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Addison's disease
OVERVIEW: Adrenal hypofunction from primary disease (partial or complete destruction) of the adrenal gland with inadequate secretion of glucocorticoids and mineralocorticoids. An autoimmune process is the most common cause (80% of the cases) followed by tuberculosis. AIDS is becoming a more frequent cause.
• Addison's disease (primary adrenocortical insufficiency) is differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes of adrenocortical insufficiency (see Differential Diagnosis)
• Addisonian (adrenal) crisis - acute complication of adrenal insufficiency (circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia); usually precipitated by acute physiologic stressor such as surgery, illness, exacerbation of co-morbid process, acute withdrawal of long term corticosteroid therapy
System(s) affected: Endocrine/Metabolic
Genetics: Autoimmune adrenal insufficiency shows some hereditary disposition. Familial glucocorticoid insufficiency may have recessive pattern; adrenomyeloneuropathy is X-linked. Frequent association with other autoimmune disorders.
Incidence/Prevalence in USA: Approximately 4:100,000
Predominant age: All ages; usually 3rd to 5th decade
Predominant sex: Females > Males (slight)
SIGNS AND SYMPTOMS: • Weakness, fatigue, tiredness
• Weight loss
• Dizziness; low blood pressure, orthostatic hypotension
• Increased pigmentation (extensor surfaces, hand creases, dental-gingival margins, buccal and vaginal mucosa, lips, areola, pressure points, scars; tanning; freckles; vitiligo)
• Anorexia; nausea; vomiting
• Chronic diarrhea
• Abdominal pain
• Decreased cold tolerance
• Salt craving
• Hair loss in females
• Depression (60-80% of patients)
CAUSES: • Autoimmune adrenal insufficiency (~80%)
• Tuberculosis (~20%)
• Waterhouse-Friderichsen syndrome (disseminated adrenal infection and subsequent infarction; meningococcemia most common; Pseudomonas aeruginosa common in children; atypical pathogens, CMV, Cryptococcus, MAC in immunosuppressed and AIDS)
• Fungal disease (histoplasmosis, blastomycosis, coccidioidomycosis)
• Bilateral adrenal hemorrhage and infarction (anticoagulants; 50% are in therapeutic range at time of hemorrhage)
• Antiphospholipid syndrome
• Metastatic (lung, breast, kidney, colon), lymphoma, Kaposi's sarcoma (tumor must destroy 90% of gland to produce hypofunction)
• Drugs (ketoconazole, etomidate)
• Surgical adrenalectomy
• Radiation therapy
• Sarcoidosis
• Hemochromatosis
• Amyloidosis
• Adrenoleukodystrophy
• Adrenomyelodystrophy
• Polyglandular endocrine syndromes
• APS I (autoimmune polyglandular syndrome 1)
• Childhood onset
• HLA-DR not associated
• Single gene mutation in APECED gene (APECED = autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)
• APS II (autoimmune polyglandular syndrome II)
• Schmidt's syndrome
• Adult onset
• HLA-DR associated
• Adrenal failure with type I diabetes mellitus and/or hypothyroidism
• Congenital (enzyme defects; hypoplasia; familial glucocorticoid insufficiency)
• Idiopathic
RISK FACTORS: • Family history of autoimmune adrenal insufficiency. About 40% of patients have a first- or second-degree relative with one of the associated disorders.
• Taking steroids for prolonged periods, then experiencing severe infection, trauma or surgical procedures
DIAGNOSIS DIFFERENTIAL DIAGNOSIS: • Secondary adrenocortical insufficiency
• Withdrawal of long-term corticosteroid use
• Sheehan's syndrome (postpartum necrosis of pituitary)
• Empty sella syndrome
• Surgical excision of pituitary
• Radiation to pituitary
• Pituitary adenomas, carcinomas (rare), craniopharyngiomas
• Infiltrative disorders of pituitary (sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X)
• Megestrol
• Tertiary adrenocortical insufficiency
• Pituitary stalk transection
• Trauma
• Disruption of production of corticotropic releasing factor (CRF)
• Hypothalamic tumors
• Myopathies
• Syndrome of inappropriate antidiuretic hormone (SIADH)
• Heavy metal ingestion
• Severe nutritional deficiencies
• Sprue syndrome
• Hyperparathyroidism
• Neurofibromatosis
• Peutz-Jeghers syndrome
• Porphyria cutanea tarda
• Salt-losing nephritis
• Bronchogenic carcinoma
• Anorexia nervosa
• Other causes of hypoglycemia
• Depression
LABORATORY: • Low serum sodium
• Elevated serum potassium
• Elevated BUN, creatinine
• Elevated serum calcium
• Hypoglycemia when fasted
• Metabolic acidosis
• Low cortisol level (between 8 and 9 a.m.)
• Elevated ACTH level
• Moderate neutropenia
• Eosinophilia
• Relative lymphocytosis
• Anemia
• Adrenal-cortex autoantibody (ACA/21-hydroxylase)
Drugs that may alter lab results: Digitalis
Disorders that may alter lab results: Diabetes mellitus
PATHOLOGICAL FINDINGS: Atrophic adrenals in autoimmune adrenalitis. Infiltrative and hemorrhagic disorders produce enlargement with destruction of entire gland.
