Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome

Abstract

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism due to an ACTH-secreting tumor or to autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Non-neoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for over fifty years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have non-neoplastic hypercortisolism—one due to a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate (dDAVP) stimulation test to aid in distinguishing neoplastic from non-neoplastic hypercortisolism.

Subtyping of Cushing’s Syndrome: A Step Ahead

“…Actually, the number of patients with obesity, cardiometabolic dysfunction, low bone density or fractures, adrenal nodules and psychiatric disorders is increasing, therefore the diagnosis of NNH has emerged as an important topic [6]. The overlap with these disorders/conditions, that may also be associated with abnormalities in the HPA axis, increases the uncertainty in making the correct diagnosis.…”

“…The overlap with these disorders/conditions, that may also be associated with abnormalities in the HPA axis, increases the uncertainty in making the correct diagnosis. Imaging studies should not be used alone to confirm the presence or absence of neoplastic hypercortisolism [6], due to the large number of patients with pituitary or adrenal incidentaloma [46,47].…”

“…spheres that can alter HPA axes regulation, and 11β-HSD1 induction secondary to alcoholic liver disease with increased conversion of cortisone to cortisol [6,50]. Diabetes mellitus type 2 is associated with hypercortisolism due to central HPA axis activation, increased 11β-HSD1 expression in adipose tissue, hippocampus damage due to glycemic decompensation.…”

“…Furthermore, in some cases non-neoplastic hypercortisolism (NNH, previously known as pseudo-Cushing) should be considered in the differential diagnosis of hypercortisolism, before the characterization of ACTH, and especially in milder forms. In clinical practice, it is common to suspect that the peculiar clinical features of hypercortisolism in some patients can be secondary to a sustained or intermittent activation of the hypothalamic-pituitary-adrenal (HPA) axis caused by psychological diseases (major depression, eating disorders), metabolic conditions (obesity, polycystic ovary syndrome, poorly controlled diabetes mellitus), as well as physical (starvation/chronic intense exercise) or chemical (alcohol) stimuli [6,7]. In these cases of NNH, the HPA activation is not secondary to a neoplasia; nonetheless, their resulting biochemical features after first line screening tests can be indistinguishable from neoplastic hypercortisolism.…”

Accuracy of the 10 μg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis

“…Evaluation of patients with suspected hypercortisolism is one of the most challenging investigations in endocrinology ( 1 ). This is due to the intermittent activation of the dynamic hypothalamic–pituitary–adrenal (HPA) axis, which results in clinical and biochemical characteristics that are indistinguishable between neoplastic and non-neoplastic forms of hypercortisolism.…”