- Adrenal gland insufficiency from partial or complete destruction of the adrenal cells with inadequate secretion of glucocorticoids and mineralocorticoids
- 80% of cases are caused by an autoimmune process, followed by tuberculosis (TB), AIDS, systemic fungal infections, and adrenoleukodystrophy
- Addison disease (primary adrenocortical insufficiency) can be differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes because mineralocorticoid function usually remains intact in secondary and tertiary causes.
- Addisonian (adrenal) crisis: Acute complication of adrenal insufficiency (circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia); usually precipitated by an acute physiologic stressor(s) such as surgery, illness, exacerbation of comorbid process, and/or acute withdrawal of long-term corticosteroid therapy
- System(s) affected: Endocrine/Metabolic
- Synonym(s): Adrenocortical insufficiency; Corticoadrenal insufficiency; Primary adrenocortical insufficiency
- Predominant age: All ages; mean age at diagnosis in adults is 40 years
- Predominant sex: Females > Males (slight)
- 40% of patients have a 1st- or 2nd-degree relative with associated disorders.
- Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures
- Autoimmune polyglandular syndrome (APS) type 2 genetics are complex. It is associated with adrenal insufficiency, type 1 diabetes, and Hashimoto disease. It is more common than APS type 1.
- APS type 1 is caused by mutations of the autoimmune regulator gene. Nearly all have the following triad: Adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis before adulthood.
- Adrenoleukodystrophy is an X-linked recessive disorder resulting in toxic accumulation of unoxidized long-chain fatty acids.
- Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA-4)
- No preventive measures known for Addison disease; focus on prevention of complications:
- Anticipate adrenal crisis and treat before symptoms begin.
- Elective surgical procedures require upward adjustment in steroid dose.
Destruction of the adrenal cortex resulting in deficiencies in cortisol, aldosterone, and androgens
- Autoimmune adrenal insufficiency (80% of cases in the US)
- Infectious causes: TB (most common infectious cause worldwide), HIV (most common infectious cause in the US), Waterhouse-Fredrickson syndrome, fungal disease
- Bilateral adrenal hemorrhage and infarction (for patients on anticoagulants, 50% are in the therapeutic range)
- Antiphospholipid syndrome
- Lymphoma, Kaposi sarcoma, metastasis (lung, breast, kidney, colon, melanoma); tumor must destroy 90% of gland to produce hypofunction
- Drugs (ketoconazole, etomidate)
- Surgical adrenalectomy, radiation therapy
- Sarcoidosis, hemochromatosis, amyloidosis
- Congenital enzyme defects (deficiency of 21-hydroxylase enzyme is most common), neonatal adrenal hypoplasia, congenital adrenal hyperplasia, familial glucocorticoid insufficiency, autoimmune polyglandular syndromes 1 and 2, adrenoleukodystrophy
Commonly Associated Conditions
- Diabetes mellitus
- Graves disease
- Hashimoto's thyroiditis
- Ovarian failure
- Pernicious anemia
- Myasthenia gravis
- Chronic moniliasis
- Sjögren syndrome
- Chronic active hepatitis
- Schmidt syndrome
- Weakness, fatigue
- Anorexia, nausea, vomiting
- Abdominal pain
- Chronic diarrhea
- Depression (60–80% of patients)
- Decreased cold tolerance
- Salt craving
- Weight loss
- Low BP, orthostatic hypotension
- Increased pigmentation (extensor surfaces, hand creases, dental-gingival margins, buccal and vaginal mucosa, lips, areola, pressure points, scars, “tanning,” freckles)
- Hair loss in females
Diagnostic Tests and Interpretation
- Basal plasma cortisol and adrenocorticotropic hormone (ACTH) (low cortisol and high ACTH indicative of Addison disease)
- Standard ACTH stimulation test: Cosyntropin 0.25 mg IV, measure preinjection baseline and 60-minute postinjection cortisol levels (patients with Addison disease have low to normal values that do not rise)
- Insulin-induced hypoglycemia test
- Metapyrone test
- Autoantibody tests: 21-hydroxylase (most common and specific), 17-hydroxylase, 17-alpha-hydroxylase (may not be associated), and adrenomedullin
- Circulating very-long-chain fatty acid levels if boy or young man
- Low serum sodium
- Elevated serum potassium
- Elevated BUN, creatinine, calcium, thyroid-stimulating hormone (TSH)
- Low serum aldosterone
- Hypoglycemia when fasting
- Metabolic acidosis
- Moderate neutropenia
- Relative lymphocytosis
- Anemia, normochromic, normocytic
- Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring of replacement therapy (1)[C].
- TSH: Repeat when condition has stabilized:
- Thyroid hormone levels may normalize with the treatment of Addison disease.
- Drugs that may alter lab results: Digitalis
- Disorders that may alter lab results: Diabetes
Initial Imaging Approach
- Abdominal CT scan: Small adrenal glands in autoimmune adrenalitis; enlarged adrenal glands in infiltrative and hemorrhagic disorders
- Abdominal radiograph may show adrenal calcifications.
- Chest x-ray may show small heart size and/or calcification of cartilage.
- MRI of pituitary and hypothalamus if secondary or tertiary cause of adrenocortical insufficiency is suspected
- Atrophic adrenals in autoimmune adrenalitis
- Infiltrative and hemorrhagic disorders produce enlargement with destruction of the entire gland.
