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Adrenal Cortical Hypofunction

Adrenal cortical hypofunction may be primary (Addison's disease) or secondary.

ADDISON'S DISEASE
(Primary or Chronic Adrenocortical Insufficiency)

An insidious, usually progressive disease resulting from adrenocortical hypofunction.

Etiology and Incidence

About 70% of cases of Addison's disease in the USA 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, which has become increasingly common recently, especially in developing countries), tumor, amyloidosis, or inflammatory necrosis. Hypoadrenocorticism can also be caused by administration, for nonendocrine reasons, of drugs that block steroid synthesis, such as ketoconazole (an antifungal drug). The incidence of hypoadrenocorticism in the general population is about 4/100,000. Addison's disease occurs in all age groups, about equally in each sex, and tends to become clinically apparent during metabolic stress or trauma.

Pathophysiology

The principal hormones produced by the adrenal cortex are cortisol (hydrocortisone), aldosterone, and dehydroepiandrosterone (DHEA). Adults secrete about 20 mg of cortisol, 2 mg of corticosterone (which has similar activity), and 0.2 mg of aldosterone daily. Although considerable quantities of androgens (primarily DHEA and androstenedione) are normally produced by the adrenal cortex, their chief physiologic activity occurs after conversion to testosterone and dihydrotestosterone.

In Addison's disease, there is increased excretion of Na and decreased excretion of K, chiefly in the urine, which is isotonic, and also in the sweat, saliva, and GI tract. Low blood concentrations of Na and Cl and a high concentration of serum K result. Inability to concentrate the urine, combined with changes in electrolyte balance, produces severe dehydration, plasma hypertonicity, acidosis, decreased circulatory volume, hypotension, and circulatory collapse.

Cortisol deficiency contributes to hypotension and produces disturbances in carbohydrate, fat, and protein metabolism and severe insulin sensitivity. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and diminished liver glycogen result. Weakness follows, due in part to deficient neuromuscular function. Resistance to infection, trauma, and other stress is diminished because of reduced adrenal output. Myocardial weakness and dehydration cause reduced cardiac output, and circulatory failure can occur. Decreased cortisol blood levels result in increased pituitary ACTH production and increased blood levels of beta-lipotropin, which has melanocyte-stimulating activity and produces the hyperpigmentation of skin and mucous membranes characteristic of Addison's disease.

Symptoms and Signs

Weakness, fatigue, and orthostatic hypotension are early symptoms. Pigmentation is usually increased except in adrenal insufficiency secondary to pituitary failure. Increased pigmentation (hyperpigmentation) is characterized by diffuse tanning of both exposed and unexposed portions of the body, especially on pressure points (bony prominences), skinfolds, scars, and extensor surfaces. Common are black freckles over the forehead, face, neck, and shoulders; areas of vitiligo; and bluish black discolorations of the areolae and of the mucous membranes of the lips, mouth, rectum, and vagina. Anorexia, nausea, vomiting, and diarrhea often occur. A decreased tolerance to cold, with hypometabolism, may be noted. Dizziness and syncope may occur. ECG may show decreased voltage and prolonged PR and QT intervals. The EEG shows a generalized slowing of the alpha rhythm. The gradual onset and nonspecific nature of early symptoms often lead to an incorrect initial diagnosis of neurosis. Weight loss, dehydration, hypotension, and small heart size are characteristic of the later stages of Addison's disease.

An adrenal crisis is characterized by profound asthenia; severe pains in the abdomen, lower back, or legs; peripheral vascular collapse; and, finally, renal shutdown with azotemia. Body temperature may be subnormal, although severe hyperthermia due to infection often occurs. Crisis is precipitated most often by acute infection (especially with septicemia), trauma, operative procedures, and Na loss due to excessive sweating during hot weather.

