Causes of Cushings Syndrome

See also Cushing's diagnosis and treatment.

Diagnoses of ectopic ACTH secretion

From Isidori 2007

ACTH levels in ACTH-dependent and -independent Cusghing's

ACTH levels in ACTH-dependent and independent Cushing's

From Klose, via Findling 2006

ACTH dependent Cushing's syndrome

Endogenous ACTH independent Cushing's syndrome

15-20% of all cases of Cushing's syndrome.

ACTH usually suppressed but occasionally low-normal.

UNILATERAL - adrenocortical adenomas and carcinomas

90% of cases of ACTH-independent CS are due to unilateral disease. Of these, about 60% are adenomas and 40% carcinomas.

Genetics. Carcinomas (ACC) may be associated with Li-Fraumeni syndrome (TP53 mutation) or sporadic somatic TP53 mutations. ACC may be associated with Beckwith-Wiedemann syndrome. Adenomas and ACC may be associated with MEN1 and Familial Adenomatous Polyposis.

BILATERAL - McCune-Albright Syndrome

Cushing's syndrome due to bilateral adrenal hyperplasia has very rarely been described in McCune-Albright syndrome. (Pituitary Cushing's disease has never been described).

BILATERAL - Primary Pigmented Nodular Adrenocortical Disease (PPNAD)

Most commonly part of the Carney complex. More than 90% of reported PPNAD are in Carney complex. PPNAD was clinically apparent in about 1/3 of known Carney complex cases, though found at autopsy in all cases.

Pathology. Small to normal-sized glands, often containing black or brown nodules, surrounded by atrophic cortex. Atrophy is pathognomonic, and reflects autonomous function of nodules.

Atypical CS. Often young adult patients. Sometimes asthenic habitus, with short stature, severe osteoporosis, muscle and skin wasting. Near-normal 24-hr UFC, or sometimes cyclical hypercortisolism. Paradoxical increase in UFC seen during second phase (high dose dex) of Liddle's test, thought to be due to increased GR-expression.

Genetics. 65% have mutations in PRKAR1A. PDE11A mutations are also seen.

BILATERAL - ACTH-independent macronodular adrenal hyperplasia (AIMAH)

About 10% of ACTH-independent CS (i.e. 1-2% of all CS cases) is due to bilateral disease.

Possible autosomal dominant inheritance. Not entirely clear because not long recognised - previously only sporadic cases recognised, but clear kindreds now reported.

Bimodal age distribution. Most in 5th and 6th decades. A subset present in infancy or childhood, usually as part of the McCune-Albright syndrome.

Equal gender distribution - compared with female preponderance in most Cushing's syndromes.

Subtle features of Cushing's - sometimes subclinical.

Gross adrenal enlargement - typically >60g and sometimes >200 g. Cortisol excess due to increased adrenocortical mass, as steroidogenesis is relatively inefficient.

Association with familial syndromes. In one series, bilateral adrenal hyperplasia seen in 7 of 33 MEN1 patients. Reports also in Familial Adenomatous Polyposis.

Aberrant hormone receptors. In most AIMAH and some adenomata, cortisol secretion is regulated by expression of membrane-bound hormone receptors that have become coupled to steroidogenesis. Theoretically, these may be identified clinically and targeted medically:

Aberrant receptor In vivo screening Medical treatment
GIP Mixed meal (not stimulated by IV glucose) Octreotide
Vasopressin Upright posture or administration of vasopressin V1a receptor antagonist
β-adrenergic Upright posture β-blockers
LH/hCG GnRH agonist Long-acting GnRH agonist
5-HT4 5-HT4 agonists (cisapride, metoclopramide) 5-HT4 antagonists
Angiotensin Upright posture ARB

Bilateral adrenalectomy is the recommended treatment. Unilateral adrenalectomy has been tried with some success, i.e. clinical improvement and normalization of 24-UFC but continued abnormal circadian rhythm.

Medical treatments. Theoretically, as described in the table above once aberrant receptor identified. Alternatively, inhibitors of steroidogenesis e.g. ketoconazole, metyrapone, mitotane.