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Key Features

Essentials of Diagnosis

  • Weakness, fatigue, weight loss; nausea, vomiting, diarrhea; abdominal pain, arthralgias; amenorrhea

  • Sparse axillary hair; increased skin pigmentation, especially of creases, pressure areas, and nipples

  • Hypotension, small heart

  • Hyponatremia; potassium, calcium, and BUN elevated; mild anemia and relative neutropenia, lymphocytosis, and eosinophilia

  • Plasma ACTH level elevated; cosyntropin unable to stimulate serum cortisol to ≥ 20 mcg/dL (550 nmol/L)

  • Acute adrenal crisis: above manifestations become critical, along with fever, shock, confusion, coma, death

General Considerations

  • Characterized by a chronic deficiency of cortisol; can present acutely but usually presents gradually over months or years

  • Acute adrenal (Addisonian) crisis

    • An emergency caused by insufficient cortisol

    • May occur in the course of treatment of chronic adrenal insufficiency

    • May be the presenting manifestation of adrenal insufficiency

  • Causes of primary adrenal insufficiency

    • Autoimmunity

      • Accounts for about 90% of spontaneous cases

      • Over half the cases of autoimmune Addison disease occur as part of autoimmune polyendocrine syndrome type-I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome

    • Infection

      • Relatively rare cause of primary adrenal insufficiency

      • Tuberculosis is the most common infection of the adrenals

      • Coccidioidomycosis and other infections are rare

    • Bilateral adrenal hemorrhage

    • Adrenoleukodystrophy

    • Congenital adrenal insufficiency occurs in several conditions

      • Familial glucocorticoid deficiency

      • Triple A (Allgrove) syndrome

      • Congenital adrenal hypoplasia

  • Rare causes of primary adrenal insufficiency

    • Lymphoma, metastatic carcinoma

    • Coccidioidomycosis, histoplasmosis, cytomegalovirus infection (more frequent in patients with AIDS)

    • Syphilitic gummas

    • Systemic sclerosis (scleroderma)

    • Amyloidosis

    • Hemochromatosis

  • Medications that cause primary adrenal insufficiency

    • Mitotane

    • Abiraterone acetate

  • Patients with treated chronic adrenal insufficiency appear to be more prone to develop pneumonia and gastrointestinal and urinary tract infections


  • Prevalence is about 90–140 cases per million

  • Annual incidence is about 5 per million in the United States

Clinical Findings

Symptoms and Signs

  • Abdominal pain, nausea, and vomiting; diarrhea can occur

  • Fevers and lymphoid tissue hyperplasia may also occur

  • Arthralgias, myalgias, chest pain, abdominal pain, back pain, leg pain, or headache

  • Psychiatric symptoms: anxiety, irritability, and depression

  • Low and orthostatic blood pressure

  • Skin hyperpigmentation and scant axillary and pubic hair

  • Anovulation and reduced fertility

  • Recurrent hypoglycemia and reduced insulin requirements in patients with preexisting type 1 diabetes mellitus

Differential Diagnosis

  • Other cause of shock

    • Sepsis

    • Cardiogenic

    • Hypovolemic

  • Hyperkalemia due to other cause (see Hyperkalemia)

  • Hyponatremia due to other cause (see Hyponatremia)

  • Abdominal pain due to other cause


Laboratory Tests

  • One or more serum anti-adrenal antibodies are found in about 50% of cases of autoimmune disease

  • Moderate neutropenia, lymphocytosis, and eosinophilia (total eosinophil count > 300/mcL)

  • Hyponatremia or hyperkalemia (or both) usually present

  • Hypoglycemia common

  • Hypercalcemia may be present

  • Blood, ...

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