Cushing's Syndrome

Cushing’s syndrome is the clinical state produced by prolonged exposure to excess glucocorticoid, from any source. The distinction that organizes everything else is whether the excess comes from outside the body or inside it.

Exogenous Cushing’s syndrome is by far the commonest cause. Prolonged treatment with corticosteroids — oral, but also inhaled, topical and injected at sufficient dose — produces the full picture while suppressing the body’s own axis. This matters clinically: the adrenal glands atrophy, and abrupt withdrawal can precipitate an adrenal crisis.

Endogenous Cushing’s syndrome is rare, and divides by whether ACTH is driving it:

• ACTH-dependent (about 80%). Cushing’s disease — a pituitary corticotroph adenoma — accounts for most of these. The term is specific: Cushing’s disease means the pituitary cause, while Cushing’s syndrome means the state from any cause. Ectopic ACTH secretion, classically from small cell lung carcinoma or a bronchial carcinoid, is the other route and tends to present more abruptly and severely.
• ACTH-independent (about 20%). An adrenal adenoma or carcinoma autonomously secreting cortisol, with ACTH suppressed.

The clinical features follow directly from what cortisol does. It is catabolic in peripheral tissue and lipogenic centrally, which produces the characteristic redistribution of fat to the trunk, face and dorsocervical region alongside wasting of the limbs. It breaks down protein, thinning skin and weakening muscle and bone. It antagonizes insulin, raising blood glucose. At high concentrations it saturates the enzyme that normally protects the renal mineralocorticoid receptor, so it acts like aldosterone — causing sodium retention, hypertension and potassium loss. It also suppresses immune function and impairs wound healing.

Onset is usually insidious, and comparing old photographs is often more revealing than examination.

Weight gain is central, with the limbs comparatively spared; the face becomes rounded and plethoric, and a dorsocervical fat pad develops. The skin becomes thin and bruises easily, heals poorly, and develops wide purple striae — over 1 cm and violaceous, distinguishing them from ordinary stretch marks. Proximal myopathy is the most discriminating physical sign: difficulty rising from a chair or climbing stairs without using the arms.

Other features include hypertension, glucose intolerance or frank diabetes, osteoporosis with fragility fractures, and susceptibility to infection. In women, hirsutism, acne and menstrual irregularity are common. Psychiatric disturbance is frequent and often underestimated — depression, irritability, emotional lability, insomnia, and occasionally frank psychosis. Children present with growth arrest alongside weight gain, a combination that is otherwise unusual and should always prompt investigation.

Marked hyperpigmentation suggests very high ACTH, and points toward an ectopic source.

Diagnosis proceeds in two distinct stages, and conflating them causes most of the confusion: first establish that cortisol excess exists, then establish where it comes from.

Confirming the excess. A careful drug history comes first, since exogenous steroid is the commonest cause and requires no further biochemistry. Screening then uses at least two of: late-night salivary cortisol, which detects loss of the normal nocturnal trough; 24-hour urinary free cortisol, repeated; and the overnight 1 mg dexamethasone suppression test, in which failure to suppress is abnormal.

Finding the source. Plasma ACTH separates the two branches — suppressed ACTH indicates an adrenal source and directs imaging to the adrenals; normal or raised ACTH indicates a pituitary or ectopic source. Pituitary MRI, high-dose dexamethasone suppression, CRH stimulation, and inferior petrosal sinus sampling are used to distinguish pituitary from ectopic disease.

Pseudo-Cushing’s states — severe depression, alcohol excess, poorly controlled diabetes, obesity and pregnancy — produce overlapping biochemistry and are a common source of false positives. They are the reason screening tests are repeated and combined rather than acted on singly.

Untreated cortisol excess carries substantial cardiovascular risk through hypertension, diabetes, dyslipidemia and a prothrombotic state, and venous thromboembolism is notably increased. Osteoporosis and vertebral fracture are common and may be the presenting problem. Immunosuppression raises the risk of opportunistic infection. Depression and cognitive impairment often persist after biochemical cure.