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

• Hyponatremia; hyperkalemia; hypoglycemia; eosinophilia

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

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

General Considerations

• Primary adrenal insufficiency (Addison disease)

  • Dysfunction or absence of the adrenal cortices

  • Chronic deficiency of cortisol

  • Plasma ACTH and α- melanocyte-stimulating hormone (MSH) levels are consequently elevated, which can cause hyperpigmentation

  • Associated with mineralocorticoid deficiency, typically with hyponatremia, volume depletion, and hyperkalemia

• Secondary adrenal insufficiency

  • Consequence of deficient secretion of ACTH

  • Mineralocorticoid deficiency is not present

• 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

  • Usual precipitants are

    • Severe stress (eg, infection, trauma, surgery, hyperthyroidism, or prolonged fasting)

    • Minor stress (eg, vaccinations) in patients with latent or treated adrenal insufficiency

    • Hyperthyroidism or thyroid hormone replacement in patients with untreated adrenal insufficiency

    • Nonadherence to glucocorticoid replacement or sudden withdrawal of adrenocortical hormone in patients with adrenal insufficiency

    • Bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal gland

    • Sudden destruction of the pituitary gland (pituitary necrosis) or damage to both adrenals (by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma)

    • Intravenous etomidate (used for rapid anesthesia induction or intubation)

• Causes of primary adrenal insufficiency

  • Autoimmunity

    • Accounts for about 90% of spontaneous cases in industrialized countries

    • 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

    • Causative neoplasms: lymphomas, breast and lung cancer

    • Causative infections: tuberculosis, coccidiomycosis, histoplasmosis, cytomegalovirus, cryptococcus, syphilis

  • Infections of the adrenal glands

    • Nearly half of patients with untreated HIV infection have cytomegalovirus infection of the adrenals; much lower percentage have clinical Addison disease

  • Bilateral adrenal hemorrhage is associated with

    • Sepsis, heparin-associated thrombocytopenia, anticoagulation, or antiphospholipid antibody syndrome

    • Major surgery or trauma (presents about 1 week later with pain, fever, and shock)

    • Spontaneous bleed, presenting with flank pain

    • Meningococcemia: purpura and adrenal insufficiency from adrenal infarction (Waterhouse-Friderichsen syndrome)

  • 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 HIV)

  • Syphilitic gummas

  • Systemic sclerosis (scleroderma)

  • Amyloidosis

  • Hemochromatosis

• Medications that cause primary adrenal insufficiency

  • Mitotane

  • Abiraterone acetate

  • Tyrosine kinase inhibitors Lenvatinib and vandetanib

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

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