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Disorders of the adrenal cortex 

Disorders of the adrenal cortex

Disorders of the adrenal cortex

P.M. Stewart



Diagnosis of Cushing’s syndrome and primary aldosteronism—minor alterations as recommended by recent Endocrine Society guidelines.

Updated on 30 Nov 2011. The previous version of this content can be found here.
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date: 23 April 2017

Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma: (1) mineralocorticoids—aldosterone, deoxycorticosterone; secreted in low amounts (100–150 µg aldosterone/day) from the zona glomerulosa, mainly under the control of angiotensin II; enhance uptake of sodium principally in the colon and kidney tubule by binding to receptors whose specificity for mineralocorticoids is established in these tissues by expression of 11 β‎-hydroxysteroid dehydrogenase 2, which converts cortisol to inactive cortisone; (2) glucocorticoids—cortisol, corticosterone; secreted in larger amounts (10–20 mg cortisol/day) from the zona fasciculata in response to stimulation by ACTH; have wide-ranging effects mediated by glucocorticoid receptors; and (3) sex steroids—principally dehydroepiandrosterone (DHEA) and its sulphated derivative (DHAS).

Classical endocrine feedback loops control secretion of these hormones: (1) aldosterone-induced retention of sodium inhibits secretion of renin; (2) cortisol inhibits secretion of both corticotropin-releasing factor (CRF) from the hypothalamus and ACTH from the pituitary.

Adrenocortical diseases are relatively uncommon, but their ease of diagnosis and the availability of effective treatment contribute to their importance in clinical practice. Hormonal deficiency or excess is usually the result of abnormal secretion, but similar functional defects may be caused by deranged metabolism of corticosteroids or by defective receptors. With increasing use of radiological investigations a frequent diagnosis is a patient with an underlying incidental tumour (‘incidentaloma’) of the adrenal: these are usually nonfunctional and benign.

Glucocorticoid excess

Cushing’s syndrome may be (1) ACTH-dependent—usually due to a pituitary adenoma (Cushing’s disease), but sometimes to nonpituitary tumours producing ACTH (most commonly small-cell carcinoma of the bronchus); (2) ACTH-independent—most often adrenal adenoma (rarely carcinoma).

Clinical features—typical presentation is with ‘classical’ manifestations of centripetal obesity, moon face, hirsutism, and plethora, with signs (when present) that best distinguish from simple obesity being bruising and muscle weakness (typically proximal).

Diagnosis of the presence of Cushing’s syndrome—this can be confirmed by finding (1) elevated 24-h urinary free cortisol; and/or (2) raised midnight salivary/plasma cortisol; and/or (3) impaired plasma cortisol suppression (09.00 h sample) in response to a low-dose overnight dexamethasone suppression test.

Diagnosis of the cause of Cushing’s syndrome—ACTH-dependent causes can be distinguished from ACTH-independent causes by measurement of plasma ACTH (09.00 h sample). Determining whether elevated ACTH is coming from the pituitary (Cushing’s disease) or from an ectopic source can be difficult, but may be achieved by consideration of (1) plasma potassium—hypokalaemia is a typical feature of ectopic ACTH but not of Cushing’s disease; (2) high-dose dexamethasone suppression test—which tends to suppress plasma cortisol in Cushing’s disease but not ectopic ACTH; (3) CRF test—producing an exaggerated rise in ACTH and cortisol in Cushing’s disease but not in ectopic ACTH; (4) inferior petrosal sinus sampling/selective venous catheterization—the most robust test to distinguish Cushing’s disease from ectopic ACTH syndrome.

Imaging—pituitary MRI is the investigation of choice if biochemical testing suggests Cushing’s disease, and abdominal CT scanning if biochemical testing suggests ACTH-independent Cushing’s syndrome.

Management—drugs that interfere with cortisol synthesis (e.g. metyrapone, ketoconazole) can lower cortisol levels, but definitive treatment depends on the cause: (1) adrenal adenomas—unilateral adrenalectomy; (2) Cushing’s disease—trans-sphenoidal removal of the pituitary tumour; (3) ectopic ACTH—surgical removal of the tumour is rarely possible but can lead to cure.

Glucocorticoid deficiency

Glucocorticoid deficiency can be due to adrenal disease (primary, in which case mineralocorticoids are also deficient) or because of deficiency of ACTH (secondary, in which case only glucocorticoids are deficient).

Aetiology—primary hypoadrenalism (Addison’s disease) is most commonly caused by autoimmune disease (>70% cases in the Western world, associated with adrenal autoantibodies in many cases, and sometimes with other organ-specific autoimmune diseases) or infection, e.g. tuberculosis (the commonest cause worldwide). The commonest cause of secondary hypoadrenalism is stopping of exogenous glucocorticoid therapy or its inadequacy in stressful situations.

Clinical features—primary adrenal failure may present (1) acutely—with hypotension and acute circulatory failure (Addisonian crisis); or (2) chronically—with vague features of ill health, sometimes including gastrointestinal symptoms, features suggestive of postural hypotension, and salt craving. Skin pigmentation is nearly always present in primary adrenal insufficiency (but not in secondary).

Biochemical diagnosis—this depends on an ACTH stimulation test: plasma cortisol should rise to over 550 nmol/litre in response to injection of tetracosactrin (Synacthen, 250 µg) and failure to do so indicates adrenal insufficiency. In primary adrenal insufficiency the plasma ACTH level is disproportionately elevated in comparison with plasma cortisol.

Management—acute adrenal insufficiency is a medical emergency requiring volume resuscitation and parenteral steroid replacement, e.g. hydrocortisone 100 mg intravenously every 6 h, along with treatment of any precipitating condition, e.g. infection. Long-term treatment requires (1) glucocorticoid replacement—typically hydrocortisone, 20 mg on wakening and 10 mg at 18.00 h, to be doubled in the event of intercurrent stress or illness; (2) mineralocorticoid replacement—fludrocortisone, 0.05 to 0.1 mg/day, is usually required in primary adrenal failure. Every patient should be advised to wear a MedicAlert bracelet or necklace and to carry a ‘steroid card’.

Mineralocorticoid excess

Primary aldosteronism (Conn’s syndrome) is the commonest cause of mineralocorticoid hypertension and may be caused by an aldosterone-producing adenoma of the adrenal gland or by bilateral adrenal hyperplasia. The presence of primary aldosteronism is not easy to diagnose, but in the absence of confounding influences is suggested by a high random plasma aldosterone (PAC)/renin (PRA) ratio if PAC is over 400 pmol/litre (15ng/dl). The cause of primary aldosteronism is also difficult to establish: adrenal MRI/CT scanning may demonstrate an adenoma; adrenal vein cannulation with sampling for estimation of aldosterone/cortisol ratio may be required in difficult cases. Treatment of adrenal adenoma is by surgical excision and of bilateral adrenal hyperplasia is medical, usually with spironolactone.

A number of single-gene defects can cause mineralocorticoid excess, including 17α‎-hydroxylase deficiency, 11β‎-hydroxylase deficiency, glucocorticoid-suppressible hyperaldosteronism (due to formation of a chimeric gene, 11β‎-hydroxylase/aldosterone synthase), and apparent mineralocorticoid excess (mutations in 11β‎-hydroxysteroid dehydrogenase type 2 gene).

Mineralocorticoid deficiency

This is most commonly seen in the context of primary hypoadrenalism (see above) but is also caused (rarely) by conditions including primary defects in aldosterone biosynthesis, defects in aldosterone action, and hyporeninaemic hypoaldosteronism (most commonly in the context of diabetic nephropathy).

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