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Addison Disease



  • 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
  • Idiopathic
  • 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)

Risk Factors

  • 40% of patients have a first- or second-degree relative with associated disorders.
  • Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures

General Prevention

  • 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
  • Hypoparathyroidism
  • Hypercalcemia
  • Ovarian failure
  • Pernicious anemia
  • Myasthenia gravis
  • Vitiligo
  • Chronic moniliasis
  • Sarcoidosis
  • Sjögren syndrome
  • Chronic active hepatitis
  • Schmidt syndrome



  • Weakness, fatigue
  • Dizziness
  • Anorexia, nausea, vomiting
  • Abdominal pain
  • Chronic diarrhea
  • Depression (60–80% of patients)
  • Decreased cold tolerance
  • Salt craving

Physical Exam

  • 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)
  • Vitiligo
  • Hair loss in females

Differential Diagnosis

  • 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
    • Trauma
    • Disruption of production of corticotropic-releasing factor
    • Hypothalamic tumors
  • Other
    • Myopathies
    • Syndrome of inappropriate antidiuretic hormone
    • Heavy metal ingestion
    • Severe nutritional deficiencies
    • Sprue syndrome
    • Hyperparathyroidism
    • Neurofibromatosis
    • Peutz-Jeghers syndrome
    • Porphyria cutanea tarda
    • Salt-losing nephritis
    • Bronchogenic carcinoma
    • Anorexia nervosa

Diagnostic Tests & Interpretation

Initial 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
  • Eosinophilia
  • 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
Diagnostic Procedures/Other
  • 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.
Test Interpretation
  • Atrophic adrenals in autoimmune adrenalitis
  • Infiltrative and hemorrhagic disorders often produce enlargement with destruction of the entire gland.


General Measures

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)


First Line
  • 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
  • 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.

Second Line

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]

Inpatient Considerations

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

Ongoing Care

Follow-up Recommendations

  • 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.

Patient Education


Requires lifetime treatment: Life expectancy approximates normal with adequate replacement therapy; without treatment, the disease is 100% lethal.


  • Hyperpyrexia
  • Psychotic reactions
  • Complications from underlying disease
  • Over- or underuse of steroid treatment
  • Hyperkalemic paralysis (rare)
  • Addisonian crisis

Additional Reading

See Also

Algorithm: Adrenocortical Insufficiency



  • 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)

Clinical Pearls

  • 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


  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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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Stephens, Mark B., et al., editors. "Addison Disease." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116008/all/Addison_Disease.
Addison Disease. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116008/all/Addison_Disease. Accessed April 25, 2019.
Addison Disease. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116008/all/Addison_Disease
Addison Disease [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 April 25]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116008/all/Addison_Disease.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Addison Disease ID - 116008 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116008/all/Addison_Disease PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -