially for the opacity (Fig. 1-103) . Later there may be lymphocytic infiltration of various structures within the globe. There is retinal vasculitis and, in some cases, hemorrhagic or inflammatory detachment of the retina in focal areas. Lymphocytic optic neuritis and meningitis may be seen (see Vol. 1, Eye and ear).
Differentiation of acute severe BVD and mucosal disease from MCF is sometimes difficult, but MCF usually affects one or more organ systems or tissues (liver, kidney, bladder, eye, brain, tracheobronchial tree) not involved in mucosal disease, and typically produces lymphoid hyperplasia in cattle, whereas lymphoid tissue in BVDV infections is expected to be atrophic. Arteritis may be seen in some cases of BVDV infection, mainly in the submucosa in the lower alimentary tract. Fortunately, arteritis is present in more than one tissue in all cases of MCF, whether peracute, acute, or mild with recovery, although it may be necessary to examine many sections to find it. The best organs to examine for vascular lesions are the brain and leptomeninges, carotid rete, kidney (renal arcuate vessels and rete mirabile), liver, adrenal capsule and medulla, salivary gland, and any area of skin or alimentary tract showing gross lesions. In bison, no single tissue can be relied on to establish a morphologic diagnosis of MCF, and a range of tissues should be examined to confirm or rule out the disease. A combination of arteritis, lymphoid hyperplasia, and lymphocytic infiltrates into affected epithelia is very characteristic of MCF.
Bali cattle as well as other species of cattle and buffalo are affected with a disease that closely resembles MCF, and both diseases occur geographically together in Indonesia. Jembrana disease is caused by a lentivirus distinct from but genetically related to bovine immunodeficiency virus, which initially was described in Bali, where it is endemic, and that has now spread to other islands in Indonesia, including Kalimantan, West as reservoirs in that the virus will be associated with the erythrocytes for the life-span of that cell. Detectable viremia in cattle is thought to be <9 weeks.
The pathogenesis of bluetongue, epizootic hemorrhagic disease, and Ibaraki disease is fundamentally similar in all species in which disease is seen. Primary viral replication following insect bite occurs in regional lymph nodes and spleen. Viremia ∼4-6 days after inoculation results in secondary infection of endothelium in arterioles, capillaries, and venules throughout the body, but especially in lung microvascular endothelium. Microscopic lesions, fever, and lymphopenia begin a day or so later, about a week after inoculation. BTV in the blood appears to be closely associated with, or in, both leukocytes and erythrocytes, and it may co-circulate with antibody.
Endothelial damage caused by viral infection initiates local microvascular thrombosis and permeability. This is reflected microscopically by the presence of swollen endothelium, and fibrin and platelet thrombi in small vessels, with edema and hemorrhage in surrounding tissue. These lesions in turn mediate the full spectrum of gross findings. These are fundamentally ischemic necrosis of many tissues; edema caused by vascular permeability; and hemorrhage resulting from vascular damage compounded ( Fig. 1-104A, B) , in severe cases, by consumption coagulopathy caused by thrombocytopenia and depletion of soluble clotting factors. Differences in the expression and activity of vasoactive and procoagulant and anticoagulant mediators by infected pulmonary endothelium may explain the greater propensity of sheep to show signs, in comparison with cattle.
BTV circulates in a broad belt across the tropics and warm temperate areas, from about latitude 49° N to 35° S, with incursions or recrudescence during the Culicoides season, annually, or at irregular longer intervals in cooler temperate areas. The condition is enzootic or seasonally epizootic in most of Africa, the Middle East, the eastern Mediterranean basin, the Indian subcontinent, the Caribbean, northern Australia, and the United States. It appears sporadically in the Okanagan valley of western Canada. It also has made persistent incursions into the Iberian peninsula, Corsica and Sardinia, Italy, the Balkans, and northern Europe, including the United Kingdom, perhaps associated with climate change. Seasonality of infection toward the periphery of its distribution probably reflects the unavailability of vectors because the virus may be able to overwinter in latently infected cells in the skin of sheep, which express virus once vector feeding occurs again.
Sheep, goats, and cattle are the primary susceptible domestic species. Severe disease has been described in numerous species of wild and domestic ruminants. South American camelids traditionally have been considered resistant to bluetongue, but serological surveys have identified apparently subclinical infection of alpacas, and lethal cases of bluetongue have been reported in llamas and alpacas. Sheep are the domestic species most highly susceptible to bluetongue, but there is considerable variation in expression of the disease, depending on the breed, age, and immune status of the sheep, the environmental circumstances under which they are held, and the strain of virus. Typically, indigenous breeds seem more resistant to clinical disease than do exotics. Goats, although susceptible to infection, rarely show signs; however, disease has occurred in goats in the Middle East and India. Infection in cattle usually produces only inapparent infection or mild clinical disease. In Africa, a wide variety of nondomestic ungulates and some small mammals may be infected inapparently; mortality has occurred in naturally or experimentally infected topi, Cape buffalo, and kudu. In North America, wildlife species, particularly white-tailed deer, black-tailed or mule deer, elk, bighorn sheep, bison, and pronghorn antelope are also infected. Bluetongue is responsible for significant mortality in all these species except elk, which usually develop mild or inapparent infection, and bison, which are infrequently demonstrated to be serologically positive. Clinical cases of bluetongue have been described only in individual South American camelids. Vaccine inadvertently contaminated with BTV and administered to dogs caused significant mortality, but BTV is not normally considered a pathogen in dogs.
Epizootic hemorrhagic disease occurs in North America, Europe, Africa, and Asia. In North America the white-tailed deer is extremely susceptible, and widespread epizootics have occurred among this species in the United States. The rate of survival is much higher among black-tailed deer and pronghorn antelope; elk are only very mildly affected.
Although sheep are not considered to develop disease when infected with EHDV, occasional mild clinical signs and lesions resembling bluetongue have been reported in sheep inoculated with some Australian isolates. In Japan, the Ibaraki virus strain of EHDV produces a clinical syndrome resembling bluetongue in cattle, but not in sheep.
BTV and EHDV circulate together in North America. Both viruses may be involved simultaneously in outbreaks of hemorrhagic disease in wild ruminants, and both have been isolated from Culicoides in a single locality at the same time. The role of cattle as reservoirs of BTV is uncertain. Cattle may act A B convalescent animals, stellate healing ulcers or scars on the wall of the forestomachs may be apparent.
Microscopically, acute lesions are characterized by microvascular thrombosis, and edema and hemorrhage in affected sites recognized at autopsy. In squamous mucosa and skin, capillaries of the proprial and dermal papillae are involved, resulting in vacuolation and necrosis of overlying epithelium. In acute lesions there is a mild, local neutrophilic infiltrate, and a similarly mild mononuclear reaction in the dermis or propria in uncomplicated chronic lesions, which may granulate if widely or deeply ulcerated. Similar microvascular lesions are associated with necrosis and fragmentation of infarcted muscle. Muscle during the reparative phase follows the usual course of regeneration of fibers or fibrous replacement, depending on whether or not the sarcolemma retains its integrity.
In cattle, clinical bluetongue is rarely apparent; in endemic areas it may never be evident. Mortality is low and it is often attributed to secondary infection. Clinical disease may be a function of hypersensitivity in previously exposed animals, and disease in experimentally infected animals is poorly defined. Fever, loss of appetite, and leukopenia are usually seen after an incubation period of 6-8 days, and there may be a drop in milk production in dairy cattle. There is reddening of the epithelium of the mucous membranes, and of thin exposed skin, especially notable on the udder and teats. Edema of the lips and conjunctiva may be present. Drooling may become profuse, and as the disease progresses over the next several days, hyperemia and congestion of the mucosae become more intense. Ulcerations of the gingival, lingual, or buccal mucosa occur, most consistently on the dental pad. There may be necrosis of epithelium on the muzzle. Muscle stiffness is a feature of the disease in some animals. Laminitis, characterized by hyperemia and edema of the sensitive laminae at the coronet, may be apparent, and in some cases, hooves on affected feet may eventually slough. Sloughing or cracking of crusts of necrotic epithelium may also occur on affected parts of the skin, but the ulcerative or erosive defects heal readily. Viral antigen and thrombosis are present in small vessels in affected tissues during the acute phase.
Although traditionally South American camelids have been considered to be resistant to BTV, individual cases of the disease have been described in alpacas and llamas with lesions including hydrothorax, hydropericardium, pulmonary edema, myocardial hemorrhage, and pericarditis, but no alimentary tract lesions. Experimental inoculation of llamas and alpacas with BTV serotype 8 produced seroconversion, but minimal and mild clinical signs and no significant gross or microscopic lesions.
EHDV can also induce disease in cattle. Clinically and pathologically, EHD in cattle is similar to bluetongue. Ibaraki disease has been described in Japan and it is produced by a virus that is now considered serotype 2 of EHDV. The signs and lesions of Ibaraki disease are similar to those of bluetongue and EHD in cattle, though more severe in some cases. As well as the signs and lesions described in cattle with bluetongue, there may be difficulty in swallowing in 20-30% of clinically affected animals, and the swollen tongue may protrude from the mouth. At autopsy, in addition to the lesions observable externally, there may be congestion, erosion, or ulceration of the mucosa of the abomasum, and less commonly, the esophagus and forestomachs. Ischemic necrosis and hemorrhage of the striated muscle in the tongue, pharynx, Bluetongue in sheep is highly variable; it may cause inapparent infection or acute fulminant disease. Typically, leukopenia and pyrexia occur, even in mild infections, coincident with viremia. The degree and duration of fever do not correlate with the severity of the syndrome otherwise.
In the early phase there is hyperemia of the oral and nasal mucosa, drooling, and nasal discharge within a day or two of the onset of fever. Hyperemia and edema of the eyelids and conjunctiva may occur, and edema of lips, ears, and the intermandibular area becomes apparent. Hyperemia may extend over the muzzle and the skin of much of the body, including the axillary and inguinal areas. Focal hemorrhage may be present on the lips and gums, and the tongue may become edematous and congested or cyanotic, giving the disease its name. Infarcted epithelium thickens and becomes excoriated; erosions and ulcerations develop along the margins of the tongue opposite the molars, and the mucosa of much of the tongue may slough.
Excoriation and ulceration also occur on the buccal mucosa, the hard palate, and dental pad. Affected areas of skin also may become encrusted and excoriated with time, and a break in the wool can result in parts or much of the fleece being tender or cast. The coronet, bulbs, and interdigital areas of the foot may become hyperemic. Coronary swelling and streaky hemorrhages in the periople may be evident as a result of lesions in the underlying sensitive laminae. These hemorrhages may persist in the hoof as brown lines that move down the hoof as it grows. A defect parallel to the coronet also may be evident in the growing hoof in recovered cases.
Internally, in acute cases, there is subcutaneous and intermuscular edema, which may be serous or suffused with blood. Superficial lymph nodes are enlarged and edematous. Bruiselike gelatinous hemorrhages and contusions, which may be small and easily overlooked if not numerous, often are present in the subcutis and intermuscular fascial planes. Focal or multifocal pallid areas of streaky myodegeneration may be present throughout the carcass, sometimes partly obscured by petechial or ecchymotic hemorrhage. Resolving muscle lesions may be mineralized or fibrous. Stiffness, reluctance to move, and recumbency seen clinically are due to these muscle lesions.
Necrosis may be present deep in the papillary muscle of the left ventricle, and elsewhere in the myocardium. The lesion that is perhaps most consistent and closest to pathognomonic for bluetongue is focal hemorrhage, petechial or up to 1 cm wide × 2-3 cm long, in the tunica media at the base of the pulmonary artery. These hemorrhages are visible from both the internal and adventitial surfaces and may be present in clinically mild cases with few other lesions. Petechial hemorrhage also may be present at the base of the aorta and in subendocardial and subepicardial locations over the heart.
There also may be edema and petechial or ecchymotic hemorrhage in the pharyngeal and laryngeal area. In severe cases the lungs may assume a purple hue, with marked edematous separation of lobules, and froth in the tracheobronchial tree, probably because of pulmonary microvascular damage and heart failure. Animals with pharyngeal or esophageal myodegeneration suffer from dysphagia, or regurgitate, and may succumb to aspiration pneumonia.
Hyperemia, occasionally marked hemorrhage, or in advanced cases, ulceration of the mucosa may occur on rumen papillae, the pillars of the rumen, and the reticular plicae. In genus Parapoxvirus, family Poxviridae, which is closely related to Pseudocowpox virus that causes pseudocowpox in cattle and milker's nodules in humans. The disease in humans is usually very mild although severe skin lesions have been reported in at least one case. BPSV is morphologically similar to, and shares antigens with, Orf virus of sheep and goats (see Vol. 1, Integumentary system). However, analysis of the genome indicates that these viruses are distinct.
BPSV is relatively host-specific. As with many of the poxviruses, neutralizing antibody is not readily demonstrated. Infection does not confer significant immunity, and successive episodes of lesions and relapses can occur. The disease is more common in calves than in older animals, although the susceptibility of, or recrudescence in, the latter may be increased by intercurrent debility, disease such as bovine viral diarrhea, infectious bovine rhinotracheitis, or other stressors.
The papular lesions of this disease occur on the muzzle and in the rostral nares, on the gums, the buccal papillae, the dental pad, the inner aspect of the lips, the hard palate ( Fig. 1-105A) , the floor of the oral cavity behind the incisors, the ventral and lateral (not dorsal) surfaces of the tongue, occasionally in the esophagus ( Fig. 1-105B ) and forestomachs.
The initial lesions, which are likely to be detected on the muzzle or lips, are erythematous roughly round macules, 2 mm-2 cm in diameter. Shortly, the central portion becomes elevated as a low papule, although the elevation is not easy to see, and by the second day a gray central zone of epithelial hyperplasia has developed on which there is superficial scaliness and necrosis. A central necrotic area may slough to form a shallow craterous defect surrounded by a slightly raised red margin. Lesions may coalesce. The course of individual lesions is about a week.
Histologically, there is focal but intense hyperemia and edema in the papillae of the lamina propria, with accumulation of a few mononuclear leukocytes. The epithelium is thickened, sometimes to twice its normal depth, by hyperplasia and ballooning degeneration in the deeper layers ( Fig. 1-105C ). The cytoplasm of affected cells is clear, and the nucleus may be shrunken. Dense eosinophilic inclusion bodies lie in the vacuolated cytoplasm, especially in cells at the active margin of the lesion. These inclusion bodies are present during the initial period of the infection but are difficult to see in the more advanced lesions. In the central, more advanced part of the lesion, a mainly neutrophilic infiltrate into the superficial propria and epithelium is associated with erosion of the upper layers of necrotic cells. The basal layer survives and may be very flattened in eroded areas. Vesicles do not form.
A chronic form has been reported, with necrotic and proliferative stomatitis, represented histologically by extensive parakeratotic hyperkeratosis, pseudoepitheliomatous hyperplasia, and occasional intracytoplasmic inclusion bodies.
Papular stomatitis is probably more common and widespread than reports indicate. Variation in the extent and gross appearance of the lesions is to be expected, depending on the usual host-parasite factors and the nature of superimposed infections. They may predispose to the development of necrotic stomatitis, and must be differentiated from the lesions of bovine viral diarrhea, foot-and-mouth disease, alimentary infectious bovine rhinotracheitis, and other causes of ulcers and erosions in the upper alimentary tract. The infection can be transmitted to humans to produce small papules that may persist for several weeks on the skin, usually of the fingers or forearms. larynx, and esophagus cause the difficulty in swallowing seen clinically, and similar changes are seen in other skeletal muscles. Necrotizing aspiration pneumonia is a sequel to dysphagia in some animals.
The hemorrhagic diseases in bighorn sheep, pronghorn antelope, and white-tailed and black-tailed or mule deer in North America resemble bluetongue in sheep. White-tailed deer and pronghorn may develop a particularly severe and fulminant hemorrhagic disease, with high mortality. There may be necrosis of velvet antler, and hooves may slough in survivors. Bluetongue in goats, although usually inapparent, can resemble bluetongue in sheep.
Bluetongue in sheep must be differentiated from foot-andmouth disease, peste des petits ruminants, contagious ecthyma, and photosensitization in particular. In cattle, the condition must be differentiated from foot-and-mouth disease, vesicular stomatitis, bovine viral diarrhea, rinderpest, malignant catarrhal fever, and photosensitivity. In Japan, Ibaraki disease of cattle in addition must be differentiated clinically from ephemeral fever virus.
In addition to the systemic disease described, abortion, perhaps unobserved, and birth of progeny with various congenital defects may follow BTV infection of pregnant sheep and cattle. In sheep, BTV infection of ewes early in gestation may result in hydranencephaly. Anomalous calves produced by BTV-infected cattle have excessive gingiva, an enlarged tongue, anomalous maxillae, dwarf-like build, and rotations and contractures of the distal extremities. Porencephaly, hydranencephaly, and arthrogryposis are also reported in calves infected in utero with BTV. Antibody may be sought in neonates that have not sucked, and attempts should be made to isolate virus, because some prenatally infected animals may have immune tolerance, and persistent infection. Anomalies of the brain are considered further in Vol. 1, Nervous system.
Bovine papular stomatitis. Papular stomatitis of cattle occurs worldwide. It is generally not a clinically significant infection, but needs to be differentiated from other more serious diseases affecting the oral cavity and skin. Bovine papular stomatitis is usually an indicator of immunity problems associated in many cases with poor colostrum administration. It is caused by species Bovine papular stomatitis virus (BPSV), material from lesions examined under the electron microscope or by PCR. Histology is highly suggestive when the characteristic inclusion bodies are present.
Contagious pustular dermatitis. Contagious pustular dermatitis, also called orf or contagious ecthyma, is a parapoxviral disease of sheep and goats that is characterized mainly by proliferative scabby lesions on the lips, face, udder, and feet (see Vol. 1, Integumentary system). The disease also has been reported in camels and a gazelle. Lesions may extend into the oral cavity, involving the tongue, gingiva, dental pad, and palate. Involvement of the esophagus and forestomachs occurs, but is very unusual. In general the evolution of the alimentary lesions is similar to papular stomatitis of cattle, although they are more exudative and usually much more proliferative. Intracytoplasmic inclusion bodies similar to those observed in bovine papular stomatitis also can be observed in the initial stages of the infection. Morbidity may be high, and death can occur in suckling animals. In the upper alimentary tract, lesions may consist of focal red, raised areas, which coalesce to form papules followed by pustules. The latter rupture, and on the muzzle and in the mouth they may become covered by a gray to brown scab, although scab formation may not occur in the mucosa of the upper alimentary tract. As with bovine papular stomatitis, rapid diagnosis is readily accomplished by demonstration of characteristic parapoxvirus particles in negatively stained material from lesions examined under the electron microscope or by PCR. Histology is highly suggestive when the characteristic inclusion bodies are present.
Species Bovine herpesvirus 1 (Infectious bovine rhinotracheitis virus, BoHV-1), genus Varicellovirus, subfamily Alphaherpesvirinae, has been associated with a wide range of clinicopathologic syndromes in cattle. These include necrotizing rhinotracheitis, conjunctivitis, infectious pustular vulvovaginitis and balanoposthitis, vesicular lesions of the udder, abortions, systemic infections in neonatal calves and latent infection (see appropriate chapters). Clinical significance of BoHV-1 in other species such as bison that have serological evidence of exposure is not known.
A systemic form of the disease, which usually involves the alimentary tract, may occur spontaneously in neonatal calves (in which it may be congenital, or acquired shortly after birth) and in feedlot cattle. It has been reproduced experimentally in young calves.
The pathogenesis of systemic infection with BoHV-1 is poorly understood. Colostrum-deprived calves are especially susceptible, and the disease can be prevented by feeding colostrum from actively immunized dams. The virus probably Rapid diagnosis is readily accomplished by demonstration of characteristic parapoxvirus particles in negatively stained are milder and generally limited to the nasal mucosa, larynx, and upper third of the trachea (see Vol. 2, Respiratory system). Gray to yellow necrotic foci 2-5 mm diameter may be evident macroscopically on the capsular and cut surfaces of the liver, the adrenal cortices, the spleen, and in Peyer's patches.
Microscopically, the lesions in the squamous mucosa are characterized by focal areas of necrosis, erosion, and ulceration. Severe necrosis may involve the entire papilla or mucosa more diffusely. Nuclear inclusions may be present in epithelial cells in the periphery of the lesion, although these are an inconsistent finding. They are more likely to be found if tissues are collected in the early stages of the disease and fixed in Bouin's fluid. The abomasal lesions consist of necrosis of glandular epithelial cells. Affected glands are dilated, and filled with necrotic debris. Focal necrotic lesions involving crypts and lamina propria may be present in both the small intestine and large bowel (Fig. 1-108) . Abomasal and intestinal lesions may predispose to the development of secondary mycosis, which is a common complication. spreads from the mucosa of the upper respiratory tract to other tissues by circulating leukocytes. Peripheral blood mononuclear leukocytes may exhibit apoptosis in response to BoHV-1, but the significance of this is unknown.
Experimental infection of calves with noncytopathic bovine viral diarrhea virus (NCP-BVDV) followed by BoHV-1 inoculation results in dissemination of the latter to a variety of tissues. BVDV impairs cell-mediated immunity, and this may allow BoHV-1 to escape from the respiratory tract and lead to a systemic infection. Dual infections of BVDV and BoHV-1 occur under field conditions, but coinfection of these two viruses is not a prerequisite for the disease to develop.
Clinically affected animals have hyperemic oral and nasal mucosae, and focal areas of necrosis, erosion, and ulceration on the nares, dental pad, gums, buccal mucosa, palate, and the caudal, ventral, and dorsal surfaces of the tongue. Characteristically, the lesions tend to be punctate with a slightly raised margin; the necrotic areas are covered by a gray-white layer of fibrinonecrotic exudate, which leaves a raw red base when removed.
The lesions may be present in the oral cavity and extend into the esophagus, usually only the upper third, and the forestomachs. In the oral cavity and esophagus, the erosions and ulcers may be irregular, circular, or linear, and often they have a punched-out appearance and a hyperemic border ( Fig. 1-106) . The ruminal lesions, which are most commonly located in the dorsal and cranioventral sacs, vary considerably. The earliest lesions consist of foci of necrosis and hemorrhage, a few millimeters in diameter. In some cases the necrosis may involve almost the entire surface of the ruminal mucosa, which becomes covered by a thick, dirty gray layer of exudate, resembling curdled milk, which adheres tightly to the wall ( Fig. 1-107) . Similar lesions may be evident in the reticulum. Focal areas of necrosis result in the formation of holes, as large as 1.5 cm in diameter, in the leaves of the omasum. In addition, these calves may have focal areas of necrosis in the abomasal mucosal folds, which may coalesce to form areas of necrosis 2-3 cm in diameter. The intestines are red and dilated, and the serosal surface may be covered by a thin layer of fibrinous exudate.
The enteric lesions may be accompanied by changes in the upper respiratory tract. When present the respiratory lesions are similar to those described for older cattle, although they contain focal to large areas of mucosal necrosis and ulceration, frequently covered by a diphtheritic membrane. The contents are yellow and mucoid. Hemorrhagic foci may be visible in the bladder mucosa. Microscopically, the lesions in the upper alimentary tract are typical areas of necrosis and erosion of squamous epithelial cells. The epithelial cells at the periphery of necrotic areas are swollen and vacuolated and these may contain typical intranuclear herpesviral inclusions. There is marked inflammatory reaction in the underlying lamina propria. The abomasal lesions consist of acute foci of mucosal necrosis. Inclusions are particularly evident in this area. Lesions in the cecum and colon are more extensive and consist of large areas of mucosal ulceration and necrosis, which may involve the entire thickness of the wall. The submucosa is edematous and markedly infiltrated by inflammatory cells. The mesenteric nodes are edematous and germinal centers are depleted of lymphoid cells. Focal areas of necrosis with a mild inflammatory cell reaction also may be present in liver, urinary bladder, and kidney. Montagnaro S, et al
Canid herpesvirus 1 causes systemic disease of neonatal puppies characterized by foci of necrosis and hemorrhage in a wide variety of organs, especially the lungs and renal cortices (see Vol. 3, Female genital system). Focal areas of necrosis may occur in the intestine as part of the systemic syndrome. A similar syndrome also has been described in an adult dog. As with most other herpesvirus, the trigeminal ganglion is an important latency site for canid herpesvirus. However, latency of this virus also occurs in the lumbosacral ganglia and retropharyngeal lymph nodes. Latently infected dogs may or may not shed virus, and shedding may occur continuously or intermittently. Felid herpesvirus 1 (feline viral rhinotracheitis virus) causes oral lesions (see previous section on Inflammation of the oral cavity). Primary infection by felid herpesvirus 1 may be followed by viremia with the virus distributed to several distant organs. Viruses antigenically related to felid herpesvirus 1 have been isolated from dogs with diarrhea, but descriptions of lesions are not available.
Natural infections with Suid herpesvirus 1 (SuHV-1; pseudorabies virus, Aujeszky's disease virus) often result in necrotizing tonsillitis. Experimental infection of pigs with SuHV-1 may cause necrotizing enteritis of the distal small intestine. The enteric lesions are characterized by focal areas of necrosis of the cryptal mucosa, muscularis mucosae, and tunica Foci of coagulative necrosis may occur in the liver, lymph nodes, thymus, Peyer's patches, spleen, and adrenal cortices. Typically there is little inflammation associated with the necrosis. Herpesviral inclusions are inconsistently seen in cells at the periphery of the necrotic foci. In a study of systemic BoHV-1 infection in neonatal calves in California, a large proportion of affected calves had histologic lesions compatible with BoHV-1 only in the adrenal gland. Although most of those animals had enteritis and/or colitis, these lesions were considered to be due to other enteric pathogens (coronavirus, cryptosporidia, rotavirus, and attaching-and-effacing E. coli) .
The lesions in the upper alimentary tract of cattle associated with BoHV-1 infection must be differentiated from those of calf diphtheria, bovine papular stomatitis, and bovine viral diarrhea. The ruminal lesions must be differentiated from those of bovine adenovirus infection and nonspecific rumenitis, described elsewhere in this chapter. The liver lesions may be confused with focal necrosis associated with septicemias, for example, listeriosis or salmonellosis (see Vol. 2, Liver and biliary system). Moeller RB Jr, et al. The disease in neonatal kids is characterized clinically by fever, conjunctivitis, ocular and nasal discharges, dyspnea, anorexia, abdominal pain, weakness, and death, usually within 1-4 days after onset of clinical signs. Affected kids have leukopenia and hypoproteinemia.
Macroscopic lesions are most obvious throughout the entire alimentary tract. Round or longitudinal erosions, which have a hyperemic border, are evident in the oral mucosa. These are particularly prominent on the gums around the incisor teeth and to a lesser extent in the pharynx and esophagus. Focal red areas of necrosis, which may be slightly elevated above the surrounding mucosa, occur in the rumen. In the abomasum, numerous longitudinal, red erosions are located in the mucosa. The most severe lesions occur in the cecum and spiral colon, which are dilated, with a thickened wall, and and are hence being renamed, such as bovine adenovirus serotype 1 (BAdV-1) becomes bovine mastadenovirus A. Infection has been mainly associated with keratoconjunctivitis and respiratory disease. Many strains have been isolated from normal cattle. Serotypes 3, 4, 7, and 10 have been associated with enteric disease. It appears that after an initial viremic stage, the virus localizes in the endothelial cells of vessels in a variety of organs, resulting in thrombosis with subsequent focal areas of ischemic necrosis.
Clinically, enteric infections with BAdV occur sporadically in 1-8 week-old calves and in feedlot animals. Affected animals have fever, and diarrhea that may contain blood, and some animals will die peracutely from dysentery. They are dehydrated and the mucous membranes of the muzzle and mouth are congested. Dry, encrusted exudate may cover the muzzle and there may be serous to mucopurulent ocular and nasal discharges.
Macroscopic lesions may be present in the forestomachs, abomasum, and intestine. Those in the forestomachs are characterized by irregular, raised, red-to-gray necrotic areas, 2-4 mm in diameter on the mucosa of both the dorsal and ventral sacs of the rumen. In some cases, the areas of necrosis coalesce to give rise to diffuse necrotizing rumenitis. Ulcers up to 1.5 cm in diameter may be located on the ruminal pillars and these may be visible through the serosa. Similar lesions may be evident in the omasum. The abomasal mucosal folds are edematous and congested, with focal necrosis and ulceration in the mucosa that, like those in the forestomachs, may be visible on the serosal surface.
The intestinal lesions vary from slight dilation and distention with excessive fluid to severe multifocal or diffuse necrosis, which may be covered by a pseudodiphtheritic membrane. In young calves, the lesions are most severe in the jejunum and ileum, especially over the Peyer's patches. In feedlot cattle, the lesions may be most prominent in the colon. The mucosa is dark red (Fig. 1-109) and there is marked edema of the mesocolon. The mesenteric lymph nodes are enlarged and edematous.
Microscopically, foci of ischemic necrosis are evident in the intestinal mucosa, and in more advanced lesions, the necrosis extends across the muscularis mucosae. Fibrinocellular exudate often covers the mucosal surface. Intestinal crypts are dilated, lined by flat epithelial cells, and usually contain necrotic debris ( Fig. 1-110A ). There is usually marked submucosal edema, congestion, and fibrinous exudation. Foci of necrosis are evident in the lymphoid follicles of the Peyer's patches, which are also depleted of lymphocytes. Large basophilic to amphophilic inclusions completely or partially fill the nuclei of endothelium in the vessels of the lamina propria and submucosa of affected areas of the rumen, abomasum, and intestine ( Fig. 1-110B) . The endothelial cells are swollen and necrotic, and muscularis. Immunohistochemically, antigen is documented in the dome area, the lymphoid follicles of Peyer's patches, and ganglion cells of Meissner's and Auerbach's plexuses.
Necrotizing enterocolitis in adult horses because of Equid herpesvirus 1 has been reported rarely. A single case with similar intestinal lesions was also reported in a yearling filly. At autopsy there are multiple areas of hemorrhage, necrosis, and ulceration, some several centimeters in diameter, of the mucosa in both small and large intestine. Microscopically, these lesions consist of erosions and ulcerations of the mucosa, and necrosis of cryptal epithelial cells in adjacent areas. Cryptal epithelial cells and some proprial mononuclear cells may have acidophilic and amphophilic nuclear inclusions. Del Piero F, et
Further reading Carman S, et al. Porcine adenovirus. According to serological surveys, the 5 serotypes of species Porcine adenovirus (PAdV), genus Mastadenovirus, are all common. Serotype 4 appears to be the most widely distributed strain of the virus in Europe and North America. Asymptomatic infections are most common in swine, and PAdV may be isolated from feces of normal pigs; PAdVs are actually of more interest as viral vaccine vectors than as pathogens.
The importance of adenoviruses as a cause of enteric disease in the field remains controversial. When disease occurs, the macroscopic lesions in the intestine consist of excessive yellow watery to pasty contents and moderate enlargement of the mesenteric lymph nodes, which cannot be differentiated from other causes of diarrhea in neonatal pigs.
In contrast to the situation in calves, in which inclusions are located mainly in the nuclei of endothelial cells, inclusions in pigs are in enterocytes in the distal jejunum and ileum, where primary viral replication likely occurs. The infected nuclei are enlarged, round, and displaced to the apical portion of the cell. The villi may be short and blunt. There may be a moderate mononuclear cell reaction in the lamina propria. Inclusions are also found in the squamous epithelial cells of the tonsils and in endothelial cells of capillary and small blood vessels throughout the body.
Ultrastructurally, infected nuclei of enterocytes are round and swollen and contain numerous typical adenoviral particles ( Fig. 1-111) . Affected enterocytes are cuboidal and the apical portion protrudes slightly into the lumen. The cell membrane and microvilli are irregular and the terminal web is absent. The rough endoplasmic reticulum shows local distension with formation of large multivesicular bodies. Eventually there is complete loss of microvilli, and the cell membrane ruptures with the release of cell contents and virus particles into the gut lumen. some veins and lymphatics contain thrombi. Similar inclusion bodies may occasionally be seen in nuclei of enterocytes. Typical inclusions also may be found in endothelial cells of vessels and sinusoids of the adrenal glands, mesenteric lymph nodes, liver, spleen, glomeruli, and interstitial capillaries in the kidney, and in the mucosa of the urinary bladder.
Confirmation of enteric BAdV infection depends on the demonstration of the virus in tissue, through electron microscopy, in situ hybridization, PCR or isolation of the virus in cell culture. The latter is often difficult because different serotypes and strains of the virus require specific cell cultures, and several blind passages may be required before cytopathic changes are evident. with abundant adenoviral inclusions in lambs and kids. In the former, inclusions were found predominantly in the lamina propria, whereas in the latter they were mostly epithelial. Goat adenovirus (GAdV) serotypes 1 and 2 can cause enteritis and diarrhea in goat kids; GAdV-1 is a serotype of Ovine adenovirus D, which also includes serotype 7 and isolate 287.
