(Primary or Chronic Adrenocortical Insufficiency)
(See also Overview of Adrenal Function.)
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, infection, or trauma.
Adrenal crisis (onset of severe symptoms) may be precipitated by acute infection (a common cause, especially with septicemia). Other causes include trauma, surgery, and sodium loss due to 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.
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, tuberculosis, histoplasmosis), tumor, amyloidosis, hemorrhage, or inflammatory necrosis. Hypoadrenocorticism can also result from administration of drugs that block corticosteroid synthesis (eg, ketoconazole, the anesthetic etomidate).
Both mineralocorticoids and glucocorticoids are deficient.
Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. A low serum concentration of sodium (hyponatremia) and a high concentration of potassium (hyperkalemia) 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 adrenocorticotropic hormone (ACTH) production (secondary adrenal insufficiency), electrolyte levels are often normal or only mildly deranged, and the circulatory problems are less severe.
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 beta-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 does not cause hyperpigmentation.
Weakness, fatigue, and orthostatic hypotension are early symptoms and signs of Addison disease.
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 is characterized by
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.
Clinical symptoms and signs suggest adrenal insufficiency. Sometimes the diagnosis is considered only on discovery of characteristic abnormalities of serum electrolytes, including low sodium (< 135 mEq/L [< 135 mmol/L]), high potassium (> 5 mEq/L [> 5 mmol/L]), low bicarbonate (< 20 mEq/L [15 to 20 mmol/L]), and high BUN (blood urea nitrogen—see table Test Results That Suggest Addison Disease).
Test Results That Suggest Addison Disease
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 sodium 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 antidiuretic hormone secretion (SIADH), and salt-losing nephritis. Unlike those with Addison disease, these patients are not likely to have hyperpigmentation, hyperkalemia, and increased BUN.
Laboratory tests, beginning with morning serum cortisol and plasma ACTH levels, confirm adrenal insufficiency (see table Confirmatory Serum Testing for Addison Disease). Elevated ACTH (≥ 50 pg/mL [≥ 11 pmol/L]) with low cortisol (< 5 mcg/dL [< 138 nmol/L]) is diagnostic, particularly in patients who are severely stressed or in shock. Low ACTH (< 5 pg/mL [< 1.1 pmol/L] ) and cortisol suggest 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, glucagon stimulation test, or insulin tolerance test. In the glucagon stimulation tests, plasma ACTH and cortisol levels fail to rise in response to glucagon in patients with secondary adrenal insufficiency. The insulin tolerance test is not recommended in patients suspected of having severe adrenal insufficiency.
ACTH stimulation testing is done by injecting cosyntropin (synthetic ACTH) 250 mcg 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 mcg IV instead of the standard 250 mcg-dose 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 mcg/dL (138 to 690 nmol/L) and double in 30 to 90 minutes, reaching at least 20 mcg/dL (552 nmol/L). Patients with Addison disease have low or low-normal preinjection values that do not rise above a peak value of 15 to 18 mcg/dL (414 to 497 nmol/L) at 30 minutes. However, the precise normal values depend on the specific cortisol assay used, and the normal range should be verified for each laboratory.
Confirmatory Serum Testing for Addison Disease
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 a day for 3 days before the ACTH stimulation test if pituitary disease is suspected.
A prolonged ACTH stimulation test (sampling for 24 hours) 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 hours, typically at 1, 6, 12, and 24 hours. Results for the first hour are similar for both the short (sampling stopped after 1 hour) and prolonged tests, but in Addison disease there is no further rise beyond 60 minutes. In secondary and tertiary adrenal insufficiency, cortisol levels continue to rise for ≥ 24 hours. 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 tuberculosis; if doubt exists, CT of the adrenals is helpful. In patients with autoimmune disease, the adrenals are atrophied, whereas in patients with tuberculosis 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.
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 bed should generally be avoided because they may cause insomnia. Alternatively, prednisone 5 mg orally in the morning and possibly an additional 2.5 mg orally in the evening may be used. Additionally, fludrocortisone 0.1 to 0.2 mg orally once a day is recommended to replace aldosterone. The easiest way to adjust the fludrocortisone dosage is to ensure that the renin level is within the normal range and that blood pressure and serum potassium level are normal.
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.
Therapy should be instituted immediately upon suspicion of adrenal crisis. (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 seconds and repeated every 6 to 8 hours for the first 24 hours. Immediate intravascular volume expansion is done by giving 1 L of a 5% dextrose in 0.9% saline solution over 1 to 2 hours. Additional 0.9% saline is given IV until hypotension, dehydration, and hyponatremia have been corrected. Serum potassium 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 IM every 6 hours can be given. Restoration of blood pressure and general improvement should occur within 1 hour 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-hour 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.
Fever > 40.6° C occasionally accompanies the rehydration process. Except in the presence of falling blood pressure, antipyretics (eg, aspirin 650 mg) may be given orally with caution. Complications of corticosteroid therapy may include psychotic reactions. If psychotic reactions occur, then the hydrocortisone dose can be reduced to the lowest level consistent with maintaining blood pressure and good cardiovascular function. Antipsychotics may be temporarily required, but use should not be prolonged.
Addison disease is primary adrenal insufficiency.
Weakness, fatigue, and hyperpigmentation (generalized tanning or focal black spots involving skin and mucous membranes) are typical.
Low serum sodium, high serum potassium, and high BUN (blood urea nitrogen) occur.
Usually, plasma ACTH is high and serum cortisol levels are low.
Replacement doses of hydrocortisone and fludrocortisone are given; doses should be increased during intercurrent illness.