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Addison Disease
Tya-Mae Y. Julien, MD
image BASICS
DESCRIPTION
  • 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 longterm corticosteroid therapy
  • System(s) affected: endocrine/metabolic
  • Synonym(s): adrenocortical insufficiency; corti-coadrenal insufficiency; primary adrenocortical insufficiency
EPIDEMIOLOGY
  • Predominant age: all ages; typical age of presentation is 30 to 50 years
  • Predominant sex: females > males (slight)
  • No racial predilection
Incidence
0.6:100,000
Prevalence
4 to 6:100,000; possibly higher
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
Genetics
  • 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 1st- or 2nd-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
image DIAGNOSIS
PHYSICAL EXAM
  • Weight loss
  • Low BP, orthostatic hypotension
  • Increased pigmentation of high friction areas (extensor surfaces, plantar or palmar creases, dentalgingival 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]
  • 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
  • Eosinophilia
  • Relative lymphocytosis
  • Anemia, normochromic, normocytic
P.23

Follow-Up Tests & Special Considerations
  • 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 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 produce enlargement with destruction of the entire gland.
image TREATMENT
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)
MEDICATION
First Line
  • Chronic adrenal insufficiency
    • Glucocorticoid supplementation (2)[A]
      • Dosing: hydrocortisone 15 to 30 mg (or therapeutic equivalent) PO in 2 to 4 divided doses (to include morning rising and bedtime doses); 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 to 0.2 mg/day PO
    • May require salt 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/day PO (typically not 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 to 150 mg 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 and may improve well-being and sexuality in some women (3,4)[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 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
IV Fluids
IV saline containing 5% dextrose and plasma expanders
image 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 longterm 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.
DIET
Maintain water, sodium, and potassium balance.
PATIENT EDUCATION
  • 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.
  • Instruct patient in self-administration of parenteral hydrocortisone for emergency situations.
PROGNOSIS
Requires lifetime treatment: Life expectancy approximates normal with adequate replacement therapy; without treatment, the disease is 100% lethal.
REFERENCES
1. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014;275(2):104-115.
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.
3. Gebre-Medhin G, Husebye ES, Mallmin H, et al. Oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease. Clin Endocrinol (Oxf). 2000;52(6):775-780.
4. 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.
See Also
Algorithm: Adrenocortical Insufficiency
Codes
ICD10
  • E27.1 Primary adrenocortical insufficiency
  • A18.7 Tuberculosis of adrenal glands
  • E27.2 Addisonian crisis
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.