Two distinct but serologically related adenoviruses have been isolated from dogs. Canine adenovirus 1 (CAdV-1) infection is usually subclinical, but it may cause infectious hepatitis, and diarrhea may be present in these cases. The virus has a particular tropism for hepatocytes and endothelial cells. The serosal hemorrhages in the gastrointestinal tract and possibly the diarrhea may be related to vascular damage in the serosa and mucosa, respectively (see Vol. 2, Liver and biliary system). CAdV-2 is usually associated with upper respiratory infections in dogs (see Vol. 2, Respiratory system). Viruses serologically similar to CAdV-2 have been isolated from feces of diarrheic dogs. DNA fingerprinting of two of these isolates indicated that they are distinct from CAdV-2. It may be that the fecal isolates are due to swallowing of virus originating from upper respiratory tract infections.
A newly recognized cervid Atadenovirus known as Odocoileus adenovirus 1 (OdAdV-1) was the cause of an outbreak of a hemorrhagic disease that caused high mortality in mule deer species in California in the 1990s. OdAdV-1 infection has since been diagnosed as a frequent cause of herd mortality in other deer species in other states of the United States and Canada. The OdAdV-1 is phylogenetically most closely related to bovine adenovirus 7, goat adenovirus 1, and ovine adenovirus 7. Experimentally, OdAdV-1 has been demonstrated to be noninfectious to cattle and sheep.
There are 2 manifestations of the disease in deer; systemic and localized. Both forms were experimentally reproduced in black and white-tailed deer. The disease mimics the orbivirus hemorrhagic diseases in that it triggers DIC through endothelial cell necrosis; however, OdAdV-1 targets first endothelial cells of medium and large vessels, whereas bluetongue and epizootic hemorrhagic disease viruses target primarily the microvasculature. With systemic infection, gross findings include pulmonary edema and/or gastrointestinal hemorrhage ( Fig. 1-112) . Microscopically there is widespread vasculitis
The significance of adenoviral inclusions in enterocytes must be interpreted with caution. A survey in Canada revealed that 4.4% of 5-day to 24-week-old pigs had adenoviral inclusions in enterocytes, mainly in the ileum. More than 50% of the pigs had diarrhea; however, other enteropathogens were found in most of these animals. Guardado-Calvo P, et al Equine adenovirus. Two serotypes of species Equine adenovirus (EAdV), genus Mastadenovirus, designated EAdV-1 and EAdV-2, have been isolated to date. EAdV-1 has a worldwide distribution and it is mainly responsible for upper respiratory tract infections in foals <3 months of age, whereas EAdV-2 has been isolated mainly from horses with gastrointestinal tract infections.
EAdV-2 has been isolated in Australia from foals with diarrhea. Rotavirus also was identified in the feces of these foals. A serologic survey showed that 77% of adult horses in the area had neutralizing antibodies to this particular serotype.
An unidentified alimentary tract adenoviral infection has been reported in an Arabian foal that did not have lesions of combined immunodeficiency. The foal had diarrhea and progressive weight loss over a 2-month period. The macroscopic lesions consisted of ulcers in the distal esophagus and nonglandular mucosa of the stomach. The intestine contained soft to semifluid ingesta. Histologically, there was necrosis and ulceration of the esophageal and gastric squamous mucosa. Typical adenoviral inclusions were found at all levels of the small intestine. These were most commonly located in the villus epithelial cells, less often in the crypts, and only occasionally in the submucosal glands. There was focal-to-diffuse villus atrophy through the small intestine. Adenoviruses in other species. Seven serotypes of Ovine adenovirus (OAdV) have been isolated from sheep. Serotypes 1-6 belong to the genus Mastadenovirus. However, serotype 7 is phylogenetically different from mastadenoviruses, and has been renamed Ovine adenovirus D, and subsequently Ovine atadenovirus D, the type species in genus Atadenovirus. Serotypes 1, 2, and 3 have been recovered from feces of normal sheep, and lambs with enteritis and pneumoenteritis. Experimental inoculation of specific-pathogen-free lambs with OAdV-4 did not cause disease but the virus was re-isolated from feces and nasal secretions for several days post infection. However, occasionally there are reports of enteritis associated
is similar in all the species studied. Coronavirus infects and replicates in the apical cytoplasm of absorptive enterocytes on the tips and sides of intestinal villi. Virions are probably taken up by the apical border of the cell, by fusion with the plasmalemma. Replication and maturation appear to involve budding of virions from the cytosol through the membrane and into the lumen of vacuoles or cisternae in the smooth endoplasmic reticulum, where they accumulate. Virions are found in tubules of the Golgi apparatus. They may exit via that route from infected cells, by exocytosis at the apical cell membrane, or on the lateral cell surface, because viral particles are often seen lined up between microvilli or in the basolateral intercellular space between infected cells. Virus also may be released by lysis of infected cells. Coronaviruses also infect some mesenchymal cells in villi and probably mesenteric lymph node.
Changes in the infected cell occur by ∼12-24 hours after infection. Mitochondria in virus-infected cells swell, cisternae of smooth and rough endoplasmic reticulum dilate, the cytoplasm of infected cells loses its electron density, and cells lose their columnar profile. The terminal web is fragmented; microvilli swell and become irregular, perhaps in association with blebbing of the apical membrane. Damaged epithelium may lyse in situ, releasing virus retained in cytoplasmic vacuoles, or it may exfoliate into the lumen. Profuse diarrhea usually begins about the time that early cytologic changes are becoming apparent, but before there is extensive epithelial exfoliation.
Exfoliation of damaged epithelium may be massive over a relatively short period of time, leading to the development of villus atrophy, the severity of which largely reflects the degree of initial viral damage. Villi may appear fused along their sides or tips, and during the exfoliative phase some villi with denuded tips may be present. The enterocytes present on villi shortly after the initial exfoliative episode are mainly poorly differentiated low columnar, cuboidal, or squamous cells, with stubby irregular microvilli. Within 2-3 days, villi begin to regenerate and the epithelium becomes progressively more columnar, although still lacking a well-developed brush border and its complement of enzymes. Defective fat absorption is reflected in the accumulation of lipid droplets in the cytoplasm of enterocytes on villi. This is particularly marked over the period of ∼2-5 days after experimental inoculation.
With progressive epithelial regeneration from the crypts, the villus fusion, which may be the result of adhesion of temporarily denuded lamina propria of adjacent villi, regresses. Separation begins along the basal margins of the adhesions and progresses toward the tips of the villi. There may be focal acute inflammation in the lamina propria of temporarily denuded villi, and a mild mononuclear infiltrate in the stroma of collapsed villi. Although several cycles of viral replication may occur, poorly differentiated enterocytes appear relatively refractory to infection, and the virus titer falls, presumably as local immune mechanisms also come into play. Hyperplasia of epithelium in crypts usually results in eventual resolution of the villus atrophy, restoring normal function. characterized by endothelial cell hypertrophy and necrosis, disruption of the tunica intima, leukocytic margination, fibrinoid necrosis, and leukocytic infiltration of the tunica intima and sometimes media. Intranuclear inclusion bodies are seen primarily in the endothelium of large vessels in the lungs and serosa and submucosa of the intestine and less often seen in endothelium of interalveolar septal capillaries in the lungs and lamina propria of the intestines. Localized infection is grossly characterized by necrosis and ulceration of the upper alimentary tract. Microscopically there is necrosis of multiple tissues in areas of gross lesions, but vasculitis with intranuclear inclusions is frequently not present.
A novel adenovirus was isolated from an alpaca presented with diarrhea and enteritis. Microscopically, multiple intranuclear inclusion bodies were seen in enterocytes throughout the small intestine.
Coronaviruses cause disease affecting a number of organ systems in a variety of species. Among domestic mammals they mainly cause enteric infections, although coronaviruses are implicated in pneumonia in swine and cattle, and in feline infectious peritonitis.
Coronaviruses have a single-stranded RNA genome. They are pleomorphic or roughly spherical and vary in size from ∼70-200 nm in diameter, averaging 100-130 nm. They have a phospholipid-bearing envelope, probably derived in part from host cell membrane. They gain their name from the characteristic "corona" of petal- or droplet-shaped radial surface projections ("peplomers") visible under the electron microscope in negatively stained preparations.
The coronaviruses infecting each species of host appear to be distinctive; some species are infected by more than one type of coronavirus. There are antigenic relationships among viruses from various hosts, and experimental cross-infection will occur between some host species, usually without pathologic consequences. Persistent infections can occur.
Coronaviruses significant is the differentiation, and low rate of turnover, of small intestinal epithelium in the neonate. The surface epithelium is mature and has an extensive vesicular network in the apical cytoplasm associated with uptake of macromolecules and colostrum during the first day or two after birth. Crypts are short and relatively inactive. Therefore the population of epithelium susceptible to infection on each villus is large, and the capacity to regenerate new enterocytes is small. By ∼3 weeks of age, epithelium is actively proliferative. Virus production by infected enterocytes in older pigs seems less efficient, and replacement of cells lost to infection is more rapid, contributing to the relative resistance seen in swine greater than ∼3 weeks of age. Piglets with TGE have the nonspecific gross appearance at autopsy of undifferentiated neonatal diarrhea. The stomach may contain a milk curd or bile-stained fluid. The small bowel is flaccid and contains yellow frothy fluid with flecks of mucus; chyle is not usually evident in mesenteric lymphatics because there is fat malabsorption.
The microscopic lesions are those of villus atrophy resulting from exfoliation of surface enterocytes (Fig. 1-113) , the severity of which is a function of the age of the pig and the stage of the disease. In young piglets, the lesions are most severe about the time of the onset of diarrhea. In later phases or in older pigs there may be subtotal to moderate atrophy, and the mucosa may be lined by cuboidal to low columnar epithelium, with irregular nuclear polarity and an indistinct brush border. Severe atrophy is readily recognized at necropsy of neonatal piglets by examination of the mucosa under a dissecting microscope. Lesions are most common in the middle and lower small intestine, and villi in the duodenum are usually tall and cylindrical. Lesions may be patchy, and several areas of lower small intestine must be examined before atrophy is considered not to be present. In animals beyond the neonatal age group, atrophy may not be so severe and readily recognized under the dissecting microscope, and the contrast with the normally shorter villi in the duodenum of older pigs is not as marked. Histologic assessment of the gut is essential.
Porcine respiratory coronavirus (PRCoV) is genetically and antigenically extremely close to TGEV. It cross-reacts serologically, and vaccinated sows successfully induce passive immunity against enteric infections. PRCoV is spread by inhalation, and infects lining cells of the upper respiratory tract. Mild bronchointerstitial pneumonia results from experimental infection, and the agent has been associated with outbreaks of respiratory disease.
many years from Europe and Asia. In 2013 a diagnosis of this condition was made in Iowa, from where it spread quickly to several other states of the United States and Canada. Traditionally the disease was considered to be essentially similar to TGE in epidemiology, pathogenesis, and lesions, but milder. However, the recent US epidemic occurred as explosive epidemics of diarrhea and vomiting affecting all ages, with 90-95% mortality in suckling pigs. Clinically, grossly, and histologically, disease produced by PEDV cannot be differentiated from TGE. The diagnosis should be confirmed by PCR or immunohistochemistry. Although PEDV is related to TGEV, diagnostic tests for TGEV will not detect PEDV.
Porcine deltacoronavirus (PDCoV), a deltacoronavirus first detected in Hong Kong in 2012 and now present in North
The diarrhea that occurs is a result of electrolyte and nutrient malabsorption, with some contribution by secretion by crypt cells, and probably by poorly differentiated surface epithelium in the reparative phase. Mechanisms of diarrhea in villus atrophy are discussed in the section on the Pathophysiology of enteric disease. Remission of signs occurs within ∼4-6 days as regeneration of villi occurs, providing the animal survives the dehydration, electrolyte depletion, and acidosis brought about by diarrhea.
Diagnosis is achieved by detection of viral particles by negative-staining electron microscopy or detection of the virus by fluorescent antibodies, immunohistochemistry, PCR, and/ or virus isolation.
Deltacoronavirus, species Porcine deltacoronavirus (PDCoV, SDCV). PEDV, TGEV, and PDCoV cause vomiting and diarrhea in suckling piglets, with high morbidity and mortality caused by severe enteritis. PHEV also causes vomiting and wasting disease in suckling piglets; but mainly mediated by infection of the central and peripheral nervous system (see Vol. 1, Nervous system).
Transmissible gastroenteritis (TGE) may affect swine of any age, causing vomiting, severe diarrhea, and, in piglets, high mortality. The disease is recognized throughout most of the world. The epidemiology of TGE depends on the overall immune status of the herd and of the various age groups within the herd. Introduction of TGEV into a naive herd results in rapid spread of disease with high morbidity affecting all age groups. Sows and older pigs show transient inappetence, and possibly diarrhea and vomiting. Signs may be more severe in sows exposed to high virus challenge from infected baby pigs. Agalactia may occur in recently farrowed sows, perhaps related to TGEV infection of the mammary gland. Suckling piglets develop severe diarrhea, and mortality may approach 100% in piglets <10-14 days old. Older pigs usually develop less severe signs and have lower mortality. In herds with enzootic infection, high piglet mortality may occur in the offspring of recently introduced naive sows, and diarrhea with lower mortality may occur in piglets greater than ∼2-3 weeks of age as milk intake and concomitant lactogenic immunity wane. Infected pigs in the late suckling or weanling age group may runt. TGE is more prevalent in the winter, perhaps because the virus is not resistant to summer environmental conditions of warmth and sunlight. Baby pigs that are chilled also seem less able to survive the effects of infection.
The severity of disease in baby pigs is partly related to their inability to withstand dehydration because of their small size, and to their susceptibility to hypoglycemia. Probably as Bovine coronavirus. In neonatal calves, Bovine coronavirus (BCoV) infection is a common cause of diarrhea, either alone or in combination with other agents, particularly Rotavirus and Cryptosporidium. The disease may be severe in combination with BVDV infection. BCoV is capable of infecting absorptive epithelium in the full length of the small intestine, and in the large bowel. Viral antigen is also found in macrophages in the lamina propria of villi and in mesenteric lymph nodes. In field infections, microscopic lesions are found most consistently in the lower small intestine and colon. Calves with BCoV infection usually develop mild depression, but continue to drink milk despite developing profuse diarrhea. With progressive dehydration, acidosis, and hyperkalemia, the animals become weak and lethargic; death can ensue as a result of hypovolemia, hypoglycemia, and potassium cardiotoxicosis. Diarrhea in survivors resolves in 5-6 days.
At autopsy, affected animals have the nonspecific lesions of undifferentiated neonatal calf diarrhea. Rarely, mild fibrinonecrotic typhlocolitis is recognized in calves with coronaviral infection. Mesenteric lymph nodes may be somewhat enlarged and wet.
Virus replication is cytocidal and initially occurs throughout the length of the villi in all levels of the small intestine, eventually spreading throughout the large intestine up to the end of the large colon and rectum, causing a malabsorptive diarrhea. Large concentration of BCoV can be typically found in the spiral colon. Infected epithelial cells die, slough off, and are replaced by immature cells. The microscopic lesions of coronaviral infection in calves vary with the severity and duration of the infection; villus atrophy in combination with mild colitis is typical (Fig. 1-114) . In the calf small intestine, villus atrophy is rarely as severe as that seen in neonatal swine with TGE. Rather, villi are moderately shortened, or have subtotal atrophy with stumpy, club-shaped, or pointed tips, and villus fusion may be common. In the early phase of the clinical disease, villi are often pointed and covered by cuboidal to squamous epithelium. Exfoliation of epithelium and microerosion may be evident. Later, the epithelium is cuboidal to low columnar, basophilic, with irregular nuclear polarity and an indistinct brush border. Cryptal epithelium is hyperplastic. The lamina propria may contain a moderate infiltrate of mainly mononuclear inflammatory cells, some of which may have pyknotic or karyorrhectic nuclei. In the early stages of infection, necrosis of cells in mesenteric lymph nodes is hyperplastic epithelium, and the surface epithelium will be restored to a cuboidal or low columnar cell type. Goblet cells are usually relatively uncommon. Colonic lesions may be recognizable in tissues from animals submitted dead, even though postmortem change has obscured changes in the small intestine. Live calves in the early stages of clinical disease are the best subjects for confirmation of an etiologic diagnosis. In calves becoming ill <7 days of age, enterotoxigenic Escherichia coli is the main alternative diagnosis. Rotavirus, Cryptosporidium, and combined infections must be considered in calves 5-15 days of age. Infectious bovine rhinotracheitis, salmonellosis, and bovine viral diarrhea must also be considered. Both salmonellosis and bovine viral diarrhea may be associated with depletion of Peyer's patches and colitis that can be confused with that of coronaviral infection; neither is common in the strictly neonatal age group (<7-14 days of age).
Respiratory tract infection also occurs in calves and feeders infected with BCoV. The virus replicates in the epithelium of the nasal turbinates and tracheobronchial tree, and respiratory infection may precede, be concurrent with, or follow enteric infection. Calf pneumonia caused by BRCoV can be observed in calves 6-9 months of age. Affected animals may develop fever, serous to mucopurulent nasal discharge, coughing, tachypnea, and dyspnea. Respiratory infections may play a role in maintaining the virus within a herd, and significant, but poorly characterized, pneumonia has been reported in some experimentally infected calves. In addition, coronaviral infection may predispose to subsequent respiratory bacterial infections or contribute to more severe respiratory disease as part of the shipping fever syndrome. Virus may be identified in tissue or nasal secretions by immunofluorescence or immunohistochemistry.
Winter dysentery is a syndrome in adult cattle that has been associated with BCoV in a number of areas around the world. Animals develop blood-tinged diarrhea, nasolacrimal discharge or cough, anorexia, and drop in milk production. Mortality is rare, but may occur. The disease is characterized by a high morbidity rate ranging from 50-100%, but usually low mortality rate, typically <2%. Winter dysentery outbreaks are predominantly seen in young postpartum dairy cows, which then experience a drop of 25-95% in milk production. Occasional cases are also observed in adult dairy and beef cattle. Despite its name, cases of winter dysentery can be observed, albeit infrequently, during the warmer season. The pathophysiologic characteristics of winter dysentery are mostly attributed to lesions of the colonic mucosa. Grossly, the colon of affected animals has linear congestion and hemorrhage along the crests of mucosal folds and there may be a large amount of blood mixed with colonic contents (Fig. 1-115) . The histologic lesions are similar to those seen in calves with classical BCoV diarrhea, although they are mostly restricted to the colon with only occasional lesions seen in the terminal small intestine. Large amount of BCoV can be detected in colonic epithelium by immunohistochemistry. Coronaviruses are commonly demonstrated in the feces of cattle with winter dysentery; seroconversions occur, and seroprevalence increases in affected herds. Coronavirus antigen is found in the colonic glands of affected animals, in which there is necrosis and exfoliation of epithelial cells. Certain management practices, notably housing animals in stanchions and use of equipment that handles both manure and feed, have been associated with the development of winter dysentery. associated with viral replication. Peyer's patches in animals examined after 4-5 days of clinical illness often appear involuted, and are dominated by histiocytic cells. Whether this is the result of viral activity or the effect of endogenous glucocorticoids is unclear.
In the colon during the early phase of infection, surface epithelium may be exfoliating, flattened, and squamous or eroded in patchy areas. Some colonic glands may be dilated, lined by flattened epithelium and contain exfoliated cells and necrotic debris. A moderate mixed inflammatory reaction is present in the lamina propria, and neutrophils may be in damaged glands or effusing into the lumen through superficial microerosions. Later in infection, some dilated debris-filled colonic glands will remain, but other glands will be lined by
Villus atrophy in the jejunum was inconsistent, but there was necrotic debris in many glands in the cecum and colon. Virusinfected cells were exfoliating into the lumen.
In the recently observed infections with pantropic coronavirus, gross lesions were mostly confined to the small intestine and included pink to red intestinal mucosa that occasionally had a slightly dry and rough surface with rare petechiae. Regional mesenteric lymph nodes and spleen were enlarged and congested. Microscopic lesions included villus atrophy and fusion together with dilated crypts containing degenerated and necrotic cells.
Our understanding of the enteric implications of coronaviral infections of cats is still incomplete. It appears that Feline enteric coronavirus (FECV) can establish persistent infection in the intestine, which in rare cases may be clinically apparent. Infection is very common. When it occurs, diarrhea is usually mild or moderate, perhaps with some blood, and kittens are most susceptible. Viral antigen is in cells on the tips of villi, and mild villus atrophy has been illustrated. Approximately 13% of all infected cats are not able to clear the virus, which persists for long periods of time in the colonic epithelium. During replication, mutations may occur in the viral genome giving rise to feline infectious peritonitis virus, which causes the highly lethal feline infectious peritonitis, a disease of far greater clinical significance.
Coronaviruses have been recovered from the feces of sheep with transient diarrhea, and they have been associated with severe villus atrophy in several spontaneous outbreaks of diarrhea. No experimental confirmation of the pathogenicity of coronavirus in sheep is available.
Equine coronavirus (EqCoV) is a betacoronavirus that has been associated with enteric and neurologic disease in horses in the United States and Japan. Necrotizing enteritis associated with EqCoV has been diagnosed in a horse in California and a donkey in Idaho. EqCoV infection of adult horses can occur in outbreaks, but is usually limited to individual cases of anorexia, lethargy, and fever.
Epizootic catarrhal enteritis of ferrets (ECE) is a highly contagious, diarrheal disease with close to 100% morbidity, but low overall mortality rate (<5%). ECE is produced by Ferret enteric coronavirus, genus Alphacoronavirus. The disease is clinically characterized by lethargy, hyporexia or anorexia, vomiting, diarrhea with a high mucus content, and dehydration. Feces of chronically affected animals frequently contain gritty material that has been described as resembling birdseed. Grossly, the affected small intestinal mucosa is hyperemic and the intestinal wall is thin. Microscopically, ECE is characterized by diffuse lymphocytic enteritis, with villus atrophy, fusion, and blunting; vacuolar degeneration and necrosis of the apical epithelium; or a combination of these lesions. Large numbers
Canine coronavirus. Canine coronavirus (CCoV) is widely prevalent in the dog population. Although dogs of all ages appear to be susceptible to infection by CCoV, the condition is probably most important as an uncommon, transient, generally nonfatal diarrhea in puppies. Fatal infections have been reported in pups previously infected with parvovirus. Infection with a pantropic canine coronavirus characterized by deadly acute systemic disease was diagnosed recently in several European countries. This was concurrent in most cases with Canine parvovirus 2c.
Viral replication occurs in the enterocytes of the small intestine, and in experimental infections in neonatal puppies, the lesion resembles the villus atrophy associated with coronaviral infection in other species. Diarrhea begins as early as 1 day after inoculation and in most animals by 4 days. Onset of signs coincides with the development of moderate villus atrophy and fusion. Enterocytes on villi become cuboidal, contain lipid vacuoles, and have an indistinct brush border. Lesions are most consistent and severe in the ileum. Resolution of villus atrophy within 7-10 days is associated with remission of signs.
Colonic infection by CCoV was not demonstrated by immunofluorescence in experimental animals, although mild colonic lesions were described, including loss of sulfomucins from goblet cells and some epithelial shedding. However, in a report of lesions caused by spontaneous CCoV infection, colonic infection and lesions were demonstrated. There was watery content in the lumen of the small and large intestine, and fibrin mixed with blood was evident in the cecum and colon. Mesenteric lymph nodes were enlarged and edematous.
Further reading Pratelli A, et viral antigen are present. Infected enterocytes lose cytoplasmic electron density, and mitochondria swell, as does the cell generally. Swollen rarified cells and syncytia may occur in the enterocytes at the villus tips, but cells are fragile and shed readily, particularly if autolysis intervenes. Syncytial cell formation has been recognized in porcine, bovine, and laboratory animal infections with rotavirus. Microvilli become irregular and somewhat stunted, and there may be some blebbing of membranes. Infected cells exfoliate into the intestinal lumen, and virus is released by lysis of damaged epithelium prior to or after exfoliation. The pathogenesis of diarrhea with rotavirus involves 3 mechanisms. First, malabsorption occurs secondary to destruction of enterocytes. Second, a vasoactive agent is released from infected epithelial cells and causes villus ischemia and activation of the enteric nervous system. Third, rotaviruses are capable of producing a nonstructural protein, NSP4, which acts as a secretory enterotoxin. This is the first viral pathogen known to produce a toxin.
Exfoliation of infected epithelium over a relatively short period of time results in villus atrophy. The mucosal surface is covered by cuboidal, poorly differentiated epithelium that has an ill-defined microvillus border and that may contain lipid droplets in the cytoplasm. Diarrhea is probably mediated by electrolyte and nutrient malabsorption, perhaps exacerbated by the effect of cryptal secretion. It begins about the time of early viral cytopathology 20-24 hours after infection, and may persist for a variable period, from a few hours to a week or more. Regeneration of the mucosa by epithelium emerging from crypts, and differentiating on reformed villi, is associated with remission of signs in animals surviving the effects of diarrhea.
Rotaviruses are widespread, if not ubiquitous, among populations of most species, and they are relatively resistant to the external environment. Protection against infection in neonates is apparently largely conferred by the presence of lactogenic immunity. Many individuals in a population probably undergo inapparent infection. Disease is seen in the various species when viral contamination of the environment is heavy, perhaps as a result of intensive husbandry practices, and lactogenic immunity is waning or absent. Although rotaviral infection is usually associated with younger age groups, and viral receptors on cells diminish with age in some species, naïve older animals may become infected, sometimes with the development of diarrhea.
Bovine rotaviral infection. Rotaviral infection is mainly implicated in diarrhea of neonatal beef and dairy calves, both suckled and artificially reared, although there are reports of its association with diarrhea in adult cattle. Combinations of agents, including Rotavirus, are frequently involved in outbreaks of diarrhea in neonatal calves. Diarrhea may be produced in calves by rotaviral infection alone, but the condition is usually considered to be relatively mild or transient in comparison with that induced by enterotoxigenic Escherichia coli or Bovine coronavirus. Rotavirus may be implicated in animals developing signs at any time over the period up to ∼2-3 weeks of age, and it is more commonly encountered in animals >4-5 days of age. Rotaviral diarrhea is most severe in calves that have slower enterocyte regeneration times. Rotavirus has a prepatent period of 1-3 days, and diarrhea lasts 2-5 days if uncomplicated.
The gross lesions of rotaviral infection are the nonspecific findings of undifferentiated neonatal diarrhea in calves, of coronavirus-infected epithelial cells can be detected by immunohistochemistry using a monoclonal antibody against group 1c coronavirus antigen. Coronavirus-like particles can be seen in cytoplasmic vacuoles of apical enterocytes and at the cell surface by transmission electron microscopy.
Members of the genus Rotavirus, in the family Reoviridae, infect the gastrointestinal tract of most mammals and birds. Rotaviruses are classified according to antigenic properties with group, subgroup, and serotype categories. Segment 6 of the Rotavirus genome codes for the VP6 intermediate capsid protein, which is used to classify the virus into seven serogroups, A-G. Group A rotaviruses (RV-A) are the most diverse and common, and infect all species of domestic animals, as well as humans, laboratory animals, and wildlife. RV-A can be subdivided into G and P serotypes based on VP7 and VP4 external capsid proteins, respectively; there are 14 G serotypes and 20 P serotypes. The serotypes isolated most commonly from piglets with diarrhea are P[7],G5, P[6],G4, P[7],G3, and P[7],G11. Individual rotavirus serotypes have a surprisingly wide range of host susceptibility. Non−group A rotaviruses infect pigs and ruminants, among domestic animals.
The ability to infect cells, and the serotype specificity of rotaviruses, are conferred by elements of the outer capsid layer. The viruses are probably generally host-specific, with little significant zoonotic potential. However, if epidemiologic circumstances are favorable, cross-species transmission may occur.
Rotaviruses infect the absorptive enterocytes and occasionally goblet cells on the tips and sides of the distal half or two thirds of villi in the small intestine. Rotaviruses infect cells on the apical half (ruminants) or the entire villus (pigs), mainly in the jejunum and ileum. Virus production and the pathogenesis of infection are similar in all species studied. Rotaviruses adhere to cell receptors (e.g., integrins, sialic acid), and inner capsid components are internalized into the cell. Granular "viroplasm" containing incomplete virions is seen in the apical cytoplasm of infected cells, and virions acquire their complete capsid after budding into dilated cisternae of endoplasmic reticulum, where they accumulate. Elongate tubular structures are found in the nuclei and rough endoplasmic reticulum of some infected cells.
Virus-infected cells are most prevalent 18-24 hours after experimental infection, and they tend to diminish in number rapidly, so that by 3-4 days after infection few cells containing alone or in combination with enterotoxigenic E. coli and/or Cryptosporidium. In older, weaned lambs, an outbreak of diarrhea with 17% mortality was reported, produced by a novel ovine rotavirus group A G8 P strain and no other intestinal pathogens associated. The pathogenesis and lesions of Rotavirus infection in lambs are like those caused in other species, with the exception that viral infection of the colon may occur.
In foals <3-4 months of age, Rotavirus infection is considered a major cause of diarrhea, although mortality is rare. Outbreaks have been reported in many areas of the world. Equine rotaviruses are ubiquitous in horse populations and dual infections with more than one strain of rotavirus, including viruses of different G types, have been reported, but the clinical significance of this is poorly understood. Co-infections with other pathogens, including Salmonella spp., Cryptosporidium spp., and equine coronavirus have also been observed. The natural and experimental disease resembles that seen in other species, with significant viral infection limited to enterocytes in the small intestine, where villus atrophy occurs.
In young puppies, especially those <1-2 weeks of age, diarrhea, occasionally fatal, may be caused by Rotavirus infection. In experimentally infected pups, green fluid content filled the lower small bowel and colon, and moderate villus atrophy was induced by exfoliation of epithelium from the distal half of villi.
Rotavirus has also been associated with diarrhea in kittens, although rotavirus also can be isolated from asymptomatically infected kittens.
Rotavirus infection should be sought in cases of diarrhea in young animals of any species and it should be particularly suspected in animals with villus atrophy in the small intestine. Rotavirus is part of the syndrome of undifferentiated neonatal diarrhea in any species. Bailey KE, et described previously. Microscopic lesions in the small intestine cannot be differentiated from those of coronaviral infection. They may vary somewhat depending on the severity of the initial viral damage and the stage of evolution of the sequelae. Blunt club-shaped villi, mild or moderate villus atrophy, and perhaps villus fusion may be present ( Fig. 1-116 ). Villi are covered by low columnar, cuboidal, or flattened surface epithelium with a poorly defined brush border. There is usually a moderate proprial infiltrate of mononuclear cells and eosinophils or neutrophils, and hypertrophic crypts may be evident. The distribution of lesions may vary between animals and perhaps with time after infection within an individual animal because the onset of maximal viral damage may not occur synchronously throughout the full length of the intestine. Lesions and viral antigen always should be sought in the distal small intestine, and preferably at several sites along its length. Rotavirus does not cause gross or microscopic lesions in the colon, in contrast to coronavirus. Swine rotaviral infection. Rotavirus infection is widespread and enzootic in most swine herds, and subclinical infection of piglets is common. It assumes particular importance as a cause of diarrhea in pigs with reduced lactogenic immunity, either as a result of early weaning or after normal weaning. High environmental levels of virus may result in disease in piglets suckling the sow, but in these circumstances the signs are usually relatively mild. Rotavirus may be a cause of "3-week," "white," or postweaning scours in piglets 2-8 weeks of age.
The signs may resemble those of transmissible gastroenteritis (TGE), although Rotavirus infection is considered to be less severe. Vomition is less commonly encountered than with TGE, but depression, diarrhea, and dehydration are usual. The character of the feces varies with the diet. Steatorrhea occurs in white scours of suckling piglets. Rotavirus infection in swine is frequently associated with other causes of diarrhea, including E. coli, coccidiosis, adenoviral infection, and Strongyloides.
The gross and microscopic lesions and pathogenesis of rotavirus infection in pigs resemble those of TGE ( Fig. 1-117) . As in TGE, severity of lesions seems inversely related to age. Rotaviral infection in other species. Neonatal lambs have proved a useful model for the demonstration of the importance of lactogenic immunity in preventing disease caused by Rotavirus. Rotavirus may cause diarrhea in neonatal lambs at the nuclear membrane. Inclusions are most prevalent late in the incubation period, before extensive exfoliation or lysis of infected cells. Hence they are not commonly encountered in animals submitted for autopsy after a period of clinical illness culminating in death. Large nucleoli, seen in proliferative cells encountered in the intestine of parvovirus-infected animals, should not be confused with intranuclear viral inclusions.