SPECIAL TESTS: • Rapid ACTH stimulation test: Cosyntropin 0.25 mg IV, measure pre-injection and 60 minute post-injection cortisol levels. Patients with Addison's disease have low to normal values that do not rise
• Metapyrone test
• Insulin-induced hypoglycemia test
• CRH may help distinguish secondary from tertiary adrenal insufficiency
• Autoantibody tests
• 21-Hydroxylase (most common and specific)
• 17-Hydroxylase
• 17-alfa-Hydroxylase (may not be associated)
• Adrenomedullin
IMAGING: • Abdominal CT scan
• Small adrenal glands in autoimmune adrenalitis
• Enlarged adrenal glands in infiltrative and hemorrhagic disorders
• Abdominal x-ray: may show adrenal calcifications
• Chest x-ray: may show adrenal calcifications, small heart size, calcification of cartilage
DIAGNOSTIC PROCEDURES: A work-up to determine the cause of Addison's disease. CT guided fine-needle biopsy of adrenal masses may be helpful.
TREATMENT APPROPRIATE HEALTH CARE: • Outpatient
• Inpatient during adrenal crisis
GENERAL MEASURES: • Treatment for adrenal insufficiency is with glucocorticoid and mineralocorticoid replacement
• 5 S's of management of adrenal crisis: salt, sugar, steroids, support, search for precipitating illness
• Appropriate treatment for underlying cause (e.g., tuberculosis)
SURGICAL MEASURES: N/A
ACTIVITY: As tolerated
DIET: Arrange for a diet that maintains water, sodium and potassium balances
PATIENT EDUCATION: • For patient education materials favorably reviewed on this topic, contact: National Addison's Disease Foundation, 505 Northern Blvd., Suite 200, Great Neck, NY 11021, (516)487-4992
• Patient should wear or carry medical identification with information about the disease and the need for hydrocortisone or other replacement therapy
• Instruct patient in self-administering of parenteral hydrocortisone for emergency situations (e.g., traveling in remote areas away from medical help)
MEDICATIONS DRUG(S) OF CHOICE: • For chronic adrenal insufficiency:
• Hydrocortisone 15-20 mg orally each morning upon arising and 10 mg at 4-5 each afternoon is usual dosage (dosage may vary and is usually less in children's),PLUS,
• Fludrocortisone 0.05-0.2 mg orally once/day plus
• Dehydroepiandrosterone 25-50 mg orally once a day (monitor lipid profile, breast or prostate cancer)
• Acute adrenal insufficiency
• Hydrocortisone hemisuccinate 100 mg IV followed by 10 mg/hr infusion
• IV glucose, saline, plasma expanders
• For acute illnesses (fever, stress, minor trauma)
• Double the patient's usual steroid dose
Contraindications: Refer to manufacturer's literature
Precautions:
• Patients with hepatic disease may need a reduced dose
• Elderly should have a slightly reduced dose
• Refer to manufacturer's literature for other precautions
Significant possible interactions: Refer to manufacturer's literature. Rifampin, phenytoin, and barbiturates may precipitate adrenal insufficiency in addisonian patients by inducing steroid-metabolizing liver enzymes
ALTERNATIVE DRUGS: Prednisone 5 mg in AM and 2.5 mg at hs plus fludrocortisone
FOLLOW UP PATIENT MONITORING: • Verify adequacy of therapy - normal blood pressure, serum electrolytes normal, normal plasma renin, improvement of appetite and strength, increase in heart size to normal, normal fasting blood glucose level
• Lifelong medical supervision for signs of continued adequate therapy and avoidance of overdose
PREVENTION/AVOIDANCE: • No preventive measures known for Addison's disease
• Prevention of complications
• Anticipate adrenal crisis and treat before symptoms begin
• If nausea and vomiting preclude oral therapy, patient should seek medical help to start parenteral therapy
• Elective surgical procedures require adjustment in steroid dose
• Prevent exposure to infections
POSSIBLE COMPLICATIONS: • Hyperpyrexia
• Psychotic reactions
• Complications from underlying disease
• Over- or under-steroid treatment
• Hyperkalemic paralysis (rare)
• Addisonian crisis
EXPECTED COURSE AND PROGNOSIS: • Good outlook with appropriate treatment. With adequate replacement therapy, life expectancy approximates normal
• 100% lethal without treatment
MISCELLANEOUS ASSOCIATED CONDITIONS: • Diabetes mellitus
• Grave's disease
• Hashimoto's thyroiditis
• Hypoparathyroidism
• Hypercalcemia
• Ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Vitiligo
• Chronic moniliasis
• Sarcoidosis
• Sjogren's syndrome
• Chronic active hepatitis
• Schmidt's syndrome (multiple endocrine deficiency syndrome)
• Adrenoleukodystrophy
AGE-RELATED FACTORS:
Pediatric:
• Hydrocortisone and fludrocortisone doses are lower than adults
• More difficult to diagnose
• Occurs in siblings
Geriatric: Acute adrenal crisis more likely
Others: N/A
PREGNANCY: N/A
SYNONYMS: • Adrenocortical insufficiency
• Waterhouse-Friderichsen syndrome (adrenal crisis)
• Corticoadrenal insufficiency
• Primary adrenocortical insufficiency
ICD-9-CM: 255.4 Corticoadrenal insufficiency
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