Cushing's syndrome

Abstract

Cushing's syndrome results from prolonged exposure to inappropriately elevated plasma corticosteroid concentrations. The condition may be (a) ACTH-dependent due to ACTH therapy, pituitary-dependent bilateral adrenal hyperplasia (Cushing's disease) or the ectopic ACTH syndrome, or (b) non-ACTH-dependent, due to corticosteroid therapy, adrenocortical adenoma or carcinoma. Excluding the iatrogenic group, diagnosis of the syndrome rests upon the association of the clinical features shown by the patient and demonstration of absence of the normal circadian rhythm of plasma corticosteroids, absence of a corticosteroid response to an adequate degree of insulin-induced hypoglycaemia, and resistance to suppression of plasma or urinary corticosteroids after administration of a low dose of dexamethasone (2 mg/day for 48 hours). Differential diagnosis between the various causes of the syndrome is most reliably made by measurement of the plasma ACTH level, low or undetectable levels being found in patients with autonomous adrenocortical tumours while ACTH is present in the ACTH-dependent causes; plasma ACTH levels in excess of 200 pg/ml suggest a diagnosis of the ectopic ACTH syndrome rather than Cushing's disease. Significant suppression of plasma or urinary corticosteroid levels during administration of a high dose of dexamethasone (8 mg/day for 48 hours) is usually seen in patients with Cushing's disease but not in those with adrenocortical tumours or the ectopic ACTH syndrome. The immediate effects of the hypercortisolaemia are rapidly improved by total adrenalectomy in Cushing's disease and removal of unilateral or bilateral adrenal tumours if this is possible. Occasionally pituitary irradiation alone may suffice in Cushing's disease but should always be considered even if adrenalectomy is performed, since it appears to prevent the postadrenalectomy hyperpigmentation syndrome of Nelson. Replacement corticosteroid therapy (hydrocortisone and fludrocortisone) is necessary after total adrenalectomy. After unilateral adrenalectomy for an adrenal tumour supportive therapy is required, often for many months, until the opposite adrenal recovers from the inevitable atrophy. Either hydrocortisone or ACTH may be used. Treatment of the ectopic ACTH syndrome is often unavailing since the tumour producing the ACTH is frequently highly malignant. If possible the primary source should be removed after which plasma ACTH and corticosteroids may return to normal. If removal is not possible radiotherapy or chemotherapy may be used to give temporary relief; assay of plasma ACTH will provide a sensitive biochemical marker of the activity of the malignant disease and its response to therapy. Plasma corticosteroids can be effectively lowered using enzyme inhibitors such as metyrapone and aminoglutethimide, but this should be done under dexamethasone cover until the correct dose of inhibitor is discovered.