ADDISON DISEASE

ADDISON DISEASE - Rick Kellerman, MD; Mark Gerstberger, DO
BASICS
DESCRIPTION
• Adrenal hypofunction from primary disease (partial or complete T-cell-mediated destruction of adrenal cells) 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 disease (primary adrenocortical insufficiency) is differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes of adrenocortical insufficiency (see Differential Diagnosis). Mineralocorticoid function usually remains intact in secondary and tertiary adrenocorticoid insufficiency
• 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; Waterhouse-Frederickson syndrome (adrenal crisis); Corticoadrenal insufficiency; Primary adrenocortical insufficiency
ALERT
Geriatric Considerations
Acute adrenal crisis is more likely in geriatric patients.
Pediatric Considerations
• Hydrocortisone and fludrocortisone doses are lower than adults
• More difficult to diagnose
• Occurs in siblings
GENERAL PREVENTION
• No preventive measures known for Addison disease.
• Prevention of complications
- Anticipate adrenal crisis and treat before symptoms begin.
- Elective surgical procedures require upward adjustment in steroid dose.
EPIDEMIOLOGY
• Predominant age: All ages; usually 3rd to fifth decade
• Predominant sex: Females > Males (slight)
Incidence
0.6:100,000
Prevalence
4:100,000
RISK FACTORS
• Family history of autoimmune adrenal insufficiency. ~40% of patients have a 1st- or 2nd-degree relative with associated disorders.
• Chronic steroid use, then experiencing severe infection, trauma, or surgical procedures
Genetics
Familial glucocorticoid insufficiency may have a recessive pattern; adrenomyeloneuropathy is X-linked. Frequent association with other autoimmune disorders. Increased risk with cytotoxic T lymphocyte antigen 4 (CTLA-4)
ETIOLOGY
• Autoimmune adrenal insufficiency (80% of cases in the U.S.)
• Tuberculosis (most common infectious cause worldwide)
• HIV (most common infectious cause in the U.S.)
• Waterhouse-Fredrickson syndrome (disseminated adrenal infection and subsequent infarction; meningococcemia most common; pseudomonas aeruginosa in children; CMV, cryptococcus, MAC in immunosuppressed, AIDS)
• Fungal disease (histoplasmosis, blastomycosis, coccidioidomycosis)
• Bilateral adrenal hemorrhage and infarction (anticoagulants; 50% are in the therapeutic range at the time of the hemorrhage)
• Antiphospholipid syndrome
• Metastatic (lung, breast, kidney, colon, melanoma), lymphoma, Kaposi sarcoma (tumor must destroy 90% of gland to produce hypofunction)
• Drugs (ketoconazole, etomidate)
• Shock
• Surgical adrenalectomy
• Radiation therapy
• Sarcoidosis
• Hemochromatosis
• Amyloidosis
• Adrenoleukodystrophy
• Adrenomyelodystrophy
• Polyglandular autoimmune 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 syndrome (50% of patients with Addison disease have Schmidt syndrome), adult onset (HLA-DR associated), adrenal failure with type I diabetes mellitus, and/or autoimmune thyroid disease (Hashimoto or Graves)
- APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy): Autosomal recessive, any 2 of chronic mucocutaneous candidiasis, hypothyroidism or Addison disease
- XPID (X-linked polyendocrinopathy, immune dysfunction, diarrhea): Rare; neonatal death
• Congenital (enzyme defects, hypoplasia, familial glucocorticoid insufficiency)
• Idiopathic
ASSOCIATED CONDITIONS
Diabetes mellitus, Grave disease, Hashimoto thyroiditis, Hypoparathyroidism, Hypercalcemia, Ovarian failure, Pernicious anemia, Myasthenia gravis, Vitiligo, Chronic moniliasis, Sarcoidosis, Sjogren syndrome, Chronic active hepatitis, Schmidt syndrome (multiple endocrine deficiency syndrome), Adrenoleukodystrophy


DIAGNOSIS
SIGNS AND SYMPTOMS
History
• Weakness, fatigue, tiredness
• 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 (extensor surfaces, hand creases, dental-gingival margins, buccal and vaginal mucosa, lips, areola, pressure points, scars, "tanning," freckles)
• Vitiligo
• Hair loss in females
TESTS
• Basal plasma cortisol and ACTH (low cortisol and high ACTH indicative of Addison disease)
• Rapid ACTH stimulation test: Cosyntropin 0.25 mg IV, measure preinjection and baseline, 30-, and 60-minute postinjection cortisol levels. (Patients with Addison 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), and adrenomedullin
Lab
• Low serum sodium
• Elevated serum potassium
• Elevated BUN, creatinine
• Elevated serum calcium
• Hypoglycemia when fasted
• Metabolic acidosis
• Low cortisol level (between 8 and 9 AM)
• Elevated ACTH level
• Moderate neutropenia
• Eosinophilia
• Relative lymphocytosis
• Anemia, normochromic, normocytic
• Adrenal-cortex autoantibody (ACA/21-hydroxylase)
• Low aldosterone levels
• 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 mellitus
Imaging
• Abdominal CT scan
- Small adrenal glands in autoimmune adrenalitis
- Enlarged adrenal glands in infiltrative and hemorrhagic disorders
• Abdominal radiograph may show adrenal calcifications.
