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Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis with cardiovascular collapse. Diagnosis is clinical and by finding elevated plasma ACTH with low plasma cortisol. Treatment depends on the cause but generally includes hydrocortisone and sometimes other hormones.
Addison disease develops in about 4/100,000 annually. It occurs in all age groups, about equally in each sex, and tends to become clinically apparent during metabolic stress or trauma. Onset of severe symptoms (adrenal crisis) may be precipitated by acute infection (a common cause, especially with septicemia). Other causes include trauma, surgery, and Na loss from excessive sweating. Even with treatment, Addison disease may cause a slight increase in mortality. It is not clear whether this increase is due to mistreated adrenal crises or long-term complications of inadvertent over-replacement.
Etiology
About 70% of cases in the US are due to idiopathic atrophy of the adrenal cortex, probably caused by autoimmune processes. The remainder result from destruction of the adrenal gland by granuloma (eg, TB, histoplasmosis), tumor, amyloidosis, hemorrhage, or inflammatory necrosis. Hypoadrenocorticism can also result from administration of drugs that block corticosteroid synthesis (eg, ketoconazole, the anesthetic etomidate). Addison disease may coexist with diabetes mellitus or hypothyroidism in polyglandular deficiency syndrome (see Polyglandular Deficiency Syndromes). In children, the most common cause of primary adrenal insufficiency is congenital adrenal hyperplasia (CAH—see also Endocrine Disorders in Children: Congenital Adrenal Hyperplasia), but other genetic disorders are being increasingly recognized as causes.
Pathophysiology
Both mineralocorticoids and glucocorticoids are deficient.
Mineralocorticoid deficiency:
Because mineralocorticoids stimulate Na reabsorption and K excretion, deficiency results in increased excretion of Na and decreased excretion of K, chiefly in urine but also in sweat, saliva, and the GI tract. A low serum concentration of Na and a high concentration of K result. Urinary salt and water loss cause severe dehydration, plasma hypertonicity, acidosis, decreased circulatory volume, hypotension, and, eventually, circulatory collapse. However, when adrenal insufficiency is caused by inadequate ACTH production (secondary adrenal insufficiency—see Adrenal Disorders: Secondary Adrenal Insufficiency), electrolyte levels are often normal or only mildly deranged.
Glucocorticoid deficiency:
Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and decreased liver glycogen result. Weakness follows, due in part to deficient neuromuscular function. Resistance to infection, trauma, and other stress is decreased. Myocardial weakness and dehydration reduce cardiac output, and circulatory failure can occur. Decreased blood cortisol results in increased pituitary ACTH production and increased blood β-lipotropin, which has melanocyte-stimulating activity and, together with ACTH, causes the hyperpigmentation of skin and mucous membranes characteristic of Addison disease. Thus, adrenal insufficiency secondary to pituitary failure (see Adrenal Disorders: Secondary Adrenal Insufficiency) does not cause hyperpigmentation.
Symptoms and Signs
Weakness, fatigue, and orthostatic hypotension are early symptoms and signs. Hyperpigmentation is characterized by diffuse tanning of exposed and, to a lesser extent, unexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces. Black freckles are common on the forehead, face, neck, and shoulders. Bluish black discolorations of the areolae and mucous membranes of the lips, mouth, rectum, and vagina occur. Anorexia, nausea, vomiting, and diarrhea often occur. Decreased tolerance to cold, with hypometabolism, may be noted. Dizziness and syncope may occur. The gradual onset and nonspecific nature of early symptoms often lead to an incorrect initial diagnosis of neurosis. Weight loss, dehydration, and hypotension are characteristic of the later stages of Addison disease.
Adrenal crisis:
Adrenal crisis is characterized by profound asthenia; severe pain in the abdomen, lower back, or legs; peripheral vascular collapse; and, finally, renal shutdown with azotemia. Body temperature may be low, although severe fever often occurs, particularly when crisis is precipitated by acute infection. A significant number of patients with partial loss of adrenal function (limited adrenocortical reserve) appear well but experience adrenal crisis when under physiologic stress (eg, surgery, infection, burns, critical illness). Shock and fever may be the only signs.
Diagnosis
Clinical symptoms and signs suggest adrenal insufficiency. Sometimes the diagnosis is considered only on discovery of characteristic abnormalities of serum electrolytes, including low Na (< 135 mEq/L), high K (> 5 mEq/L), low HCO3 (15 to 20 mEq/L), and high BUN (see Table 1: Adrenal Disorders: Test Results That Suggest Addison Disease ).
