Addison Disease



  • Primary adrenal gland insufficiency, which results from partial or complete (>90%) 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 mineralocorticoids are intact in secondary and tertiary.
  • 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 (defined as >3 months use of steroid)
  • 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 and children > males (slight)
  • No racial predilection


40 to 60 cases in 1 million population

Etiology and Pathophysiology

  • Autoimmune adrenal insufficiency (~80% in United States)
  • Infectious causes: TB (most common cause worldwide), HIV (most common infectious cause in 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)
  • 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, methadone, mitotane, megestrol, medroxyprogesterone acetate, chronic opiate use, metyrapone, aminoglutethimide)
  • 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
  • Abnormalities of β-oxidation of very long–chain fatty acids, most common cause of adrenal insufficiency in male child <7 years of age
  • 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.
  • 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

  • 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
  • Anorexia, nausea, vomiting
  • Abdominal pain
  • Chronic diarrhea
  • Depression (60–80% of patients)
  • Decreased cold tolerance
  • Salt craving
  • Myalgia, flaccid muscle paralysis (hyperkalemia)
  • Heightened sense of smell, taste, hearing
  • Hypoglycemic episodes
  • Decreased libido and impotence
  • Amenorrhea

Physical Exam

  • Weight loss
  • Low blood pressure (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
  • Calcification of ear and costochondral junctions is a rare physical finding.

Differential Diagnosis

  • Secondary adrenocortical insufficiency (pituitary failure)
    • Withdrawal of long-term corticosteroid use
    • Sheehan syndrome (postpartum necrosis of pituitary)
    • Empty sella syndrome
    • Apoplexy
    • Infections/abscess
    • Genetic mutations
    • Radiation to pituitary
    • Pituitary adenomas, craniopharyngiomas
    • Infiltrative disorders of pituitary (hypophysitis, sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X)
  • Tertiary adrenocortical insufficiency (hypothalamic failure)
    • Pituitary stalk transection
    • Trauma
    • Disruption of production of corticotropic-releasing factor
    • Hypothalamic tumors
    • Metastatic tumors in lung, breast, etc.
    • Radiation for CNS and nasopharyngeal malignancies
    • Tuberculous meningitis
    • Stroke, TBI
    • Infiltrative disorders (sarcoidosis, Langerhans cell histiocytosis)

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 potassium
  • Elevated BUN, creatinine, calcium, thyroid-stimulating hormone (TSH)
  • Hypoglycemia when fasting
  • Nonanion gap metabolic acidosis
  • Elevated urine sodium
  • Decreased GFR
  • Elevated prolactin levels (due to hyperresponsiveness of the lactotroph to TRH in the absence of steroid-induced or steroid-enhanced hypothalamic dopaminergic tone)
  • Moderate neutropenia; eosinophilia; relative lymphocytosis
  • Anemia, normochromic, normocytic

Follow-Up Tests & Special Considerations

  • Standard ACTH stimulation test: cosyntropin 0.25 mg IV or IM; 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
  • TSH: Thyroid hormone levels may normalize with the treatment of Addison disease.

Diagnostic Procedures/Other

  • Abdominal CT scan: small adrenal glands in autoimmune adrenalitis; enlarged adrenal glands may be seen in infiltrative and hemorrhagic disorders.
  • Abdominal x-ray may show adrenal calcifications.
  • Chest x-ray may show small heart size and/or calcification of cartilage; evidence of TB or fungal infection may be seen on chest x-ray.
  • MRI of pituitary and hypothalamus if secondary or tertiary cause is suspected
  • CT-guided fine-needle biopsy of adrenal masses may identify diagnoses.
  • ECG: low voltage QRS with nonspecific ST-T changes due to hyperkalemia

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
    • 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
  • Large-bore IV access for fluid resuscitation with isotonic normal saline to restore volume deficit and correct hypotension
    • Hydrocortisone 100 mg in 100 cc of isotonic saline IV injection followed by hydrocortisone 200 mg IV over 24 hours (by continuous infusion at the rate of 10 to 12 cc per hour or dosed as a bolus of 100 mg every 6 to 8 hours and then 100 mg/day on following day based on clinical status)
    • Clinical improvement, especially BP response, evident in 4 to 6 hours of hydrocortisone infusion
    • After 2 to 3 days, the stress hydrocortisone dose should be reduced to 100 to 150 μg infused over 24 hours to avoid stress GI bleed.
    • Fludrocortisone is typically not required because high-dose hydrocortisone is an effective mineralocorticoid.
  • Acute illnesses (fever, stress, minor trauma)—double the patient’s usual steroid dose, taper the dose gradually, and monitor vital signs and serum sodium.
  • Supplementation for minor to moderate surgical procedures
    • Administer hydrocortisone 25 to 75 mg/day IV 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 selected women (5)[A]

Admission, Inpatient, and Nursing Considerations

Admission criteria/initial stabilization

  • Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia
  • Addisonian crisis:
    • Airway, breathing, and circulation management
    • IV saline containing 5% dextrose and plasma expanders
    • Administer hydrocortisone 100 mg IV bolus and 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 and then 200 mg IV over 24 hours followed by rapid taper

Ongoing Care

Follow-up Recommendations

  • Monitor BP, electrolytes, plasma renin, and fasting blood glucose level.
  • Periodically evaluate for long-term complications of corticosteroid use; screen 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

  • National Adrenal Diseases Foundation, Great Neck, NY 11021, (516) 487-4992 (
  • Patient should wear or carry medical identification about the disease and the need for hydrocortisone or other replacement therapy.
  • Steroid card samples:
  • Instruct patient in self-administration of parenteral hydrocortisone for emergency situations. Patient should be instructed to double or triple their steroid replacement in stressful situations like common cold, tooth extraction, etc. They should be instructed how to give themselves IM injection.


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



  • 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.


Sara Bakhtiar, MBBS
Sahil Mullick, 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 replacement 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 Endocrinol Metab. 2009;94(10):3676–3681. [PMID:19773400]
  5. McHenry CM, Bell PM, Hunter SJ, et al. Effects of dehydroepiandrosterone sulphate (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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