July 7, 2020
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? Cushing's

Cushings syndrome may be ACTH dependent, and due to a pituitary tumour or an ectopic source, or ACTH independent and due to an adrenal tumour.

There are two different patterns of ACTH dependent Cushing's syndrome. Cushing's disease is due to a pituitary adenoma secreting ACTH. It is an indolent process which presents with a plethora of signs: typical facies, obesity, proximal myopathy, secondary diabetes, hypertension, hypogonadism, osteoporosis, purple striae, hirsuties and acne, ankle oedema and buffalo hump. Following the diagnosis, the disease can often be retrospectively detected on old photographs where clinical signs may have been present for many years.

Ectopic ACTH can be secreted by tiny (and often unlocalisable) benign tumour which mimics the natural history of a pituitary adenoma. However, secretion from malignant tumours results in a metabolic condition of excessive mineralocorticoid action with predominant muscle weakness due to hypokalaemic alkalosis with plasma potassium often < 2.0 mmol/L. These patients are usually thin and deeply pigmented and have an extremely poor prognosis with a 50% survival of only 6 weeks.

Cushing's disease is one of the most difficult problems in clinical endocrinology. It is frequently suspected but rarely diagnosed. There are two phases: the diagnosis of hypercortisolism and secondly the localisation of the source. For the former, we propose an overnight dexamethasone suppression test with/without 24 hour urinary cortisol as screening tests. This has a relatively high false positive rate but very low false negative. The localisation of the source of ACTH is extremely difficult and it is probably appropriate to refer patients to an endocrinologist when non-suppressible cortisol has been demonstrated; and for this reason we have not included a protocol for the low dose dexamethasone suppression test. Following the confirmation of hypercorticolism, adrenal causes are best detected by imaging techniques.

If the diagnosis is strongly suspected and the screening tests are negative, the diagnosis should not be discounted as there are well recorded cases of cyclical Cushing's disease with episodes of clinical and biochemical normality between episodes of typical clinical and biochemical disease.

Diagnostic tests for Cushing's disease




UFC (urinary free cortisol)



1mg Dexamethasone Suppression test





False positives

False negatives


Physical stress eg trauma, exercise, malnutrition
Mental stress eg depression, alcohol or drug abuse/withdrawal
Metabolic eg raised CBG, glucocorticoid resistance, complicated diabetes

Renal failure

1mg Dexamethasone Suppression test

Severe systemic illness,
Renal failure on dialysis,
Chronic alcohol abuse,
Old age,
Anorexia nervosa,
Hepatic enzyme inducing drugs eg rifampicin, phenytoin,
Drugs which increase CBG eg HRT, oral contraceptives, tamoxifen
Malignancy (Jenkins et al BJC 1999)

very rarely in patients with Cushing's disease - if clinical suspicion is high continue investigating!


  • Wood P, Barth JH, Freedman DB, Perry L, Sheridan B. Evidence for the low dose dexamethasone suppression test to screen for Cushing’s syndrome - recommendations for a protocol for UK biochemistry laboratories. Ann Clin Biochem 1997;34:222-229.
  • Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, Ennis R, Erwin PJ, Montori VM. Accuracy of Diagnostic Tests for Cushing’s Syndrome: A Systematic Review and Metaanalyses. J Clin Endocrinol Metab 2008;93:1553-1562.
  • Kaye TB, Crapo L. The Cushing Syndrome: an update on diagnostic tests. Ann Intern Med 1990;112:434-444.
  • Jenkins PJ, Sohaib SA, Trainer PJ, Lister TA, Besser GM, Reznek R. Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy. Br J Cancer 1999;80:1815-9.
  • Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab 2008;93:1526-1540.

JHB 29 Dec 2008


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