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Table 1
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| Test Results That Suggest Addison Disease |
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Test
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Result
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Blood chemistry
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Serum Na
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< 135 mEq/L
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Serum K
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> 5 mEq/L
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Ratio of serum Na:K
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< 30:1
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Plasma glucose, fasting
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< 50 mg/dL (< 2.78 mmol/L)
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Plasma HCO3
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< 15–20 mEq/L
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BUN
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> 20 mg/dL (> 7.1 mmol/L)
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Hematology
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Hct
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Elevated
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WBC count
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Low
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Lymphocytes
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Relative lymphocytosis
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Eosinophils
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Increased
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Imaging
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Evidence of
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Differential diagnosis:
Hyperpigmentation can result from bronchogenic carcinoma, ingestion of heavy metals (eg, iron, silver), chronic skin conditions, or hemochromatosis. Peutz-Jeghers syndrome is characterized by pigmentation of the buccal and rectal mucosa. Frequently, hyperpigmentation occurs with vitiligo, which may indicate Addison disease, although other diseases can cause this association.
Weakness resulting from Addison disease subsides with rest, unlike neuropsychiatric weakness, which is often worse in the morning than after activity. Most myopathies that cause weakness can be differentiated by their distribution, lack of abnormal pigmentation, and characteristic laboratory findings.
Patients with adrenal insufficiency develop hypoglycemia after fasting because of decreased gluconeogenesis. In contrast, patients with hypoglycemia due to oversecretion of insulin can have attacks at any time, usually have increased appetite with weight gain, and have normal adrenal function.
Low serum Na due to Addison disease must be differentiated from that of edematous patients with cardiac or liver disease (particularly those taking diuretics), the dilutional hyponatremia of the syndrome of inappropriate ADH secretion, and salt-losing nephritis. These patients are not likely to have hyperpigmentation, hyperkalemia, and increased BUN.
Testing:
Laboratory tests, beginning with serum cortisol and ACTH levels, confirm adrenal insufficiency. Elevated ACTH (≥ 50 pg/mL) with low cortisol (< 5 μg/dL [< 138 nmol/L]) is diagnostic, particularly in patients who are severely stressed or in shock. Low ACTH (< 5 pg/mL) and cortisol suggest secondary adrenal insufficiency (see Adrenal Disorders: Secondary Adrenal Insufficiency). It is important to note that ACTH levels within the normal range are inappropriate when cortisol levels are very low.
If ACTH and cortisol levels are borderline and adrenal insufficiency is clinically suspected—particularly in a patient who is about to undergo major surgery—provocative testing must be done. If time is too short (eg, emergency surgery), the patient is given hydrocortisone empirically (eg, 100 mg IV or IM), and provocative testing is done subsequently.
Addison disease is diagnosed by showing failure of exogenous ACTH to increase serum cortisol. Secondary adrenal insufficiency is diagnosed by a prolonged ACTH stimulation test, insulin tolerance test, or glucagon test.
ACTH stimulation testing is done by injecting cosyntropin (synthetic ACTH) 250 μg IV or IM followed by measurement of serum cortisol levels. Some authorities believe that in patients with suspected secondary adrenal insufficiency, a low-dose ACTH stimulation test using 1 μg IV instead of the standard 250 μg should be done, because such patients may react normally to the higher dose. Patients taking glucocorticoid supplements or spironolactone should not take them on the day of the test. Normal preinjection serum cortisol levels vary somewhat depending on the laboratory assay in use but typically range from 5 to 25 μg/dL (138 to 690 nmol/L) and double in 30 to 90 min, reaching at least 20 μg/dL (552 nmol/L). Patients with Addison disease have low or low-normal values that do not rise above 20 μg/dL at 30 min. A normal response to cosyntropin may occur in secondary adrenal insufficiency. However, because pituitary failure may cause adrenal atrophy (and hence failure to respond to ACTH), the patient may need to be primed with long-acting ACTH 1 mg IM once/day for 3 days before the ACTH stimulation test if pituitary disease is suspected.
A prolonged ACTH stimulation test (sampling for 24 h) may be used to diagnose secondary (or tertiary, ie, hypothalamic) adrenal insufficiency. Cosyntropin 1 mg IM is given, and cortisol is measured at intervals for 24 h, typically at 1, 6, 12, and 24 h. Results for the first hour are similar for both the short (sampling stopped after 1 h) and prolonged tests, but in Addison disease there is no further rise beyond 60 min. In secondary and tertiary adrenal insufficiency, cortisol levels continue to rise for ≥ 24 h. Only in cases of prolonged adrenal atrophy is adrenal priming (with long-acting ACTH) necessary. The simple short test is usually done initially, because a normal response obviates the need for further investigation.