The pathogenesis of FPV and of CPV-2 infection is sufficiently similar for them to be considered together here, followed by separate discussions of the specific diseases. Oronasal exposure results in uptake of virus by epithelium over tonsils and Peyer's patches. Infection of draining lymphoid tissue is indicated by isolation of virus from mesenteric lymph nodes 1-2 days after experimental inoculation. Release of virus into lymph, and dissemination of infected lymphoblasts from these sites, may result in infection of other central and peripheral lymphoid tissues, including thymus, spleen, lymph nodes, and Peyer's patches, 3-4 days after infection. Lymphocytolysis in these tissues releases virus, reinforcing cell-free viremia. Viremia is terminated when neutralizing antibody appears in circulation ∼5-7 days after infection. Moderate pyrexia occurs at about this time.
Cell invasion is mediated via capsid-mediated attachment to one or more receptors on cell membranes and receptormediated endocytosis. In the dog, capsid proteins bind to transferrin receptors, whereas in the cat capsid proteins bind to neuraminic acid and transferrin receptors. These receptors confer cell and animal-species specificity to each parvovirus strain. After the replication cycle is completed, parvovirus particles are released from infected crypt enterocytes, killing the cells. Infection of the gastrointestinal epithelium is a secondary event, following dissemination of virus by circulating lymphocytes and cell-free viremia. Peyer's patches are consistently infected at all levels of the intestine, and epithelium in crypts of Lieberkühn over or adjacent to Peyer's patches usually becomes infected a day or so later. Infection of gastrointestinal epithelium at other sites in the gut is less consistent, but is usually more severe in the lower small intestine. It may be the result of virus free in circulation, or carried by infected lymphocytes homing to the mucosa. Maximal infection of cryptal epithelium occurs during the period ∼5-9 days after infection.
The occurrence and severity of enteric signs are determined by the degree and extent of damage to epithelium in intestinal crypts. This seems to be a function of two main factors. The first is the availability of virus, which is influenced by the rate of proliferation of lymphocytes, and therefore their susceptibility to virus replication and lysis. The second factor influencing the degree of epithelial damage is the rate of proliferation in the progenitor compartment in crypts of Lieberkühn. If many cells are entering mitosis, large numbers will support virus replication and subsequently lyse. Destruction of cells in the crypts of Lieberkühn, if severe enough, ultimately results in focal or widespread villus atrophy and perhaps mucosal erosion or ulceration. The recognition, evolution, and sequelae of radiomimetic insult to the intestine, such as that caused by parvovirus, are described elsewhere (see previous section on Epithelial renewal in health and disease).
Regeneration of cryptal epithelium and partial or complete restoration of mucosal architecture will occur, if undamaged stem cells persist in most affected crypts, and the animal survives the acute phase of clinical illness. In some survivors, focal Kang BK, et al.
The Parvoviridae are small nonenveloped viral particles ∼18-26 nm in diameter, with icosahedral symmetry and a short single-stranded DNA genome. They replicate and produce inclusion bodies in the nucleus of infected cells. Members of the genus Parvovirus infect many species of laboratory and domestic animals. Among syndromes associated with parvovirus infection are: disease in cats, dogs, and mink (distinct from Aleutian mink disease virus) dominated clinically by enteritis; diarrhea in neonatal calves; and reproductive wastage in swine. Feline panleukopenia virus (FPV), Mink enteritis virus (MEV), and Canine parvovirus 2 (CPV-2) are considered host range variants or strains of the species Feline panleukopenia virus within the genus Parvovirus. Based on the nucleotide sequence in the gene for capsid proteins, VP1/VP2, FPV, and MEV are very closely related to each other, and somewhat less related to CPV-2. These viruses are nonetheless biologically distinct, varying in their hemagglutination characteristics, in vitro host cell ranges, and virulence in experimentally inoculated hosts. CPV has been shown to evolve very rapidly in comparison to FPV. Antigenic differences can be detected by monoclonal antibodies and there are differences in host specificity conferred by variations in only very small segments of the viral genome. However, host range is overlapping. Although the originally identified cause of canine parvoviral enteritis (CPV-2) was unable to infect cats, two new antigenic types have evolved from CPV-2, namely, CPV-2a and CPV-2b, which are able to replicate and cause disease in cats. Another variant, CPV-2c, has a more diverse carnivore host range, including skunks, raccoons, foxes, dogs, and cats. Although it is controversial whether CPV-2c is more virulent than other types, CPV-2c is shed at high concentration in feces and it is extremely stable.
The host ranges of FPV and CPV are determined by receptor binding, particularly to the transferrin receptor TfR. Canine parvovirus 2 is distinct from canine minute virus (CMV, or canine parvovirus 1) that also has enteric lesions associated with infection.
Although autonomous parvoviruses may infect cells at any phase of the cell cycle, replication is dependent on cellular mechanisms only functional during nucleoprotein synthesis before mitosis. Hence the effects of parvoviral infection are greatest in tissues with a high mitotic rate. These may include a variety of tissues during organogenesis in the fetus and neonate. In older animals, the proliferative elements of the enteric epithelium, hematopoietic and lymphoid tissue are particularly susceptible. At the time of virus assembly, large basophilic or amphophilic Feulgen-positive nuclear inclusions may be found in infected cells, especially in Bouin's fixed tissues. Parvovirus is demonstrated in these inclusions by electron microscopy. The chromatin in inclusion-bearing nuclei is usually clumped
When it occurs, signs usually begin during the late viremic phase, ∼5-7 days after infection. Severe enteric damage is the major cause of mortality. Shedding of infective virus in feces begins ∼3-5 days after infection, when Peyer's patches and cryptal epithelium first become infected. Virus shedding persists until coproantibody appears to neutralize virus entering the gut, ∼6-9 days after infection. Virus-infected cells may still be detected in crypts and Peyer's patches at this time, and virus complexed with antibody may be found in feces or intestinal content by direct electron microscopy. However, attempts to demonstrate virus in tissues or feces after several days of clinical disease, or at death, are often thwarted by the fact that virus is neutralized by antibody present in tissue fluids. Persistent or sporadic shedding of virus by recovered animals may be the result of virus replication in cells entering mitosis days or weeks after they were infected during the viremic phase.
Infection of the fetus during late prenatal life by FPV causes anomalies of the central nervous system, mainly hypoplasia of the cerebellum; anomalies of the central nervous system have not been reported in puppies with CPV-2, although there is mounting evidence from polymerase chain reaction studies that central nervous system lesions in puppies can be induced by fetal CPV-2 infections. Infection of proliferating cardiac myocytes in young puppies with CPV-2 results in nonsuppurative myocarditis and sequelae of acute or chronic heart failure (see Vol. 3, Cardiovascular system), but this is rarely seen in populations with a high prevalence of maternal immunity. A tentative association has been made between infection of kittens with FPV and myocarditis, as well as subsequent cardiomyopathy.
infects all members of the Felidae, as well as mink, raccoons, and some other members of the Procyonidae. FPV is ubiquitous in environments frequented by cats, and infection is common, although generally subclinical. The disease panleukopenia (infectious feline enteritis, feline distemper) usually occurs in young animals exposed after decay of passively acquired maternal antibody, but it may occur in naïve cats of any age. Clinical signs of several days' duration, including pyrexia, depression, inappetence, vomition, diarrhea, dehydration, and perhaps anemia may be evident in the history. However, many cases, particularly poorly observed animals or those prone to wander, may be presented as "sudden death." The pathogenesis of panleukopenia has been considered villus atrophy is associated with persistent dilated crypts containing cellular debris, and with local "drop-out" of crypts completely destroyed by infection. In rare animals that have recovered from acute disease, chronic malabsorption and protein-losing enteropathy are associated with persistent areas of ulceration caused by more extensive loss of crypts and collapse of the mucosa.
The low rate of replication of intestinal epithelium in germ-free cats explains failure to produce significant intestinal lesions and clinical panleukopenia in experimentally infected animals. In spontaneous cases, the lower prevalence of parvoviral lesions in the colon and stomach, in comparison with the small intestine, reflects the relatively lower rate of epithelial proliferation in those tissues. The consistency of epithelial lesions in the mucosa over Peyer's patches probably results from high local concentrations of virus derived from infected lymphocytes in the dome and follicle. This may be coupled with local stimulation of epithelial turnover by cytokines released by T lymphocytes in the vicinity. Variations in the rate of epithelial proliferation related to age, starvation, and refeeding, or concomitant parasitic, bacterial, or viral infections, may also influence the susceptibility of crypt epithelium to infection, and therefore affect the extent and severity of intestinal lesions and signs.
Diarrhea in parvoviral infections is mainly the result of reduced functional absorptive surface in the small intestine. Effusion of tissue fluids and blood from a mucosa at least focally denuded of epithelium probably also contributes to diarrhea. Dehydration and electrolyte depletion are the result of reduced fluid intake, enteric malabsorption, effusion of tissue fluid, and, in some animals, vomition. Hypoproteinemia is common, and anemia may occur because of enteric blood loss; both are exacerbated by rehydration. Anemia reflects hemorrhage into the gut.
Proliferating cells in the bone marrow also are infected during viremia. Lysis of many infected cells is reflected in hypocellularity of the marrow caused by depletion of myeloid and erythroid elements, particularly the former. Megakaryocytes also may be lost, but seem the least sensitive cell population in the marrow. The number of neutrophils in circulation drops quickly in severely affected animals. This is due to failure of recruitment from the damaged marrow, and peripheral consumption, especially in the intestine. Transient neutropenia, of ∼2-3 days' duration, occurs consistently in cats, and less commonly in dogs. In surviving animals, regeneration of depleted myeloid elements from remaining stem cells restores the circulating population of granulocytes within a few days. Neutrophilia with left shift may occur during recovery.
Lymphopenia, relative or absolute, results from viral lymphocytolysis in all infected lymphoid tissue. Relative lymphopenia is more consistently observed in dogs than neutropenia. When lymphopenia and neutropenia occur together, the combined leukopenia may be profound in both dogs and cats. In dogs surviving the lymphopenic phase, circulating lymphocytes return to normal numbers within 2-5 days, as regenerative hyperplasia occurs in lymphoid tissue throughout the body. Lymphocyte numbers increase rapidly, sometimes producing lymphocytosis in recovering dogs. However, there may be transient immunosuppression in gnotobiotic pups subclinically infected with CPV-2. Transient depression of T-cell response to mitogens occurs in cats a week after experimental infection with FPV. But immunosuppression by these agents appears to be of little clinical significance. severely attenuated cells. The lamina propria between crypts contains numerous neutrophils and eosinophils at this time, and some emigrate into the lumen of crypts, where they join the epithelial debris.
Subsequently severely damaged crypts may be lined by extremely flattened cells, and by scattered large bizarre cells with swollen nuclei and prominent nucleoli ( Fig. 1-119) . Enterocytes covering villi are not affected. But as they progress off the villus, they are replaced by a few cuboidal, squamous, or bizarre epithelial cells, so that villi in affected areas undergo progressive collapse. If cryptal damage is severe and widespread, the mucosa becomes thin and eroded or ulcerated, with effusion of tissue fluids, fibrin, and erythrocytes. Inflammatory cells are usually sparse in the gut of such animals, and superficial masses of bacteria may be present, occasionally accompanied by locally invasive fungal hyphae. In less severely affected animals with disease of longer duration, corresponding to ∼8-10 days after infection, scattered focal drop-out of crypts, or focal mucosal collapse and erosion or ulceration, may be evident. In these animals, remaining crypts recovering from milder viral damage show regenerative epithelial hyperplasia. Mucosal lesions are often most marked in the vicinity of Peyer's patches.
Lesions in the colon generally resemble those found in the small bowel, although they are often less severe or more patchy in distribution. Colonic lesions are present in about half of fatal cases of panleukopenia. Gastric lesions resulting from damage to mitotic epithelium are relatively uncommon in cats. They are recognized by flattening of basophilic cells lining the narrowed isthmus of gastric fundic glands, with some reduction in number of parietal cells in the upper portion of the neck of glands.
Lesions of lymphoid organs during the early phase of the disease consist of lymphocytolysis in follicles and paracortical tissue in lymph nodes, thymic cortex and splenic white pulp, and gut-associated lymphoid tissue. Lymphoid necrosis has been associated with induced apoptosis of virus-infected lymphocytes. Lymphocytes are markedly depleted in affected tissue and large histiocytes are prominent, often containing the fragmented remnants of nuclear debris. Follicular hyalinosis, the presence of amorphous eosinophilic material in the center of depleted follicles, may be seen. Erythrophagocytosis above. Lesions of the central nervous system in kittens are considered in Vol. 1, Nervous system.
At autopsy, external evidence of diarrhea may be present, the eyes may be sunken, and the skin is usually inelastic, with a tacky subcutis reflecting dehydration. Rehydrated animals may have edema, hydrothorax, and ascites resulting from hypoproteinemia. There is pallor of mucous membranes and internal tissues in anemic animals. Gross lesions of internal organs most consistently involve the thymus and the intestine. The thymus is markedly involuted and reduced in mass in young kittens. Enteric lesions may be subtle and easily overlooked. Hence it is mandatory that intestine be examined microscopically despite the apparent absence of gross change.
The intestinal serosa may appear dry and nonreflective, with an opaque ground-glass appearance. Uncommonly in cats, there may be petechiae or more extensive hemorrhage in the subserosa, muscularis, or submucosa of the intestinal wall. The small bowel may be segmentally dilated and can acquire a hose-like turgidity in places, perhaps because of submucosal edema (Fig. 1-118) . However, turgidity is difficult to assess in the intestine of the cat. The content is usually foul-smelling, scant, and watery, and yellow-gray at all levels of the intestine. The mucosa may be glistening gray or pink, with petechiae, perhaps covered by fine strands of fibrin. Patchy diphtheritic lesions may be present, especially over Peyer's patches in the ileum. Flecks of fibrin and sometimes casts may be in the content in the lumen. Formed feces are not evident in the colon. Lymph nodes may be prominent at the root of the mesentery. Gross lesions elsewhere in the carcass are usually restricted to pulmonary congestion and edema in some animals, and pale gelatinous marrow in normally active hematopoietic sites.
Microscopic lesions are consistently found in the intestinal tract in fatal cases, and are usual in lymphoid organs and bone marrow. The intestinal lesions vary with the severity and duration of the disease. Lesions may be patchy, and several levels of gut should be examined, preferably including ileum and, if possible, Peyer's patch. During the late incubation period and early phase of clinical disease, crypt-lining epithelium is infected. Intranuclear inclusions may be found, and damaged epithelium containing inclusions exfoliates into the lumen of crypts. Crypts are dilated and lined by cuboidal or more bitches unable to protect pups with maternal antibody during the first 15 days of life, when replicating myocardial cells are susceptible to parvoviral damage. Myocardial disease in pups caused by CPV-2 is now fairly uncommon, as most bitches have antibody. Enteric and myocardial diseases rarely occur together in the same individual or cohort of animals. Occasional cases of generalized parvoviral infection have been reported in susceptible neonates. Necrosis and inclusion bodies are found in organs such as kidney, liver, lung, heart, gut, and vascular endothelium. They are presumably related to mitotic activity during organogenesis. Dogs with typical disease caused by CPV-2 become anorectic and lethargic and may vomit and develop diarrhea, perhaps in association with transient moderate pyrexia. Relative or absolute lymphopenia or leukopenia of 1-2 days' duration may occur. Diarrhea may be mucoid or liquid, sometimes bloody, and is malodorous. After a period of 2-3 days, dogs either succumb to the effects of dehydration, hypoproteinemia, and anemia, or begin to recover.
Gross findings at autopsy of fatal cases are those of dehydration, accompanied by enteric lesions characteristic of the disease. There is often segmental or widespread subserosal intestinal hemorrhage, which may extend into the muscularis and submucosa. The serosa frequently appears hemorrhagic and granular because of superficial fibrinous effusion ( Fig. 1-120) . Peyer's patches may be evident from the serosal and mucosal aspects as deep red oval areas several centimeters long. The intestinal contents may be mucoid or fluid; sometimes they look like tomato soup because of hemorrhage. The mucosa is usually deeply congested and glistening, or covered by patchy fibrinous exudate. Severe mucosal lesions may be widespread or segmental, and their distribution is irregular; thus tissues from several levels of the small intestine should be selected for microscopic examination. Gross changes in the colon are similar but less common. The stomach may have a congested mucosa and contain scant bloody or bile-stained fluid. Mesenteric lymph nodes may be enlarged, congested, and wet, or be reduced in size. Thymic atrophy is consistently by sinus histiocytes may occur in lymph nodes, especially those draining the gut. Severely depleted Peyer's patches may be difficult to recognize microscopically. Later in the course of clinical disease, corresponding to the period beyond ∼7-8 days after infection, prominent regenerative lymphoid hyperplasia may be found.
In severely affected animals at the nadir of the leukopenia, virtually all proliferating elements in the bone marrow may be depleted. The extremely hypocellular, moderately congested marrow is only populated by scattered stem cells. Milder lesions mainly affect the neutrophil series, generally sparing megakaryocytes and the committed erythroid elements. During the later phases of the disease, marked hyperplasia of stem cells, and eventually of amplifier populations in the various cell lines, is evident.
In the liver, dissociation and rounding up of hepatocytes, and perhaps some periacinar atrophy and congestion, may be evident. This is probably associated with dehydration and anemia. Pancreatic acinar atrophy also is common, reflecting inappetence. The lung may be congested and edematous. In leukopenic animals, few leukocytes are seen in circulation in any organ.
A diagnosis of feline panleukopenia may be made on the basis of the characteristic microscopic intestinal lesions, in association with evidence of involution or regenerative hyperplasia of lymphoid and hematopoietic tissues. Inclusion bodies may be sought in these tissues, but are usually present in significant numbers only during the late incubation and early clinical period. Cryptal necrosis is also reported in the intestines of some cats with FeLV infection, which must be differentiated from feline panleukopenia. Application of immunohistochemical techniques may identify viral antigen in tissue as late as 8-10 days after infection. Viral antigen also may be identified in intestinal content or feces by ELISA or PCR testing. Streck AF, et Canine parvovirus 2 infection. Canine parvovirus 2 (CPV-2) resulted from mutation of a closely related virus, likely an FPV-like virus from wild carnivores, such as foxes. It appeared spontaneously and virtually simultaneously in populations of dogs on several continents in 1978, and rapidly spread worldwide. Retrospective serologic studies suggest that it was circulating unnoticed in western Europe by 1976. In addition to domestic dogs, several species of wild canids, including coyotes, gray wolves, and raccoon dogs, are susceptible to infection.
Enteric disease caused by this virus was epizootic for several years in naive populations of dogs, affecting animals of all ages. As the prevalence of antibody caused by natural infection and vaccination increased, the problem subsided to one of an enzootic disease. It now affects those animals with reduced levels of passively acquired maternal immunity, or scattered naive individuals.
During the epizootic period, nonsuppurative viral myocarditis caused by CPV-2 was prevalent in the offspring of naive
Further reading Ikeda Y, et al. Bovine parvovirus infection. The antigenically distinct species Bovine parvovirus (BPV) also known as hemadsorbing enteric virus, is the type species of genus Bocavirus, with 3 significant subspecies: BPV1, 2, and 3. BPV has been recognized for many years and occurs widely in cattle populations on all continents. It has been isolated from the feces of normal and recently diarrheic calves as well as from conjunctiva and aborted fetuses. The status of BPV as an enteric pathogen is unclear, although it is believed to cause diarrhea in neonatal calves and respiratory and reproductive disease in adult cattle. Virus shedding is not always associated with diarrhea, and it may be part of a mixed infection in diarrheic animals. Serologic prevalence of antibodies to BPV is high, with 83% of cattle and 100% of herds being positive over 2 years of testing in one study. It is rarely diagnosed as a cause of death, and unless sought specifically by culture, direct electron microscopy, or molecular probe, would be missed as a cause of clinical diarrhea. Its significance may be greatest in neonatal calves and animals exposed while passive maternal antibody levels are waning, or in animals in the postweaning period.
The pathogenesis of infection with BPV resembles that in carnivores. Initial viral replication following oral inoculation is in tonsils and gut, with spread to systemic lymphoid tissues, resulting in transient lymphopenia. Viral antigen has been identified in the nuclei of epithelium in intestinal crypts and in cells in thymus, lymph nodes, adrenal glands, and heart present in young animals, and the organ may be so reduced in size as to be difficult to find. The lungs often appear congested and have a rubbery texture.
The microscopic lesions in stomach, small intestine ( Fig. 1-121) , colon, lymphoid tissue, and bone marrow caused by CPV-2 infection do not differ significantly from those described earlier in cats with panleukopenia. Gastric lesions are perhaps more frequently encountered in dogs with parvoviral infection. Small intestinal lesions are invariably severe in fatal cases. The colon is involved in a minority of animals. Pulmonary lesions such as alveolar septal thickening by mononuclear cells, congestion, and effusion of edema fluid and fibrin into the lumina of alveoli may be related to terminal gram-negative sepsis and endotoxemia, which is common in fatal cases. Periacinar atrophy and congestion in the liver are attributable to anemia, hypovolemia, and shock, and prominent Kupffer cells probably reflect endotoxemia. Some studies have shown that viral inclusions may occur in tongue epithelium cells as well. Although these inclusions are nuclear, they often appear to be in the cytoplasm (pseudocytoplasmic). A case of erythema multiforme as a result of CPV-2 infection of keratinocytes has been described in a dog with concurrent parvoviral enteritis; viral inclusions were present in oral and skin epithelial cells.
The diagnosis of parvoviral enteritis in dogs follows the principles described for that of panleukopenia in cats. The disease must be differentiated from Canine coronavirus infection, which is very rarely fatal, and from canine intestinal hemorrhage syndrome, shock gut, intoxication with heavy metals or warfarin, infectious canine hepatitis, and other causes of hemorrhagic diathesis. Involution of gut-associated lymphoid tissue and cryptal necrosis caused by parvovirus must be differentiated from similar lesions occasionally seen in canine distemper.
Escherichia coli have several virulence attributes that result in disease in animals. Principally, these promote colonization or adhesion to the mucosa; they cause metabolic dysfunction or death of enterocytes; they affect the local or systemic vasculature; or they promote invasion and septicemia. Disease syndromes caused by E. coli in domestic animals can be related to the combinations of virulence attributes expressed. Many terms have been applied to the mechanisms of action of E. coli, with some becoming obsolete and others applying mainly to E. coli infections of laboratory animals and humans, rather than to domestic animals.
"Enterotoxigenic" E. coli (ETEC) cause secretory smallbowel diarrhea stimulated by enterotoxins produced by E. coli colonizing the mucosa of the small intestine. This condition is an important, common cause of diarrhea in neonatal animals of many species, and in postweaning pigs.
"Enteropathogenic" E. coli (EPEC) in humans and animals may colonize the mucosa of the intestine by a mechanism involving adhesion-effacement ("enteroadherent" E. coli [EAEC] or "attaching-effacing" E. coli [AEEC] ). Some do not produce recognized toxins, but are associated with villus atrophy; they are an uncommon cause of disease in domestic animals.
Other strains of E. coli, many of which are attachingeffacing, in addition secrete cytotoxins (Shiga toxins = verotoxins) that have an effect locally or systemically. Depending on the manifestation of this effect, such E. coli have been categorized as "Shiga toxin-producing" (STEC) = "verotoxinproducing" (VTEC), or "enterohemorrhagic" (EHEC). EHEC are a serious cause of foodborne illness in humans and have been incriminated as a cause of hemorrhagic enterocolitis in calves <1 month of age. The reservoir for EHEC that cause human disease is thought to be ruminants.
Shigatoxigenic infections in swine that are not attachingeffacing are associated with some outbreaks of postweaning E. coli enteritis and also cause edema disease of weaned pigs, which is a systemic toxemia.
"Enteroinvasive" E. coli (EIEC) can be internalized by surface enterocytes and subsequently disseminate through the body to become septicemic. Although EIEC are poorly documented in domestic animals, septicemic colibacillosis is a common manifestation of E. coli infection caused by strains adapted to avoid specific or innate systemic defense mechanisms, often in compromised hosts. The intestine is not necessarily the portal of entry and there may not be alimentary disease. The signs of E. coli septicemia are mainly referable to bacteremia, endotoxemia, and the effect of bacterial localization in a variety of tissue spaces throughout the body.
Evolutionary processes for bacterial survival, persistence, and proliferation are controlled by virulence genes and are subject to complex mechanisms of regulation of expression. Similarly, evolutionary processes for resisting the effects of bacteria on the host are determined by genetic factors and equally complex regulatory processes in the host. Bacterial virulence can be resolved into 5 components: (1) attachment;
(2) colonization or entry into the host; (3) evasion of host defense; (4) multiplication and/or spread within the host, and damage to the host, by direct virulence attributes, or by stimulation of an immunoinflammatory response; and (5) transmission to other susceptible animals. The interplay between host and pathogen has been extensively studied for a number of important enteric bacterial pathogens, including Salmonella and Escherichia coli. Genes encoding a range of virulence characteristics in pathogenic bacteria, including adhesion factors, toxins, proteolytic enzymes, and other agents that promote tissue invasion, are often clustered in discrete regions of the genome known as pathogenicity islands. These appear to be sites of relative instability, and are thought to facilitate the horizontal transfer of virulence factors between bacteria, and their continued evolution. Similarities in the regulatory mechanisms for pathogenicity islands of important enteric pathogens, including Salmonella, Shigella, Vibrio, Yersinia, and E. coli, are providing new insights into the reasons why strains of many genera of bacteria vary greatly in their host range and ability to cause disease. Among the factors in the mucosal barrier that resist pathogen virulence there is growing interest in the role of the luminal microbiota and their metabolites. Disruption of the intestinal microbiota may facilitate virulence factors of invading pathogens listed earlier. They are antigenically distinct, permitting recognition by specific antibody. Fimbrial adhesins include F5 (K99) and F41 in strains affecting calves, lambs, and pigs; F42, F165, F17, F18 in calves and pigs; and F4 (K88), F6 (987P), F18 in pigs. Combinations of adhesins may be expressed by the same strain of ETEC; typically, F41 is expressed by strains also expressing F5, and seems to be of minor importance. Bacteria possessing F4 colonize the entire small bowel, whereas those with F5, F6, and F41 mainly adhere in the jejunum and ileum.
Susceptibility to bacterial fimbrial adhesins, especially F5 and F6, appears to be somewhat age-related; the ability of fimbria-bearing E. coli to colonize the small intestine is greatest in animals only a few days old. F5 receptors on enterocytes decline in availability with age, whereas receptors for F6 are shed into the lumen in older pigs, facilitating clearance of bacteria from the mucosa, and interfering with colonization. F18 receptors are not found in neonatal pigs, but are produced with increasing age to weaning. Stimulation of maternal immunity to fimbrial antigens causes secretion of lactogenic antibody, which combines with adhesins in the gut lumen, preventing colonization of the gut of suckling animals.
A nonfimbrial plasmid-encoded adhesin involved in diffuse adherence (AIDA) of E. coli to enterocytes in humans also occurs in strains from pigs associated with edema disease and postweaning diarrhea, often in combination with F18.
Enterotoxigenic strains of E. coli produce 2 classes of plasmid-encoded proteins-heat-labile toxin (LT) and heatstable toxin (ST)-which act locally in the intestine to alter secretion and absorption of electrolyte and water by enterocytes. However, these toxins usually do not alter enterocyte morphology.
Heat-labile toxin is a large immunogenic plasmid-encoded molecule, with two subgroups (LTI and LTII) and comprised Enterotoxigenic colibacillosis. Enterotoxigenic colibacillosis caused by enterotoxigenic E. coli (ETEC) is one of the major forms of diarrhea in neonatal pigs, calves, and lambs, as well as in humans.
Two major attributes confer virulence on these strains of E. coli. These are the ability to colonize the intestine, and the capacity to produce toxins that stimulate secretion of electrolyte and water by the intestinal mucosa. Colonization and enterotoxin production must occur together for disease to ensue. The diarrhea produced by ETEC is accompanied by relatively minor microscopic evidence of inflammation, and by little or no architectural change in the mucosa. As a result, overt enteritis is usually not evident at autopsy, and the disease is part of the syndrome of undifferentiated diarrhea of neonatal animals.
Intestinal colonization results from the adhesion of E. coli to the surface of enterocytes on villi in the small intestine, and proliferation there (Fig. 1-122A) . By adhering to the mucosa, bacteria are able to resist the normal peristaltic clearance mechanisms. Large numbers of organisms, of the order of >10 7 per gram of mucosa, or 20-30 per enterocyte, cover the surface of villi. The ability to attach to enterocytes is conferred on ETEC by pili, and may be enhanced by the presence of a capsule.
Fimbriae or pili (also known as colonization factor antigens [CFA], with specific names in transition to a system of "F" numbers) are rod-like or filamentous projections from the cell wall of E. coli that attach to specific glycoconjugate receptors on the surface of enterocytes ( Fig. 1-122B ). They are distinct may be present in the proprial core of villi, and transmigrating the epithelium into the lumen. The involvement of ETEC expressing F4 in postweaning diarrhea of pigs >3 weeks of age, and distinct from postweaning colibacillosis caused by VTEC, discussed later, may be related to colonization of intestine in weaned pigs in which Rotavirus infection, changes in diet, or villus atrophy associated with hypersensitivity to dietary protein constituents, provide adhesin-bearing E. coli with a competitive advantage. It causes diarrhea for up to a week or so, with ill-thrift, but is uncommonly fatal, although a syndrome probably caused by endotoxic shock, similar to that associated with shigatoxigenic stains associated with postweaning colibacillosis, described later, may occur.
In calves, many cases of undifferentiated neonatal diarrhea are accounted for by enterotoxigenic colibacillosis, usually involving strains of serogroups O8, O9, O20, O64, O101 with fimbrial adhesins F5 and F41, and producing STa. Infection is typically restricted to the first 2-3 days of life, probably because of the loss of receptors for F5 in older calves. of a small A subunit with two fragments (A1 and A2), which links A1 to a large pentamer of five B subunits. LTI is antigenically similar to cholera toxin, whereas LTII toxins have B subunits that differ from LTI. The B subunits bind to ganglioside receptors (GM1 gangliosides) on the enterocyte surface; the toxin complex then dissociates, and the A1 subunit is internalized into the cell. It operates via an adenylate cyclase pathway to cause chloride secretion by enterocytes, sodium, and water following osmotically from the mucosa. Co-transport of sodium chloride by enterocytes, and associated water uptake, is probably also shut down at the same time. LT may also promote mucosal secretion by stimulation of local prostaglandin production, the enteric nervous system, and cytokine activation. LT has been shown to decrease host defenses through interference with antimicrobial peptide production by human enterocytes. LT has a latent period before the development of secretion, but the effects on the cell are irreversible.
Heat-stable toxin is classified as STa and STb based on biological properties, and is plasmid-encoded. STa causes an increase in cyclic guanosine monophosphate, which inhibits Na/Cl co-transport and therefore water absorption by surface enterocytes, whereas in crypt epithelium it promotes Cland water secretion. STb acts through a different mechanism than STa and is mainly produced by ETEC associated with pigs. STb causes increased intracellular calcium, chloride secretion, and may cause secretion by stimulation of prostaglandin E 2 and 5-hydroxytryptamine production. In pigs, STb can cause exfoliation of surface enterocytes, resulting in mild atrophy of villi.
Enteroaggregative E. coli heat stabile toxin (EAST1) has also been reported in ETEC isolated from pigs and cattle. This toxin has been associated with E. coli-induced diarrhea in children. However, the role of EAST1 in E. coli disease in pigs and cattle is not certain.
Enterotoxigenic colibacillosis is among the commonest causes of diarrhea in neonatal pigs, from a few hours to ∼1 week of age. ETEC are present in the environment and are ingested. Commonly, serogroups O8, O45, O138, O141, O147, O149, and O157, expressing F4, are involved in enterotoxigenic colibacillosis in piglets, though the prevalence of F4-bearing strains may be declining because of vaccination of sows. Less commonly, F5, F6, and F41 pilus adhesins are involved. STb is the most common toxin produced by porcine ETEC; when LT is found, it is in association with STb, which may be encoded on the same plasmid. STa also occurs in strains of ETEC in swine, alone or in combination with other enterotoxins.