• CXR may show small heart size, and/or calcification of cartilage.
Diagnostic Procedures/Surgery
CT guided fine-needle biopsy of adrenal masses may be helpful.
Pathological Findings
• Atrophic adrenals in autoimmune adrenalitis
• Infiltrative and hemorrhagic disorders produce enlargement with destruction of the entire gland.
DIFFERENTIAL DIAGNOSIS
• Secondary adrenocortical insufficiency (pituitary failure)
- Withdrawal of long-term corticosteroid use: Adrenal insufficiency from hypothalamic-pituitary axis depression from long-term corticosteroid use is much more common than Addison disease.
- Sheehan 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 (hypothalamic failure)
- Pituitary stalk transection
- Trauma
- Disruption of production of corticotropic releasing factor (CRF)
- Hypothalamic tumors
• Myopathies
• Secretion 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
TREATMENT
STABILIZATION
• Outpatient
• Inpatient during adrenal crisis
GENERAL MEASURES
• Treatment for adrenal insufficiency is with glucocorticoid and mineralocorticoid replacement.
- The 5 S's of 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.
• Appropriate treatment for underlying cause
Diet
Diet to maintains water, sodium, and potassium balances.
Activity
As tolerated
MEDICATION (DRUGS)
First Line
• Chronic adrenal insufficiency
- Hydrocortisone 15-20 mg PO each morning on rising, and 10 mg at 4-5 PM each afternoon is the usual dosage (dosage may vary and is usually less in children's).
- Fludrocortisone 0.05-0.2 mg PO once daily plus
- Dehydroepiandrosterone 25-50 mg PO once daily (monitor lipid profile, breast or prostate cancer)
- May require salt supplementation
• Acute adrenal insufficiency
- Hydrocortisone 100 mg IV followed by 10 mg/h infusion
- IV glucose, saline, and plasma expanders
- Fludrocortisone 0.05 mg/d
• Acute illnesses (fever, stress, minor trauma):
- Double the patient's usual steroid dose; taper the dose gradually over a week or more, and monitor VS and serum sodium.
• Supplement for surgical procedures: Administer 25-150 mg hydrocortisone or 5-30 mg methylprednisolone IV on the day of the procedure in addition to maintenance therapy. Taper gradually to the usual dose over 1-2 days.
• Precautions
- Patients with hepatic disease may need a reduced dose of steroids.
- Excessive corticosteroid doses or excessive duration of supplemental treatment of those who are acutely ill or undergoing surgery may increase the mortality rate.
- Rifampin, phenytoin, and barbiturates may precipitate adrenal insufficiency in Addisonian patients by inducing steroid-metabolizing liver enzymes.
- Patients on these drugs may require higher doses of corticosteroid due to increased steroid metabolism.
- Refer to manufacturer's literature for other precautions
- Significant possible interactions: Refer to manufacturer's literature
Second Line
Prednisone 5 mg in the morning and 2.5 mg at night plus fludrocortisone, and DHEA; dexamethasone 0.5 mg in the morning plus fludrocortisone plus DHEA
ALERT
Geriatric Considerations
Elderly should have a slightly reduced dose.
FOLLOW-UP
PROGNOSIS
• Requires lifetime treatment
• Good outlook with appropriate treatment
• With adequate replacement therapy, life expectancy approximates normal.
• Without treatment, the disease is 100% lethal.
COMPLICATIONS
• Hyperpyrexia
• Psychotic reactions
• Complications from underlying disease
• Oversteroid or understeroid treatment
• Hyperkalemic paralysis (rare)
• Addisonian crisis
PATIENT MONITORING
• Verify adequacy of therapy: Normal BP, serum electrolytes normal, normal plasma renin, improvement of appetite and strength, increase in heart size to normal, and normal fasting blood glucose level
• Lifelong medical supervision for signs of adequate therapy and avoidance of overdose
REFERENCES
1. http://www.utdol.com/utd/content/topic.do?topicKey= adrenal/abstract.do?topicKey=adrenal/4314refNum=12
2. King MS. Adrenal insufficiency: An uncommon cause of fatigue. J Am Board Fam Pract. 1999;12:386-390. (C)
3. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency [see comments]. N Engl J Med. 1999;341:1013-1020. (A)