Sections View Full Chapter Figures Tables Videos Full Chapter Figures Tables Videos Supplementary Content + Print Section ++ For further information, see CMDT Part 26-19: Primary Adrenal Insufficiency (Addison Disease) + Key Features Print Section ++ ++ 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 + Clinical Findings Print Section ++ ++ 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 Print Section ++ ++ 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 + Treatment Print Section ++ ++ 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 + Outcome Print Section ++ ++ 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 + References Print Section ++ + +Bensing S et al. Epidemiology, quality of life and complications of primary adrenal insufficiency: a review. Eur J Endocrinol. 2016 Sep;175(3):R107–16. [PubMed: 27068688] + +Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364–89. [PubMed: 26760044] + +Cadegiani FA et al. Adrenal fatigue does not exist: a systematic review. BMC Endocr Disord. 2016 Aug 24;16(1):48. Erratum in: BMC Endocr Disord. 2016 Nov 16;16(1):63. [PubMed: 27557747] + +Esposito D et al. Primary adrenal insufficiency: managing mineralocorticoid replacement therapy. J Clin Endocrinol Metab. 2018 Feb 1;103(2):376–87. [PubMed: 29156052] + +Hahner S. Acute adrenal crisis and mortality in adrenal insufficiency: still a concern in 2018! Ann Endocrinol (Paris). 2018 Jun;79(3):164–6. [PubMed: 29716733] + +Ospina NS et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016 Feb;10(2):427–34. [PubMed: 26649617] + +Speiser PW et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Nov;103(11):4043–88. [PubMed: 30272171]