At autopsy, enterotoxigenic colibacillosis cannot be readily separated from the other common causes of undifferentiated neonatal diarrhea without laboratory assistance. Generally there is dehydration, usually with evidence of diarrhea, or a history of its occurrence in the herd. Lipopolysaccharide (LPS) from the bacterial cell membrane may promote inflammatory cascades and contribute to shock. Other than the presence of characteristic fluid content in the flaccid small and large bowel, usually with clotted milk still in the stomach, the internal findings are unremarkable.
In contrast to the viruses and Cystoisospora, ETEC usually does not cause significant villus atrophy (Fig. 1-123A ). Small clumps, or a continuous layer, of bacteria may be found on the surface of enterocytes on villi in mucosal tissue sections, most consistently in ileum (Fig. 1-123B) . Some neutrophils A B F4-bearing E. coli, despite the presence of F4 receptors on enterocytes, and it seems that ETEC has little significance in this species.
Strains of E. coli have been associated with diarrhea in neonates of other species of animals, especially young dogs, where they mainly produce STa. Generally the enterotoxigenicity and other attributes of virulence have not been well described in strains from other species.
Enteropathogenic colibacillosis. Enteropathogenic E. coli (EPEC) are those that cause direct damage to the mucosa, through a characteristic mechanism of attachment to, and effacement of, epithelium. These attaching-effacing E. coli (AEEC) are more common in humans than in animals, where they are most important in pigs, dogs, and rabbits, although they also have been isolated from cats. Control of attaching-effacing activity resides in the locus for enterocyte effacement (LEE), a chromosomal pathogenicity island. EPEC have a complicated and sequential relationship with host cells. Long polar fimbriae may mediate initial bacterial interaction with the enterocyte. Secretion of bacterial proteins ensues, including intimin, which is an adhesin. A second protein, the translocated intimin receptor, is transported via a type III secretion system into the enterocyte cytoplasm, emerging on the cell membrane as the intimin receptor. In response to translocated EPEC proteins, the cell's cytoskeleton is reorganized, resulting in formation of cupped pedestal-like structures beneath the attached bacteria, and the subsequent loss of microvilli (Figs. 1-125 and 1-126) . Paracellular permeability increases as tight junctions between enterocytes loosen, and neutrophils migrate between cells into the lumen.
In animals and humans, some strains of AEEC are pathogenic despite failure to secrete enterotoxins or cytotoxins. A heavy layer of plump coccobacilli may be found over the luminal aspect of enterocytes on villi throughout the small intestine, and on the surface of the large intestine. The degree of diarrhea seems related to the extent of bacterial colonization, which is most consistent in lower small intestine and large bowel. Enterocytes to which bacteria are adherent round up or contract, and exfoliate from the mucosa singly or in clumps, ETEC must be differentiated from the other major causes of undifferentiated diarrhea in neonatal calves-Bovine coronavirus (BCoV), Coronavirus, Rotavirus, and Cryptosporidiumwhich typically dominate in calves older than a few days of age. However, ETEC is commonly found in combination with BCoV or Rotavirus infection.
The gross findings in calves with enterotoxigenic colibacillosis are the nonspecific appearance of diarrhea and dehydration. The infection is differentiated in tissue sections from the other infectious causes of this syndrome by the absence of severe villus atrophy (Fig. 1-124A ) and by the presence of bacteria on the surfaces of villi in the distal small intestine (Fig. 1-124B) . As in piglets, application of a variety of presumptive or specific tests for the presence of ETEC in the intestine confirms the diagnosis.
Enterotoxigenic colibacillosis is a significant problem in lambs in some areas. The serotypes involved, pathogenesis, and diagnosis of the condition are similar to those in calves. Synergism with Rotavirus infection may occur.
There are several reports of ETEC isolated from foals with diarrhea. The organisms have pili, probably F41, and secrete LT or STa. However, their capacity to produce disease in foals is unproved. Diarrhea has not ensued in foals inoculated with A B resulting in mild to severe atrophy of villi in the small bowel, and attenuation of surface cells, or microerosions, in the large intestine. Fusion of villi may occur in small intestine, and goblet cell numbers are depleted in both large and small bowel. There is moderate mucosal congestion and local infiltration by neutrophils.
Diarrhea is presumably related to maldigestion and malabsorption of nutrients and electrolytes in small intestine, perhaps with the additive effect of increased mucosal permeability, overloading the colon, the absorptive ability of which is also compromised by damage to surface cells. Microscopic diagnosis is based on recognition of bacteria on the mucosal surface.
In pigs, EPEC belonging to serogroups O45 and O103, infecting small and large intestine, are responsible for some cases of postweaning diarrhea. In young dogs, and occasionally in cats, EPEC have been associated with diarrhea, often as a component of co-infections with viral or protozoal agents. Microscopic lesions characteristic of AEEC are typically found in the jejunum and ileum, less commonly in the colon, and in dogs, sometimes in the stomach.
A distinct subset of EPEC is the Shiga toxin-producing E.
In addition to their ability to attach and efface, these strains produce cytotoxic Shiga toxins (Stx1 and its homologue Stx2 with its variants, c, d, e, f). Shigatoxin 1 is structurally identical to the Shiga toxin produced by Shigella dysenteriae, which has a profound cytopathic effect. Because of their effect on Vero cells in culture, these E. coli are also referred to as verotoxinproducing E. coli (VTEC) . Shiga toxins, encoded in the genome of bacteriophages, are composed of an A subunit that has enzymatic activity and a B subunit that binds the toxin to the glycolipid receptor globotriaosylceramide (Gb3) on the cell surface. Once endocytosed and transferred via the Golgi apparatus to the rough endoplasmic reticulum, the toxin inhibits protein synthesis, which may be lethal to the target cell, and via separate mechanisms may induce apoptosis. The presence or absence of Gb3 on cell surfaces is a major determinant of the distribution of tissue susceptibility to Shiga toxins, which mainly affect intestinal epithelium and vascular endothelium. Some EHEC also produce hemolysins, which may assist survival in the gut by increasing iron availability. Acid tolerance may also promote colonization efficiency by enhancing survival in the stomach.
The EHEC strains produce disease predominantly in humans, although involvement of domestic animals has been highlighted in the public health arena because of the tendency for cattle and some other species to carry the organism asymptomatically, adherent to epithelium over lymphoid follicles in the rectal mucosa. Different variants of the Stx encoded by phage have been associated with clinical disease and carrier states in cattle. The most widely recognized EHEC serotype is O157:H7, a major pathogen in humans, although >200 other STEC serotypes have been identified. In addition to Shiga toxin production, virulence is attributable to attaching and effacing capability, encoded on the LEE.
In calves <4 weeks of age (generally >3 days of age, and most commonly in the second week of life), strains of EHEC (O5:NM, O8:H9, O26:H11, O103:H2, O111:NM, O111:H8, and O111:H11) have been associated with a syndrome of erosive fibrinohemorrhagic enterocolitis, with the development of dysentery. Fever is not characteristic, and animals may remain bright until the effects of dehydration and blood loss flattened epithelium, and filled with sloughed epithelium and leukocytes. In the small intestine, foci of bacterial adhesion may be patchy, on the sides of the upper third of villi, with extensive surrounding areas of normal epithelium. Crypts in areas of atrophic small intestine may be elongate, with numerous mitotic figures. In severely affected bowel, the mucosa and submucosa are congested, edematous, and occasional microvascular thrombi may be present. Sloughed enterocytes, erythrocytes, neutrophils, fibrin, and bacteria are in the lumen.
In dogs, STEC have been associated with dysentery, and in some dogs, hemolytic uremic syndrome and cutaneous edema and ulceration. In Greyhounds, the syndrome involving this triad has been termed cutaneous and renal glomerular vasculopathy, and has been attributed to consumption of beef contaminated with O157:H7 E. coli, and other STEC. Renal and cutaneous lesions are attributable to vascular damage caused by Shiga toxin (see Vol. 2, Urinary system; Vol. 1, Integumentary system).
Edema disease and postweaning E. coli enteritis. Edema disease is a distinct syndrome in pigs, characterized by sudden death, or the development of nervous signs associated with enteric colonization by STEC, especially serotypes O138, O139, and O141. The disease occurs most commonly in pigs within a few weeks after weaning, or after other change in feeding or management. Colonization may be related to transient enterocyte malabsorption soon after weaning, which allows for increased dietary protein accumulation in the gut lumen. It often occurs in association with outbreaks of postweaning E. coli enteritis. Rare reports exist of edema disease in suckling and mature animals. The disease may be sporadic or occur as an outbreak, usually affecting the best animals in a group, and mortality often approaches 100% of affected animals. Edema disease and postweaning E. coli enteritis have apparently declined in prevalence in parts of North America, supervene. Death may occur within several days of onset of illness, but some cases will recover in 7-10 days.
At autopsy, gross lesions are usually confined to the spiral colon and rectum, although the ileum and cecum are occasionally involved with mild fibrinous or fibrinohemorrhagic enteritis/typhlitis. In the colon, changes vary from mild patchy congestion of the mucosa to marked mucosal reddening, with adherent mucus, necrotic debris, and blood; colonic contents are fluid and frequently blood-tinged ( Fig. 1-127 ). There may be congestion of the margins of mucosal folds in the rectum, or overt fibrinohemorrhagic proctitis. Mesenteric lymph nodes are often enlarged, especially along the ileum, and occasionally there are lesions (arthritis, serositis) suggesting septicemia.
Microscopically, in affected small intestine the profile of villi is ragged or markedly scalloped, and they are blunted, moderately atrophic, or fused. Epithelial cells on villi in small bowel, and on the colonic surface, where lesions are most severe, are short, rounded up, and in some cases exfoliating singly or in small clumps, causing focal microerosions. Cells in some areas may be markedly attenuated. The microvillus border is indistinct, and covered by a heavy layer of prominent gramnegative coccobacilli ( Fig. 1-128) . Lesions in large bowel may extend down into glands, which may be dilated, lined by relatively empty and the mucosa is grossly normal. The colon may contain somewhat inspissated feces.
In swine dying after a more prolonged clinical course, gross edema is often not present, although enlargement of mesenteric lymph nodes is present in a large proportion of cases. A few pigs may show foci of yellow malacia, usually bilaterally symmetrical, in the brainstem at various levels from basal ganglia to medulla.
Microscopically edema in the sites of predilection mentioned earlier is the main lesion in swine dying acutely. It is generally devoid of much protein and contains few erythrocytes and inflammatory cells. A proportion of animals also will have meningeal edema and distended Virchow-Robin spaces in the brain. Vascular lesions may not be well-developed in pigs dying suddenly. When present they usually consist of edema, hemorrhage, myocyte necrosis, and hyaline degeneration in the tunica media. Angiopathy is more consistently found in cases of longer standing. Affected vessels may be found in any tissue in the carcass. Brain edema and focal encephalomalacia in the brainstem are associated with the presence of lesions in cerebral vessels; necrosis may be a sequel to edema and ischemia. Cerebrospinal angiopathy of swine is probably a manifestation of edema disease.
A diagnosis of edema disease is based on nervous signs or sudden death in growing pigs, in association with typical gross and microscopic lesions, when they are present. In acute cases, heavy growth of hemolytic E. coli of one of the serotypes known to produce Stx2e is essential.
Edema disease must be differentiated from enteritis and endotoxemia resulting from E. coli in postweaning pigs; from mulberry heart disease in animals dying suddenly; and from salt poisoning, Salmonella meningoencephalitis, and other infectious encephalitides, in animals with nervous signs.
Postweaning E. coli enteritis (coliform enteritis of weaned pigs) typically occurs during the first week or two following weaning, or after some other change in feed or management. Postweaning diarrhea may be caused by classical enterotoxigenic F4 (K88) E. coli, but it is often associated with hemolytic E. coli of the same serotypes primarily implicated in edema disease, as well as serotype O149. The two diseases often perhaps with the use of concentrate rations based largely on soybeans and corn, rather than other grains.
Bacterial colonization of the gut is mediated by F18ab fimbriae. Susceptibility of pigs is genetic and related to the presence of receptors for the fimbriae. A Shiga toxin (Stx2e) producing vascular injury and edema has been incriminated in the pathogenesis of edema disease, and vaccination with Stx2e toxoid almost entirely prevents edema disease.
Some strains of E. coli that cause edema disease also produce secretory enterotoxin. Diarrhea is not a usual concomitant of edema disease in individual animals. Significant gross or microscopic lesions in the intestinal mucosa do not occur in edema disease, which appears to be a classical enterotoxemia, the active principle being absorbed from the gut and acting at a distant site. However, the means by which the toxin enters the circulation is unknown. Stx2e can bind to erythrocytes which may promote its dissemination from the intestine.
Experimentally, the target of Stx2e, like other Shiga toxins, is vascular endothelium, particularly of small arteries and arterioles. Preferentially affected organs include spinal cord, cerebellum, eyelid, and colon. However, a study to determine preferential binding sites for Stx2e found receptors on a variety of tissues, not just the aforementioned. Stx2e causes angiopathy, which, in its early stages in experimental intoxication, is recognized by swelling of endothelial cells and mild intramural and perivascular hemorrhage. Pyknosis and karyorrhexis of smooth-muscle nuclei, often accompanied by fibrinoid degeneration or hyaline change in the tunica media, may be seen in subacute spontaneous cases. Proliferative mesenchymal elements are found in the tunica media and tunica adventitia in more advanced cases. However, inflammation is not at any stage a prominent component of the angiopathy, nor of the associated edema in most sites, and thrombosis of vessels is rarely encountered. Edema is probably caused by vessel damage during the early stages of the angiopathy. The lesions are distinct from those expected with endotoxemia.
Swine with edema disease may die without premonitory signs. Others may have anorexia, or, more characteristically, show nervous signs, usually of <1 day's duration. An unsteady staggering gait, knuckling, ataxia, prostration and tremors, convulsions, and paddling occur. A hoarse squeal, the hoarseness attributed to laryngeal edema and dyspnea, also may be noted clinically.
At autopsy, gross lesions in acute deaths may be subtle or absent. Typically, edema is variably present in one or more sites. However, it may be mild and must be carefully sought, especially by "slipping" the suspected area over subjacent tissue. Subcutaneous edema may be present in the frontal area and over the snout, in the eyelids, and in the submandibular, ventral abdominal, and inguinal areas. Internally, there may be some hydropericardium, and serous pleural and peritoneal effusion, perhaps accompanied by mild or moderate pulmonary edema. More commonly, the serous surfaces merely appear glistening and wet. Edema of the mesocolon, of the submucosa of the cardiac glandular area of the stomach over the greater curvature, and of mesenteric lymph nodes is most consistently found. The gastric submucosal edema should be sought by carefully cutting through the muscularis to the submucosa. The edema fluid is clear and slightly gelatinous ( Fig. 1-129) . It is rarely blood-tinged, and overt hemorrhage is usually not present in uncomplicated edema disease. The stomach is often full of feed, but the small intestine is 1-132). Experimentally, stress and decreased mucosal immune functions associated with early weaning have been associated with ETEC and postweaning diarrhea. Like edema disease, high protein levels in the intestinal lumen at weaning may play a role in colonization and disease development. Atrophy of villi does not seem to be evident, and diarrhea is presumed to be mediated by enterotoxins. Mortality may be ascribed to dehydration in animals with prolonged diarrhea and few gross intestinal or extraintestinal lesions. In animals dying of more acute disease, there is local microvascular thrombosis in sections of congested mucosa, and the gross and microscopic lesions in other organs, especially those related to gastric mucosal and submucosal thrombosis and venous infarction, are suggestive of endotoxemia. Hemolytic E. coli of the implicated strains are consistently isolated in virtually pure culture from the lower small intestine and colon. However, they are present in the spleen and liver in only a few cases, suggesting terminal bacteremia.
The factors predisposing to the massive colonization of hemolytic E. coli are unclear. Loss of lactogenic immunity, a favorable environment for proliferation of bacterial strains with specific nutrient requirements, and promotion of epithelial colonization by the effects of antecedent Rotavirus infection have been variously implicated.
A diagnosis of postweaning colibacillosis is suggested by the gross lesions in animals dying acutely or subacutely, and it is confirmed by culture and serotyping of associated strains of E. coli. The fatal disease must be differentiated from edema disease, proliferative hemorrhagic enteropathy, salmonellosis, and swine dysentery. Postweaning diarrhea caused by uncomplicated Rotavirus infection, transmissible gastroenteritis virus, or associated with attaching-effacing O45:K "E65" E. coli, is usually nonfatal. occur in the same population of pigs, although usually affecting different animals. Typically, postweaning colibacillosis is a disease of high morbidity and variable mortality, with loss of condition in pigs suffering prolonged illness. Diarrhea is usually yellow and fluid, and stains the perineum. Deaths that occur may or may not follow a prior episode of diarrhea, and often appear to be related to endotoxemia. In fatal cases there may be blue-red discoloration of the skin and evidence of dehydration. Deep red gastric venous infarcts are present in almost all cases (Fig. 1-130) . The small intestine is flaccid. The mucosa may be normal in color and the content creamy. In other animals the mucosa of the distal small intestine is congested and the contents watery and perhaps blood-tinged or brown with flecks of yellow mucus or fibrin (Fig. 1-131) . Cecal and colonic lesions are usually mild, but there may be some congestion and fibrinous exudate in the proximal large bowel. Mesenteric lymph nodes may be somewhat enlarged, congested, and juicy. Other organs are usually unremarkable grossly.
The pathogenesis of postweaning E. coli enteritis caused by non-F4 E. coli is poorly understood, and the microscopic pathology is not well described. In swine with diarrhea, E. coli may be attached to the surface of villi by F18ac fimbriae (Fig. Figure 1-130 Deep red areas of venous infarction in the gastric mucosa in postweaning colibacillosis in a pig. from the mucosa by antimicrobial therapy. It is hypothesized that a genetic predisposition to this invasive E. coli exists in these breeds. There are similarities between this E. coli and adherent and invasive E. coli (AIEC) described as playing a role in human inflammatory bowel disease.
Generalized systemic infection with E. coli occurs commonly in calves, and less commonly or sporadically, especially among young animals of the other domestic species. Predisposition to infection is a prerequisite for E. coli septicemia. This usually results from reduced transfer or absorption of maternal colostral immunoglobulin, or from intercurrent disease or debilitation. But certain strains of E. coli, especially O8, O9, O15, O26, O35, O45, O78, O86, O101, O117, and O137 in calves and lambs, and O115 in pigs and calves, are particularly associated with septicemia, and may possess characteristics that enhance their ability to invade and proliferate systemically in compromised animals.
Among factors conferring virulence upon these strains are plasmids coding for colicin V (Col V). Col V plasmids carry genes coding for aerobactin, a bacterial hydroxamate siderophore permitting survival in low-iron extracellular environments; outer-membrane proteins resisting bactericidal effects of serum, such as complement activation; and hydrophobic properties that impede phagocytosis, conferred by a capsule. Some produce cytolethal distending toxin, or fimbriae that impede phagocytosis. Endotoxin released by dying bacteria causes the vascular damage and shock associated with E. coli septicemia.
The portal of entry of E. coli causing septicemia probably varies somewhat. The navel in the neonate, the upper respiratory tract and possibly the tonsil, and the intestine are likely sites. In calves, adhesins such as P, F17, AfaE-VIII, and CS31A may promote enteric colonization and invasion. Enteritis is not a necessary, or even common, concomitant of colisepticemia in animals.
Colisepticemia is most commonly a disease of neonates, and may vary from peracute septicemia and endotoxemia resulting in sudden death, to subacute or chronic disease in which signs are related to sites of bacterial localization, especially in the meninges, joints, and eyes.
The lesions associated with colisepticemia in young animals of any species, especially calves, lambs, and foals, may vary from subtle to obvious. Mortality in hypogammaglobulinemic neonates may occur acutely with little in the way of abnormal gross findings. These may be limited to mildly congested or blue-red, slightly rubbery lungs, and a firm spleen, perhaps with evidence of omphalitis. Microscopic changes in the lungs Enteroinvasive E. coli. Strains of E. coli are recognized, infecting humans and certain other species, which have the capacity to invade or to be internalized by surface enterocytes of the small and large intestine, in which they multiply. In this sense they resemble Shigella in primates, and Salmonella. The enteroinvasiveness of Shigella and some strains of E. coli appears to be correlated with the presence of a high-molecularweight plasmid coding for outer-membrane proteins involved in invasion. Multiplication of the organism within epithelial cells results in local erosion and ulceration, associated with acute inflammation in the mucosa.
Among domestic animals, enteroinvasive colibacillosis has only been confirmed experimentally in neonatal swine, using a strain of O101 E. coli. Spontaneous enteritis that appears to be due to enteroinvasive E. coli is rarely encountered in piglets up to weaning and in calves <2 weeks of age. Diarrhea in experimentally infected piglets is described as gray-yellow, watery, and containing small clots. The gross findings may not be remarkable, or the intestine may appear congested in comparison with that in most diarrheic piglets. In spontaneous cases suspected of being due to enteroinvasive E. coli, the gastric fundus also may be congested, and this correlates with the presence of venous infarction visible microscopically. Experimental enteroinvasive colibacillosis in piglets causes villus atrophy that is comparable in severity to that induced by the common viruses of neonates. Enterocytes appear cuboidal or flattened and some are seen lysing. The lamina propria is edematous; capillaries are congested and infiltrated by neutrophils and other inflammatory cells. In spontaneous cases, thrombi may be evident in proprial capillaries and submucosal lymphatics. Neutrophils and tissue fluid effuse into the lumen between villi through epithelial discontinuities. Similar microthrombosis, proprial inflammation, enterocyte destruction, and effusion may be found in the cecum and colon. Intracellular organisms of O serogroup 101 were demonstrated by immunoperoxidase staining in the experimental study, but are not generally recognized in spontaneous cases suspected to be due to enteroinvasive E. coli. Edema and neutrophil accumulation in sinusoids of mesenteric lymph nodes are present. Experimental enteroinvasive colibacillosis in piglets has been associated with malabsorption and protein loss into the gut, presumably a result of villus atrophy and effusive enteritis, respectively.
There is growing evidence that an invasive E. coli is involved in the histiocytic and ulcerative colitis of Boxers and French Bulldogs. In these dogs, E. coli are noted within lamina propria macrophages and mesenteric lymph nodes. A role for this agent in disease development is supported by improvement of clinical signs and mucosal inflammation after its removal
Further reading Simpson KW, et
The taxonomy of Salmonella is currently based on molecular genetic analysis. The genus Salmonella is considered to be comprised of 2 species, S. bongori and S. enterica. There are 6 subspecies of S. enterica (enterica, salamae, arizonae, diarizonae, indica, and houtenae) and many (>2,400) antigenically distinct serotypes or serovars. About 60% of Salmonella serotypes belong to S. enterica subsp. enterica, and occur in birds and mammals. Members of S. e. enterica are the predominant cause of salmonellosis in humans and domestic animals, but <50 of these serotypes have been isolated from mammals or birds with any frequency worldwide. The remainder of S. enterica and S. bongori serotypes are found in ectothermic animals or the environment. In conventional terminology, the serotypes have been treated as species, but in the new terminology the names of serotypes are capitalized, but not italicized (e.g., S. enterica Typhimurium when first used, followed later by S. Typhimurium). They are usually named on the basis of the locality in which the serotype was first isolated or identified, or on their host association and the clinical syndrome they may produce. Identification of isolates at the subserotype level, by phage typing, plasmid profile analysis, or other molecular techniques, is desirable when there is evidence of zoonotic transmission, or when epidemiologic tracing is necessary.
The clinical and pathologic syndromes of salmonellosis typically vary from localized enterocolitis to septicemia; abortion may also occur, with or without obvious systemic disease. Although some serotypes are strongly host-adapted, others have a very wide host range. Highly host-adapted serotypes, such as S. Typhi (humans), S. Dublin (cattle), and S. Choleraesuis (swine), tend to produce severe systemic disease in adult, as well as juvenile animals, whereas serotypes with a broad host range, e.g., S. Typhimurium, tend to affect predominantly young animals in most species, and mainly cause enterocolitis, though septicemia may occur. There may be overlap between the two forms of disease, and if the animal survives, a carrier state of variable duration usually follows.
Asymptomatic carriage of Salmonella may be common, depending on the species, and transmission can occur directly, or indirectly, by contamination of feed, water, or the environment from which the organism is ingested or inhaled. Stressors that compromise immune competence or disrupt the enteric bacterial ecosystem are often implicated in salmonellosis, and disease is usually more common and severe in young animals. The more common stressors associated with include thickening of alveolar septa by mononuclear cells and neutrophils, and effusion of lightly fibrinous exudate and a few neutrophils into alveoli. There may be a corona of neutrophils around white pulp in the spleen, and neutrophils may be present in abnormal numbers in circulation in many organs, including lung and hepatic sinusoids. Kupffer cells also may be prominent in sinusoids in the liver. Fibrin thrombi may be evident in pulmonary capillaries, glomeruli, and hepatic sinusoids. Some calves develop acute interstitial nephritis with foci of neutrophil accumulation, which with time evolve into "white-spotted kidney" in surviving animals.
More severe acute cases show evidence of serosal hemorrhage, with perhaps some serosanguineous pericardial fluid. The lungs may be deep red-blue, rubbery, and fail to collapse. Interlobular septa may be slightly separated by edema, and froth or fluid may be present in the major airways. Meningeal vessels may be congested, and the meninges wet. The abomasum or stomach may have focal superficial ulcers, or more extensive deep red areas of venous infarction. There may be evidence of diarrhea and dehydration, with congestion of the small intestine. Microscopic lesions resemble those previously described, with more severe congestion, thrombosis, and edema in lungs, and perhaps other tissues. In cases not examined for some time after death, clumps of small bacilli may be seen in vessels throughout the body. The vascular permeability, thrombosis, and hemorrhage reflect endotoxemia and its sequelae.
Subacute cases may develop localized infection on serous surfaces, in the joints and meninges. Fibrinous peritonitis, pleuritis, and pericarditis, fibrinopurulent arthritis and meningitis, and hypopyon are commonly found, alone or in various combinations. Affected animals may have a history of lameness ascribable to arthritis, nervous signs caused by meningitis, or general debilitation. Microscopic examination reveals the lesions already described in animals with active systemic disease, with the addition of extensive congestion and edema of inflamed serous surfaces, associated with an acute fibrinous inflammatory exudate.
In lambs, congestion and edema of the mucosa of turbinates and sinuses, perhaps with mucopurulent to hemorrhagic sinusitis, have been described. Fibrinous polyserositis and arthritis are sporadic manifestations of E. coli septicemia in growing or adult swine, and must be differentiated from the more significant Haemophilus, Mycoplasma, and streptococcal infections causing these lesions. Colisepticemia is a sporadic cause of mortality in litters of young puppies.
Diagnosis of colisepticemia is based on the isolation of E. coli in large numbers from more than one parenchymatous organ or other internal site, other than mesenteric lymph node (preferably liver, spleen, lung, or kidney), or from a site of serosal localization, in conjunction with compatible gross and/ or microscopic lesions. "Watery mouth," a syndrome characterized by drooling, depression, loss of appetite, and abomasal and abdominal distention, is associated with E. coli infection/bacteremia in lambs <3 days of age in the United Kingdom. At autopsy affected lambs are in poor condition. They may have unclotted milk and mucinous fluid in the distended abomasum; there is gas in the abomasum and intestine, and meconium retention is common. It is hypothesized that E. coli colonize the bowel, and in some manner cause loss of motility and functional obstruction. Fluid and gas accumulate in the abomasum. Bacteremia/septicemia is terminal. chromosomes in clusters of genes known as Salmonella pathogenicity islands (SPI).
Invasion of enterocytes, especially those in the ileum, occurs within 12 hours of oral infection. Ability to invade cells is dependent on a type III protein secretion system encoded in SPI-1. Protein targets of the secretion system are translocated into host cells, where they facilitate bacterial invasion by causing changes in the cytosol and ruffling of the cell membrane. Outer membrane vesicles are secreted from the surface of the bacterium and are internalized by the host cells. These vesicles also carry bacterial proteins into the cell that are important for internalization.
Motility, associated with the presence of flagella, is characteristic of many Salmonella serovars. Bacterial motility is generally not considered to be an important virulence determinant. However, it may enhance the movement of bacteria through the glycocalyx and facilitate attachment to specific receptor sites on enterocytes.
Fimbriae (pilus adhesins) encoded in chromosomes and on virulence plasmids are present on salmonellae, and they may play a role in colonization of the gut. Adherence of Salmonella to intestinal epithelial cells takes place in 2 stages. The first step is reversible because the organisms can be easily washed off. Weak ionic and nonionic interactions between bacterial and host cell membrane surfaces are thought to be the binding forces responsible for this attachment. The second stage, referred to as receptor-mediated endocytosis, is irreversible. It occurs after a lag period and it is characterized by degeneration of the microvilli on the epithelial cells, "ruffling" of the cell membrane, and macropinocytosis, resulting in internalization into membrane-bound vacuoles (endosomes) containing Salmonella.
The ultrastructural changes of Salmonella infection in the intestine were first described in experimental infections of guinea pigs. Large numbers of organisms are present in the lumen, on the surface of the brush border, and in enterocytes. There is an increase in the number of neutrophils in the gut lumen and within intercellular spaces, and some of these contain bacteria. Degeneration of microvilli, characterized by loss of filamentous cores, is associated with close adherence of bacteria. Other changes consist of elongation, swelling, budding and fusion of microvilli, and loss of the terminal web.
The organisms usually invade the cells through the brush border; however, they may also enter the mucosa through the intercellular junctional complex. In the cytoplasm, the bacteria are located within membrane-bound vacuoles, which may also contain remnants of microvilli and cytoplasmic debris. Most organisms remain intact and multiply during their transcellular migration in endosomes. Often, many bacteria are present in a single enterocyte during the early stages of infection, but cellular damage is mild and transient. The Salmonellareceptor complex dissociates as a result of the acidification of the endosomal content, allowing the receptor site to return to the apical plasma membrane and repeat the processes of endocytosis. After 24 hours, most bacteria are located within membrane-bound vacuoles in macrophages in the lamina propria. Many organisms are evident in the lumina of crypts, but invasion of cryptal epithelial cells evidently does not take place.
The lipopolysaccharide (LPS) moiety of Salmonella with smooth cell walls consists of an O-specific side chain, a core portion, and a lipid A portion. Most Salmonella isolated from animals have smooth cell walls, which influences virulence in salmonellosis in domestic animals include transportation, starvation, changes in the ration, overcrowding, pregnancy, parturition, exertion, anesthesia, surgery, intercurrent disease, immunosuppressive drugs, and oral treatment with antibiotics and anthelmintics. Consequent changes in the anaerobic bacterial ecosystem that alter the volatile fatty acid composition of the enteric environment are permissive of Salmonella colonization.
There are many examples of enhanced susceptibility to salmonellosis associated with intercurrent disease. The best known is that between the Classical swine fever virus and S. Choleraesuis, an association so close as to have caused early pathologists to disregard the bacterium as a significant pathogen. The disease in adult cattle is usually sporadic, and often there are predisposing conditions, such as parturient paresis, ketosis, mastitis, and parasitic infestations. The stress of anesthesia and surgery may account in part for the serious outbreaks of salmonellosis that occur in hospitalized animals, especially horses, at veterinary schools.
The pathogenesis of salmonellosis may be divided into several stages: entry of the bacteria into the host and attainment of the primary site of infection, usually the enterocyte; attachment to the surface (colonization); and invasion of enterocytes.
For infection to take place, Salmonella must be present in sufficient numbers; generally a minimal infective oral dose of 10 7 -10 9 organisms is needed to infect large domestic animals. After ingestion, the Salmonella must overcome nonspecific resistance factors, including the bactericidal effects of salivary enzymes, and the acid pH of the gastric environment. Mucus and lysozymes in the glycocalyx, peristalsis, commensal luminal microbial population, and constant sloughing of enterocytes may interfere with attachment. Those organisms that survive the nonspecific resistance factors may colonize and invade enterocytes.
Invading Salmonella in some species enter the mucosa through M cells in the Peyer's patches, and host specificity of some Salmonella serotypes may be associated in part with specific receptor sites on these cells. Salmonella have been demonstrated in the Peyer's patches as early as 6 hours postinoculation. When bacteria invade through M cells, smaller numbers of Salmonella may enter through enterocytes in other areas of the small intestine. However, the M cell is not the main site of attachment in some circumstances, for instance in S. Typhimurium infections of calves and pigs.
In salmonellosis characterized primarily by enterocolitis, the organisms do not usually disseminate beyond the mucosa and the mesenteric lymph nodes, and the ensuing inflammation remains confined to the intestine. In those cases where bacteremia ensues, the organisms must be able to survive and replicate in macrophages and disseminate to other systemic sites, such as liver, lung, joints, meninges, or placenta and fetus. In S. Dublin infection, the bacteria are present within macrophages in the intestinal mucosa, but are free in lymph in the draining lymphatics and dissemination is likely via lymphatics.
