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Key Features

Essentials of Diagnosis

  • Deficiency of cortisol and mineralocorticoid from destruction of the adrenal cortex

  • Weakness, vomiting, diarrhea; abdominal pain, arthralgias; amenorrhea

  • Increased skin pigmentation, especially of creases, pressure areas, and nipples

  • Hypovolemic hypotension, small heart

  • Hyponatremia; hyperkalemia (may be absent with vomiting and diarrhea); hypoglycemia; eosinophilia

  • Elevated plasma ACTH level; cosyntropin unable to stimulate serum cortisol to 20 mcg/dL (550 nmol/L) or more

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

General Considerations

  • Refers to chronic deficiency of cortisol caused by adrenocortical insufficiency

  • 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

    • Bilateral adrenal infiltrative diseases

      • Cause primary adrenal insufficiency

      • Causative neoplasms include lymphomas, breast cancer, and lung cancer

    • Infections

      • Tuberculosis

      • Coccidiomycosis

      • Histoplasmosis

      • Cytomegalovirus

      • Cryptococcus

      • Syphilitic gummas

    • 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

    • Scleroderma

    • Amyloidosis

    • Hemochromatosis

  • Drugs that cause primary adrenal insufficiency include

    • Mitotane

    • Abiraterone acetate

    • Lenvatinib

    • Vandetanib

Demographics

  • Prevalence of about 90–140 per million

  • Annual incidence of about 5–6 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

Diagnosis

Laboratory Tests

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

  • Mild anemia, moderate neutropenia, lymphocytosis, and eosinophilia (total eosinophil count > 300/mcL)

  • Hyponatremia or hyperkalemia (or both) usually present

  • Hypoglycemia common

  • Hypercalcemia may be present

  • Blood, sputum, or urine culture may be positive if bacterial infection is precipitating cause

  • Cosyntropin stimulation test

    • Synthetic cosyntropin, 0.25 mg, given intramuscularly

    • Serum cortisol obtained 30–60 min later

    • Normally, cortisol rises ...

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