Adrenal insufficiency

It is decreased production or resistance to the action of adrenal hormones including glucocorticoids and /or mineralocorticoids and androgens. It may be primary, secondary or tertiary. Primary adrenal insufficiency is due to the disorders in the adrenal cortex, secondary is from anterior pituitary disorders while tertiary is from hypothalamic disorders. Both primary and secondary adrenal insufficiency are seen more commonly in women.

Causes of adrenal insufficiency

Addison’s disease

It is an autoimmune disorder characterized by the destruction of the adrenal cortex by cell mediated immunity. Antibodies to 21 hydroxylase are present. It is associated with HLADR3-DQ2, DR4-DQ8, PTPN22, CTLA4 and CIITA. Destruction of the adrenal tissue is mediated by direct cytotoxicity by lymphocytes that induce apoptosis, gamma interferon, TNF alpha, IL 1, free radicals and complement activation. Adrenal reserves are decreased which leads to an adrenal crisis in the event of a stressor like viral infection, surgery etc. It presents with weakness, fatigue, anorexia, abdominal pain, weight loss, orthostatic hypotension and salt craving. Compensatory increase in ACTH (which has melanocyte stimulating hormone or MSH like properties) causes shin and mucosal hyperpigmentation which is characteristic. Chronic cases also present with hyperkalemia, hyponatremia and metabolic acidosis.

In secondary or tertiary adrenal insufficiency, the resultant ACTH deficiency leads to decreased secretion of cortisol and adrenal androgens, while mineralocorticoid production remains normal. There is atrophy of the zona fasciculata and reticularis of the adrenal cortex. Hypotension and hyperkalemia are not seen in secondary and tertiary types while hypoglycemia is more common than primary.

After clinical history, the first step in diagnosis of adrenal insufficiency is decreased cortisol secretion determined by decreased serum, morning salivary and/or urinary free cortisol. Urine 17 hydroxycorticosteroid excretion is low. ACTH is increased in primary and decreased in secondary and tertiary adrenal insufficiency. Plasma renin is normal or high and aldosterone levels are low in primary while plasma renin and aldosterone are normal in secondary and tertiary adrenal insufficiency. Standard dose ACTH stimulation test with 250 microgram ACTH followed by measurement of cortisol concentrations will show no rise in serum cortisol in primary adrenal insufficiency. The more sensitive, low dose ACTH stimulation test shows decreased cortisol secretion in all types of adrenal insufficiency after administration of 500 nanograms of ACTH. Insulin induced hypoglycemia test is used to confirm the diagnosis of secondary adrenal insufficiency. It measures serum cortisol levels in response to hypoglycemia induced by administration of insulin. Cortisol levels fail to rise in secondary adrenal insufficiency. This test is contraindicated in patients with the history of cardiovascular disease or seizures.

CRH test can differentiate between secondary and tertiary adrenal insufficiency. Normally, administration of CRH is followed by an increase in serum ACTH and cortisol. Patients with secondary adrenal insufficiency demonstrate little or no ACTH response, whereas patients with tertiary adrenal insufficiency show an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response.

Plasma very long chain fatty acids are increased in adrenoleukodystrophy. CT of the adrenals or MRI of the brain can be done to reveal underlying conditions.

Patients with primary adrenal insufficiency should be treated with hydrocortisone (preferred) or cortisone acetate. Doses are temporarily increased during illnesses or surgery. Fludrocortisone is given as mineralocorticoid replacement therapy. Androgen replacement is required in women in the form of DHEA. Adrenal crisis is treated with intravenous hydrocortisone and rehydration with normal saline. Fludrocortisone plus glucocorticoid replacement therapy is given lifelong.

Secondary and tertiary adrenal insufficiency are treated with glucocorticoid replacement alone, as mineralocorticoid replacement is not needed. Other hormones deficient due to underlying pituitary or hypothalamic defects need to be replaced as well.

iii) Hypoaldosteronism: It is actual deficiency of aldosterone or tissue resistance to aldosterone action and results from defective stimulation of aldosterone secretion, primary defects in adrenal synthesis or secretion of aldosterone and aldosterone resistance.

Defective stimulation of aldosterone secretion is seen in conditions that show low renin secretion or defect in conversion of angiotensin I to II. Causes are congenital or acquired in DM, renal diseases like glomerulonephritis, pyelonephritis, analgesic nephropathy, amyloidosis, cryoglobulinemia, multiple myeloma; autoimmune disorders, cirrhosis, lead poisoning, Sjogren’s syndrome, drugs like NSAIDS, mitomycin C, cosyntropin, ACE inhibitors, beta blockers, prostaglandin synthetase inhibitors and calcium channel blockers. Low plasma renin, low plasma and urinary aldosterone are seen in hyporeninemic hypoaldosteronism. With ACE inhibitors, angiotensin II levels are low which causes high renin and low plasma aldosterone. Hyporeninemic hypoaldosteronism is associated with hyperkalemia, hyperchloremic metabolic acidosis (RTA type IV), muscle weakness, cardiac arrhythmias and hypotension. Renal insufficiency may occur. Treatment is by management of the underlying condition and fludrocortisone in resistant cases.

Defective synthesis of aldosterone is seen in CAH, aldosterone synthase deficiency (primary hypoaldosteronism), adrenoleukodystrophy, Addison’s disease,sepsis, pneumonia, liver failure, ketoconazole, heparin , discontinuation of fludrocortisone therapy and conditions causing adrenal insufficiency. Laboratory findings show that corticosterone is increased and aldosterone is decreased with high renin. Clinical features and treatment are similar to hyporeninemic hypoaldosteronism.

Aldosterone resistance is seen in pseudohypoaldosteronism and secondary to drugs like amiloride, spironolactone,progestins, triamterene, trimethoprim, cyclosporine, tacrolimus and pentamidine. Laboratory findings include high renin and high aldosterone with clinical features of hypoaldosteronism. Management is with salt supplementation and carbenoxolone. Drugs or disorders causing secondary hypoaldosteronism need to be stopped or treated respectively.