The ability to attach, invade, and penetrate enterocytes is crucial to virulence, and the first step in the development of salmonellosis. A number of known virulence factors contribute to the pathogenesis of salmonellosis, including motility, pili, or fimbriae, effector proteins modifying the metabolism or causing death of host cells, and lipopolysaccharides. The information for such virulence attributes is often encoded in killing of Salmonella in cytoplasmic vacuoles, and in some species by factors encoded in SPI-2 and SPI-3. The virulence of several serotypes commonly associated with systemic infections in animals, including S. Typhimurium, S. Dublin, and S. Choleraesuis, is enhanced by intracellular survival in macrophages mediated by attributes encoded on virulence plasmids.
Salmonella taken up by resident macrophages elicit a major immune response in the host. Initiation of the innate immune response commences with pattern recognition receptors, such as toll-like receptors (TLR), which recognize conserved bacterial motifs. Ligation of these receptors promotes proinflammatory cytokine production and recruitment of neutrophils. There is considerable controversy about the roles played by cell-mediated and humoral immunity in the pathogenesis of salmonellosis, but Salmonella infection results in the release of cytokines by specifically stimulated T lymphocytes. They activate macrophages that phagocytose the organisms, and in such a circumstance, cell-mediated immunity is of paramount importance.
Once Salmonella bacteria have crossed the mucosa, they may enter the bloodstream via the lymphatics, perhaps carried in macrophages, and cause septicemia or transient bacteremia.
Or they may remain indefinitely in the gut-associated lymphoid tissues and mesenteric lymph nodes. Increased susceptibility to salmonellosis in animals with intercurrent disease, or subjected to stress, may be related to relaxation of cellmediated immunity to the organism. Septicemia may be of variable duration and severity but, as a rule, it is rapidly fatal in young animals. If, however, there is transient bacteremia, the organisms are removed by fixed macrophages, especially those of the spleen, liver, and bone marrow. They may continue to proliferate in such extravascular locations and subsequently may cause another bacteremic phase that may result in fatal septicemia or secondary localization in other tissues.
The carrier state is important in the epidemiology of the disease. Whether Salmonella can maintain themselves in the intestinal lumen is not clear; to some extent fecal shedding is likely to depend on intermittent seeding from the bile, or from macrophages in the lamina propria and gut-associated lymphoid tissue. The duration of the carrier state may be prolonged, or animals may rid themselves of the infection, probably by means of cell-mediated immunity. The carrier state is an unstable one, for it appears that if the carrier is subjected to some stress or debilitating disease it may succumb to disease; this often seems to occur in adult cattle. The carrier animal is a potential threat to any other animal that it contacts, either directly or through the medium of its excreta, or by-products such as bone or meat meal. several ways. These strains are more invasive, and are more successful at avoiding phagocytosis, and lysis in phagolysosomes after invasion, than are "rough" counterparts with incomplete LPS. LPSs reduce the susceptibility of the organisms to the host's cationic proteins; they stimulate local prostaglandin synthesis; and they prevent the activation and deposition of complement on the bacterial surface.
The main function of LPS may be to facilitate survival in the intestinal mucosa and eventual entry into deeper tissues. The involvement of LPS in invasion apparently varies among Salmonella serotypes because some strains of S. Typhimurium do not require intact LPS to invade epithelial cells in vitro. On the other hand, more host-specific Salmonella serotypes, such as S. Typhi and S. Choleraesuis, require intact LPS or O-side chains. The lipid A portion of LPS is responsible for the endotoxin-mediated effects of Salmonella infection that are seen in systemic disease. Septicemia (endotoxemia) typically causes fever, leukopenia, hemoconcentration, lactic acidosis, coagulopathies, hypotension, and death.
Diarrhea in salmonellosis is not mediated by enterotoxins such as those involved in cholera and E. coli infections. Rather, effector proteins associated with SPI-1 induce secretory diarrhea by blocking chloride channel closure, whereas others attract neutrophils and induce apoptosis of enterocytes. Proteins encoded in SPI-5 also promote neutrophil recruitment and electrolyte secretion. Mucosal inflammation leads to the accumulation of a number of mediators, including prostaglandin E 2 , capable of causing hypersecretion of chloride by enterocytes, and consequent passive osmotic movement of water into the lumen. Loss of enterocytes, dying as a sequel to Salmonella invasion and neutrophil-induced tissue injury, results in a reduction in absorptive surface area, and causes defects in mucosal integrity, through which the protein- and neutrophil-rich exudate leaking from permeable vessels effuses.
Thus diarrhea is an outcome of active secretion of electrolyte, malabsorption resulting from reduced mucosal surface area and enterocyte competence, and inflammatory exudation, which may contain sufficient fibrinogen to form a pseudomembrane over the affected surface. The volume of fluid originating in lesions in the small intestine may overwhelm the capacity of the colon to compensate; as often as not in salmonellosis, the large intestinal mucosa is also involved, further compounding the compromise to electrolyte and water homeostasis in the gut.
Thrombosis of mucosal venules is common in Salmonella enteritis, and may contribute to loss of mucosal viability. Such lesions may be due in part to the large amounts of endotoxin absorbed through the damaged mucosa, or released locally.
Enteritis in salmonellosis is thus characterized by fibrinous or fibrinohemorrhagic exudates over denuded small and large intestinal mucosae, directly mediated by the apoptosis and necrosis induced by invading bacteria, and by the necrotizing effects of local neutrophil activity and microvascular thrombosis.
The systemic outcome of an infection with Salmonella is determined by the genetic virulence determinants of the invading organism and the ensuing innate, humoral, and cellmediated immune response of the host. Salmonella are considered to be facultative intracellular pathogens, and invading strains must have the ability to survive and replicate within macrophages to cause bacteremia or septicemia. This capacity is conferred by components coded in SPI-2, perhaps largely through inhibition of NADPH oxidase-mediated oxidative yellow feces containing flakes of fibrin, progressive emaciation and debility, and eventual death. Some recover but fail to thrive, often partly owing to chronic bronchopneumonia.
At autopsy, there is blue or purple discoloration of the skin, which may be very intense about the head and ears. There may be superficial ischemic necrosis of the ears. Typically there are petechial hemorrhages in many organs and tissues. The lymph nodes are almost invariably hemorrhagic. The visceral nodes are more frequently and obviously involved than the peripheral ones, with the exception of those of the throat, which are usually hemorrhagic. The mesenteric lymph nodes are greatly enlarged, and they may be speckled with hemorrhages.
There may be hemorrhages, petechial or as small discrete ecchymoses, on the laryngeal mucosa. The lungs do not collapse because there is frothy fluid in the respiratory passages. They may be pale blue or purple. Beneath the visceral pleura there are small dark foci of hemorrhage. The lungs are wet and there is fluid in the interlobular tissue. The changes are best appreciated in the caudal lobes because the cranial lobes are often the seat of acute lobular pneumonia. These pulmonary changes, attributable in part to endotoxin, account for the respiratory signs observed clinically. The pneumonia is interstitial because of endotoxemia and embolic organisms. The lobar cranioventral pneumonia may be due to ascending Salmonella alveolitis and bronchiolitis. Occasionally, the injury to the alveolar septa by Salmonella results in extensive fibrinous pneumonia of the caudal lobes. The cardiac serosae often bear petechiae, and in some more virulent infections there is fibrinohemorrhagic pericarditis with scant fluid exudation.
The spleen is enlarged, deep blue, firm with sharp edges; little blood oozes from the cut surface. There may be petechiae on the capsule, but the marginal infarcts of classical swine fever are not present. Other causes of splenomegaly, such as erysipelas, other septicemias, and African swine fever, must be differentiated.
The liver is usually congested, and focal hemorrhages may be visible in the capsule. In some cases the hemorrhages are very large, involving up to half of the central area in a lobule. They may be scattered at random throughout the liver or grouped, often at the edge of a lobe. In some, there are tiny Salmonellosis in swine. Many serotypes of Salmonella have been isolated from swine, and with poultry and cattle they form an important reservoir of the organism. The bacteria are carried in the lamina propria of the intestine, but also in the regional lymph nodes of the alimentary tract, so that carrier animals may not excrete the organism in the feces.
Three syndromes are associated with Salmonella infections in swine. (1) Septicemic salmonellosis is usually associated with the host-adapted S. Choleraesuis var. kunzendorf, although enteric lesions may be present with this serovar. Sporadic infections with S. Dublin have also been associated with septicemia in nursing pigs. (2) S. Typhimurium most commonly causes acute or chronic enterocolitis, including necrotizing proctitis which may lead to rectal stricture. (3) S. Typhisuis infection is characterized by ulcerative enterocolitis, as well as caseous tonsillitis and lymphadenitis. S. Choleraesuis and S. Typhimurium are the most common serovars that cause disease in pigs. However, S. Derby is also frequently detected in pigs.
Salmonella Choleraesuis was once thought to be the cause of classical swine fever (formerly hog cholera) because gross lesions of septicemic salmonellosis and acute classical swine fever are similar. The latter disease is often complicated by S. Choleraesuis, the bacterium being recovered from 10-50% of pigs with classical swine fever.
The major clinical manifestations of S. Choleraesuis infection are septicemia and enteritis; they usually occur separately and septicemia is more common. S. Choleraesuis can cause disease in both young and adult pigs. Oral inoculation of S. Choleraesuis initially results in septicemia and acute enterocolitis, followed in some cases by large necrotic and ulcerative lesions (button ulcers) in the colonic mucosa. Enteritis is not necessarily chronic, or even clinically evident. Interstitial pneumonia and multifocal hepatic necrosis are the most consistent systemic lesions. In Europe, infection has also been associated with the development of fulminant fibrinous pneumonia. Immunohistochemical techniques reveal the preferential location of S. Choleraesuis in the colon and surface of ileal M cells in Peyer's patches. The invasive capability of this serovar is indicated by the presence of large numbers of organisms in proprial macrophages and regional lymph nodes.
Salmonellosis that is clinically septicemic is usually fatal. Death may occur quickly without observed illness, or after a course of a week or more. There is a high fever; characteristic but not pathognomonic blue discoloration of the skin, especially of the tail, snout, and ears ( Fig. 1-133) ; caudal weakness; dyspnea that often leads to misdiagnosis of primary pneumonia; and sometimes terminal convulsions. Sows may abort during the septicemic phase of infection. Pigs that have recovered from this phase may have dry gangrene of the ears and tail, caudal paralysis, blindness, and diphtheritic enteritis. The chronic or enteric form may develop from the acute, but is usually insidious from the onset. It is characterized by loose resulting from endotoxin, and focal localization of bacteria. The discoloration of the skin is initially caused by intense dilation, congestion, and thrombosis of capillaries and venules in the dermal papillae. There is activation and necrosis of the endothelial cells in affected vessels. The renal lesions vary but principally affect the glomeruli. In some there is diffuse glomerulitis, and this is associated with mild nephrosis and hyaline casts. In others the glomerulitis is exudative and hemorrhagic and in these a great many capillary loops contain hyaline thrombi. Embolic bacterial colonies are occasionally seen in the glomerular and intertubular capillaries. Fibrin thrombi also may be found in the afferent arterioles and interlobular arteries.
The pulmonary lesions are also characterized by thrombosis and vasculitis and a largely mononuclear cellular response in alveolar septa. There is flooding of the alveoli by edema fluid and moderate numbers of alveolar macrophages. This is the usual histologic picture; the extremes are acute fibrinous inflammation or a few scattered parenchymal hemorrhages.
In the liver the paratyphoid nodules may be found in all transitional stages from foci of nonspecific necrosis to reactive granulomas. Typically there are few neutrophils, and whether the nodules are necrotic or reactive depends on their duration. The initial change is focal coagulative necrosis. Macrophages accumulate about the margin, expanding and displacing the surrounding parenchymal cords.
In the spleen there are scattered hemorrhages, but the overall histologic impression is of increased histiocytes with a scattering of neutrophils. The follicles are small and rather inactive. Very small foci of necrosis, containing many bacteria, may be sparse or relatively numerous, and these develop a reactive macrophage response and form the typical paratyphoid nodules.
Meningoencephalomyelitis occurs in a proportion of cases of septicemic salmonellosis. The lesion is fundamentally a vasculitis. There may be petechiae in the meninges but, microscopically, there is infiltration of large mononuclear cells in the pia-arachnoid and concentrated about the veins. The organism is relatively fastidious and cultures from postmortem samples may not be uniformly positive.
Salmonella Typhimurium infection in swine produces a syndrome that differs from S. Choleraesuis in a number of ways. Clinically, the disease occurs in feeder pigs and is characterized by fever, inanition, and yellow watery diarrhea that may contain blood and mucus, especially in the later stages. The diarrhea may be chronic and intermittent. There is high morbidity but low mortality. Most pigs recover but may remain carriers for variable periods of time; some may develop rectal stricture. The organism persists in tonsils, lower intestinal tract, and submandibular and ileocolic lymph nodes.
The pathogenesis and morphology of the enteric lesions differ from those described for S. Choleraesuis enteritis. The lesions with S. Typhimurium infection are mainly confined to the colon, cecum, and rectum, with minor involvement of the distal small intestine. There is acute enterocolitis with formation of a diphtheritic membrane on the mucosal surface ( Fig. 1-136) . Button ulcers are not associated with this or other non−host-adapted serovars. Systemic dissemination and septicemia are rare.
Rectal stricture is thought to be a sequel in most cases to ulcerative proctitis of ischemic origin, caused by S. Typhimurium. It is characterized clinically by marked progressive distention of the abdomen, loss of appetite, emaciation, and soft feces. yellow foci of necrosis, referred to as paratyphoid nodules. Pinpoint hemorrhages are consistently present in the renal cortex ( Fig. 1-134 ). There may be only a few in each kidney or they may be so numerous as to cause the "turkey egg" appearance.
The stomach shows the intense red-black color of the severe congestion and venous infarction common to endotoxemia in pigs. If the animal survives a week or more, the superficial necrotic layer of the affected gastric mucosa sloughs. There may be no lesions in the intestine. There may be catarrhal enteritis or, more frequently, the enteritis is hemorrhagic, increasing in severity lower in the tract and terminating in a hemorrhagic ileitis. The mucosae of the colon and cecum may be normal but, if the course is prolonged, there is hyperemia, fibrinohemorrhagic inflammation, or button ulcers ( Fig. 1-135) .
Petechial hemorrhages may occur in the meninges and brain, but there is no gross inflammation. Localization sometimes occurs in synovial membranes, producing polysynovitis and sometimes polyarthritis. It is more usual to have an increase in the volume of fluid with red velvety hypertrophy of the synovial villi. The gross features described are usually not all present in any one case.
The histologic changes that occur in internal organs in acute disease are mainly associated with endothelial damage Salmonella Typhisuis infection is an uncommon condition in pigs. The disease, called paratyphoid in Europe, is now known to cause disease in pigs in the Americas and Asia. It is a progressive disease of 2-4 month-old pigs that is clinically characterized by intermittent diarrhea, emaciation, and frequently, massive enlargement of the neck region, the latter associated with caseous palatine tonsillitis, cervical lymphadenitis, and parotid sialoadenitis. There is also circular or button-like to confluent ulceration of the mucosa of the ileum, cecum, colon, and rectum. Other less frequent findings are caseous lymphadenitis of the mesenteric lymph nodes, interstitial pneumonia, hepatitis, and pericarditis. Barrow PA, et
The most common serovar in horses in most areas is S. Typhimurium, and its prevalence is increasing, especially that of multidrug-resistant definitive phage type 104 (DT104). Other serovars are usually associated with sporadic cases of disease. Many horses are Salmonella carriers, and when they are stressed, diarrhea follows. Abortion of pregnant mares has been associated with S. Abortusequi. Salmonella Infantum has been associated with disseminated infection localizing in a variety of tissues, including muscle, in a horse.
Treatment with antibiotics, especially orally, increases the risk of salmonellosis. Resistance to certain antibiotics is associated with the presence of resistance (R) plasmids that may be transferred to other bacteria, of the same or different species, by conjugation or transduction. Antibiotic-resistant Salmonella may not respond to treatment, and antimicrobial therapy may increase the potential for infection and disease because of the suppression of the normal intestinal microbiota. Antibiotic-resistant strains have been associated with outbreaks of salmonellosis at veterinary teaching hospitals.
Salmonellosis in horses may be manifested clinically as peracute (usually septicemic), acute, and chronic forms, and as an asymptomatic carrier state.
The septicemic form occurs most commonly in foals 1-6 months of age. These animals are usually with their dams at pasture and predisposing factors are unclear. The infection in foals tends to be fatal. Affected animals are lethargic and develop severe diarrhea, often with characteristic green color, which may contain casts and blood. They are febrile and waste rapidly, to die in 2-3 days. Some survive for a week or more and these may develop signs of pneumonia, osteitis, polyarthritis, and meningoencephalitis.
The primarily enteric forms of the disease are more likely to occur in older horses. Most of the predisposing factors At autopsy, there is marked dilation of the colon, which is caused by narrowing of the rectum, 1-10 cm cranial to the anus ( Fig. 1-137) . The stricture is usually <1.0 cm in diameter and varies in length from 0.5 to 20 cm. There is marked fibrous thickening of the rectal wall, which may contain microabscesses. The dilation of the colon, proximal to the stricture, may consist of a well-demarcated widened area several centimeters long and wide. The colonic mucosa in this area is usually ulcerated and may be covered by fibrinous exudate. In some cases there is more gradual but sometimes massive dilation of the entire colon and cecum, which are full of digesta, with ulceration of the mucosa just proximal to the stricture. The mucosa is always excessively corrugated; this is mainly the result of marked thickening of the internal muscularis. Anastomoses of the small intestine and/or colon to the dilated portion of the descending colon may occur. Localized chronic peritonitis is often associated with the dilated segments of the colon.
The stricture is located in an area of rectum that has a relatively poor blood supply, namely, the junction of the circulatory fields of the caudal mesenteric and pudendal arteries. Ulcerative proctitis is consistently found in swine with typhlocolitis caused by S. Typhimurium infection. Granulation of such lesions probably leads to cicatrization and stricture. The location, the persistent nature of this lesion in some pigs, and its limited capacity to heal are probably related to the restricted blood supply of the affected area. mentioned earlier apply to horses. Salmonellosis is an occupational hazard of horses, since many are exposed to long periods of transport, and to exertion owing to overwork or excessive training.
Clinically, the acute disease is characterized by diarrhea and fever for a period of 1-2 weeks, followed by recovery or death. The chronic form persists for weeks or months. Affected horses pass soft, unformed manure that resembles cow feces. They lose their appetite, with subsequent progressive loss of weight and condition. In later stages they become dehydrated and emaciated.
The gross lesions are those of enteritis and/or septicemia; the former are most consistently found at autopsy. As a rule, the longer the course, the lower in the intestine does one find the most severe lesions.
Acute septicemic cases have small hemorrhages on the serous or mucosal membranes. The visceral lymph nodes are always enlarged, juicy, and often hemorrhagic. Marked pulmonary congestion and edema, and renal cortical pallor and medullary congestion may occur. The main lesions are in the stomach and intestines. In peracute or septicemic cases there is intense hyperemia of the gastric mucosa, probably venous infarction, with some edema and scattered hemorrhage. The small intestine may be congested with a mucous or hemorrhagic exudate. In acute cases there is diffuse and intense fibrinohemorrhagic inflammation of the cecum and colon overshadowing any lesions in the upper intestine, and leading rapidly to superficial necrosis of the mucosa and a gray-red pseudomembrane ( Fig. 1-138A) . In chronic salmonellosis, enteric lesions may be few or subtle. Some animals have extensive or patchy fibrinous or ulcerative lesions of the cecum and colon. In others, raised circumscribed lesions ∼2-3 cm in diameter may be evident, with a gelatinous submucosa and ulcerated mucosa. Some such lesions are more fibrinous, and resemble button ulcers ( Fig. 1-138B) .
Histologic alterations of significance are usually limited to the intestine. However, in septicemic animals lesions typical of endotoxemia are present in lung, liver, kidney, spleen, and adrenal. There may be acute ileocecocolic lymphadenitis, and inflammation in sites of localization, such as growth plates in long bones and the meninges. Depending on the duration of the enteritis, hemorrhage, necrosis, or diphtheresis may predominate, but the infiltrating leukocytes are largely mononuclear. The superficial coagulative necrosis of the mucosa may extend over large areas. A layer of fibrinocellular exudate may cover the necrotic mucosa. Fibrin thrombi are frequently present in the capillaries or venules of the lamina propria ( Fig. 1-138C ). There is usually marked congestion of submucosal vessels, which is accompanied by considerable edema. A B C infection of calves with S. Typhimurium, the numbers of bacteria are generally lower in the abomasum and duodenum than in the lower intestinal tract, whereas they are relatively constant from the jejunum through to the rectum. The early microscopic lesions in the small intestine consist of a thin layer of fibrinocellular exudate on the surface of short and blunt villi. This is followed by extensive necrosis and ulceration of the mucosa, with fibrin and neutrophils exuding from the ulcerated areas into the lumen. The lamina propria may be moderately infiltrated by mononuclear inflammatory cells. Fibrin thrombi are often evident in proprial capillaries and venules. There is also marked submucosal edema and the centers of lymphoid follicles in the Peyer's patches are completely involuted. Similar erosion, ulceration, and fibrinous effusion occur in the proximal large bowel (Fig. 1-140) .
Scanning electron microscopy of small intestine shows large numbers of bacteria on a tattered mucosal surface. Clusters of enterocytes slough off short villi ( Fig. 1-141) . Strands of fibrin emerge from the mucosal defects and cover the mucosa. Ultrastructurally, the lesions are similar to those described originally in guinea pigs, except that there is more damage to epithelium in calves experimentally infected with S. Typhimurium.
Characteristic changes usually occur in the liver and spleen, but may be absent in peracute septicemic cases. There is often fibrinous cholecystitis. In acute cases the spleen is enlarged and pulpy as a result of congestion, but this is soon replaced by acute splenitis, present as miliary, tiny foci of necrosis or as reactive nodules. The liver is often pale with many minute paratyphoid nodules. In the spleen, macrophage reaction is sometimes diffuse. Paratyphoid granulomas also may be found microscopically in the kidney, lymph nodes, and bone marrow. These probably represent a cell-mediated immune response to embolic bacteria. In those animals that survive the acute phase of the disease, the inflammatory changes in lymphoid tissues progress to an immunologic response, characterized by a diffuse reaction of medium-sized and large lymphocytes in the follicles, and plasma cells in the sinusoids. There may be marked cortical atrophy of the thymus. In calves with acute septicemia, pulmonary congestion and edema are visible at Salmonellosis in cattle. The serotypes usually incriminated are S. Typhimurium and S. Dublin; both are distributed worldwide. Wherever S. Dublin is found, it tends to be adapted to cattle and to occur in epizootics, whereas other serotypes usually cause more sporadic disease. S. Newport has been identified as an emerging pathogen in cattle.
It is unusual to find salmonellosis in calves <1 week of age, in contrast to enteric and septicemic colibacillosis, which usually affect very young animals. In calves, salmonellosis is a febrile disease typified by dejection, dehydration, and usually diarrhea. Diarrhea is not always present, but when it is, the feces are yellow or gray, and have a very unpleasant odor. In older calves, there may be blood and mucus in the feces. In less acute cases there may be delayed evidence of localization in the lung and synovial structures. Morbidity and mortality may be considerable, especially in calves that are confined, such as in vealer operations. Experimental infections in calves indicate that survival is inversely related to the numbers of Salmonella in the inoculum, and directly to the age of the calves.
The general appearance at autopsy of a calf with salmonellosis may resemble one with septicemic colibacillosis. However, enlargement of mesenteric lymph nodes and gross enteric lesions are generally observed in salmonellosis. There is moderately severe gastrointestinal inflammation, acute swelling, and hemorrhage of the visceral lymph nodes, and some petechiation of serous membranes. The enteritis may be catarrhal, but sometimes it is hemorrhagic or more commonly causes exudation of yellow fibrin ( Fig. 1-139) . The mucosa overlying the lymphoid tissues may become necrotic and slough. In animals with fibrinous enteritis, the bowel wall is somewhat turgid and the serosa may have a ground-glass appearance. There is often diffuse, but perhaps mild, fibrinous peritonitis.
The intestinal lesions are usually most severe in the ileum, especially during the early stages of the disease. With time the jejunum and colon become involved but the duodenum remains relatively normal. The regional distribution of the lesions may, in part, be related to differences in the level of bacterial colonization of the mucosa. Twelve hours after oral of the United States is the leading cause of bovine salmonellosis. The potential for this strain to emerge as a major foodborne pathogen has caused great consternation among both agricultural and public health communities. Multidrugresistant strains of S. Newport have also been identified.
As well as abortion caused by S. Abortus-ovis, abortion and neonatal death may follow infection of pregnant ewes by any species of Salmonella. Although the prevalence of S. Abortus-ovis in the United Kingdom seems to be waning, S. Montevideo, on the other hand, has been associated with abortions in several flocks in the British Isles. S. Brandenburg has been reported in sheep in New Zealand.
Salmonellosis is not a common disease in sheep, but outbreaks are always severe and may cause very heavy losses. Predisposing influences are necessary, and these are usually provided by circumstances that enforce congregation. Deprivation of food and water for 2-3 days may be sufficient and, coupled with fatigue, is the usual predisposing factor when sheep are transported or confined in holding yards. Deaths usually continue for 7-10 days after debilitating circumstances have been remedied.
The serovars usually found in sheep are S. Typhimurium, S. Arizonae, and S. Enteritidis. Salmonella Dublin is increasing in prevalence in the United Kingdom and the midwestern states of the United States. Experimental inoculation of sheep with S. Arizonae produces infection but rarely disease. Under natural conditions this host-adapted organism is frequently considered to be an infection secondary to some other disease, or an incidental finding in apparently healthy animals. Most serovars produce the same sort of disease, which closely resembles that seen in cattle both clinically and at autopsy. The major findings are fibrinohemorrhagic enteritis and septicemia. autopsy, with interstitial thickening of pulmonary alveolar septa by mononuclear cells in tissue section. There may be thrombosis of septal capillaries, and some effusion of edema fluid and macrophages into alveolar spaces.
In subacute salmonellosis of calves, there may be cranial bronchopneumonia, usually with adhesions and abscessation. Purulent exudate is in synovial cavities, and the organism is recoverable in pure culture from such affected joints and tendon sheaths. It may be mixed with Trueperella pyogenes and Pasteurella in the lungs.
Salmonellosis in adult cattle may occur in outbreaks as it does in calves, but more often it is sporadic, and it may cause chronic diarrhea and loss of condition. The source of infection is usually the carrier animal. Other sources, such as feed containing protein of animal origin, or bone meal, should be considered when the disease is caused by an uncommon serovar. Abortions are most common with S. Dublin, but may occur with any serovar. In some herds, this may be the only clinical evidence of infection, although other animals often excrete the offending serovar in the feces. The carrier state of S. Dublin infection in adult cattle may persist for years, sometimes for life, in contrast to infections with other serovars, which rarely persist >18 months. Dairy cows may persistently shed Salmonella, especially S. Dublin, in milk and cause infections in humans who drink raw milk. In cattle admitted to a teaching hospital a higher risk for shedding was identified in those that were admitted to the hospital in the fall, suggesting a seasonality to shedding. The morbid changes in adult cattle correspond to those in calves except that there is more pleural hemorrhage and the enteritis may be more hemorrhagic and fibrinous. The histologic changes in the liver and other organs are the same as those seen in calves.
The multidrug-resistant strain Salmonella Typhimurium definitive phage type 104 (DT104), first seen in the UK in the late 1980s, has now spread worldwide and in some parts epididymitis-orchitis, mastitis and pneumonia. Y. pestis, the cause of plague in animals and humans, is not considered here.
The epidemiology of yersiniosis is complex and poorly understood. These organisms may be shed in the feces by asymptomatic animals in the herd or flock, and by other species, such as rodents and birds, in the environment. The organisms can survive and grow in the environment at low temperatures, and in cool weather environmental contamination by Yersinia spp. may be considerable, resulting in significant oral challenge. Disease may in part be due to compromise of cell-mediated immunity, permitting establishment of invading organisms, or recrudescence of latent infection. Often, outbreaks occur under stressful circumstances, such as poor weather, flooding, after transport, during the breeding season, or in animals on a poor plane of nutrition.
Subsequent to ingestion, the organisms invade through the intestinal epithelium or M cells overlying Peyer's patches and reach the lamina propria or submucosal lymphoid follicles. Enormous recruitment of neutrophils and ensuing destruction of cytoarchitecture of the Peyer's patch and overlying epithelium result in formation of suppurative foci in place of follicles in Peyer's patches, and microabscesses in the lamina propria of the small or large intestine if invasion occurs elsewhere. Yersinia spp. disseminates via lymphatics and hepatic portal venous drainage to mesenteric lymph nodes or to liver and the systemic circulation.
Pathogenicity in the main Yersinia species is associated primarily with the 70-kb virulence plasmid, pYV, and with other proteins that are chromosomally encoded. After bacteria are ingested and they reach the terminal ileum, they present on their surface the outer membrane protein invasin; this protein is expressed in stationary phase at low temperatures. Invasin facilitates translocation of the bacteria across the intestinal epithelium, after which invasin binds to β1 integrins in the host tissue, which induces production of chemokines such as IL-8. In the Peyer's patches, bacteria replicate and express another adhesin, YadA. The latter down-regulates expression of invasin and protects bacteria against phagocytosis. YadA and another protein, Ail, protect bacteria against the host immune system enabling bacterial propagation to mesenteric lymph nodes and, occasionally, other tissues.
Although Yersinia reside extracellularly as microcolonies in suppurative foci in the lamina propria of the intestine and lymph nodes, at least some appear to reside intracellularly, since a T-cell-mediated immune response is required to clear infection. Giant cells wall off foci of infection in subacute to chronic lesions, hence the specific name pseudotuberculosis.
Disease may be gradual in onset, subtle and chronic, producing a syndrome of diarrhea and ill-thrift in cattle, sheep, and goats. Mild diarrhea and enteritis with low mortality has been reported in Australia in weaned pigs with Y. pseudotuberculosis. More fulminant disease, characterized by severe, sometimes hemorrhagic, diarrhea, systemic infection, and prostration, may occur in cattle, some species of deer, especially chital and red deer, water buffalo, and exotic ungulates. Yersiniosis is an apparently uncommon cause of diarrhea, and occasionally fatal enterocolitis, mesenteric lymphadenitis, and systemic infection in carnivores. Yersinia also causes sporadic pneumonia and septicemia in foals.
Yersiniosis has been described worldwide, as a cause of disease in sheep, cattle, goats, deer, and pigs. The lesions of Y. pseudotuberculosis and Y. enterocolitica cannot be differentiated reliably grossly or microscopically.
Salmonella can often be recovered from apparently healthy dogs and cats. However, primary disease rarely occurs. Salmonella has been recovered in high frequency from normal sled dogs lacking clinical disease. Raw meat fed to dogs has been shown to have a high incidence of Salmonella contamination. In dogs and cats, nosocomial infections are sometimes associated with hospitalization and antibiotic therapy. In dogs, salmonellosis may be secondary to canine distemper. It can cause bronchopneumonia, acute hemorrhagic gastroenteritis, swelling of the spleen and mesenteric lymph nodes, serosal hemorrhages, and foci of necrosis in the liver and other organs. Septicemia in puppies has been associated with S. Dublin infection. Salmonellosis has been reported in dogs with lymphosarcoma, shortly after the initiation of chemotherapy. The immunosuppressive effect of the treatment, or depressed cell-mediated immunity, probably predisposes to the development of disease.
Various serovars have been isolated from cats and most of these appear to cause subclinical infections. However, salmonellosis may be a problem in catteries and hospitals, affecting animals that are subjected to stressful conditions. Spillover of Salmonella spp. from wildlife populations to cats through predator/prey relationships has been documented. Immunosuppression associated with feline leukemia virus, feline immunodeficiency virus, Salmonella-contaminated panleukopenia vaccine, or other intercurrent diseases is thought to predispose to salmonellosis in cats. S. Typhimurium is most commonly associated with such outbreaks. The disease is characterized by gastroenteritis and septicemia or a more chronic, nonspecific febrile illness, with neutrophilia and left shift.
Because of their close association with humans, especially children and the aged, dogs and cats that are carriers are a potential source of zoonotic infection. pyogranulomas surrounded by macrophages or giant cells, and sometimes containing bacterial microcolonies, may be present in the subcapsular and medullary sinuses of mesenteric lymph nodes.
