Group 5: PH with unclear or multifactorial etiologies

Group 5.1 Hematologic disorders 
PH has been reported in chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia [79,80]. Several mechanisms may be implicated in PH associated with chronic myeloproliferative disorders including high cardiac output, asplenia, direct obstruction of pulmonary arteries by circulating megakaryocytes [81], CTEPH [82], portal PH, and congestive heart failure. Splenectomy as a result of trauma or as a treatment for hematologic disorders may increase the risk of developing PH [83]. As described above, dasatinib use may be one cause of PAH, particularly in chronic myeloid leukemia [23].

Group 5.2 Systemic disorders 
The second subgroup includes systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis or vasculitis.
PH is a well recognized complication of sarcoidosis [84], with a reported prevalence of 1–28% [84]. PH is multifactorial and usually attributed to the destruction of capillary bed by the fibrotic process and/or the result of chronic hypoxemia [85]. However, the severity of PH is frequently out of proportion to the degree of parenchymal lung disease and blood gas abnormalities, suggesting specific pulmonary vascular involvement [86]. Such mechanisms may include extrinsic compression of large pulmonary arteries by lymph node enlargement, and granulomatous infiltration of the pulmonary vasculature, especially the pulmonary veins, which sometimes mimic PVOD [87].
Pulmonary Langerhans cell histiocytosis is an uncommon cause of infiltrative and destructive lung disease. Severe PH is a common feature in patients with end stage disease [88] and PH in these patients is usually related to chronic hypoxemia and/or abnormal pulmonary mechanics. Histopathologic examination has shown severe diffuse pulmonary vasculopathy involving predominantly intralobular pulmonary veins and, to a lesser extent, muscular pulmonary arteries [89].
Lymphangioleiomyomatosis is a rare multisystem disorder predominantly affecting women, characterized by cystic lung destruction, lymphatic abnormalities, and abdominal tumors. PH is relatively uncommon in patients with lymphangioleiomyomatosis [90]. Recently, a series of 20 cases of lymphangioleiomyomatosis associated PH has been reported showing that PH is usually moderate in this setting and associated with pulmonary function impairment [91].
Neurofibromatosis type 1, also known as von Recklinghausen’s disease, is an autosomal-dominant disease. The disease is occasionally complicated by systemic vasculopathy. A series of cases of PH have been reported in the setting of Neurofibromatosis type-1 [92].

Group 5.3 Metabolic disorders 
PH has been reported in a few cases of type Ia glycogen storage disease, a rare autosomal-recessive disorder caused by a deficiency of glucose-6-phosphatase [93-95]. The mechanisms of PH are uncertain but portocaval shunts, atrial septal defects, severe restrictive pulmonary function defects or thrombosis are thought to play a role. In one case, autopsy findings revealed the presence of plexiform lesions [96].
Gaucher’s disease is a rare disorder characterized by a deficiency of lysosomal B glucosidase, which results in an accumulation of glucocerebroside in reticuloendothelial cells. In a study of 134 patients with Gaucher’s disease who were systematically screened by echocardiography, PH was not uncommon [97]. In this setting, several potential mechanisms for PH have been suggested, including interstitial lung disease, chronic hypoxemia, capillary plugging by Gaucher cells and splenectomy [97,98].
The association between thyroid diseases and PH has been reported in some studies [99]. A prospective study of 63 consecutive adult patients with PAH found a prevalence of autoimmune thyroid disease, including both hypothyroidism and hyperthyroidism, in 49%, suggesting that these conditions may share a common immunogenetic susceptibility [100].

Group 5.4 Miscellaneous conditions 
The last subgroup includes a number of miscellaneous conditions, including tumoral obstruction, fibrosing mediastinitis or chronic renal failure on dialysis.
A progressive obstruction of proximal pulmonary arteries leading to PH may be observed in tumor obstruction when a tumor grows into the central pulmonary arteries with additional thrombosis. Such cases are due principally to pulmonary artery sarcomas, which occur rarely but are usually rapidly fatal [101-103]. The differential diagnosis with CTEPH can be difficult and CT angiography may be useful to differenciate an obstruction by tumor or thrombotic material. Occlusion of the microvasculature by metastatic tumor emboli represents a cause of rapidly progressive PH.
Fibrosing mediastinitis have been mainly reported in sarcoidosis, tuberculosis, histoplasmosis and after radiotherapy. Fibrosing mediastinitis may be associated with severe PH due to compression of both pulmonary arteries and veins.
Lastly, PH has been reported in patients with end-stage renal disease maintained on long-term hemodialysis. Based on echocardiographic studies, the prevalence of PH in this patient population is estimated up to 40% [104]. PH in these patients may be explained by high cardiac output (resulting from the arteriovenous access, anemia and fluid overload) and potential diastolic and systolic left heart dysfunctions. Furthermore, hormonal and metabolic modification associated with end-stage renal disease might lead to dysfunction of normal pulmonary vascular tone.