Adrenal Insufficiency, Primary (Addison Disease)

For further information, see CMDT Part 26-19: Primary Adrenal Insufficiency (Addison Disease)

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

  • Scleroderma

  • Amyloidosis

  • Hemochromatosis

• Drugs that cause primary adrenal insufficiency

  • Mitotane

  • Abiraterone acetate

Demographics

• Prevalence of about 140 per million

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

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, 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 to ≥ 20 mcg/dL

  • For patients taking corticosteroids, hydrocortisone must not be given for at least 8 h before test

  • Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol

  • Cosyntropin is usually well tolerated, but infrequent (< 5%) side effects have included hypersensitivity reactions with

    • Nausea

    • Headache

    • Dizziness

    • Dyspnea

    • Palpitations

    • Flushing

    • Edema

    • Local injection site reactions

• Serum DHEA levels < 1000 ng/mL (< 350 nmol/L) are found in 100% of patients with adrenal insufficiency and but also in about 15% of the general population, particularly children and elderly individuals

• Plasma ACTH is markedly elevated, generally > 200 pg/mL (> 44 pmol/L) if the patient has primary adrenal insufficiency

• Elevated plasma renin activity (PRA) indicates

  • Presence of depleted intravascular volume

  • Need for fludrocortisone administration

• In acute adrenal crisis, blood, sputum, or urine cultures may be positive if bacterial infection is the precipitating cause

Imaging Studies

• CT scan should be obtained when adrenal insufficiency is clearly not autoimmune

Medications

• If acute adrenal crisis is suspected

  • Draw blood sample for routine emergency laboratory tests, blood cultures, serum cortisol, and ACTH determinations

  • Without waiting for results, treat immediately with hydrocortisone phosphate 100–300 mg intravenously or hydrocortisone sodium succinate 100–300 mg intravenously and saline solution

• Then, continue hydrocortisone 50–100 mg every 6 hours intravenously for first day; dosage may be reduced according to clinical picture and laboratory test results

• Broad-spectrum antibiotics should be given empirically while waiting for initial culture results

• Electrolyte abnormalities, hypoglycemia, and dehydration must be treated, as indicated

• Glucocorticoid replacement therapy

  • Maintenance therapy for most patients involves 15–30 mg of hydrocortisone orally daily in 2–3 divided doses; eg, 10 mg at 7 AM, 10 mg at 1 PM, and 5 mg at 7 PM

    • Some patients respond better to 3-6 mg daily of prednisone or methylprednisolone in divided doses

    • Adjustments in dosage are made according to the clinical response

  • Plenadren MR (5 or 20 mg modified-release tablets)

    • A once-daily dual-release preparation of hydrocortisone that may be administered once daily in the morning (usual dose range is 20–30 mg daily)

    • May improve quality of life in some patients with adrenal insufficiency

    • Not available in the United States but is available in Canada and elsewhere

  • Glucocorticoid dosing should be increased in following circumstances:

    • Presence of infection or trauma

    • Surgery or stressful diagnostic procedures are required (example dosage: hydrocortisone, 50–100 mg intravenously or intramuscularly, followed by 50 mg every 6 hours)

    • Administration of rifampin

    • Patient in third trimester of pregnancy

  • Glucocorticoid dosing should be decreased when medications are prescribed that inhibit glucocorticoid metabolism by blocking the isoenzyme CYP34A (particularly ketoconazole or itraconazole, nefazadone, anti-HIV protease inhibitors, and cobistat)

• For immunizations that are given with an adjuvant, such as varicella zoster (Shingrix), there is sufficient local inflammation that an increased dose of hydrocortisone is recommended for 4–5 days following the immunization

• Mineralocorticoid therapy

  • Not needed when large amounts of hydrocortisone are being given

  • However, as the dose is reduced, may need to add fludrocortisone, 0.05–0.2 mg once daily orally

  • Some patients never require fludrocortisone or become edematous at doses > 0.05 mg once or twice weekly

• DHEA

  • Women taking DHEA 50 mg orally each morning experienced an improved sense of well-being, increased muscle mass, and a reversal in bone loss at the femoral neck

  • Did not improve fatigue, cognitive problems, or sexual dysfunction

  • Older women who receive DHEA should be monitored for androgenic effects

Therapeutic Procedures

• Once the crisis is over, must assess degree of permanent adrenal insufficiency and establish cause if possible

Follow-Up

• Repeat cosyntropin stimulation test

Complications

• Shock and death if untreated

• Sequelae of infection that commonly precipitate adrenal crisis

Prognosis

• Rapid treatment usually lifesaving

• Frequently unrecognized and untreated since manifestations mimic more common conditions

• Lack of treatment leads to shock that is unresponsive to volume replacement and vasopressors, resulting in death