Laboratory Findings

Abnormal serum electrolyte levels, including low Na (< 130 mEq/L), high K (> 5 mEq/L), low HCO3 (15 to 20 mEq/L) and high BUN, together with a characteristic clinical picture, suggest Addison's disease. The plasma renin and ACTH levels are increased. When adrenal failure is caused by inadequate ACTH production by the pituitary gland, electrolyte levels are usually normal.

Adrenal insufficiency can be diagnosed by demonstrating failure to increase plasma cortisol levels, or urinary free-cortisol excretion, upon administration of ACTH. Urinary-free cortisol excretion in the absence of exogenous ACTH stimulation is unreliable as an index of adrenocortical functional capacity, since baseline excretion does not adequately separate the low-normal from the abnormally low value. A single determination of plasma cortisol or 24-h urinary-free cortisol excretion is not useful and may be misleading in diagnosing adrenal insufficiency. However, if the patient is severely stressed or in shock, a single depressed plasma cortisol determination is highly suggestive. An elevated plasma ACTH level in association with a low plasma cortisol level is diagnostic.

Testing for adrenal insufficiency: Testing is performed by injecting cosyntropin 5 to 250 µg IV. Normal preinjection plasma cortisol ranges from 5 to 25 µg/dL (138 to 690 nmol/L) and doubles at 30 to 90 min, with a minimum of 20 µg/dL (552 nmol/L). Patients with Addison's disease have low or normal values that do not rise.

Distinguishing between primary and secondary adrenal insufficiency: Most instances of secondary hypoadrenocorticism are caused by destruction of the pituitary. CT or MRI of the sella may, therefore, be useful in ruling out tumor or atrophy. The empty sella syndrome (see also Ch. 7) is not, however, invariably associated with pituitary insufficiency, so even when changes occur in the pituitary image, function tests must be performed. In patients with primary disease of the adrenal, the plasma ACTH level is high (>= 50 pg/mL). Patients with pituitary failure or with isolated ACTH deficiency have a low ACTH level. If ACTH determination is unavailable, a metyrapone test should be performed. Plasma cortisol levels are reduced by blocking the 11-hydroxylation of the cortisol precursors with metyrapone. In normal persons, the decreased cortisol stimulates increased secretion of ACTH and leads to increased production of cortisol precursors, particularly 11-deoxycortisol ("compound S"), which is secreted in the urine as its metabolite, tetrahydro-S. The best and simplest method is to administer metyrapone 30 mg/kg po at midnight with a little food to avoid gastric irritation. The plasma cortisol at 8 am the next morning should be < 10 µg/dL (< 276 nmol/L), and the plasma 11-deoxycortisol should be 7 to 22 µg/dL (0.2 to 0.6 µmol/L). For patients who do not respond to metyrapone, a cosyntropin test must be performed. Patients with primary adrenal failure will have low levels of both steroids and will not respond to cosyntropin; those with hypopituitarism will respond to cosyntropin but not to metyrapone. It may be necessary to prime the patient with long-acting ACTH 20 U IM bid for 3 days before performing the cosyntropin test to prevent failure of adrenal response because of atrophy in patients with pituitary failure. Priming is advisable if an inadequate but definite response to metyrapone occurs.

Response to corticotropin-releasing hormone (CRH) can be used to distinguish between hypothalamic and pituitary failure. After administering CRH 100 µg (or 1 µg/kg) IV, the normal response is a rise of plasma ACTH of 30 to 40 pg/mL; patients with pituitary failure do not respond, whereas those with hypothalamic disease usually do respond.

Plasma and urinary cortisol levels are usually determined by radioimmunoassay.

Diagnosis

The diagnosis is suspected on the basis of symptoms and signs and confirmed by laboratory tests as described above. Note that many patients with some adrenal function but limited reserves appear well until stress precipitates acute adrenal insufficiency.

