Key Points

• Primary adrenal insufficiency is defined as the failure of the adrenal cortex to produce glucocorticoids and mineralocorticoids.

• The most frequent cause of primary adrenal insufficiency is autoimmune. In the developing world, however, tuberculosis remains the most common cause.

• Symptoms are usually insidious, including fatigue, orthostatic hypotension, weight loss, and hyperpigmentation.

• Acute adrenal insufficiency should be considered in critically ill patients with unexplained hypotension.

• A baseline cortisol and ACTH level followed by an ACTH stimulation test can establish diagnosis.

• Detection of adrenal cortex antibodies or 21-hydroxylase autoantibodies supports the diagnosis of autoimmune adrenalitis. Abdominal CT may be helpful if other causes are suspected.

Primary adrenal insufficiency (AI) is defined as the failure of the adrenal cortex to produce adequate amounts of glu-cocorticoids and mineralocorticoids. Primary AI can result from processes that damage the adrenal glands or from drugs (ketoconazole, etomidate) that block the synthesis of cortisol. All causes of primary AI involve the adrenal cortex as a whole and result in a deficiency of cortisol and aldosterone (plus adrenal androgen), although the severity of the deficiencies may vary. An exception is the syndrome of isolated glucocorticoid deficiency. The reported prevalence of primary AI (Addison's disease) in developed countries is 39 to 60 per 1 million population. In adult patients, mean age at diagnosis is 40 years (range, 17-72).

The most frequent cause of primary AI in developed countries is autoimmune adrenalitis. However, in the developing world, tuberculosis remains the most common cause of adrenal failure. Autoimmune adrenalitis is sometimes accompanied by other autoimmune endocrine deficiencies (autoimmune polyglandular syndromes, APS). The adult form (type II, Schmidt's syndrome) of polyglandular syndrome consists mainly of AI, autoimmune thyroid disease, and insulin-dependent (type 1) diabetes mellitus. Several infectious processes associated with acquired immunodeficiency syndrome (AIDS) such as cytomegalovirus (CMV), Mycobacterium tuberculosis, Cryptococcus neoformans, Mycobacterium avium intracellulare, Histoplasma capsulatum, and Kaposi's sarcoma, may damage the adrenal gland and lead to insufficiency. In young males, adrenoleukodystrophy (or the less severe adrenomyeloneuropathy), an X-linked recessive disorder of metabolism of long-chain fatty acids, can cause spastic paralysis and adrenal insufficiency. AI can precede neurologic symptoms and should prompt the clinician to perform careful neurologic examination in young males with primary AI. Other causes are listed in Box 35-7.

Box 35-7 Causes of Primary Adrenal Insufficiency

Autoimmune

Isolated adrenal insufficiency (Addison's disease) Polyglandular autoimmune syndrome types I and II

Infectious

Tuberculosis Fungal

Histoplasmosis Paracoccidioidomycosis HIV/AIDS Cytomegalovirus Syphilis

African trypanosomiasis Vascular

Bilateral adrenal hemorrhage

Sepsis (Waterhouse-Friderichsen syndrome)

Coagulopathy

Thrombosis, embolism

Infarction

Infiltrative

Metastatic carcinoma (most often lung, breast, stomach, colon)

Lymphoma

Sarcoidosis

Amyloidosis

Hemochromatosis

Congenital

Congenital adrenal hyperplasia 21a-Hydroxylase deficiency 11 ^-Hydroxylase deficiency 3|-ol-Dehydrogenase deficiency 20,22-Desmolase deficiency

Familial adrenocorticotropic hormone resistance syndromes Familial glucocorticoid deficiency Adrenoleukodystrophy Adrenomyeloneuropathy Adrenal hypoplasia

Iatrogenic

Bilateral adrenalectomy Anticoagulation therapy Drugs

Adrenolytic: mitotane, aminoglutethimide, metyrapone, trilostane

Other: ketoconazole, rifampin, etomidate, phenytoin, barbiturates, megestrol acetate

