Neoplastic/pathological and nonneoplastic/physiological hypercortisolism: Cushing versus pseudo-cushing syndromes

Abstract

The diagnosis of endogenous hypercortisolism (Cushing syndrome) is the most challenging problem in clinical endocrinology. Neoplastic (pathological) hypercortisolism is usually due to an ACTH-secreting neoplasm or autonomous cortisol secretion from benign or malignant adrenal neoplasms. Nonneoplastic (physiological) hypercortisolism is common in many medical disorders such as chronic alcoholism, chronic kidney disease, pregnancy, depression/neuropsychiatric disorders, and starvation. The clinical features of hypercortisolism may be apparent in both pathological and physiological hypercortisolism and present a significant diagnostic challenge. A careful history and good examination are usually the most helpful means to identify patients with nonneoplastic/physiological Cushing syndrome. Simple biochemical tests such as late-night salivary cortisol and the overnight 1 mg dexamethasone suppression test have a good negative predictive value and are recommended as first line diagnostic testing in suspected hypercortisolism. Secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may be required in some patients to confirm the presence or absence of neoplastic/pathological Cushing syndrome. This review describes the medical disorders and physiological conditions associated with chronic activation of the hypothalamic-pituitary-adrenal axis and provides a rational clinical and biochemical approach to distinguish them from patients with neoplastic/pathological Cushing syndrome.