In fulminant Yersinia infection in all species, there is fibrinous or fibrinohemorrhagic enterocolitis, with heavy local mucosal colonization by masses of coccobacilli, and marked neutrophil infiltration ( Fig. 1-142B) . Peyer's patches may be particularly involved, with grossly visible foci or confluent masses of caseous necrotic debris, as may be found in draining mesenteric lymph nodes, which are enlarged. There may be serosal hemorrhages on the gut, fibrinous peritonitis and pleuritis, and foci of necrosis also may be present in the liver, lungs, and occasionally other parenchymatous organs; the characteristic microcolonies of coccobacilli are usually evident in them.
Caseous mesenteric lymphadenitis, with mature pyogranulomas containing microcolonies of bacteria, surrounded by neutrophils and giant cells, may occasionally be found as an incidental lesion, or in animals with Yersinia abscesses in other organs.
Yersiniosis is diagnosed in tissue section by finding characteristic microcolonies of coccobacilli in microabscesses (see Fig. 1-142B ), and is confirmed by bacterial isolation. Microscopic lesions may not be detected in the intestinal mucosa of some clinically affected animals from which isolates are made, perhaps because lesions are patchy. Because Yersinia spp. are psychrophiles, cold enrichment and culture at temperatures <37° C are used in their isolation.
Lawsonia intracellularis infects a variety of species including swine, horses, donkeys, deer, rodents, rabbits, foxes, dogs, ferrets, and nonhuman primates. It causes a characteristic proliferative lesion of cryptal epithelium in distal small and/or large intestine that is associated with diarrhea and ill thrift. L. intracellularis is a microaerophilic nonflagellated gram-negative, curved or S-shaped rod bacterium. Because it is an obligate intracellular organism, cultivation requires use of tissue culture. Formerly referred to as intestinal adenomatosis complex, the conditions in swine now known to be caused by L. intracellularis including porcine intestinal adenomatosis, necrotic In all species, gross lesions in clinically subacute to chronic yersiniosis may be mild. They are usually limited to abnormally fluid intestinal content, with congestion, edema, roughening, and perhaps small foci of pallor, focal hemorrhages, erosion, or mild ulceration and fibrin effusion. Raised nodules up to 5 mm in diameter, with depressed centers, or ulcers may be evident in affected large bowel ( Fig. 1-142A) . Mesenteric lymph nodes are enlarged, congested, and edematous, perhaps with foci of necrosis. There may be mild fibrinous cholecystitis, and pale foci of necrosis scattered in the liver.
The infection is characterized histologically by masses of gram-negative coccobacilli forming microcolonies, in the lamina propria of villi and around the necks of crypts in the distal half of the small intestine, in Peyer's patches, and in the superficial mucosa of the large intestine. Intense local infiltrates of inflammatory cells, predominantly neutrophils, accumulate to form microabscesses up to about 300 µm in diameter around the bacteria, and effuse into the lumen through microerosions on the mucosal surface or in crypts. Small crypt abscesses may be present. In small intestine, there may be moderate atrophy of villi and hyperplasia of crypts, associated with increased infiltrates of chronic inflammatory cells. Microabscesses, or
A enteritis, and proliferative hemorrhagic enteropathy are collectively known as porcine proliferative enteropathy (PPE). Identification of the etiologic agent was elusive for decades. The intracellular bacterium was initially thought to be Campylobacter spp., then putatively identified as ileal symbiont intracellularis, until the taxonomy was formalized as Lawsonia intracellularis in 1995.
PPE is a prevalent and important infection in swine worldwide. The syndrome occurs mostly in postweaned pigs; however, pigs from 3 weeks of age to adults may be affected. Severity of clinical effects varies from mild subclinical disease with reduced growth rate to persistent diarrhea and severe weight loss. Once infected, pigs shed the organism for weeks. Death may follow a period of diarrhea and progressive cachexia, or it may occasionally occur as a result of perforation of an ulcerated intestine, or through peracute hemorrhage. Mortality may be very high.
Development of disease is dependent on undefined interactions with other bacteria in the gut, because gnotobiotic pigs inoculated with L. intracellularis fail to develop disease, whereas conventional pigs are quite susceptible. Experimental studies and mild spontaneous cases suggest that infection occurs first in glandular epithelial cells near lymphoid aggregates of the ileocecocolic region, whereas the cecal and colonic cryptal epithelial cells are infected later in the course of disease. The pathogenesis of PPE is related to active uptake of L. intracellularis by epithelial cells, although specific receptors remain unknown. Once endocytosed by the host cell, the entry vacuole breaks down and the bacteria persist and replicate freely within the apical cytoplasm, causing hyperplasia and propagation of the bacteria throughout the epithelium. Cell division is required for bacterial replication, which may explain its tissue tropism. Bacteria are passed on to daughter epithelial cells and exit via extrusion from the cytoplasm of enterocytes on villi or between crypt openings. Disruption of intestinal cell differentiation by the pathogen is theorized to be a central event; however, specific virulence factors of L. intracellularis and molecular details of the host cell-pathogen interaction remain undescribed.
Infected epithelium is thus transformed into a population of mitotically active and poorly differentiated cells. Glands are lined by dysplastic pseudostratified columnar epithelial cells with basophilic cytoplasm; goblet cells often are reduced in number. Mucosal glands are elongated, dilated, and branched, resulting in a thickened mucosal layer ( Fig. 1-143A) . Hyperplastic glands may protrude multifocally into the underlying submucosal lymphoid tissue or epithelial cells may form elevated plaques above the mucosal surface; use of the term adenomatosis to describe such a change is obvious. Occasionally, microscopic foci of adenomatous epithelium may be found in submucosal lymphatics or the regional lymph node. Small intestinal villi in infected animals undergo progressive atrophy, and they may be absent in well-established lesions. The proliferative lesion in the crypts is considered a primary lesion, and not a secondary hyperplastic response to increased epithelial exfoliation. L. intracellularis organisms are readily recognized as curved rods within the apical cytoplasm of glandular epithelial cells in silver-stained tissue sections ( Fig. 1-143B ) or by immunohistochemistry ( Fig. 1-143C ). L. intracellularis also have been identified ultrastructurally in degenerate cells and macrophages in the lamina propria. Inflammation in areas of uncomplicated adenomatosis is usually not a prominent feature. In the least complicated forms of the disease, lesions are always found in the terminal portion of the ileum, extending proximally for a variable distance, usually <1 meter. In a significant proportion of cases, lesions occur in the cecum and proximal spiral colon primarily, or in addition to the ileum. In mild cases, only a few ridges or plaque-like thickened areas Microscopically, coagulative necrosis of the mucosal epithelium may be focal and superficial but can involve the full thickness of the mucosa or even extend into the submucosa. A few islands of viable hyperplastic crypts or glands may remain, and masses of bacteria, presumably fecal anaerobes, are observed among the necrotic debris. With time, granulation tissue develops in ulcerated areas. Proximal ileum along the margin of the zone of mucosal necrosis should be examined for hyperplastic epithelium because, in severe cases of necrotic enteritis, few remnants of mucosa persist. Repeated bouts of epithelial proliferation, necrosis, ulceration, and granulation may result in progressive stricture of the lumen that may be accompanied by hypertrophy of the external muscle layer. This should be differentiated from idiopathic ileal muscular hypertrophy of swine, which is known to occur independent of antecedent PPE.
Acute or subacute intestinal hemorrhage and anemia also occur in PPE, and is generally considered as a distinct syndrome referred to as proliferative hemorrhagic enteropathy. Some animals exsanguinate and die quickly without hematochezia, whereas others display melena or hematochezia for several days. This syndrome is more common in young adults than in growing pigs. It is usually sporadic and of relatively low morbidity, but up to half of clinically recognized cases may die. Animals that die of massive intestinal hemorrhage are pale, and the perianal area may be smeared with blood. The typical cerebriform pattern is evident on the serosal surface of the distal ileum, which is thickened and turgid. The ileum may contain variable combinations of free blood, fibrin or clotted blood, and the cecum and colon may contain dark bloody digesta (Fig. 1-146) . The ileal mucosa usually resembles that in uncomplicated PPE. Overt regions of hemorrhage or ulceration are rarely discernible grossly, and there appears to be widespread mucosal diapedesis. Microscopically, there is extensive proliferation, erosion, and necrosis of superficial project above the normal mucosa; however, there are typically more widespread lesions with thickened mucosa and irregular longitudinal or transverse folds or ridges ( Fig. 1-144A ). The mucosal surface in proliferative lesions of the small or large intestine may be intact, but small foci of necrosis or fibrin exudation may be evident. In affected small or large intestine, hyperplastic mucosal epithelium and some degree of submucosal edema is reflected in the cerebriform pattern of projections and depressions on the serosal aspect of the intestine, which is virtually pathognomonic for this condition (Fig. 1-144B) . The ileocolic lymph nodes are enlarged and hyperplastic.
Coagulative necrosis of adenomatous mucosa commonly occurs and when extensive areas are affected, this form of the disease is referred to as necrotic enteritis. It may be partly the result of pathogenic anaerobic large-bowel flora colonizing the affected terminal ileum and large intestine. Necrotic epithelial cells, neutrophils, and fibrin exudation from superficial lesions contribute to formation of diphtheritic membranes or luminal fibrin casts, which can be found in the small or large intestine ( Fig. 1-145) . The cerebriform pattern of serosal folding is evident in necrotic enteritis. Necrotic enteritis may be a sequel to other enterocolitides in swine, PPE caused by L intracellularis infection is the most common primary lesion.
Campylobacter spp. are common causes of gastrointestinal disease in humans, and some species also may be capable of causing enteritis in animals. Campylobacter jejuni and C. coli are the most studied, but recent work has implicated other fastidious Campylobacter species as pathogens in humans and animals. Pathogenic strains penetrate the surface mucus layer, then adhere to and invade the epithelial cells where they avoid delivery to lysosomal compartments and thus prolong their intracellular survival. Central to the pathogenesis of Campylobacter-associated disease are type IV and VI secretion systems and the production of toxins, most notably the cytolethal distending toxin. Many human infections are acquired by ingestion of contaminated milk products, water, meat, or other animal products, making this an important potential zoonosis. Chickens are common asymptomatic shedders of C. jejuni, and C. coli can be frequently isolated from the feces of diarrheic or asymptomatic swine.
C. jejuni has been associated with diarrhea characterized by the presence of blood and mucus in some dogs, despite the fact that it can often be isolated from asymptomatic animals. It has also been isolated from dogs with parvoviral enteritis or other viral infections; pre-existing infections may predispose to the development of pathologic effects of C. jejuni. C. jejuni has been implicated as the primary pathogen in some canine cases of mild to moderate lymphoplasmacytic enterocolitis by associating large numbers of the organism with the lesions and by ruling out other known etiologies. In experimentally infected gnotobiotic and conventional dogs, lesions are limited to mild mucosal colitis. Mild to moderate inflammatory lesions limited to the colon has been documented in some pigs where Campylobacter sp. was the only potential pathogen isolated. Erosive colitis has been associated with C. jejuni infection in mink, and was reproduced experimentally. Young cats are probably asymptomatic carriers of C. jejuni. Several Campylobacter spp., including C. jejuni, C. coli, and C. fetus subsp. fetus, rarely have been associated with diarrhea and enterocolitis in young foals; the pathogenesis is not clear and infection may be more common in immunocompromised individuals.
Weaner colitis of sheep is described in Australia as a diarrheal syndrome of high morbidity and low mortality, and is associated with an unidentified Campylobacter sp., not C. jejuni. Affected sheep have watery colonic content; chronically affected animals may have edema and loss of body condition suggestive of enteric protein loss. Histologically there is mild erosive to ulcerative typhlocolitis with a layer of bacteria adherent to surface epithelial cells and in crypts. The disease epithelium. An acute inflammatory infiltrate is present in the superficial lamina propria. Small blood vessels are frequently thrombosed and there is effusion of neutrophils, fibrin and extensive hemorrhage into intestinal glands, and onto the mucosal surface and intestinal lumen.
In horses, the lesions and pathogenesis of equine proliferative enteritis (EPE) are similar to those in PPE. This disease affects mostly weanling foals, and causes fever, lethargy, diarrhea, hypoproteinemia, edema, and weight loss. Thickening of the mucosa is most commonly observed in the distal small intestine near the ileal-cecal junction; however, gross lesions are not always evident, or they are subtle and can be easily overlooked. In severe or long-standing cases, there can be marked irregular hyperplasia and thickening of the mucosa with fibrinonecrotic membrane and variable edema of the submucosa. As for PPE, EPE is definitively diagnosed by documenting adenomatous proliferation of epithelial cells in the crypts of the small intestine and by demonstrating the intracellular curved bacteria in the apical cytoplasm of enterocytes using silver stains or by immunohistochemistry. The epidemiology of EPE remains incompletely understood and the source of infection for horses remains unconfirmed, although rodents and rabbits have been proposed as reservoir hosts. Pigs have been suggested as a potential source of infection for horses; however, in most equine cases no evidence of exposure to pig feces has been documented.
In all species, including swine, diarrhea is probably related to loss of functional mucosal surface area in distal small intestine and large bowel, whereas ill-thrift or wasting syndromes are attributable to protein-losing enteropathy. A presumptive diagnosis of proliferative enteritis in any species can be based on typical gross and histologic lesions, and supported by Warthin-Starry staining to visualize the intracellular bacteria. Confirmation can be obtained by immunohistochemistry using a specific antibody for L. intracellularis or by polymerase chain reaction. The pathogenesis of swine dysentery is still incompletely understood, but gene studies have identified virulence traits for Brachyspira that include hemolysins, cytotoxins, outer membrane proteins, motility factors such as flagella, and NADH oxidase that is thought to be required for the bacterium to successfully colonize the colonic epithelium. B. hyodysenteriae first colonizes mucus on the luminal surface of the large bowel before invading the cytoplasm of enterocytes and goblet cells; spirochetes can be observed by electron microscopy or in situ hybridization. This process is likely mediated by flagella and outer membrane proteins that enable the pathogen to successfully colonize the host. Following invasion by the pathogen, there is enhanced and altered mucin secretion, degeneration, and necrosis of epithelial cells and hemorrhage, which are thought to be mediated by cytotoxins and endotoxin. Exfoliation of surface epithelial cells has been associated with large numbers of spirochetes and other anaerobic bacteria on the mucosa. Brachyspira do not usually invade beyond the epithelial cells, and the result is mucosal colitis characterized by superficial erosion with hyperplasia of cells in colonic glands, hypersecretion of mucus, and a mixed inflammatory infiltrate in the lamina propria. Thrombosis of capillaries and venules in the superficial areas of the colonic mucosa is probably due to absorption of endotoxin through the damaged mucosal epithelium. Diarrhea is due to malabsorption of fluids and electrolytes in the colon; this presumably results from damage to the superficial epithelium of the colon, which in the pig normally has tremendous absorptive capacity. Active fluid secretion by the colon, associated with bacterial enterotoxins, probably does not play a major role in swine dysentery.
Transmission occurs by ingestion of feces, and introduction of asymptomatic carrier pigs into a herd usually precedes an outbreak; the involvement of vectors including rodents is also considered a risk factor. Once established in a herd, the infection tends to remain enzootic, and although treatment can effect a rapid clinical amelioration, relapses often occur cyclically in individuals or groups. The morbidity and mortality may reach 90% and 30%, respectively. Immunity is variable following bouts of dysentery, and recovered pigs are apparently protected against subsequent challenge for several months though some animals remain susceptible.
The disease occurs in pigs of all ages >2 or 3 weeks old, but particularly in pigs 8-14 weeks of age. Once initiated, it spreads rapidly by pen contact. The disease is initially febrile, and the initial diarrheic feces are thin, semisolid, and lack blood or mucus. After 1-2 days, blood and copious mucus appear in the feces and this progresses to watery feces with blood, mucus, and fibrin. Some pigs die peracutely without showing diarrhea, but most pigs recover slowly, although their rate of growth is reduced. Experimentally, the severity of disease depends on overall stress on the animals, diet, body weight, group size, and the quantity and growth phase of the inoculum.
Early intestinal lesions can be subtle and include hyperemia and edema of the colonic walls and mesentery with mucosal exudate containing small amounts of fibrin or blood ( Fig. 1-147) . Mucosal lesions become more severe as the disease progresses, and there is increased mucus, fibrin, hemorrhage, and perhaps a fibrinonecrotic membrane forming along the mucosal surfaces of the large intestine and cecum. Lesions can be multifocal, patchy, or involve the entire large intestine. The colonic content in these cases is usually scant, and has been reproduced by inoculation of the thermophilic catalase-negative Campylobacter-like organism previously isolated from spontaneous cases. Backert S, et al.
Swine dysentery caused by Brachyspira (formerly Serpulina, Treponema) hyodysenteriae, family Spirochaetaceae, is a historically well-recognized and now re-emergent productionlimiting disease of swine worldwide, characterized by moderate to severe mucohemorrhagic to fibrinous colitis. Porcine spirochetal colitis refers to a less severe nonhemorrhagic colitis caused by B. pilosicoli, which is discussed later. Additional Brachyspira species, such as B. murdochii, B. intermedia, and B. innocens, have been associated with variably severe disease.
Strains have traditionally been distinguished by morphologic and phenotypic features, including biochemical properties and strength of beta-hemolysis. Recent work in Canada and the United States has documented mucohemorrhagic diarrhea in pigs, indistinguishable from classic swine dysentery caused by B. hyodysenteriae, that is caused by emergent, strongly betahemolytic but phylogenetically distinct strains of the proposed novel species "B. hampsonii." The virulence of these novel species has been experimentally confirmed in both mice and pigs. Since 1921, classical swine dysentery has been recognized as a highly infectious disease, mainly of weaned pigs. B. hyodysenteriae is a gram-negative, anaerobic, oxygen-tolerant, strongly beta-hemolytic spirochete. The loosely coiled motile organism has 7-13 periplasmic flagella. Although the bacterial genus Brachyspira includes several species capable of colonizing a wide spectrum of hosts, B. hyodysenteriae is predominantly a pathogen of pigs, although the bacterium has been associated with necrotizing typhlocolitis in rheas. Experimental reproduction of swine dysentery in gnotobiotic pigs requires the presence of anaerobic bacteria indigenous to the normal colon, along with B. hyodysenteriae; there is apparently a synergistic action between B. hyodysenteriae and the intestinal microbiota, mainly Bacteroides and Fusobacterium. Several studies have implicated dietary factors, specifically an elevated protein : carbohydrate ratio in the hindgut, as a predisposing factor for enhanced pathogenicity of B. hyodysenteriae in pigs. The mechanisms remain poorly understood; however, alterations in fermentation activity and altered microbiota in the hindgut likely are important. exudation of fibrin, which intermixes with necrotic debris and hemorrhage on the mucosal surface forming a diphtheritic membrane.
Virulence factors of B. pilosicoli are also still poorly defined, but motility and chemotaxis for mucus may be important. The organism is capable of polar attachment by one end of the bacterium to the apical membrane of colonic or rectal epithelial cells, resulting in a palisade of upright bacteria perpendicular to the epithelial cells and displacement or effacement of microvilli. Thus spirochetes can often be observed histologically as a false brush border on the luminal surface early in infection; visualization of the bacteria is enhanced by Warthin-Starry silver stains or fluorescence in-situ hybridization. Although the molecular receptors for attachment have not been identified, the organism can invade paracellularly, especially at the extrusion zone between colonic crypt units. B. pilosicoli can be observed within colonic crypts, goblet cells, or invading tight junctions into the lamina propria, but is not disseminated systemically in pigs. In chronic infections, there are large numbers of inflammatory cells in the lamina propria, including lymphocytes, plasma cells, and monocytes. There is also goblet cell hyperplasia and crypt hyperplasia so that porridge-like dirty gray to red-brown and greasy in appearance. The most severe lesions can appear similar to those of salmonellosis in extent and severity. The production of mucus in swine dysentery becomes copious in many chronic cases because of remarkable goblet cell hyperplasia.
The earliest microscopic lesions are also limited to the colon and cecum. Lesions are characterized by discrete areas of epithelial erosion and necrosis of the superficial mucosa. Thin layers of exudate composed of mucus, fibrin, neutrophils, and erythrocytes cover the areas of damaged epithelium ( Fig. 1-148A) . In more advanced cases these areas become more diffuse and exudation is more copious; however, deep ulceration is not common. There may be minor bleeding or small fibrin thrombi in the superficial vessels of the lamina propria underlying eroded mucosa. There is usually some edema of the lamina propria, submucosa, and serosa. Initially mucus is expelled from the basilar portions of the crypts. In concert with the increased turnover of epithelial cells associated with the superficial erosion, there is hyperplasia of goblet cells as well as epithelial cells deeper in the glands. The crypts are elongated and lined by proliferative basophilic epithelial cells with large hyperchromatic nuclei, and few differentiated goblet cells. Crypts often subsequently become dilated and contain necrotic debris; some have marked goblet cell hyperplasia, and copious mucus production.. Large delicate spirochetes can be observed within dilated crypts and goblet cells using Warthin-Starry staining ( Fig. 1-148B) .
Porcine intestinal spirochetosis is caused by Brachyspira pilosicoli (formerly Anguillina coli), which differs from B. hyodysenteriae in that it is weakly beta-hemolytic. B. pilosicoli has a wide host range and has been isolated from a number of other animal species with lesions of intestinal spirochetosis, and it may be zoonotic.
Porcine intestinal spirochetosis has been seen in most major swine-producing areas of the world. The disease is characterized by generally transient watery to mucoid diarrhea without blood. Reduced weight gain is a significant clinical finding. As for B. hyodysenteriae, gross lesions are limited to the colon and cecum and may be subtle. Mesocolonic edema, swollen lymph nodes, variable mucosal erosion, and abundant watery large intestinal contents are early gross lesions. Later, the mucosa becomes thickened and in severe cases there is which are also critical for virulence of a given strain. There is not always a clear distinction between the different types of C. perfringens. Some strains lose their ability to produce one or more of their toxins when stored or cultured, and this complicates the identification of isolates and the assessment of their significance in disease outbreaks. Additionally, plasmid conjugation occurs both in vitro and in vivo and it is now thought that previously avirulent strains may become virulent by acquiring toxin genes.
The 4 major typing toxins are produced during active growth.
• The alpha toxin is a lecithinase that acts on cell membranes, producing hemolysis and necrosis of cells. The role of alpha toxin in intestinal disease of mammals is controversial, although most evidence indicates that this toxin on its own does not produce significant intestinal damage. • The beta toxin is a pore-forming toxin that induces intestinal necrosis and occasionally a variety of neurologic effects through a yet unknown mechanism. This toxin is exquisitely sensitive to the action of trypsin, which inactivates it in a few minutes; this property is very important for the pathogenesis of beta toxin-related diseases as explained later in this chapter. • The epsilon toxin is produced as a relatively inactive prototoxin that is activated by enzymatic digestion. Intestinal trypsin and chymotrypsin, and lambda toxin produced by C. perfringens itself are the main enzymes responsible for activation of epsilon prototoxin. Epsilon toxin is also a pore-forming toxin that induces mainly neurologic and respiratory effects, which are mostly the result of increased vascular permeability, although there is evidence that this toxin can also produce a direct effect on neurons in the brain. • The iota toxin is a binary toxin with 2 components, iota a and iota b, which is also elaborated as a prototoxin and activated by proteolytic enzymes. • Beta2 toxin, which despite its name is not related to beta toxin, has been associated with enteric disease in swine and horses caused by C. perfringens type A, although its pathogenicity is uncertain. • Some strains of C. perfringens, especially type A, produce enterotoxin, which is a specific toxin; the name enterotoxin should therefore not be used to refer to all C. perfringens crypts are lined by immature basophilic mitotically active cells. The diarrhea and ill-thrift characteristic of infection may be related to loss of absorptive function, secondary to disruption of the brush border of enterocytes, and increased exfoliation of poorly differentiated cells and perhaps enteric loss of plasma protein. Given the existence of long-term colonization by B. pilosicoli in pigs, it is unlikely that protective immunity develops after infection; however, the immune responses against this organism are poorly understood. In dogs, colonic spirochetosis with mucosal colitis has also been described, in association with B. pilosicoli and perhaps with other Brachyspira spp., but a causal relationship has not been established experimentally.
Most of the important enteric clostridial diseases occur in herbivores and are caused by 1 of the 5 toxigenic types of Clostridium perfringens or by Clostridium difficile. Enteritis in dogs is associated with C. perfringens and C. difficile. Clostridium piliforme (formerly Bacillus piliformis) causes Tyzzer's disease, characterized by multifocal necrotic hepatitis and occasionally enteritis, colitis and myocarditis, in many animal species. C. chauvoei may affect the tongue causing blackleglike glossitis (see Vol. 1, Muscle and tendon). Enteritis produced by C. chauvoei has also been described in an outbreak in heifers. C. septicum causes clostridial abomasitis (braxy) in sheep and calves, discussed in the earlier section, Stomach and abomasum. C. botulinum causes botulism in horses, cattle, and several other species by ingestion of preformed toxins (see Vol. 1, Nervous system).
The virulence of C. perfringens is mostly attributable to its capacity to produce up to 16 toxins, including 4 so-called major (typing) toxins (i.e., alpha, beta, epsilon, and iota) , which are used to classify this microorganism into 5 toxinotypes, designated A-E (Table 1 -2). However, no single strain produces this entire toxin set. Besides producing 1 or more of the 4 typing toxins (see Table 1 -2), some C. perfringens strains produce additional toxins, such as enterotoxin, beta 2, necrotic enteritis B-like toxin (NetB), kappa, and lambda, some of that in the alimentary tract infects small intestinal or colonic epithelial cells causing necrosis and inflammation. The pathogenesis of Tyzzer's disease is not clearly dependent on toxin production, although some strains do produce cytotoxic proteins. Diagnosis of disease because of the toxin-producing clostridia is mostly dependent on demonstration of toxin in gut content or feces of affected animals, by the most specific test available. Although the presence of large numbers of a particular type of C. perfringens suggests causation of the disease, some types of this organism are commonly present in the gut in a variety of circumstances, where they cannot be implicated as etiologic agents. C. perfringens type A is by far the most ubiquitous toxinotype in the intestine of animals, and isolation of this type alone is the least significant from a diagnostic standpoint. However, other types (e.g., type B and C) are less frequently found in the intestine of healthy animals, which makes isolation of these types more diagnostically significant.
Clostridium perfringens type A. C. perfringens type A is the toxinotype most commonly found in the environment and in the intestine of clinically healthy animals. Its major toxin is the alpha toxin; and some strains may also produce beta 2 toxin and enterotoxin in addition to a variable number of other toxins. This is one of several clostridia that produce gas gangrene in humans and animals. The production of gas gangrene in wound and puerperal infections is mostly mediated by alpha toxin with assistance by perfringolysin O. C. perfringens type A is responsible for necrotic enteritis in chickens, and it has been associated with several alimentary syndromes in mammals, including enteritis in foals; enterocolitis in horses; necrotizing enterocolitis in neonatal piglets; enterotoxemia and hemorrhagic enteritis in lambs and neonatal calves and older cattle; and diarrhea and hemorrhagic enteritis in dogs. However, absolute proof of involvement of C. perfringens type A in these alimentary syndromes of mammals is lacking.
Many strains of C. perfringens type A produce beta2 (CPB2) toxin and recent information suggests a role for this toxin in porcine clostridial enteritis, as nearly all type A strains isolated from pigs with enteric disease carried the cpb2 gene for CPB2 toxin. Involvement of CPB2 toxin-producing C. perfringens in enterocolitis of horses also has been suggested.
A very rare disease of lambs characterized by acute intravascular hemolysis, known as yellow lamb disease, has also been associated with type A infections and, at least in one occasion, with type D infection. Affected animals may be found dead or moribund, and jaundice and hemoglobinuria may be toxins produced in the intestine. The enterotoxin is only elaborated during sporulation and is released upon lysis of vegetative cells. It may be produced by most strains, but most cases of disease are associated with type A. Enterotoxin-producing C. perfringens type A is the second and third most important cause of human food poisoning in humans in the United States over the past decades. Enterotoxigenic type A strains are also associated with antibiotic treatment-related diarrhea in humans. The significance of enterotoxin in animal disease is limited. It is also a pore-forming toxin. Clostridial diseases originating in the intestine are often called enterotoxemias, which by definition are diseases produced by toxins generated in the intestine and absorbed into the circulation and that act on distant organs such as the brain and lungs. However, although several clostridial diseases of the intestine are true enterotoxemias, some of them are not. For instance, disease produced in sheep by C. perfringens type D, whose epsilon exotoxin is elaborated in the intestine but in this species exerts its important effects on distant organs such as brain and lungs, is a true enterotoxemia. The same toxinotype can produce an enterocolitis in goats with, in the chronic cases, no systemic absorption of epsilon toxin, in which case, no enterotoxemia occurs.
The pathogenesis of enteric infection with C. perfringens and C. difficile requires: (1) the presence of these microorganisms in the intestine (sometimes they can be normal inhabitants of the gut), and (2) a change in the enteric microenvironment favorable to massive expansion of luminal populations of clostridia and/or production of their toxins. Such changes may include a change in feed, abnormally nutrient-rich digesta, antimicrobial therapy, altered pancreatic exocrine function or trypsin inhibitors, reduced motility, and/or primary infections with agents such as coccidia.
C. perfringens bacteria alone are most likely nonpathogenic; exotoxins are required to induce disease, as it has been recently demonstrated in several animal experiments using so-called reverse genetics, in which bacterial strains genetically engineered to remove one or more toxin genes were inoculated into animals. The absence of a particular toxin gene eliminated the virulence, which was, however, restored when that gene was reintroduced into the genome.
C. difficile produces 2 exotoxins: A, which is an enterotoxin, and B, which is a cytotoxin but also an enterotoxin. Tissue damage is probably due to the effects one or of both toxins, which glycosylate and inactivate Ras GTPases, disabling signaling pathways in the cell. As well, they glycosylate Rho and interfere with its ability to regulate cytoskeletal actin. Under the influence of these toxins, the cytoskeleton condenses, tight junctions open, cells round up and undergo apoptosis. They also cause release of proinflammatory mediators, attracting neutrophils, and activate secretion stimulated by the enteric nervous system. Hence, disease is characterized by fluid intestinal content, with focal or diffuse small intestinal or colonic epithelial necrosis, through which neutrophils may exude into the lumen, producing a so-called "volcano" lesion. Not all isolates of C. difficile are toxigenic; 34 toxinotypes, based on sequence variations in the genes for the A and B toxin molecules, have now been described. Molecular epidemiologic investigation may permit associations of toxinotype with virulence.
C. piliforme, the cause of Tyzzer's disease and the only gram-negative clostridia, is an obligate intracellular pathogen causes "lamb dysentery," usually in lambs up to 10-14 days of age, dysentery in calves of approximately the same age, and rarely dysentery in foals within the first few days of life.
In lambs, death may occur without premonitory signs, but there is usually abdominal pain, especially when animals are forced to rise, and passage of semifluid dark feces mixed or coated with blood. The abdomen is often tympanitic. A more chronic form in older lambs, which among other diseases is known as "pine" in England, is characterized by unthriftiness and depression, reluctance to suckle, and a peculiar stretching when the animal rises; such cases are reputed to respond well to specific antiserum.
Typical gross lesions are usually present, although in exceptional peracute cases they may be absent. The characteristic lesion is extensive necrohemorrhagic enteritis. The peritoneal cavity often contains a small amount of serous or blood-stained fluid. In cases with more severe and deeply penetrating mucosal ulcerations, there may be overlying peritonitis with red fibrin strands on the local mesentery and intestinal adhesions. On the mucosal surface, the ulcers are irregular but are well defined by a sharp margin and rim of intense hyperemia, and they contain a yellow necrotic deposit; they may coalesce to form extensive areas of necrosis. Usually the intestinal contents are blood stained and may appear to be composed of pure blood, but in lambs that live for 3-4 days, there may be little or no hemorrhage evident. Histologically, the wall of the intestine is hemorrhagic, and the areas of necrosis extend deeply into the mucous membrane, in some cases penetrating to the external muscle layers and serosa. There are large numbers of typical bacilli in the necrotic tissue, but few inflammatory cells.
The lesions present in other organs are those of severe toxemia. The liver is usually pale and friable, but may be congested. The spleen is normal or slightly enlarged and pulpy. The kidneys may be enlarged, edematous, pale, and soft from toxic degeneration. The pericardial sac contains abundant clear gelatinous fluid, the myocardium is pale and soft, and epicardial and endocardial hemorrhages are almost constant. The lungs are often slightly congested and very edematous. Occasionally foci of symmetrical encephalomalacia similar to those observed in cases of type D enterotoxemia are observed in chronic cases.
