Cushing Syndrome

Cushing syndrome results from prolonged exposure to excess glucocorticoid, whether from an endogenous source or, most commonly overall, from exogenous corticosteroid administration.

Exogenous, iatrogenic Cushing syndrome from therapeutic corticosteroid use is by far the most common cause encountered in general clinical practice, and should always be actively considered and excluded through careful medication history before pursuing investigation for an endogenous cause.

Endogenous causes are subdivided by whether the process is ACTH dependent or ACTH independent. ACTH dependent causes include a pituitary corticotroph adenoma (Cushing disease, the most common endogenous cause) and ectopic ACTH secretion from a non-pituitary tumor, classically small cell lung cancer or a bronchial carcinoid, among others (see Lung Cancer entry).

ACTH independent causes arise from autonomous cortisol secretion by the adrenal gland itself, most commonly an adrenal adenoma, less commonly adrenal carcinoma or bilateral adrenal hyperplasia.

The clinical features of Cushing syndrome reflect the widespread metabolic and tissue effects of chronic glucocorticoid excess, and tend to be more specific and discriminating the more centrally they relate to fat redistribution and catabolic tissue effects, rather than the more common and less specific features shared with many other conditions.

Central, more discriminating features include truncal obesity with relatively spared limbs, a rounded, plethoric facial appearance (moon face), a dorsocervical fat pad (buffalo hump), and, most specifically, wide, purple striae (typically over the abdomen), proximal muscle weakness from catabolic muscle wasting, and easy bruising with thin, fragile skin.

Less specific but common features include hypertension, glucose intolerance or frank diabetes, weight gain, menstrual irregularity, hirsutism (particularly when there is a significant adrenal androgen contribution), acne, and psychiatric disturbance, ranging from irritability and mood lability through to significant depression or, less commonly, psychosis.

Osteoporosis with an increased fragility fracture risk is a recognized complication of chronic glucocorticoid excess of any cause (see Osteoporosis entry), as is an increased susceptibility to infection.

Before pursuing any biochemical workup, exogenous corticosteroid use, whether oral, topical, inhaled, or injected, must be carefully and specifically excluded through history, since this remains the most common overall cause and, if present, obviates the need for further endogenous workup (beyond managing the exogenous exposure itself).

Screening for endogenous Cushing syndrome uses one or more of several tests, given that no single test has perfect sensitivity and specificity in isolation. The overnight low dose dexamethasone suppression test (1 mg dexamethasone given at night, with cortisol measured the following morning) relies on the principle that a normal hypothalamic pituitary adrenal axis will suppress cortisol production in response to the exogenous steroid, whereas this suppression fails to occur in Cushing syndrome.

24 hour urinary free cortisol, collected over multiple days for reliability, provides an integrated measure of cortisol production. Late night salivary cortisol exploits the loss of the normal diurnal cortisol rhythm in Cushing syndrome, where cortisol should normally be at its lowest in the late evening.

Once biochemical confirmation of endogenous hypercortisolism is obtained, plasma ACTH is measured to distinguish ACTH dependent from ACTH independent causes: a low or suppressed ACTH points toward a primary adrenal cause, while a normal or elevated ACTH points toward a pituitary or ectopic source.

Further localization testing depends on this ACTH result. For ACTH dependent disease, pituitary MRI looks for a corticotroph adenoma, though small microadenomas can be difficult to visualize and, where the diagnosis remains uncertain or pituitary imaging is negative despite biochemical evidence of a pituitary source, inferior petrosal sinus sampling provides more definitive localization by comparing ACTH levels sampled directly from the venous drainage of the pituitary against peripheral levels.

Where ectopic ACTH secretion is suspected, CT chest, abdomen, and pelvis, and, increasingly, specific functional imaging, are used to search for the causative tumor, commonly in the lung.

For ACTH independent disease, CT or MRI of the adrenal glands identifies the causative adrenal lesion.

Differentials include the pseudo-Cushing states, in which cortisol dysregulation occurs secondary to another condition, such as significant alcohol excess, severe depression, or poorly controlled obesity, and can produce a biochemical and even some clinical overlap with true Cushing syndrome, requiring careful clinical correlation and, sometimes, specialist input to distinguish.

Exogenous, iatrogenic Cushing syndrome is managed by minimizing corticosteroid exposure to the lowest effective dose for the underlying condition being treated, and, where feasible, gradually tapering rather than abruptly stopping, given the risk of adrenal insufficiency from suppression of the patient's own hypothalamic pituitary adrenal axis during prolonged exogenous steroid exposure (see Addison Disease entry for further detail on this specific risk).

Cushing disease, from a pituitary corticotroph adenoma, is treated primarily with transsphenoidalsurgical resection of the adenoma, offering the best chance of cure.

Where surgery fails to achieve remission, or is not feasible, options include repeat surgery, pituitary directed radiotherapy, medical therapy to reduce cortisol production or block its effect (including steroidogenesis inhibitors such as metyrapone or ketoconazole, and, in refractory cases, bilateral adrenalectomy as a more definitive but more invasive option).

Ectopic ACTH secretion is treated primarily by identifying and, where possible, resecting the causative tumor, alongside medical cortisol lowering therapy while this is being pursued or where the tumor is not resectable, following a broadly similar approach to that used for medically managing Cushing disease.

Adrenal causes of Cushing syndrome are treated with surgical adrenalectomy of the affected gland (unilateral for an adenoma or carcinoma, with the approach to bilateral hyperplasia individualized), with careful attention to the need for glucocorticoid replacement postoperatively, since the contralateral, previously suppressed adrenal gland requires time to recover normal function.

Complications of established Cushing syndrome, including hypertension, diabetes, and osteoporosis, require their own specific, concurrent management following the principles detailed in the relevant separate entries, and often improve, though not always completely, once the underlying hypercortisolism is corrected.

Referral: endocrinology for all suspected cases, given the complexity of the diagnostic pathway; neurosurgery for pituitary directed surgery; specialist adrenal or endocrine surgery for adrenal causes.