Addison's disease is usually suspected after the discovery of hyperpigmentation, although in some patients this may be minimal. In the early stages of the disease, weakness, although prominent, is benefited by rest, unlike neuropsychiatric weaknesses, which are often worse in the morning than after activity. Most myopathies can be differentiated by their distribution and the lack of pigmentation and by characteristic laboratory findings. Patients with hypoglycemia due to oversecretion of insulin may have attacks at any time, usually have increased appetite with weight gain, and have normal adrenal function. Patients with adrenal insufficiency develop hypoglycemia after fasting because of their decreased ability to carry out gluconeogenesis. The low serum Na must be differentiated from that of edematous patients with cardiac or liver disease (particularly those taking diuretics), the dilutional hyponatremia of inappropriate ADH syndrome, and the rare salt-losing nephritis. These patients are not likely to show hyperpigmentation, hyperkalemia, and increased BUN, which are characteristic of adrenal insufficiency. Hyperpigmentation due to bronchogenic carcinoma, ingestion of heavy metals such as iron or silver, chronic skin conditions, or hemochromatosis should be considered. The characteristic pigmentation of the buccal and rectal mucosa seen in Peutz-Jeghers syndrome should not cause confusion. Frequently, vitiligo is associated with hyperpigmentation, which may be a helpful indication of Addison's disease, although other diseases can cause this association.

Prognosis

With continued substitution therapy, the prognosis is excellent and a patient with Addison's disease should be able to lead a full life.

Treatment

In addition to appropriate treatment of complicating infections (eg, TB), the following conditions should be treated.

Acute adrenal insufficiency: Therapy should be instituted immediately once a provisional diagnosis of adrenocortical failure has been made. If the patient is acutely ill, confirmation by an ACTH response test should be postponed until the patient has recovered. Hydrocortisone 100 mg as a water-soluble ester (usually the succinate or phosphate) is injected IV over 30 sec, followed by an infusion of 1 L of a 5% dextrose in 0.9% sodium chloride solution containing 100 mg hydrocortisone ester given over 2 h. Additional 0.9% sodium chloride is given until dehydration and hyponatremia have been corrected. Serum K may fall during rehydration, requiring careful replacement. Hydrocortisone therapy is given continuously to a total dosage in 24 h of > 300 mg. Mineralocorticoids are not required when high-dose hydrocortisone is given.

Restoration of BP and general improvement may be expected within 1 h after the initial dose of hydrocortisone. Vasopressor drugs may be needed until the full effect of hydrocortisone is apparent. An IV infusion of metaraminol bitartrate, 100 mg in 500 mL of sodium chloride injection, may be given at a rate adjusted to maintain BP. (Caution: In acute addisonian crisis, a delay in instituting corticosteroid therapy may result in the patient's death, particularly if hypoglycemia and hypotension are present.) A total dose of 150 mg hydrocortisone is usually given over the second 24-h period if the patient has improved markedly, and 75 mg is given on the third day. Maintenance oral doses of hydrocortisone (30 mg) and fludrocortisone acetate (0.1 mg) are given daily thereafter, as described under treatment of chronic adrenal insufficiency, below. Recovery depends on treatment of the underlying cause (eg, infection, trauma, metabolic stress) and adequate hydrocortisone therapy.

Recognition of patients with Addison's disease is not difficult. However, a significant number of patients with "limited adrenocortical reserve" who appear healthy experience acute adrenocortical insufficiency when under stress. Shock and fever may be the only signs observed. Treatment should not be delayed until the diagnosis is certain; but hydrocortisone should be given as described above. Sodium and water requirements may be considerably less than in patients with total deficiency.

Treatment of complications: These complications include hyperpyrexia and psychotic reactions. Fever > 40.6° C (105° F) orally occasionally accompanies the rehydration process. Except in the presence of a falling BP, antipyretics (eg, aspirin 600 mg) may be given orally with caution q 30 min until the temperature begins to fall. If psychotic reactions occur after the first 12 h of therapy, hydrocortisone dosage should be reduced to the lowest level consistent with maintenance of BP and good cardiovascular function.

