Clinical Manifestations of Cushing's Syndrome

Cushing’s syndrome is defined by a chronic excess of glucocorticoids. Because glucocorticoid receptors are present in most cells of the body, that excess produces a wide and variable set of manifestations, and the variability itself is part of the clinical problem: most individual findings are common in the general population, so the syndrome is recognised by the pattern and not by any single symptom.

The table lists the features with which patients present and how often each occurs.

Non-specific and specific features

The majority of the signs and symptoms seen in Cushing’s syndrome are non-specific, such as hirsutism with frontal balding, diastolic hypertension and depression. Because they are so common on their own, clinical suspicion should be considered when several of them are present simultaneously at an unexpected age — for example, osteoporosis in a young adult.

A few features are specific enough to be more useful. These are fragility and thinning of the skin, easy bruising with broad lesions larger than 1 cm, and proximal myopathy.

What the excess does to protein and fat

The most prominent features of Cushing’s syndrome are related to the increase of lipolysis (breakdown of fat stores) and protein catabolism (breakdown of body protein). Cortisol drives the liver to make glucose from amino acids, so protein is broken down to supply them: muscle breaks down, producing the proximal myopathy (weakness of the muscles near the trunk) and the weakness and tiredness in the table, and the same process thins the dermis, which explains the skin fragility, the purple striae and the easy bruising. Bone matrix is protein too, so protein catabolism contributes to the fractures.

Fat, at the same time, is redistributed to the trunk, the face and the dorsocervical region, so weight gain is accompanied by a round face and truncal obesity rather than by uniform fat accumulation.

Not every feature comes from catabolism. Hirsutism (excess hair growth in a male pattern), acne and female balding follow a different route. In ACTH-dependent disease and ectopic carcinoma, hyperandrogenism is common because the high ACTH also drives adrenal androgen production alongside cortisol; in ACTH-independent disease there is mostly only the excess glucocorticoid.

Mineralocorticoid effects when cortisol is very high

Protein loss and androgen excess do not account for every feature: some come from cortisol acting on a receptor that normally belongs to aldosterone. Cortisol and aldosterone both activate the mineralocorticoid receptor, the receptor through which aldosterone retains sodium and loses potassium. The kidney normally protects that receptor with the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts cortisol to inactive cortisone before it can act. When cortisol production is high enough, the enzyme can no longer keep up, cortisol escapes inactivation and exerts mineralocorticoid effects. These are hypokalemia (low serum potassium), with a serum potassium level less than 3.3 mmol/l in more than 70% of cases of ectopic ACTH, together with diastolic hypertension and edema. The mineralocorticoid effect appears when the urine level of cortisol is more than 4100 nmol/day.

Suppression of other pituitary axes

Beyond the mineralocorticoid receptor, high cortisol also acts centrally on the hypothalamus and pituitary. It suppresses the gonadotropins (the pituitary hormones that drive the gonads), producing hypogonadotropic hypogonadism with amenorrhea, hypogonadism and an irregular menstrual cycle, and it suppresses the hypothalamic-pituitary-thyroid (HPT) axis, giving a low level of TSH (thyroid-stimulating hormone).

Changes in blood cells

Cortisol also changes the blood count. A raised white cell count, or leukocytosis, can occur in patients with Cushing’s syndrome because neutrophils are demarginated from the vascular walls into the circulating pool, that is, released from the vessel wall where they had been resting.

The ectopic presentation and its diagnostic hints

Mostly, the signs and symptoms of Cushing’s syndrome do not separate the different etiological causes, but a few hints point toward ectopic ACTH, meaning ACTH made by a tumour outside the pituitary. These are hyperpigmentation of the knuckles and rapid progression of edema, hypokalemia and hypertension. The hyperpigmentation is a consequence of POMC (pro-opiomelanocortin), the precursor from which ACTH is cleaved: alongside ACTH, the tumour processes peptides that stimulate the skin’s melanocytes, so a tumour that produces large amounts of POMC darkens the skin.

Patients with ectopic ACTH-dependent Cushing’s syndrome mostly present with severe and rapidly progressive signs and symptoms, such as anorexia, myopathy, glucose intolerance and hypokalemic alkalosis. The combination of rapid deterioration, hypokalemic alkalosis, knuckle hyperpigmentation and clinical signs of hypercortisolemia should trigger a high suspicion of small cell lung carcinoma with ACTH secretion or high-grade bronchial carcinoma.