Addison Disease

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 long-term corticosteroid therapy
• System(s) affected: endocrine/metabolic
• Synonym(s): adrenocortical insufficiency; corticoadrenal 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
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

History

• 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

• 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

• 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.

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

• 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.

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

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.

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.
• Steroid card samples http://www.ese-hormones.org/professional/docs/ExistingEmergencyCards.pdf
• 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.

Complications

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

See Also

Algorithm: Adrenocortical Insufficiency

ICD-10

• A18.7 Tuberculosis of adrenal glands
• E27.1 Primary adrenocortical insufficiency
• E27.2 Addisonian crisis

ICD-9

• 017.60 Tuberculosis of adrenal glands, unspecified
• 255.41 Glucocorticoid deficiency

SNOMED

• 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)