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; 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
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
- Sj ¶gren syndrome
- Chronic active hepatitis
- Schmidt syndrome
DIAGNOSIS
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
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
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.
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 two to four 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
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 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.
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.
COMPLICATIONS
- Hyperpyrexia
- Psychotic reactions
- Complications from underlying disease
- Over- or underuse of steroid treatment
- Hyperkalemic paralysis (rare)
- Addisonian crisis
REFERENCES
11 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):104-115.22 Ekman B, Bachrach-Lindstr ¶m M, Lindstr ¶m T, et al. A randomized, double blind-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):18-25.33 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):775-780.44 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
ICD9
- 255.41 Glucocorticoid deficiency
- 017.60 Tuberculosis of adrenal glands, unspecified
SNOMED
- 363732003 Addison's disease (disorder)
- 186270000 Tuberculous Addison's disease
- 76715008 Addison's disease due to autoimmunity (disorder)
- 237760008 Addison's disease with adrenoleucodystrophy (disorder)
- 24867002 Severe adrenal insufficiency (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.