Adrenal Insufficiency, Primary (Addison Disease)

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 ...