Chronic adrenal insufficiency: Normal hydration and absence of orthostatic hypotension are criteria for adequate replacement therapy. Adequacy of mineralocorticoid replacement should be checked also by restoration of elevated levels of plasma renin activity to normal. Hydrocortisone 20 mg po is usually given in the morning and 10 mg in the afternoon. A daily dosage of 40 mg may be required. Night doses should be avoided, as they may produce insomnia. Normally, hydrocortisone is secreted maximally in the early morning hours and minimally at night. Additionally, fludrocortisone 0.1 mg to 0.2 mg po once/day is recommended. This mineralocorticoid replaces aldosterone, which is normally secreted in healthy persons. It is often necessary to reduce the initial dosage of fludrocortisone to 0.05 mg every 2nd day because of ankle edema, but the patient usually adjusts and can then take the larger doses. Fludrocortisone produces hypertension in some patients. This should be treated by reducing the dosage or starting a nondiuretic drug for hypertension. However, restoration of a normal renin level is the best proof of adequate treatment with fludrocortisone. There is a tendency to give too little fludrocortisone and to use too few modern hypotensive drugs. Intercurrent illnesses (eg, infections) should be regarded as potentially serious, and the patient should double his hydrocortisone dosage until he is well. If nausea and vomiting preclude oral therapy, medical attention should be sought immediately and parenteral therapy started. Patients living or traveling where medical care is not readily available should be instructed in self-administration of parenteral hydrocortisone.

Coexisting diabetes mellitus and Addison's disease: In this common manifestation of polyglandular deficiency syndrome, hydrocortisone dosage usually should not be > 30 mg/day; otherwise, insulin requirements are increased. It is often difficult to completely control hyperglycemia in this syndrome. In coexisting thyrotoxicosis and Addison's disease, definitive treatment for adrenal failure should be given early, without waiting for results from treatment of the thyroid disease. The patient should be maintained on oral hydrocortisone 20 to 30 mg/day after total bilateral adrenalectomy for hyperadrenocorticism, carcinoma of the breast, or hypertension. In addition, a mineralocorticoid should be given as described above.

SECONDARY ADRENAL INSUFFICIENCY

Adrenal hypofunction due to a lack of ACTH.

Adequacy of the hypothalamic-pituitary-adrenal axis during long-term steroid treatment can be determined by injecting 5 to 250 µg cosyntropin IV. Thirty minutes thereafter, the plasma cortisol level should be > 20 µg/dL (> 552 nmol/L). Isolated ACTH deficiency is idiopathic and extremely rare.

Symptoms and Signs

Patients with secondary adrenal insufficiency are not hyperpigmented, as are those with Addison's disease. They have relatively normal electrolyte levels. Hyperkalemia and elevated BUN generally are not present because of the near-normal secretion of aldosterone in these patients. Hyponatremia may occur on a dilutional basis. Persons with panhypopituitarism, however, have depressed thyroid and gonadal function and hypoglycemia, and coma may supervene when symptomatic secondary adrenal insufficiency occurs.

Diagnosis

Tests to differentiate primary and secondary adrenal insufficiency are discussed under Addison's Disease, above. Evidence of a pituitary mass or of pituitary atrophy strongly suggests secondary adrenal insufficiency.

Treatment

Treatment of secondary adrenal insufficiency is similar to that for Addison's disease. Each case varies regarding the type and degree of specific adrenocortical hormone deficiencies. Generally, fludrocortisone is not required, since aldosterone is produced. These patients may do better on lower doses of hydrocortisone than patients with primary insufficiency. During acute febrile illness or after trauma, patients receiving corticosteroids for nonendocrine disorders may require supplemental doses to augment their endogenous hydrocortisone production.

From The Merck Manual of Diagnosis and Therapy, Edition 17, edited by Mark H. Beers and Robert Berkow. Copyright 1999 by Merck & Co., Inc., Whitehouse Station, NJ.

 

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