The disease in calves caused by type B C. perfringens closely resembles that in lambs, usually affecting sucklings <10 days of age, with a course of 2-4 days characterized by prostration and dysentery. Older calves up to 10 weeks of age are sometimes affected. It appears that calves are more likely to recover, albeit slowly, than are lambs. The intestinal lesion is acute hemorrhagic enteritis with extensive mucosal necrosis and patchy diphtheritic membrane formations, especially in the ileum. Information on the disease in foals is very scant as only a few cases in this species have been reported. Clostridium perfringens type C. Clostridium perfringens type C is present worldwide, and causes disease mostly in neonatal individuals of several species, including particularly evident clinically. At autopsy, icterus, anemia, hemoglobinuric nephrosis, and other changes of severe, acute, intravascular hemolysis are prominent. Microscopically the most prominent changes are centrilobular hepatic necrosis and hemoglobinuric nephrosis, both presumably associated with acute intravascular hemolysis and anemia. This hemolytic disease must be distinguished from other causes of acute intravascular hemolysis such as leptospirosis, necrotic hepatitis, and bacillary hemoglobinuria caused by C. novyi type B and D, respectively, and chronic copper poisoning. Presumably, the hemolytic effect of alpha toxin is responsible for the intravascular hemolysis. Given that type A strains and alpha toxin are commonly found in the intestines of ruminants, diagnosis of this condition cannot be confirmed by detection of either of these and it has to be established presumptively based on clinical, gross, and microscopic findings coupled with ruling out other possible causes of intravascular hemolysis. It has been suggested that the disease is associated with unusually high alpha toxin type A strains, although this has not been confirmed.
Strains of C. perfringens type A, some determined to be enterotoxin producers, have been associated with diarrhea, sometimes bloody, in dogs. Hemorrhagic canine gastroenteritis (canine gastrointestinal hemorrhage syndrome) is a sporadic, peracute, hemorrhagic gastroenteritis, associated in some cases with C. perfringens type A, although in other cases the etiology has not been identified. Dogs with the peracute hemorrhagic disease are often found dead lying in a pool of bloody excreta; sometimes hemorrhagic diarrhea is noted before death. Autopsy reveals hemorrhagic enteritis and colitis, and sometimes hemorrhagic gastritis is present. Colonic lesions tend to be more severe. Microscopically there is hemorrhagic necrosis of the gastrointestinal mucosa, which extends from the luminal surface into the mucosa. Numerous clostridia may line the necrotic intestinal structures or be distributed through the detritus, but they do not invade the intact tissue. Recurrent diarrhea, sometimes bloody, has been associated with enterotoxin-secreting type A strains. Multiple serotypes of clostridia have been associated with nosocomial, usually nonfatal, cases of diarrhea in dogs. C. perfringens enterotoxin has been demonstrated twice as frequently in hospitalized dogs with diarrhea compared with controls without diarrhea. Giannitti F, et al., Clostridium perfringens type B. Clostridium perfringens type B has been reported from Europe, South Africa, and the Middle East, but not from the Americas and Australasia. It
Further reading Gkiourtzidis K, et al. PCR detection and prevalence of alpha-, beta-, beta 2-, epsilon-, iota-and enterotoxin genes in Clostridium perfringens isolated from lambs with clostridial dysentery. Vet Microbiol 2001; 82:39-43. distribution of gram-positive bacilli free in the intestinal lumen is common. Although they may be in close contact with the mucosa and attachment has been suggested, no definitive evidence of attachment has been demonstrated in C. perfringens infections in ruminants.
In adult sheep, C. perfringens type C causes "struck," a disease of pastured animals that has a mortality rate of 5-15% in some areas. Death usually occurs suddenly with terminal convulsive episodes, but less acute cases may adopt a straining position that probably indicates acute abdominal pain. In adult sheep, diarrhea or convulsions rarely occur. Gross and microscopic lesions are similar to those described in lambs except that small intestinal ulceration may be prominent and the mucosal necrosis is deeper, with a peripheral leukocytic rim separating the more or less normal deeper layers of the intestine.
Calves with type C disease show abdominal pain, some show diarrhea of sudden onset, and death may be preceded by spasmodic convulsions. Occasionally, sudden death occurs without premonitory clinical signs. Gross and microscopic lesions in calves are similar to those described in lambs.
Type C disease can apparently also occur, albeit rarely, in feedlot cattle. The condition is similar to "struck." Animals are found either dead or moribund, and congestion and hemorrhage of the gastrointestinal tract are prominent. The jejunal and ileal content are bloody with fibrin clots and necrotic debris. Excessive straw-colored pleural and pericardial fluid and petechiation of epicardium and endocardium are present. Autolysis and postmortem bloat occur rapidly, and differentiation from ruminal tympany and other clostridial diseases is necessary.
C. perfringens type C also causes necrohemorrhagic enteritis mostly in neonatal piglets. Rarely, epizootics occur in 2-4 week-old and weaned pigs. The disease occurs as epizootics in affected herds and regions, and may then remain enzootic. Poor hygienic conditions, overcrowding, and antibiotic treatment are thought to be predisposing factors in some outbreaks. Clinical disease can be peracute, acute, or chronic, with signs of the acute and peracute condition including intense abdominal pain, depression, and bloody diarrhea, which begins 8-22 hours after exposure to C. perfringens type C. Sow feces contain small numbers of type C organisms, and these multiply rapidly in the small intestine of piglets, outcompeting other bacteria and becoming the dominant organisms in the population. The course of the disease is usually 24 hours or less in 1- to 2-day-old piglets, but chronic disease (usually in older animals) can persist for 1 or 2 weeks and is characterized by persistent diarrhea without blood and dehydration. Marked anal hyperemia can be observed just before death in both acute and chronic forms.
Beta toxin has been shown to bind to small intestinal mucosa endothelial cells of piglets with type C infection. It was therefore suggested that beta toxin-induced endothelial cell damage plays an important role in the early lesion development of C. perfringens type C enteritis in pigs. The predominant lesions occur in the small intestine, especially the jejunum, but the cecum and spiral colon are often involved, and occasionally lesions are confined to the large intestine. Gross lesions are similar in all areas of the intestine, and in acute cases consist of intestinal and mesenteric hyperemia, extensive necrosis of the intestinal mucosa, which may be covered by a pseudomembrane (Fig. 1-149A) , and blood-staining of the contents. There may be emphysema of the intestinal wall, which sheep, cattle, horses, and pigs. Occasionally, type C disease occurs in adult individuals of these species. The main virulence factor of C. perfringens type C is beta toxin as demonstrated in animal experiments using toxin mutants of this microorganism in rabbits, mice, and goats. Beta toxin is trypsinlabile, and circumstances such as low trypsin levels in neonatal animals, trypsin inhibitors in the diet and/or very high levels of toxin are critical in the pathogenesis of type C disease. The high susceptibility of neonatal animals to type C disease is considered to be a consequence of the trypsin inhibitor effect of colostrum, a mechanism apparently aimed to protect immunoglobulins present in the colostrum. "Pig-bel," also known as "enteritis necroticans," is a necrotizing enteritis of humans caused by C. perfringens type C, which was the most important cause of human deaths in the 1960s in Papua New Guinea and still occurs sporadically in that island and other countries of the region. The disease has been associated with consumption of trypsin inhibitors in sweet potatoes, a significant component of the diet in Papua New Guinea. This, coupled with the low level of protein in the diet, results in low trypsin in the intestine, which allows persistence of beta toxin in the intestinal lumen. Intraduodenal inoculation of C. perfringens type C in combination with trypsin inhibitor produces acute necrohemorrhagic enteritis and/or enterotoxemia in guinea pigs, rabbits, lambs, and goats.
The diseases caused by type C in lambs, calves, piglets, goat kids, and foals are very similar. Affected animals are usually neonates, which contract the disease within the first few days of life, often within the first few hours.
Sick lambs may shiver, show abdominal pain, abdominal distention, diarrhea, and prostration, and die in 12 hours or less. Frequently, lambs with type C disease are found dead without clinical signs having been observed. In lambs, the gross intestinal changes are characterized by acute necrohemorrhagic enteritis that may be segmental and can sometimes be confused with intestinal strangulation. The most prominent changes occur in the jejunum and ileum, the lumen of which may contain free blood, which forms a clotted cast in fresh cadavers. Sometimes there is merely acute hyperemia of a segment of jejunum with edema of the wall, scant creamy intestinal content, and a few small ulcerations of the mucosa. A fibrinous pseudomembrane may be observed over the mucosa of the small intestine. The peritoneal cavity contains a small quantity of serous blood-stained fluid, and the local mesentery and peritoneum are often mildly to severely hyperemic, and bear red strands of fibrin. The mesenteric nodes are enlarged, edematous, and congested. There is usually excess pericardial fluid and pulmonary interstitial edema. Ecchymoses on the serous membranes are nearly constant, and in a few cadavers all tissues, but especially the meninges and brain, are liberally sprinkled with small hemorrhages. There might be terminal bacteremia by C. perfringens with bacterial embolism in multiple organs.
Histopathologic changes in lambs with type C disease are not specific, but can be highly suggestive of this infection. The changes consist of acute necrosis that involves mostly the intestinal mucosa, although it can progress to be transmural in severe cases. In most cases this is coagulative necrosis, but in animals that survive longer, the mucosa is completely replaced by a fibrinous pseudomembrane. Thrombosis of mucosal and submucosal vessels is a common finding, and inflammation is usually not a striking component, although it might be more marked in subacute cases. Diffuse or multifocal lymphatics and in the interstitium. Diffuse edema with variable amounts of protein and inflammatory cell exudate can be seen throughout all intestinal layers, including serosa. The mucosa is severely thickened by edema and inflammatory exudate. As the infection progresses, necrosis becomes deeper, including epithelium of crypts and glands and, later, all intestinal layers. Severe congestion of subserosal vessels is observed throughout the course of the infection. Lesions are usually diffuse, although they can be multifocal. Mucosal necrosis without hemorrhage may be observed in older pigs with chronic disease.
The disease caused by C. perfringens type C in foals has been reported from the United States, Canada, Australia, and several European countries. It usually occurs in foals <4 days of age, although occasional cases in older foals and adult horses may also occur. Typical clinical signs include weakness, yellow to brown watery diarrhea, colic, and dehydration. Affected foals usually die in <24 hours. Sudden death without clinical signs being observed may also occasionally occur. Gross lesions are those of acute hemorrhagic necrotizing enteritis, usually in the distal two thirds of the small intestine ( Fig. 1-150A, B) , although in some cases most of the small and large intestine may be affected. The microscopic lesions are similar to those described previously for C. perfringens type C infection in other species (Fig. 1-151 ) and in foals, histologically the lesions are very similar to those caused by C. difficile and Salmonella sp. In a series of cases of combined infection with C. perfringens Histologically, the hallmark of acute disease in young piglets is hemorrhagic necrosis of the intestinal wall, which starts in the mucosa but usually progresses to affect all layers of the intestine. Lesions are morphologically similar in all segments of intestine; the luminal surface is covered by a pseudomembrane composed of degenerate and necrotic desquamated epithelial cells, cell debris, inflammatory cells including neutrophils, lymphocytes, plasma cells, and macrophages, fibrin ( Fig. 1-149B) , and a variable number of large, thick bacilli with square ends with occasional subterminal spores. These bacteria occur singly or in clusters, free in the lumen, or lining the margin of the denuded mucosal surface. Although the bacterial population is usually greater in the central intestinal lumen, a few bacilli also can be seen in crypts and glands and invading necrotic lamina propria. Superficial epithelium and superficial layers of lamina propria are necrotic, showing a homogeneous acidophilic appearance with scattered pyknotic or karyorrhectic nuclei and an inflammatory cell infiltrate composed of neutrophils and mononuclear cells. Fibrin thrombi occluding superficial arteries and veins of the lamina propria and submucosa are characteristic of this condition. Fibrin also can be seen in mucosal and submucosal manifestations of the subacute and chronic forms of type D enterotoxemia.
By definition, type D isolates must produce both alpha and epsilon toxins, although some type D isolates can express several other toxins. However, it has been demonstrated by the use of reverse genetic experiments in animal models that epsilon toxin is sufficient to cause all the clinical signs and lesions of type D enterotoxemia in sheep and goats. Epsilon toxin is the third most potent clostridial toxin (after botulinum and tetanus toxins) and, until recently it was considered a class B select agent by the USDA and CDC in the United States. Activated epsilon toxin apparently facilitates its own absorption through the intestinal mucosa and it is then transported to several target organs, including the brain, lungs, and kidneys. In the brain and possibly also in other organs, epsilon toxin affects endothelial cells, producing the lesions described later. It also has been suggested that epsilon toxin acts directly on neurons within the brain.
Lambs and goats suddenly fed large amounts of grain or concentrate are highly susceptible; thus the synonym overeating disease. The manner in which overeating leads to clostridial enterotoxemia is complex and not fully understood. Cultures of C. perfringens type D given orally are largely destroyed in the rumen and abomasum. However, when the intestinal environment is favorable, the few organisms that reach the intestine proliferate rapidly and produce toxin.
It was accepted traditionally that the critical factor for type D enterotoxemia to occur is the presence of undigested starch in the small intestine, providing a suitable substrate for these saccharolytic bacteria, which allows them to proliferate to immense numbers-perhaps >10 9 organisms per gram of intestinal contents-and produce correspondingly large amounts of toxin. However, it has been demonstrated in vitro that the absence of glucose in a culture medium stimulates epsilon toxin production. Therefore it is possible that the presence of starch in the intestine stimulates the growth of C. perfringens type D, whereas the absence of glucose stimulates epsilon toxin production. When the animal is suddenly provided with excessive quantities of food, particularly starch-rich food, there is a delay before the ruminal flora can adapt. In this period, undigested or partially digested starch may escape into the intestine, and C. perfringens type D is likely to take advantage of it. The lack of digestion of starch also would be responsible for the absence of glucose in the small intestine. The epsilon prototoxin is produced as a relatively inactive prototoxin, which is fully activated by digestive enzymes, especially the combination of trypsin and chymotrypsin, but also by some proteases produced by C. perfringens itself.
Epsilon toxin facilitates its own absorption from the intestine, probably in part by increasing the permeability of the mucosa. No damage to the intestinal mucosa, except for occasional congestion and mild hemorrhage, is observed in sheep, as opposed to goats, in which severe necrotizing colitis and/ or enterocolitis is frequently observed.
The acute disease in goats likely has a similar pathogenesis as in sheep, but the chronic disease, with lesions confined to the intestine, appears to be caused by local effects of type D toxins. Although very little information is available in cattle, probably the disease develops in the same way in cattle as in sheep.
Type D enterotoxemia may occur in lambs >2 weeks or adult sheep. In most lambs with type D enterotoxemia, the type C and C. difficile in foals, both the gross and microscopic pathology were indistinguishable from those in foals infected with either of these two microorganisms individually.
A disease clinically and pathologically identical to that described in sheep has been experimentally produced in goats inoculated intraduodenally with C. perfringens type C.
A presumptive diagnosis of type C disease can be established based on clinical and pathologic findings, but confirmation of the disease relies on detection of beta toxin in intestinal contents and/or feces. However, because this toxin is so sensitive to trypsin, failure to detect this toxin in intestinal content does not preclude a diagnosis of C. perfringens type C infection. Because this microorganism is infrequently found in the intestine of normal animals, isolation is considered to be diagnostically significant. Diab SS, et Clostridium perfringens type D. Enterotoxemia ("pulpy kidney" disease, "overeating" disease) caused by Clostridium perfringens type D is an important disease of sheep and goats with a worldwide distribution. It occurs occasionally in cattle. The rarely observed subacute and chronic forms of the disease in sheep have been called focal symmetrical encephalomalacia (FSE), because for many years they were thought to be a different disease, but FSE is only one of pathologic Diab SS, et al. Vet Pathol 2012; 49:255-263.) small intestine occasionally may be distended with gas and be hyperemic.
The so-called "pulpy kidney" (softening of the renal parenchyma) may be present in a small proportion of cases, but it is of little diagnostic significance because its occurrence is so inconsistent. It is best regarded as a poorly understood example of accelerated autolysis because it is not seen in freshly dead carcasses. Glucosuria is present in a relatively small percentage of animals with type D enterotoxemia and it is a useful, though nonspecific, diagnostic indicator when detected. The absence of glucosuria does not preclude a diagnosis of type D enterotoxemia.
In adult sheep, the gross lesions are the same as those in lambs, but are more consistent and more advanced. Brain gross lesions may occur in lambs and older sheep with subacute or chronic enterotoxemia and these are sufficiently unique to be of diagnostic significance. They include herniation of the cerebellar vermis (Fig. 1-153) and/or focal symmetrical encephalomalacia (FSE) (Fig. 1-154) . The commonest distribution of FSE involves the corpus striatum, thalamus, and cerebellar peduncles; there are some minor variations of the pattern, but course is acute and the animal is found dead without clinical signs being observed or after a short period of acute neurological and respiratory signs, including convulsions and tachypnea, and often bawling as from severe pain. Animals that survive longer may show drooling, rapid breathing, hyperesthesia, wide stance, blindness, opisthotonos, and terminal coma or convulsions. In older sheep or younger but vaccinated sheep, subacute or chronic cases are most frequently seen. Neurologic clinical signs are characteristic of the subacute and chronic forms of type D disease and include blindness, ataxia, head pressing, and paraparesis. Diarrhea occasionally may be observed, although this is not a common clinical sign in sheep type D disease.
In goats, type D produces acute, subacute, or chronic disease as well. The acute form occurs more frequently in young, unvaccinated animals and is clinically similar to the acute disease in sheep and characterized by sudden death or acute neurologic signs. The subacute form is more frequently seen in adult goats, vaccinated or not, and is characterized by hemorrhagic diarrhea, abdominal discomfort, tachypnea, opisthotonos, and convulsions. The disease may result in death 2-4 days after onset, but some animals recover. Adult animals, often vaccinated, can also exhibit chronic disease, which is characterized by profuse, watery diarrhea (often containing blood and mucus), abdominal discomfort, weakness, anorexia, and agalactia in milking does. This chronic form may last for days or weeks and may culminate in either death or recovery.
Grossly, in sheep dead of acute enterotoxemia, the carcass is usually well nourished. In those with a course of 1-2 days, there may be occasional evidence of scours about the rump, although diarrhea is rarely observed. Often there is excessive straw-colored pericardial, thoracic, and abdominal fluid with strands of fibrin ( Fig. 1-152 ) that clots on exposure to air, and congestion and edema of the lungs that may be severe enough to produce froth in all the respiratory passages; and hemorrhage beneath the endocardium of the left and occasionally right ventricles of the heart. There may be hemorrhages beneath other serous membranes such as the epicardium, and blotchy hemorrhages beneath the parietal peritoneum are characteristic. Sometimes the liver is congested and the spleen enlarged and pulpy. There is no gastrointestinal inflammation visible at autopsy, although the content of the small and large intestine may be moderately fluid and short lengths of the surrounding areas of vasculopathy, suggesting that neuronal stress is an early event in ovine enterotoxemia.
Type D enterotoxemia may be seen in both adult goats and kids. As in sheep, 3 forms of the disease are recognized in goats: acute, subacute, and chronic. The acute disease is similar to that seen in lambs, and usually manifests as sudden death. The subacute form is characterized by diarrhea and severe abdominal discomfort with or without neurologic signs. Affected animals usually die within 1-2 days of the onset of clinical signs. The chronic form of the disease may last for a few days or weeks. Weight loss and diarrhea are its main clinical features. The principal gross lesions in the acute form of the disease are similar to those seen in sheep, except that gross brain lesions are absent. In the subacute and chronic disease, there is mild to severe mesocolonic edema, hyperemia, and ulceration of the mucosa (Fig. 1-156A) , especially of the distal small intestine, cecum, and spiral colon. The affected areas the lesions are always of the same type. Less frequently FSE can be seen also in substantia nigra, white matter of the frontal gyri, rostral cerebral peduncles and other areas. The white matter is preferentially affected in all of these areas.
The histologic changes in the brains of sheep with type D enterotoxemia are unique and pathognomonic, and although they are present in the vast majority of cases, occasionally they may be absent. The most consistent change, observed in ∼90% of acute and subacute cases, is perivascular proteinaceous edema, also known as microangiopathy, which is seen mostly as homogeneous acidophilic accumulations of protein surrounding small-and medium-sized arteries and veins ( Fig. 1-155) . Occasionally, accumulation of protein hyaline droplets around small vessels is also seen. These lesions are first evident a few hours after onset of clinical signs. Apparently, no other conditions of sheep produce this highly proteinaceous perivascular edema in brain, and this change therefore should be considered diagnostic for type D enterotoxemia in this species. In subacute and chronic disease, FSE can be observed. This lesion is usually multifocal and characterized by degeneration of white matter, hemorrhage, and astrocyte and axonal swelling. Perivascular edema and FSE in the brain are always bilateral and roughly symmetrical, and they have been described most frequently in corpus striatum, thalamus, midbrain, cerebellar peduncles, and cerebellar white matter. These areas are not exclusively affected, and lesions sometimes can be seen in other parts of the brain, such as cortex and hippocampus. Usually, no significant histologic changes are found in intestines of sheep dying from enterotoxemia. Histologic changes were not observed in kidneys of experimentally inoculated lambs autopsied immediately after death, supporting suggestions that these lesions are due to postmortem change.
Thus microscopic lesions in kidney should not be considered a diagnostic indicator of ovine enterotoxemia.
Ultrastructurally, severe damage to vascular endothelium is apparent and there is swelling of protoplasmic astrocytes. The foot processes around blood vessels and the processes around neurons are most severely swollen.
Immunohistochemistry has revealed that Alzheimer precursor protein 1 (APP1) is very early upregulated in axons
Clostridium perfringens type E. Clostridium perfringens type E has been blamed for enterotoxemia of lambs, calves, and rabbits. Pathogenesis of type E infections is not very well understood, although it is assumed that iota toxin plays an important role.
In the few reported cases of this condition in calves, the animals died acutely and had a congested ulcerated abomasum and hemorrhagic enteritis that occurred segmentally along the small intestine. Mesenteric nodes were enlarged and red, and pericardial effusion and serosal hemorrhages may be present.
No comprehensive descriptions of clinical disease, gross and microscopic lesions of type E enterotoxemia in other ruminants.
The few diagnoses of type E enteritis that have been reported were based on isolation of C. perfringens type E from the intestinal content of sick animals. This procedure, however, is not universally accepted as a diagnostic criterion for C. perfringens intestinal diseases because this organism is present in many healthy animals.
Although C. perfringens type E also has been suspected as a cause of enterotoxemia in rabbits, cross-reactivity of the iota toxin with the toxins of C. spiroforme, has created doubt regarding the role of C. perfringens type E in disease in rabbits. Songer Clostridium difficile. Clostridium difficile is a grampositive rod that may be found in the soil and gut of many animal species. C. difficile is the most commonly identified cause of antibiotic-associated and nosocomial diarrhea in humans but, in the past few years, it has also been associated with cases of colitis and diarrhea in people that have not been treated with antibiotics or exposed to hospital environments (community-associated C. difficile infections). C. difficile disease occurs spontaneously in several animal species including horses, hares, rabbits, pigs, nonhuman primates, dogs, cats, ostriches, and black-tailed prairie dogs. C. difficile has been may be covered by a layer of fibrin that reveals multifocal to diffuse ulceration when peeled off. The intestinal contents are olive-green to red and mucoid and frequently contain strands of fibrin. The mesenteric lymph nodes are enlarged and edematous. Hydropericardium, ascites, and pulmonary edema can be seen in the subacute form but not in the chronic form of the disease. FSE similar to that describe in sheep has been described in one case of subacute enterotoxemia in goats.
Microscopic changes are usually absent in acute cases, but perivascular edema similar to that described in sheep occasionally may be observed. The main microscopic lesions in subacute and chronic forms are seen in the colon and, occasionally in the caudal segments of the small intestine. These lesions vary from a mild pleocellular leukocytic reaction in the lamina propria to a suppurative and fibrinonecrotizing enteritis, colitis, and/or enterocolitis ( Fig. 1-156B) . Changes in the lungs may be similar to, but are less consistent than, those seen in lambs. Only rarely has FSE been described in subacute type D enterotoxemia of goats. The reasons for the different manifestations of enterotoxemia in sheep and goats are unknown.
Information on type D enterotoxemia in cattle is sparse and the disease seems to occur very rarely in this species. A spontaneous disease with gross brain lesions similar to those observed in FSE of sheep occasionally is seen in cattle. However, a causal relationship between the lesions and C. perfringens type D or its epsilon toxin has not been established in any of these cases, and the etiology of these lesions in cattle remains undetermined.
Experimentally, a disease very similar to the acute form of type D enterotoxemia in sheep was observed in calves inoculated intravenously with epsilon toxin. These animals developed severe respiratory and neurologic clinical signs very shortly after inoculation. Gross findings included severe pulmonary edema and hydropericardium. Histologic changes were proteinaceous perivascular edema of the brain and lungs. Intraduodenal inoculation of calves with C. perfringens type D also resulted in a disease similar to the acute form of type D enterotoxemia in sheep, with clinical and pathologic findings similar to those seen in epsilon toxin inoculated calves in most animals; one animal developing chronic neurologic disease with gross and microscopic lesions of FSE as described in the subacute and chronic ovine form of the disease.
These experimental results indicate that cattle are susceptible to C. perfringens type D infection and its epsilon toxin. However, natural type D disease in this species seems to be a rare occurrence. Microangiopathy similar to that described in in sheep and goat enterotoxemia was described in the brain of two 1-day-old calves and in a heifer, in which epsilon toxin was detected in the intestinal content.
A diagnosis of type D disease in sheep can be established based on the presence of FSE and/or perivascular edema in the brain. The same applies for goats in the rare cases in which these lesions are present. Absence of these lesions in either species does not preclude a diagnosis of enterotoxemia. Although it has been suggested that epsilon toxin may be produced in the intestine after death, this has never been proved, and demonstration of epsilon toxin in intestinal content is therefore considered diagnostic for the disease in both animal species. It is likely that the same diagnostic criteria apply for enterotoxemia in cattle, although much less information is available about the disease in this species and diagnostic criteria have not been established in cattle.
severity. The main clinical sign is diarrhea, which may be accompanied by hyperemic mucous membranes, prolonged capillary refill time, pyrexia, tachycardia, tachypnea, dehydration, abdominal distention, and colic. The mortality rate in foals and adults varies from 0 to 42%. A syndrome known as duodenitis-proximal jejunitis, characterized clinically by large volumes of enterogastric reflux, has been known since the early 1980s. Although an association has been suggested between C. difficile and duodenitis-proximal jejunitis, a conclusive relationship has been neither proved nor ruled out.
C. difficile gross and microscopic lesions may be characteristic but are not pathognomonic, as other infectious (C. perfringens type C, Salmonella sp., and Neorickettsia risticii) and noninfectious (NSAIDs) causes of intestinal disease can produce very similar lesions.
Grossly, the serosa of the small and large intestine is multifocally red or blue as the result of intense hyperemia and/or hemorrhage ( Fig. 1-157) . The wall of the small intestine can be slightly thickened; the mucosa is often diffusely reddened and may have an overlying, multifocal, tan to orange pseudomembrane. The wall of the colon and cecum is typically diffusely and severely thickened by clear to hemorrhagic, gelatinous submucosal and mucosal edema; the mucosa is multifocally or diffusely dull green or red and may be multifocally covered by a tan or light green pseudomembrane ( Fig. 1-158) . The intestinal content in young foals is often hemorrhagic but may be yellow and pasty or green/brown and watery. In older foals and adult horses, the colon and cecum are characteristically filled with large amounts of green or light brown, watery contents, and occasionally dark brown or red, hemorrhagic, watery contents ( Fig. 1-159) . Bloody content may be present caudally to the small colon and rectum. When present, gross lesions outside the gastrointestinal tract are those of endotoxic shock and/or disseminated intravascular coagulation, including serous or serosanguineous pericardial effusion, pulmonary edema and congestion, and multifocal subendocardial and subserosal petechiae and ecchymoses.
Microscopic lesions in horses are mostly restricted to the gastrointestinal tract and they can be present in the small and/ or large intestine. They are almost identical to those seen in horses with C. perfringens type C infection and consist mainly of multifocal to diffuse, often hemorrhagic, coagulative isolated from cattle with enteritis but also infected by other pathogens, and although it is very likely that this microorganism plays a role in enteritis of cattle, final evidence to support this assertion is lacking.
C. difficile disease has been reproduced experimentally in several animal species that are used as models for human disease, including Syrian hamsters, guinea pigs, mice, rats, and rabbits. Lesions in most nonhuman mammals are similar to those in humans, but vary extensively in severity and distribution within the gastrointestinal tract. Differences in distribution of lesions within the gastrointestinal tract also exist between different age groups of the same animal species. Over the past few years, highly virulent ribotypes responsible for severe human outbreaks (i.e., 027 and 078) have been associated with disease in several animal species, prompting speculation that animal-to-human transmission and/or vice versa occurs.
Pathogenesis of C. difficile disease in domestic animals is likely mediated by toxins A (an enterotoxin) and B (a cytotoxin and also an enterotoxin). Much controversy exists about the relative importance of each of these toxins in the pathogenesis of C. difficile infection. However, animal experiments using toxin mutant strains of C. difficile (i.e., strains that do not produce toxin A or B or both), have shown that both toxins are able to cause lesions and disease.
The major predisposing factors for C. difficile disease in most species are antibiotic therapy and, at least for humans and horses, hospitalization. Although clindamycin and vancomycin therapy pose a higher risk than other antibiotics for many animal species, disturbance of normal flora with development of C. difficile disease can occur after administration of almost any antibiotic, including antibiotics that are effective against C. difficile itself. However, in horses the disease has been most frequently associated with administration of β-lactam antibiotics, probably because of the prevalence of their use.
Confirmation of a diagnosis of C. difficile disease should be based on identification of toxins A, B, or both in gut content or feces by tests with high sensitivity and specificity, mostly ELISAs. However, because of the lower carrier rate of this microorganism in some animal species (e.g., horses), isolation of toxigenic strains of this microorganism from intestinal content and/or feces is considered diagnostically significant for C. difficile infection by some authors. Typing of isolates is necessary because nontoxic strains can occur and isolation of those is of no diagnostic significance.
In horses, C. difficile causes enteritis, enterocolitis, and/or colitis. Diarrhea and colic have been reproduced in foals using inocula of C. difficile spores and vegetative cells. Horses of any age can be affected and although there are exceptions, it is generally accepted that the distribution of lesions throughout the intestinal tract seems to be dependent on the age of the horse. In foals <1 month old, the small intestine is invariably affected, whereas colon and cecum may or may not have lesions. In older foals and adult horses, the disease has a more caudal distribution, affecting the colon and sometimes the cecum, and generally sparing the small intestine. Although this age-related distribution of lesions within the gastrointestinal tract is seen in the majority of cases, exceptions do occur and lesion distribution should not be used to confirm/rule out C. difficile infection in horses.
The clinical signs of C. difficile disease in horses are highly variable, not specific and may occur with highly variable necrosis of the mucosa, which may be covered by a pseudomembrane, frequently accompanied by submucosal edema and congestion. Thrombosis of small to mid-size blood vessels in the mucosa and/or submucosa is a very frequent, although not constant, finding, and it is especially useful in those cases in which autolysis has partially masked the mucosal necrosis. Mild to moderate mucosal and submucosal fibrino-neutrophilic infiltration with fewer plasma cells, lymphocytes, and macrophages is frequently observed. The so-called "volcano" lesions, as described in the human disease and characterized by patchy focal erosions on the small intestinal or colonic mucosa through which fibrin and neutrophils exude, are not very frequently seen in horses and it has been speculated that the reason is that, at the time of autopsy and sample collection, the lesions are usually too advanced to show the delicate volcano-like lesions. Few to numerous clusters of short and thick, gram-positive rods can be observed in the intestinal lumen and/or on the surface or within the necrotic mucosa.
Co-infection of foals with C. difficile and C. perfringens type C can also occur. The clinical signs, gross and microscopic lesions are almost identical to those produced by either of these microorganisms alone.
C. difficile is increasingly being recognized as a cause of diarrhea resulting from fibrinous colitis in neonatal pigs under about a week of age, and the disease has been reproduced experimentally using pure cultures of the organism. Piglets have diarrhea, dyspnea, scrotal edema, and mild abdominal distention. Affected litters experience lost productivity (mainly shown as decreased weaning weight).