- Secondary adrenocortical insufficiency (pituitary failure):
- Withdrawal of long-term corticosteroid use
- Sheehan syndrome (postpartum necrosis of pituitary)
- Empty sella syndrome
- Radiation to pituitary
- Pituitary adenomas, craniopharyngiomas
- Infiltrative disorders of pituitary (sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X)
- Tertiary adrenocortical insufficiency (hypothalamic failure):
- Pituitary stalk transection
- Disruption of production of corticotropic-releasing factor
- Hypothalamic tumors
- Syndrome of inappropriate antidiuretic hormone
- Heavy-metal ingestion
- Severe nutritional deficiencies
- Sprue syndrome
- Peutz-Jegher syndrome
- Porphyria cutanea tarda
- Salt-losing nephritis
- Bronchogenic carcinoma
- Anorexia nervosa
- Chronic adrenal insufficiency:
- Glucocorticoid supplementation:
- Dosing: Hydrocortisone 15–20 mg (or therapeutic equivalent) PO each morning upon rising and 10 mg at 4–5 PM each afternoon (3)[C]; dosage may vary and is usually lower in children and the elderly
- Precautions: Hepatic disease, fluid disturbances, immunosuppression, peptic ulcer disease, pregnancy, osteoporosis
- Adverse reactions: Immunosuppression, osteoporosis, gastric ulcers, depression, hyperglycemia, weight gain, glaucoma
- Drug interactions: Concomitant use of rifampin, phenytoin, or barbiturates
- Mineralocorticoid supplementation:
- Dosing: Fludrocortisone 0.05–0.2 mg/d PO
- May require salt supplementation
- Glucocorticoid supplementation:
- Addisonian crisis:
- Hydrocortisone 100 mg IV followed by 10 mg/hr infusion, or hydrocortisone 100 mg IV bolus q6–8h
- IV glucose, saline, and plasma expanders
- Fludrocortisone 0.05 mg/d PO (may not be required; high-dose hydrocortisone is an effective mineralocorticoid)
- Acute illnesses (fever, stress, minor trauma):
- Double the patient’s usual steroid dose, taper the dose gradually over a week or more, and monitor vital signs and serum sodium.
- Supplementation for surgical procedures:
- Administer hydrocortisone 25–150 mg or methylprednisolone 5–30 mg IV on the day of the procedure in addition to maintenance therapy; taper gradually to the usual dose over 1–2 days.
Addition of androgen therapy:
Consider the 5 Ss for the management of adrenal crisis:
- Salt, sugar, steroids, support, and search for a precipitating illness (usually infection, trauma, recent surgery, or not taking prescribed replacement therapy)
- Airway, breathing, and circulation management
- Establish IV access; 5% dextrose and normal saline.
- Administer hydrocortisone 100 mg IV bolus q6–8h; replacement with fludrocortisone is not necessary (high-dose hydrocortisone is an effective mineralocorticoid).
- Correct electrolyte abnormalities.
- BP support for hypotension
- Antibiotics if infection suspected
- Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia
- Intensive care unit admission for unstable cases
IV saline containing 5% dextrose and plasma expanders
- Verify adequacy of therapy: Normal BP, serum electrolytes, plasma renin, and fasting blood glucose level
- Periodically assess for the development of long-term complications of corticosteroid use, including screening for osteoporosis, gastric ulcers, depression, and glaucoma.
- Lifelong medical supervision for signs of adequate therapy and avoidance of overdose
Maintain water, sodium, and potassium balance.
- National Adrenal Disease Foundation, Great Neck, NY 11021, (516) 487-4992 ( http://www.medhelp.org/nadf)
- Patient should wear or carry medical identification about the disease and the need for hydrocortisone or other replacement therapy.
- Instruct patient in self-administration of parenteral hydrocortisone for emergency situations.
Requires lifetime treatment: Life expectancy approximates normal with adequate replacement therapy; without treatment, the disease is 100% lethal.
- Psychotic reactions
- Complications from underlying disease
- Over- or underuse of steroid treatment
- Hyperkalemic paralysis (rare)
- Addisonian crisis
- 017.60 Tuberculosis of adrenal glands, unspecified
- 255.41 Glucocorticoid deficiency
- E27.1 Primary adrenocortical insufficiency
- A18.7 Tuberculosis of adrenal glands
- 363732003 Addison's disease (disorder)
- 186270000 Tuberculous Addison's disease
- 237760008 Addison's disease with adrenoleucodystrophy (disorder)
- 80% of cases are caused by an autoimmune process; the average age of diagnosis in adults is 40 years.
- Consider the 5 Ss for the management of Addison disease: Salt, sugar, steroids, support, and search for an underlying cause.
- The goal of steroid replacement therapy should be the lowest dose that alleviates patient symptoms while preventing adverse drug events.
- Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring for efficacy of replacement therapy.
- Long-term use of steroids predisposes patients to the development of osteoporosis; screen accordingly and encourage calcium and vitamin D supplementation.
Michele L. Matthews, PharmD, CPE, BCACP
- Nieman LK, Chanco Turner ML. Addison's disease. Clin Dermatol. 2006;24:276–280. [PMID:16828409]
- Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335:1206–1212. [PMID:8815944]
- Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002;287:236–240. [PMID:11779267]
- Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. 1999;341:1013–1020. [PMID:10502590]
© Wolters Kluwer Health Lippincott Williams & Wilkins