If adrenal crisis is suspected, confirmation of Addison disease by ACTH stimulation testing is deferred until the patient has recovered. If ACTH stimulation testing is done, elevated ACTH levels together with low cortisol levels confirm the diagnosis.
In Western societies, the cause is usually assumed to be autoimmune, unless there is evidence otherwise. Adrenal autoantibodies can be assessed. A chest x-ray should be done for TB; if doubt exists, CT of the adrenals is helpful. In patients with autoimmune disease, the adrenals are atrophied, whereas in patients with TB or other granulomas, the adrenals are enlarged (initially) with frequent calcification. Bilateral adrenal hyperplasia, particularly in children and young adults, suggests a genetic enzyme defect.
Treatment
Normally, cortisol is secreted maximally in the early morning and minimally at night. Thus, hydrocortisone (identical to cortisol) is given in 2 or 3 divided doses with a typical total daily dose of 15 to 30 mg. One regimen gives half the total in the morning, and the remaining half split between lunchtime and early evening (eg, 10 mg, 5 mg, 5 mg). Others give two thirds in the morning and one third in the evening. Doses immediately before retiring should generally be avoided because they may cause insomnia. Alternatively, prednisone 5 mg po in the morning and 2.5 mg po in the evening may be used. Additionally, fludrocortisone 0.1 to 0.2 mg po once/day is recommended to replace aldosterone. The easiest way to adjust the dosage is to ensure that the renin level is within the normal range. Normal hydration and absence of orthostatic hypotension are evidence of adequate replacement therapy. In some patients, fludrocortisone causes hypertension, which is treated by reducing the dosage or starting a nondiuretic antihypertensive. Some clinicians tend to give too little fludrocortisone in an effort to avoid use of antihypertensives.
Intercurrent illnesses (eg, infections) are potentially serious and should be vigorously treated; the patient's hydrocortisone dose should be doubled during the illness. If nausea and vomiting preclude oral therapy, parenteral therapy is necessary. Patients should be instructed when to take supplemental prednisone or hydrocortisone and taught to self-administer parenteral hydrocortisone for urgent situations. A preloaded syringe with 100 mg hydrocortisone should be available to the patient. A bracelet or wallet card giving the diagnosis and corticosteroid dose may help in case of adrenal crisis that renders the patient unable to communicate. When salt loss is severe, as in very hot climates, the dose of fludrocortisone may need to be increased.
In coexisting diabetes mellitus and Addison disease, the hydrocortisone dose usually should not be > 30 mg/day; otherwise, insulin requirements are increased.
Adrenal crisis:
Therapy should be instituted immediately upon suspicion. (Caution:
In adrenal crisis, a delay in instituting corticosteroid therapy, particularly if there is hypoglycemia and hypotension, may be fatal.) If the patient is acutely ill, confirmation by an ACTH stimulation test should be postponed until the patient has recovered.
Hydrocortisone 100 mg is injected IV over 30 sec and repeated q 6 to 8 h for the first 24 h. Immediate intravascular volume expansion is done by giving 1 L of a 5% dextrose in 0.9% saline solution over 1 to 2 h. Additional 0.9% saline is given IV until hypotension, dehydration, and hyponatremia have been corrected. Serum K may fall during rehydration, requiring replacement. Mineralocorticoids are not required when high-dose hydrocortisone is given. When illness is less acute, hydrocortisone 50 or 100 mg can be given IM q 6 h. Restoration of BP and general improvement should occur within 1 h after the initial dose of hydrocortisone. Inotropic agents may be needed until the effects of hydrocortisone are achieved.
A total dose of 150 mg hydrocortisone is usually given over the 2nd 24-h period if the patient has improved markedly, and 75 mg is given on the 3rd day. Maintenance oral doses of hydrocortisone (15 to 30 mg) and fludrocortisone (0.1 mg) are given daily thereafter, as described above. Recovery depends on treatment of the underlying cause (eg, infection, trauma, metabolic stress) and adequate hydrocortisone therapy.
For patients with some residual adrenal function who develop adrenal crisis when under stress, hydrocortisone treatment is the same, but fluid requirements may be much lower.
Treatment of complications:
Fever > 40.6° C occasionally accompanies the rehydration process. Except in the presence of falling BP, antipyretics (eg, aspirin 650 mg) may be given po with caution. Complications of corticosteroid therapy may include psychotic reactions. If psychotic reactions occur after the first 12 h of therapy, the hydrocortisone dose should be reduced to the lowest level consistent with maintaining BP and good cardiovascular function. Antipsychotics may be temporarily required, but use should not be prolonged.
Key Points
Last full review/revision August 2012 by Ashley B. Grossman, MD, FRCP, FMedSci
Content last modified November 2012
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