- Primary adrenal gland insufficiency, which results 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; typical age of presentation is 30 to 50 years.
- Predominant sex: females > males (slight)
- No racial predilection
10 to 14: 100,000
Etiology and Pathophysiology
- Autoimmune adrenal insufficiency (~80% of cases in the United States)
- Infectious causes: TB (most common infectious cause worldwide), HIV (most common infectious cause in the United States, often with concomitant infections such as cytomegalovirus), Waterhouse-Friderichsen syndrome (most commonly meningococcus), fungal disease
- Bilateral adrenal hemorrhage and infarction (for patients on anticoagulants, 50% are in the therapeutic range)
- Antiphospholipid antibody syndrome
- Lymphoma, Kaposi sarcoma, metastasis (lung, breast, kidney, colon, melanoma); tumor must destroy 90% of gland to produce hypofunction
- Drugs (e.g., ketoconazole, fluconazole, 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 autoimmune syndromes 1 and 2, adrenoleukodystrophy
- Destruction of the adrenal cortex resulting in deficiencies in cortisol, aldosterone, and androgens
- Autoimmune polyglandular syndrome (APS) type 2 genetics are complex and are associated with adrenal insufficiency, type 1 diabetes, and Hashimoto disease. APS type 2 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)
- 40% of patients have a first- or second-degree relative with associated disorders.
- Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures
- 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.
Commonly Associated Conditions
- Diabetes mellitus
- Graves disease
- Hashimoto 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 of high friction areas (extensor surfaces, plantar or palmar creases, dental-gingival margins, buccal and vaginal mucosae, lips, areolae, pressure points, scars, “tanning,” freckles)
- Hair loss in females
- 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-Jeghers syndrome
- Porphyria cutanea tarda
- Salt-losing nephritis
- Bronchogenic carcinoma
- Anorexia nervosa
Diagnostic Tests & InterpretationInitial Tests (lab, imaging)
- Basal plasma cortisol and adrenocorticotropic hormone (ACTH) (low cortisol and high ACTH indicative of Addison disease) (1)[C]
- Low serum sodium
- Elevated serum potassium
- Elevated BUN, creatinine, calcium, thyroid-stimulating hormone (TSH)
- Hypoglycemia when fasting
- Metabolic acidosis
- Moderate neutropenia
- Relative lymphocytosis
- Anemia, normochromic, normocytic
Follow-Up Tests & Special Considerations
- 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 appropriately) (1)[C].
- Check plasma ACTH with baseline or AM cortisol level; in confirmed cortisol deficiency, ACTH > 2xULN consistent with Addison disease
- Plasma renin and aldosterone levels to determine mineralocorticoid deficiency
- Insulin-induced hypoglycemia test
- Autoantibody tests: 21-hydroxylase (most common and specific), 17-hydroxylase, 17-α-hydroxylase (may not be associated), and adrenomedullin
- Circulating very-long-chain fatty acid levels if boy or young man to screen for adrenoleukodystrophy
- Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring of replacement therapy.
- 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
- Abdominal CT scan: small adrenal glands in autoimmune adrenalitis; enlarged adrenal glands may be seen 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.
- CT-guided fine-needle biopsy of adrenal masses may identify diagnoses.
- Atrophic adrenals in autoimmune adrenalitis
- Infiltrative and hemorrhagic disorders often produce enlargement with destruction of the entire gland.
Consider the 5 S’s 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)
- Chronic adrenal insufficiency
- Glucocorticoid supplementation (2)[A]
- Dosing: hydrocortisone 15 to 25 mg (or therapeutic equivalent) PO in 2 to 4 divided doses (with the highest dose given in the morning upon rising); dosage may vary and is usually lower in children and the elderly.
- Continuous subcutaneous hydrocortisone infusion may more effectively normalize circadian ACTH and cortisol levels, with less depression and improved daytime energy; may also result in improved glucose homeostasis (3)[A]
- 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 to 0.20 mg/day PO taken in morning
- Assess clinically (salt craving, orthostatic hypotension, edema).