Chronic (Primary) Adrenal Insufficiency

Most of the symptoms are nonspecific and occur insidiously. Chronic AI manifestations include weakness, chronic fatigue, anorexia, unintentional weight loss, listlessness, joint pain, and orthostatic hypotension. Some patients may initially present with GI symptoms (abdominal pain, nausea, vomiting, diarrhea), whereas others may present with symptoms that can be attributed to depression or anorexia nervosa. In contrast to secondary AI, primary AI is often associated with lack of aldosterone as well as cortisol. Thus, signs of mineralocorticoid deficiency (salt craving, postural hypotension, electrolyte abnormalities) are usually indicative of primary AI. The most specific sign of primary AI is hyperpigmentation of the skin and mucosal surfaces, which results from the melanocyte-stimulating activity of p-lipotropin derived from the same precursor as ACTH. Patients with autoimmune adrenalitis present with vitiligo, Hashimoto's thyroiditis (70% in APS-II), type 1 diabetes, and pernicious anemia. Thinning or loss of pubic and axillary hair may occur in women as a result of lack of androgen production by the adrenal cortex. Both systolic and diastolic blood pressure (BP) are usually reduced (systolic BP <110 mm Hg).

Acute (Primary) Adrenal Insufficiency

In critically ill patients, it is crucial to consider the possibility of adrenal insufficiency. AI should be suspected in the presence of unexplained catecholamine-resistant hypotension, especially if the patient has pallor, hyperpigmentation, vitiligo, scanty axillary and pubic hair, hyponatremia, or hyper-kalemia. Furthermore, AI due to adrenal hemorrhage and adrenal vein thrombosis should be considered in a severely ill patient with abdominal pain or rigidity, vomiting, confusion, and arterial hypotension. In acutely ill patients, plasma cortisol level greater than 25 g/dL rules out adrenal insufficiency, but a level in the normal range does not; further testing may be required.

Laboratory Evaluation

Patients with adrenal insufficiency present with hyponatre-mia (frequent), hyperkalemia, acidosis, mild elevation of plasma creatinine concentrations, hypoglycemia, hypercalcemia (rare), mild normocytic anemia, lymphocytosis, and mild eosinophilia. In addition, hormone levels are useful in diagnosis. A random measurement of serum cortisol level is usually inadequate to assess adrenal function because of the pulsatile and diurnal variation of cortisol secretion. However, a morning cortisol level (8-9 am) of 3 ^/dL or less indicates primary AI and obviates the need for further tests; a level of 19 ^/dL or greater rules AI out; patients with levels of 3 to 19 ^/dL need further testing. If primary AI is suspected, basal ACTH and cortisol levels should be measured, followed by a short ACTH stimulation test. For testing, synthetic ACTH (cosyntropin) is given IV or IM at 250 ^.g and serum cortisol is measured 60 minutes after injection. A normal response to this test (cortisol 20 ^/dL or higher) excludes primary AI. In patients with severe secondary AI, plasma cortisol increases little or not at all after the administration of cosyntropin because of adrenocortical atrophy.

Detection of adrenocortical antibodies or 21-hydroxy-lase autoantibodies supports the diagnosis of autoimmune adrenalitis. Antibodies against other endocrine glands are common in patients with autoimmune AI, and evaluation might be warranted. However, the incidence of antiadrenal antibodies in serum from patients with normal adrenal function who have other autoimmune endocrine diseases is low (2%), with the exception of those with hypoparathyroidism (16%). Abdominal CT scan may be helpful if infection, hemorrhage, infiltration, or neoplastic disease is suspected.

Treatment

In chronic AI, any underlying cause, such as infection or malignancy, should be treated. Glucocorticoid replacement is usually required for symptomatic patients and is given in two or three daily doses with half to two thirds of the daily dose given in the morning to mimic the physiologic daily pattern of cortisol secretion. Hydrocortisone (15-25 mg/day) or cortisone acetate (25-37.5 mg/day) is preferred because of its mineralocorticoid action and shorter biologic half-life, which prevents unfavorably high nighttime glucocorticoid activity. The goal is to use the smallest dose that relieves the patient's symptoms to prevent side effects from steroid use, such as weight gain and osteoporosis. Because a reliable marker of glucocorticoid action is lacking, clinical judgment and careful assessment of clinical signs and symptoms guide treatment.

In patients with primary AI, mineralocorticoid replacement is necessary and is attained by fludrocortisone, in a single daily dose of 0.05 to 0.2 mg, as a substitute for aldo-sterone. The dose can be adjusted based on measurements of BP, serum sodium and potassium, and renin activity (aiming at concentrations within the middle or upper-normal range). All patients should carry a card or wear a medical alert bracelet or necklace with information on current treatment and recommendations in emergency situations. Patients should be advised to double or triple the dose of hydrocortisone temporarily when they have a febrile illness or injury. In addition, they should be given ampules of glucocorticoid for self-injection or glucocorticoid suppositories to be used in case of vomiting.

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