Grossly, hydrothorax and characteristic although not pathognomonic, edema of the mesocolon (Fig. 1-160 ) are evident grossly, usually in association with patchy to extensive fibrinous typhlocolitis ( Fig. 1-161A) , with yellow pasty to fluid content and feces. Microscopically, fibrinous colitis similar to that described in horses is a common lesion, with colonic serosal and mesenteric edema and infiltration of mononuclear inflammatory cells and neutrophils in the lamina propria. Segmental erosion and ulceration of colonic mucosal epithelium is common, and volcano lesions may be seen in acute cases of the disease ( Fig. 1-161B ). Occasionally deeper necrosis of the mucosa and colonic wall may occur.
Information on C. difficile infection in domestic dogs and cats is scant and the role of this microorganism in canine and feline enteric disease is currently unclear. Although a possible association between the detection of C. difficile toxins in feces of dogs and disease has been reported in multiple studies, diagnostic criteria for C. difficile infection in these species have not been defined. This is complicated by the fact that prevalence of C. difficile in normal dogs and cats may be up to 50% and C. difficile toxins also have been detected in a small percentage of asymptomatic dogs. Descriptions of lesions of C. difficile infections in dogs or cats are not available.
The role of C. difficile in enteric disease of cattle has been proposed in several studies, but no conclusive evidence has been provided to confirm or rule out this possibility. This microorganism, including the highly virulent ribotypes 027 and 078, and its toxins, has been detected in the intestine of healthy and diarrheic calves. Ribotype 078 has been found to be predominant strain in cattle in North America. The fact that several of the highly virulent ribotypes of C. difficile for humans have been found in cattle suggests that zoonotic transmission (and/or vice versa) may occur. There is growing concern that some C. difficile infections may be acquired from
A ingestion of C. difficile spores in contaminated foods of animal origin. Although a correlation between the presence of fecal C. difficile and its toxins and calf diarrhea was found, frequently this microorganism is detected in diarrheic calves together with other enteropathogens (e.g., bovine coronavirus, bovine rotavirus, Cryptosporidium spp.), and ascribing the enteropathogenic effects to one of these pathogens alone is difficult. One study failed in the attempt to provoke diarrhea in calves by oral administration of virulent C. difficile strains.
Tyzzer's disease is caused by the obligate intracellular bacterium Clostridium piliforme, the only gram-negative organism among the pathogenic clostridia. It is a disease of many species of mammals, among them horses, cats, dogs, rabbits, hamsters, and cattle, although there seem to be bacterial strain differences that determine host susceptibility. Affected animals are often very young or appear to be immunocompromised in some way.
The classical triad of lesions in most animal species include changes in the heart, intestinal tract, and liver. However, frequently lesions are observed only in the liver, which is the organ most frequently affected in the majority of animal species. Animals become infected initially through the epithelium of the ileum, cecum, and colon, where, when present, inflammation may vary from subtle catarrhal to fibrinohemorrhagic. Bacilli can be observed faintly in hematoxylin and eosin preparations but are better demonstrated using silver stains, often forming characteristic "pick-up-sticks" arrays, in the cytoplasm of enterocytes. Ultimately, in most cases they disseminate elsewhere in the body, especially to liver and myocardium, where they cause acute to subacute necrotic lesions. The organism cannot be cultured in conventional media and diagnosis is usually based on histologic examination by demonstration of the classical intracellular bacilli. The disease is discussed more fully in Vol. 2, Liver and biliary system.
Johne's disease is caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. The etiologic agent of Johne's disease is classified as a subspecies within the M. avium complex based on DNA hybridization studies and other genotypic and phenotypic tests. MAP in culture is slow growing, and its dependence on the iron chelator mycobactin classically has been the key distinguishing phenotypic characteristic. Genetically, the IS900 insertion sequence element seems unique to MAP, and has been used broadly as a diagnostic tool in animals and humans. Highly homologous but not identical IS900-like sequences have been detected in other mycobacteria. At least 2 distinct MAP strains are known to cause paratuberculosis in various hosts, and these are generally referred to as type I, or S strain first isolated from sheep, and type II, or C strain first isolated from cattle. Type I strains have been isolated mostly from sheep, particularly in Australia; there are rare reports of cattle infected with type I strains. Type II strains, on the other hand, are the most common; they have a broad host range and have been isolated from domestic and wildlife species as well as nonruminants. The strains have distinct phenotypic, genotypic, host preference, virulence, and pathogenic traits that continue to be clarified.
Paratuberculosis is most common in domestic ruminants, but spontaneous disease also occurs rarely in a number of free-ranging and captive nondomestic ruminants, camelids and rabbits, equids, swine, and captive primates. Wild mammals including lagomorphs, rodents, and carnivores, and several species of wild birds are naturally infected with MAP, but do not necessarily develop disease. MAP has been recovered from clinical disease, the population of MAP within the intestinal mucosa increases and live MAP are shed in the feces more frequently and in greater numbers. Appetite often remains normal, and intermittent to progressive diarrhea may persist for weeks before eventual development of hypoproteinemia, cachexia, emaciation, and death.
The major lesions of Johne's disease are usually confined to the ileum, large intestine, and draining lymph nodes; however, the infection is generalized and the organism is widely distributed in lymph nodes, and can be cultured from a variety of parenchymatous organs or even blood in fulminating infections. Diarrhea during Johne's disease is related to the granulomatous inflammatory response in the lamina propria of the small intestine, and the associated villus atrophy that develops. Malabsorption and filtration secretion caused by the inflamed small intestinal mucosa overloads the capacity of the colon to resorb electrolytes and fluid. The function of the colon itself may be compromised by MAP infection, especially in severe or advanced cases. There is malabsorption of amino acids, enteric loss of plasma protein, and hypoproteinemia causing reduced productive efficiency, and when negative nitrogen balance occurs, a decline in body condition, and ultimate emaciation.
The gross lesions of Johne's disease include small intestinal mucosal lesions that may be segmental or continuous, and can be distributed from the duodenum to the rectum. Lesions are usually best developed in the lower ileum and upper large intestine. The ileocecal valve is considered by some to be the site that is earliest and most consistently affected; however, lesions in the ileocecal valve can be variable. The classic intestinal change is diffuse thickening of the mucosa, which is folded into transverse rugae, the crests of which may be congested ( Fig. 1-162) . Mucosal thickening is due to accumulation of predominantly macrophages, as well as edema fluid, in the mucosa and submucosa. The mucosa and/or serosa may have a slightly granular appearance because of increased cellularity and edema. The ileocecal and mesenteric lymph nodes are enlarged, pale, and edematous. Lymphangitis is common, and the lymphatic vessels can often be traced as thickened cords from tissue and blood samples of human patients inflicted with Crohn's disease, a chronic granulomatous enteritis of importance in humans that shares several pathologic and immunologic features with Johne's disease. These findings are suggestive of a causal relationship; however, Koch's postulates have not yet been fulfilled, so it seems more likely that MAP is coincidental, or plays a potentially opportunistic role in these cases.
The epidemiology and pathogenesis of Johne's disease are best understood in cattle, and are assumed to be similar in other species. MAP is transmitted predominantly by the fecaloral route, either directly by ingestion in feces or indirectly via MAP-contaminated milk, colostrum, or water. Organisms may be present in semen or urine, and may cross the placenta, particularly during advanced disease. A distinct age-dependent susceptibility to MAP infection is observed; the infectious dose for adults is considerable higher than for neonates. The basis for this is unknown, and control programs aimed at blocking transmission are almost exclusively focused on neonates. Johne's disease is often categorized into 3 (or 4) stages: silent infection, subclinical infection, clinical disease (and advanced clinical disease), based on severity of clinical signs, potential for shedding of MAP organisms into the environment, and ease of diagnosis. Of particular importance is the subclinical period, which can last 2-5 years before infected animals develop clinical signs. Because shedding of MAP into the environment by subclinical cows is variable and progressive, this period represents a significant risk for spread of the infection to susceptible herdmates. This long and unpredictable incubation period has given rise to the concept of the iceberg effect because in any infected herd, although few animals may be showing clinical signs of Johne's disease, a much greater number of animals are likely MAP infected. Sheep, goats, and cervids are considered to be more susceptible to MAP infection compared with cattle, and have a shorter incubation period before development of clinical signs. Survivability of MAP in the environment is proposed to have a significant effect on the epidemiology of MAP infection in animals; however, the biologic relevance of these factors for transmission of infection is still unclear.
MAP gains access to the small intestinal mucosa and subepithelial dome via microfold (M cells) or epithelial cells overlying submucosal Peyer's patches. Macrophages are the preferred host cell for MAP, and the ability of pathogenic mycobacteria including MAP to inhibit phagosome-lysosome fusion is fundamental to its survival and persistence within the host. Experimental in vitro and in vivo work indicates that MAP-infected cattle develop a proinflammatory immune response early after intestinal infection, which is probably driven by innate intestinal T lymphocytes including gammadelta T cells and natural killer cells. However, in animals that fail to clear the infection, the early proinflammatory response eventually gives way to an apparently ineffective but robust MAP-specific antibody response. This transition correlates with the progression from subclinical to clinical disease in affected adults, but the mechanisms for this remain largely unknown. The rate of disease progression and the length of the subclinical period of Johne's disease are irregular and can be protracted; clinical cows are rarely <2 years of age. The reasons for this remain unclear, although there is likely a complex interplay of factors, including age of initial exposure, dose, re-exposure over time, environment, nutrition, production stage, and genetics. As an animal progresses toward the intestinal serosa through the mesentery to the mesenteric nodes ( Fig. 1-163) . In some cases mucosal lesions are subtle and lymphangitis is the only readily recognizable gross lesion, which is specific enough to justify a presumptive diagnosis of Johne's disease at gross postmortem examination. Additionally, there is marked loss of muscle mass and serous atrophy of fat depots, intermandibular edema, and fluid effusion in various body cavities. Plaques of intimal fibrosis and mineralization may be evident in the thoracic aorta.
When gross lesions are well developed, the characteristic microscopic lesions of transmural granulomatous enteritis and lymphangitis are obvious (Figs. 1-164 and 1-165) , although in cattle with minimal gross lesion, microscopic abnormalities can be more subtle. Depending on the severity and stage of the infection, villi are moderately to markedly atrophic; macrophages are increased in number and are focally or diffusely distributed in the lamina propria, submucosa, muscular layers or the serosa of the intestine. Epithelioid macrophages and Langhans-type multinucleated giant cells are often present in aggregates or diffuse sheets. The inflammatory infiltrate may abnormally separate and displace crypts, which are elongate and lined by hyperplastic epithelial cells. Crypts may be distended with mucus and exfoliated cells, probably because of compression and obstruction of their mouths by inflammatory cells and edema. Foci of necrosis may occur within these aggregates of macrophages, but in cattle formation of classic tuberculoid granulomas with caseation and mineralization are extremely rare.
Granulomatous lymphangitis is one of the most consistent changes, and inflammatory cells can be observed along the lacteal vessels of villi, or in the submucosa (see Fig. 1-165) . Initially the lymphatics are surrounded by lymphocytes and plasma cells and many contain plugs of epithelioid cells in the lumen. Granulomas may form in the wall and project into the lumen. These nodules may undergo some central necrosis. Granulomatous lymphadenitis occurs in ileocecal or mesenteric lymph nodes in advanced cases. In the early stages, there are increased numbers of macrophages within the subcapsular sinuses; with time, these progress to nodular or diffuse infiltrates of epithelioid macrophages and giant cells that replace much of the lymph node cortex and infiltrate the medullary sinusoids.
Of the other organs and tissues from which MAP can be isolated in cattle, focal granulomas attributable to MAP have only been described in the liver, hepatic lymph nodes, and very nodes. These nodules may be grossly visible as white foci 1-4 mm in diameter. Scattered lymph nodes elsewhere in the body, and liver, lung, spleen, and other organs, may contain focal granulomatous lesions in sheep and goats. Pigmented strains of MAP have been described in sheep, and in these cases the mucosa and lymph nodes may be discolored orange.
The organism is usually readily demonstrable by acid-fast staining within macrophages and giant cells in the lesions, especially in diffuse multibacillary forms of the disease (Fig. 1-166) . However, some clinical cases may have multifocal paucibacillary lesions in sheep, so an extensive search must be made for individual macrophages or giant cells bearing low numbers of acid-fast bacilli. Antibodies with well-defined specificity for MAP have allowed the development of immunohistochemical tests, but these are typically not helpful when there are very few organisms. Polymerase chain reaction techniques are useful for confirming the diagnosis in individual cases. Culture can be reliable to detect MAP in goats, because they tend to be infected with the cattle strain; however, culture of MAP from sheep is difficult because of its fastidious growth requirements.
Rhodococcus equi is an intracellular pathogen found in soil and as part of the normal intestinal flora of horses and other animals. This microorganism is a major pathogen of horses, and it also causes disease in pigs and cattle. In the past few years, R. equi pneumonia in HIV-infected or otherwise immunocompromised humans has become common.
R. equi isolated from foals and many recovered from humans carry an approximately 81-kb plasmid named pVAPA1037. This plasmid is essential for disease in horses; removal of this plasmid results in loss of the capacity of R. equi to replicate in macrophages. The genes on the virulence plasmid are divided into 4 groups, but only the genes within 1 of those groups, the PAI region, have been evaluated and reported to play significant roles in virulence. In particular, the rarely, the kidney and lungs. Granulomas are most common in the liver, and are found in portal triads or scattered throughout the hepatic parenchyma. Acid-fast bacilli are usually demonstrable in these lesions.
In sheep and goats, Johne's disease mainly occurs in adults and is characterized by chronic wasting; there may be breaks in the wool in sheep, and submandibular edema resulting from hypoproteinemia. Feces are often normal and may be soft and unpelleted, but overt diarrhea is unusual except intermittently in the terminal stages of disease. The reason for this is unknown, but may relate to the innately greater efficiency of electrolyte and fluid absorption in the colon of these species. In farmed deer, Johne's disease is clinically similar, but there are reports of disease in animals well under a year old.
In sheep, goats, and deer, a distinct age and dose susceptibility pattern has been described such that animals exposed to higher doses of MAP at earlier ages probably progress faster and develop more severe disease. Goats are thought to be more susceptible to MAP infection compared with sheep or cattle. Enteric gross lesions in sheep and goats tend to be more sporadic and subtle compared with cattle. Lesions appear to occur most commonly in the distal jejunum, and can range from focal or multifocal subtle lesions that are easily missed at postmortem examination, to diffuse and severe intestinal thickening with prominent transverse ridges and mesenteric adhesions. There may be lymphadenomegaly and lymphangitis as seen in cattle. Microscopically, there can be focal or multifocal accumulations of epithelioid cells and lymphocytes, with relatively few organisms; this is the paucibacillary form. Others may have a dense transmural intestinal inflammatory infiltrate with abundant organisms; this is the multibacillary form. Microscopic lesions also tend to be most severe in the distal jejunum and/or the ileocecal valve. Goats and sometimes sheep develop foci of tubercle-like caseation necrosis, often with mineralization and fibrosis in the mucosa, submucosa, serosa, and lymphatics of the intestine or in the lymph
Enterococcus spp. are gram-positive cocci, which are common inhabitants of the environment and gastrointestinal tract of clinically healthy humans and several animal species. However, some enterococci, mainly Enterococcus hirae and Enterococcus durans, may colonize extensively the mucosal surface of the small intestine in piglets, puppies, foals, calves, and suckling rats, in a manner similar to that of enteropathogenic E. coli and produce diarrhea. These bacteria adhere to the microvillus surface of enterocytes by fine filamentous pili. In tissue section they form a layer of small cocci crowded on the entire surface of epithelial cells, from the tips to the base of villi. There may be mild to moderate villus atrophy and some desquamating enterocytes. The organisms from rats have been described, on genetic grounds, as E. ratti, whereas those from piglets have been described as E. villorum or E. porcini, which may be synonyms. E. faecalis that had numerous virulence traits and was resistant to multiple antimicrobials was isolated from young kittens with enteritis, diarrhea and up to 15% mortality. These kittens had been given probiotics that contained enterococci.
Malabsorption associated with reduced brush border enzyme activity may explain diarrhea in all animal species. Although in spontaneous cases in piglets, Enterococcus is frequently associated with other pathogens, the organism isolated from foals produced diarrhea when inoculated alone into gnotobiotic pigs.
PAI-encoded, virulence-associated protein A (vapA) and its positive regulators (virR and ORF8) are critical for resistance to macrophage attack and for bacterial multiplication in vivo. A R. equi vapA knockout mutant is incapable of intracellular replication and unable to establish a persistent infection in severe combined immunodeficient mice. There are both virulent and avirulent strains in nature, and on farms where disease caused by R. equi is endemic, there is a much higher proportion of virulent forms. Virulence factors may not be necessary for production of disease in an immunocompromised host. R. equi is usually associated with suppurative bronchopneumonia of foals. Abdominal lesions are identified in ∼50% of foals with R. equi pneumonia that are presented for autopsy, and include any of the following, alone or in combination(s): pyogranulomatous enterotyphylocolitis, pyogranulomatous lymphadenitis of the mesenteric or colonic lymph nodes, large intra-abdominal abscesses, and peritonitis.
The development of intestinal lesions appears to be doserelated, in that experimental reproduction of the disease requires repeated oral infection. In natural disease, continual exposure to bacteria in swallowed respiratory exudate is probably an important source of infection in those animals with pneumonia.
Gross lesions may occur throughout the small and large intestines, but are usually most severe over Peyer's patches in small intestine, and in the cecum, large colon, and related lymph nodes (Figs. 1-167, 1-168) . Mucosal lesions consist of multifocal irregular, elevated, and crateriform lesions with central ulcers up to 1-2 cm in diameter, often covered by purulent or necrotic debris (see Fig. 1-167) . Edema of the wall of the gut may be severe. Mesenteric or colonic lymph nodes often are massively enlarged by edema and caseous or purulent foci that may obliterate the structure of the node. Occasionally, massively enlarged abscessed lymph nodes (see Fig. 1 -168) are found without evidence of concurrent enteritis or colitis.
Microscopically, infection seems to occur by penetration of the specialized epithelium over Peyer's patches or intestinal lymphoid follicles. An initial neutrophilic response occurs and erosions of the epithelium develop subsequently. Macrophages and neutrophils accumulate in the lamina propria. The macrophages contain aggregates of R. equi but do not destroy them. Later necrosis of lymphoid follicles occurs, and deep ulcers develop that contain masses of neutrophils,
Members of the family Chlamydiaceae are obligate intracellular parasites. The order Chlamydiales has been re-classified several times over the last decades. The latest revision led to the separation of the family Chlamydiaceae into the genera Chlamydophila and Chlamydia, with a total of 9 species, namely, Chlamydophila abortus, Chlamydophila pecorum, Chlamydophila psittaci, Chlamydophila pneumoniae, Chlamydophila felis, Chlamydophila caviae, Chlamydia trachomatis, Chlamydia suis, and Chlamydia muridarum. However, this division into 2 Chlamydiaceae genera has been widely criticized, and it was recently proposed that all Chlamydiaceae species should be grouped into a single Chlamydia genus. Among all the Chlamydiaceae species, only Chlamydia pecorum and C. suis are associated with enteritis, in cattle and pigs, respectively. Other syndromes associated with Chlamydiaceae in domestic animals include respiratory disease, polyarthritis, orchitis, hepatitis, conjunctivitis, abortion, and encephalomyelitis, discussed in appropriate chapters elsewhere in these volumes.
The intestinal tract is the natural habitat for C. pecorum. Most infections are probably inapparent, but the intestine may be an important portal of entry in the development of systemic infections leading to hepatitis, arthritis, encephalitis, and pneumonia in ruminants. Enteritis may accompany or presage these diseases, and occasionally C. pecorum causes severe enteric disease in calves. Also, asymptomatic calves with C. pecorum intestinal infections may suffer up to 48% reduction in growth rates. This is associated with increased conjunctival reddening, increased serum globulin, and decreased plasma albumin and insulin-like growth factor-1. Based on these results, it was suggested that suppression of chlamydial asymptomatic infections may be a major contributor to the growth promoting effect of feed-additive antibiotics.
Following oral infection, C. pecorum infects mainly the enterocytes on the tips of ileal villi. These cells are in the G 1 phase of the cell cycle, which is required by Chlamydia for multiplication. C. pecorum also infects other cells, including goblet cells, enterochromaffin cells, and macrophages, and the latter cells may transport the organisms systemically before being destroyed by them.
C. pecorum adsorbs to the brush border of enterocytes and enters the cell by pinocytosis. Following multiplication of organisms in the supranuclear region, the cells degenerate. C. pecorum is released into the gut lumen and the lamina propria, where it infects endothelial cells of lacteals, whence they are released and become systemic.
Gastrointestinal disease caused by C. pecorum is usually a problem of calves <10 days old, but it may affect older calves, and can produce recurrent diarrhea. Watery diarrhea, dehydration, and death are often accompanied by lesions, although not necessarily signs, of hepatitis, interstitial pneumonia, and arthritis. Gross lesions may occur in the abomasum and throughout the intestinal tract but are most consistent and severe in the terminal ileum. Mucosal edema, congestion, and petechiae, sometimes with ulceration, are usually observed. Serosal hemorrhages and focal peritonitis may occur. Histologically, chlamydial inclusions may be demonstrable with Giemsa, Jimenez, Macchiavello, or immunoperoxidase staining. Central lacteals and capillaries are dilated, and neutrophils and monocytes infiltrate the lamina propria. Occasionally, granulomatous inflammation occurs in the intestinal submucosa and extends into the mesentery and to the serosa,
Bacteroides fragilis is a non-spore-forming obligate anaerobe that is part of the normal enteric flora. Some enterotoxinsecreting strains have been associated with diarrhea in piglets, calves, lambs, foals, and humans. This enterotoxin is a protease, and probably damages the zonula adherens at the tight junction between enterocytes. Enterotoxigenic strains or cell-free culture filtrates cause secretion in ligated lamb or calf intestinal loops, and bacterial inocula cause diarrhea when administered orally to gnotobiotic piglets. Bacteria do not adhere to the surface. Enterocytes round up and exfoliate, with villus attenuation and crypt elongation and hyperplasia. Infiltration of neutrophils is common. Damage may be seen in both small and large intestines. Ultrastructurally, affected cells lose their intercellular interdigitations, microvilli are shortened or absent, and the terminal web is disrupted.
The genus Anaerobiospirillum, small spiral gram-negative bacteria, comprises 2 species, A. succiniciproducens and A. thomasii, which have been isolated from dogs and cats, although only a few studies have related them to diarrhea. In cats, ileocolitis has been associated with Anaerobiospirillum. Cats may be asymptomatic, lethargic, and anorexic, or have vomiting and diarrhea. Microscopically, exfoliated epithelial cells and neutrophils are in dilated crypts in the ileum and colon, and bacteria stained with silver can be found in the lumen of crypts, in goblet cells, and sometimes in the lamina propria. Septicemia may occur, and renal failure has been associated. infected adult insects that may accumulate in water containers. Insectivorous birds and bats are definitive hosts, which themselves become infected with N. risticii. Experimental infection has been produced with oral administration of infected insects and subcutaneous inoculation of N. risticii. All attempts to transmit the disease using ticks have failed. The disease may be highly variable. Many infected horses seem not to get sick. Others develop severe colic, subcutaneous edema, laminitis, and shock: mortality can be up to 30% in untreated cases. Abortions of pregnant mares have been attributed to N. risticii infection.
The incubation period in experimental infections is ∼9-14 days, and diarrhea begins 1-3 days after the onset of fever. Not all experimentally infected animals develop disease.
At autopsy of spontaneous cases, small vesicles are reported in the oral cavity, and epicardial hemorrhages and pulmonary congestion and hemorrhage, compatible with endotoxemia, are described. These are not reported in experimental cases, nor is laminitis. The lesions of the gastrointestinal tract are the most significant, in both spontaneous and experimental cases. In some animals there may be focal or more extensive erosions in the gastric mucosa, sometimes with overlying fibrinous exudate. Lesions in the small intestine are generally limited to segmental areas of mucosal congestion or hyperemia, with occasional focal ulcers or hemorrhage, and are much less consistent and severe than those in the cecum and colon. The content of the large bowel is abnormally fluid, and may have a brown or red-brown color, and foul odor. In the cecum and colon, there may be patches of hyperemia 5-10 cm in diameter, aggregates of small ulcers a few millimeters in diameter, and petechial hemorrhages. Sometimes the mucosa of the entire cecum is widely hyperemic. Ulcers and petechial hemorrhage are more severe and consistent in the right dorsal colon. The small colon is usually unaffected grossly.
Microscopic lesions are most consistent in the large intestine; similar changes may be evident in the small bowel. In areas of gross hyperemia, there is marked congestion and superficial hemorrhage in the mucosa. Associated with these lesions are superficial epithelial necrosis, erosion, and fibrin effusion. The mucosal surface is denuded, or perhaps covered by fibrinocellular exudate, and epithelium in the upper half of crypts is attenuated. Deeper parts of crypts are dilated and may contain necrotic epithelium and inflammatory cells. An abnormally intense mixed inflammatory cell population is in the lamina propria, and sometimes, the submucosa. Lymphoid tissue in the gut, mesenteric lymph nodes, and spleen is moderately involuted, compatible with the effects of the stress of systemic illness.
Organisms are not evident in hematoxylin and eosinstained tissue. They are visible in large colon, and less consistently, in cecum, small colon, and small intestine, with modified Steiner silver stain. They appear as small clusters of 10-15 fine brown dots, <1 µm in diameter, in the apical cytoplasm of epithelial cells deep in crypts, or as more numerous, smaller black structures distributed in the cytoplasm of macrophages in the periglandular lamina propria, or in a few glandular epithelial cells. Ultrastructurally, small dense elementary bodies may be found, alone or in small clusters in vacuoles in the cytoplasm of macrophages, mast cells, and crypt epithelium, or as morulae-aggregates of larger, more open organisms, in the same locations. N. risticii can be identified in feces or peripheral blood buffy coat by polymerase chain reaction, providing a more sensitive and specific means of diagnosis.
producing the peritonitis observed grossly. Crypts in the small and large intestine may be dilated, lined by flattened epithelium, and contain inflammatory exudate. The centers of lymphoid follicles in Peyer's patches are necrotic.
C. suis in swine has been associated with conjunctivitis, rhinitis, pneumonia, enteritis, reproductive disorders, and asymptomatic infections. C. suis has been recognized in the intestinal mucosa of swine, with approximately equal frequency in diarrheic and nondiarrheic animals. Enteric chlamydial infections of pigs with C. suis are frequent and often subclinical. After experimental inoculation of C. suis into gnotobiotic piglets, there was moderate diarrhea, anorexia, weakness, and body weight loss. Microscopic changes consisted of necrosis and exfoliation of enterocytes on the apical half of villi, resulting in mild to severe villus atrophy in the distal jejunum and ileum. Lymphangitis and perilymphangitis were also evident in affected gut. Chlamydial replication was particularly marked at 2-4 days postinoculation and primarily located in the small intestinal villus enterocytes. Further sites of replication included large intestinal enterocytes, lamina propria, submucosa, and the mesenteric lymph nodes. In weanling pigs, similar lesions, but no diarrhea, were induced.
This condition, also described as equine monocytic ehrlichiosis, equine ehrlichial colitis, and equine neorickettsiosis, was first defined clinically in 1979, and is characterized by fever, leukopenia, depression, loss of appetite, colic, diarrhea, and lameness. It is caused by Neorickettsia (formerly Ehrlichia) risticii, a member of the order Rickettsiales, which are obligate intracellular bacterial pathogens. Potomac horse fever typically occurs in the summer. It was first described in the Potomac river valley of Maryland, Virginia, and Pennsylvania but it is now found in most areas of the United States and Canada, with cases also reported in Brazil and Uruguay, where it has been known for many years as churrido. Considering the current distribution of the disease, the name Potomac horse fever is probably no longer appropriate, and the term equine neorickettsiosis has been proposed. Neorickettsia spp. replicate within the phagosome in the host cell, and use trematodes as hosts. The life cycle of the fluke includes freshwater snails from where it goes back into water, where it is ingested by the larval stages of several aquatic insects, including caddis flies and mayflies. The main mode of infection is most likely by accidental ingestion of tract; however, the rumen and omasum are the most common sites. Aspergillus tends to be most common in the abomasum. These organisms have a propensity to invade mucosal and submucosal veins, producing thrombosis and venous infarction. Characteristic gross lesions are focal or multifocal areas of edema and red-black discoloration caused by venous stasis and hemorrhage. Histologic lesions include mucosal to transmural necrosis of the gastrointestinal wall, and there may be a relatively mild inflammatory response to the fungi. Dissemination to the liver and more distant organs via the portal and systemic circulations is not uncommon.
Mycotic ileitis and colitis in cats (Aspergillus spp.) has been described, and may be associated with feline parvovirus infection or antibiotic therapy. Intestinal lesions can be subtle, particularly in the face of concurrent intestinal pathogens, but are hemorrhagic and necrotizing with a cellular immune response; dissemination to other organs can also occur and the lung appears to be the favored site in cats. Mycotic enteritis with dissemination is a rare sequel to canine parvovirus-2 enteritis in dogs.
The gastrointestinal tract is probably a common portal of entry for many sporadic, disseminated zygomycoses and aspergillosis in animals. Fungi may produce a localized granulomatous lesion in the Peyer's patches or be carried to the regional mesenteric lymph node while the mucosal lesion heals. The presence of zygomycete fungal hyphae in mesenteric lymph node granulomas of clinically normal feedlot cattle is recognized, and indicates that invasion by these agents across the intestinal mucosa does not lead invariably to systemic disease. Grossly, affected lymph nodes are variably enlarged with areas of necrosis and fibrosis evident on the cut surface. Histologically, there is granulomatous inflammation with numerous foreign body and Langhans-type giant cells. The lesions also contain areas of mineralization, variable degrees of fibrosis and PAS and/or GMS-positive fungal hyphae free or within the cytoplasm of giant cells. Asteroid bodies may form around Aspergillus spp. or zygomycetes.
Entomophthoromycosis involving the gastrointestinal tract is far less common and sporadic, but has been rarely reported in dogs. Basidiobolus ranarum has been associated with subcutaneous, respiratory, or intestinal infections involving the stomach and small intestine, whereas Condiobolus sp. has been more commonly associated with cutaneous or rhinofacial and nasopharyngeal lesions in humans, horses, dogs, and sheep. Histologically, there is granulomatous inflammation with thinwalled non- or poorly septate hyphal organisms.
Definitive diagnosis of mycotic lesions requires culture, which may be difficult, and molecular genetic identification of the isolate. Granulomatous lesions of the gut should be cultured for fungi as well as bacteria, to increase the frequency of an etiologic diagnosis. Mycotic lymphadenitis must be differentiated from a mycobacterial, actinomycotic, or nocardial lesion. A presumptive diagnosis may be based on morphologic characteristics of organisms in tissue sections. Immunochemical procedures using specific antibody may add to the confidence of a morphologic diagnosis. Njaa BL, et al. Gross lesions
Baird JD, Arroyo LG. Historical aspects of Potomac horse fever in Ontario (1924 Ontario ( -2010
Formerly referred to as phycomycosis, the term zygomycosis denotes infections caused by one of several genera of fungi in the class Zygomycetes, which is divided into the orders of Mucorales and Entomophthorales. The gastrointestinal mucosa is the main portal of entry; fungal invasion is a common sequel to many mucosal diseases and lesions, and it may be the precursor to systemic infection. Heavy fungal challenge, disruption of the normal flora, a primary local lesion, and/or lowered host resistance are probably required for establishment of mycotic disease in the gut. Spores are probably normally carried across the mucosa by macrophages, and only if host immunity is compromised in some way will they establish in the deeper tissues or become disseminated. The most common organisms associated with alimentary tract mycoses are zygomycetes of the family Mucoraceae (Lichtheimia, Mortierella, Mucor, Rhizomucor, and Rhizopus) ; other organisms that also may be involved include family Entomophthoraceae (Basidiobolus and Conidiobolus) and rarely Aspergillus sp., Candida spp., and Histoplasma capsulatum also may invade the wall of the alimentary canal; these are considered separately later in this chapter. Mucoraceae are characterized in their invasive mycelial form by broad (6-25 µm), coarse irregular hyphae, with infrequent septation and random branching, sometimes surrounded by an eosinophilic sleeve in tissue sections. Entomophthoraceae hyphae vary from 5 to 25 µm in diameter, with thin irregularly parallel walls, infrequent septa, and rare random branching. They are characteristically surrounded by a wide sheath or sleeve of eosinophilic material in tissue section. Aspergillus has relatively uniform narrow (3-6 µm) septate hyphae; it typically displays acute angled dichotomous branching.
Lesions occur anywhere in the gastrointestinal tra