- May require salt supplementation
- Glucocorticoid supplementation (2)[A]
- Addisonian crisis
- Hydrocortisone100 mg IV injection followed by hydrocortisone 200 mg IV over 24 hours (by continuous infusion or dosed every 6 hours) and then 100 mg/day on following day based on clinical status
- IV glucose, saline, and plasma expanders
- Fludrocortisone is typically not required as 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 minor-moderate surgical procedures
- Administer hydrocortisone 25 to 75 mg IV/day or methylprednisolone 5 to 30 mg IV on the day of the procedure in addition to maintenance therapy; taper gradually to the usual dose over 1 to 2 days.
Addition of androgen therapy:
- Dehydroepiandrosterone (DHEA) 25 to 50 mg PO once daily is sufficient to restore androgen levels to within normal range with minimal side effects.
- DHEA is of limited clinical benefit and thus not routinely recommended (4)[A].
- May be appropriate to improve quality of life and libido in select women (5)[A]
Admission criteria/initial stabilization
- Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia
- ICU admission for unstable cases
- Addisonian crisis:
- Airway, breathing, and circulation management
- Establish IV access; 5% dextrose and normal saline
- Administer hydrocortisone 100 mg IV bolus then hydrocortisone 200 mg IV over 24 hours continuous infusion or dosed q6.
- Correct electrolyte abnormalities.
- BP support for hypotension
- Antibiotics if infection suspected
- Supplementation for major surgery with general anesthesia, trauma, ICU: hydrocortisone 100 mg IV injection then 200 mg IV over 24 hours followed by rapid taper
- 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
- Monitor for development of new autoimmune diseases such as autoimmune thyroiditis, autoimmune gastritis and celiac disease.
Maintain water, sodium, and potassium balance.
- National Adrenal Diseases Foundation, Great Neck, NY 11021, (516) 487-4992 (http://www.nadf.us/)
- Patient should wear or carry medical identification about the disease and the need for hydrocortisone or other replacement therapy.
- Steroid card samples http://www.ese-hormones.org/professional/docs/ExistingEmergencyCards.pdf
- 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
- A18.7 Tuberculosis of adrenal glands
- E27.1 Primary adrenocortical insufficiency
- E27.2 Addisonian crisis
- 017.60 Tuberculosis of adrenal glands, unspecified
- 255.41 Glucocorticoid deficiency
- 186270000 Tuberculous Addison’s disease
- 237760008 Addison’s disease with adrenoleucodystrophy (disorder)
- 24867002 Severe adrenal insufficiency (disorder)
- 363732003 Addison’s disease (disorder)
- 76715008 Addison’s disease due to autoimmunity (disorder)
- 80% of cases are caused by an autoimmune process; the average age of diagnosis in adults is 40 years.
- Consider the 5 S’s 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 consistently correlate with treatment and should not be used alone 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.
Tya-Mae Y. Julien, MD
- Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. [PMID:26760044]
- Ekman B, Bachrach-Lindström M, Lindström T, et al. A randomized, double-blind, crossover study comparing two- and four-dose hydrocortisone regimen with regard to quality of life, cortisol and ACTH profiles in patients with primary adrenal insufficiency. Clin Endocrinol (Oxf). 2012;77(1):18–25. [PMID:22288685]
- Björnsdottir S, Øksnes M, Isaksson M, et al. Circadian hormone profiles and insulin sensitivity in patients with Addison’s disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid therapy. Clin Endocrinol(Oxf). 2015;83(1):28–35. [PMID:25400085]
- Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J Clin Endocrine Metab. 2009;94(10):3676–3681. [PMID:19773400]
- McHenry CM, Bell PM, Hunter SJ, et al. Effects of dehydroepiandrosterone sulfate (DHEAS) replacement on insulin action and quality of life in hypopituitary females: a double-blind, placebo-controlled study. Clin Endocrinol (Oxf). 2012;77(3):423–429. [PMID:22420492]
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