Subclinical CD: a conundrum
Hypercortisolemia resultant from an aberrant HPA axis can be mild, which leads to challenges with appropriately diagnosing the patient. As in most cases of subtle disease, definition of ‘subclinical’ Cushing’s syndrome (SCS), or endogenous hypercortisolemia, is somewhat ambiguous, controversial, and ill-defined. The term, almost invariably related to adrenocortical tumors, is used to describe mild hypercortisolism in the absence of the cardinal features such as violaceous striae and proximal myopathy that are commonly observed in overt Cushing’s syndrome.
Surprisingly, SCS is not a term used to call attention to the subtle hypercortisolemia commonly observed following adenomectomy for CD. Furthermore, to the best of our knowledge, there are no controlled studies focusing on the consequences of subtle or intermittent hypercortisolism in patients who have undergone surgery. This knowledge gap may, in part, be as a result of difficulties inherent to the diagnosis of mild forms of CD in the early post-operative period. Similarly, the lack of a standardized approach to evaluate the HPA axis in patients with CD following surgery may be partially due to the inconsistency and unreliability of diagnostic tests under different circumstances or severity of disease. This phenomenon, or spectrum effect, is used to emphasize this concept in which the sensitivity and specificity of tests are not fixed, but rather vary with the severity or temporal state of the disease being considered [37].
Somatic consequences of mild hypercortisolemia may be subtle or subclinical, but over time will be additive and inexorable. Evidence implies that patients may develop complications associated with long-term exposure to hypercortisolemia, such as diabetes mellitus, metabolic disturbances, and obesity [38]. More importantly, patients with SCS caused by hormonally active adrenal tumors may exhibit slow, long-term progression of these symptoms if not surgically treated. A retrospective study involving >100 patients suggested that treating SCS by means of laparoscopic adrenalectomy may improve blood pressure control, weight control, and carbohydrate metabolism [39].
In summary, persistent, subtle, autonomous ACTH secretion that engenders mild, yet continually elevated levels of cortisol is difficult to diagnose due to the presence of interfering clinical conditions, such as obesity and depression, which are more prevalent in the general population, and heterogeneity in severity or temporal stage of the disease among subgroups of examined patients. This problem can be mitigated by developing a structured and standardized approach to the evaluation of patients who undergo pituitary surgery for CD.