Addison Disease BasicsDescription • Insufficiency of the adrenal gland from primary disease (partial or complete destruction of 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 can be differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes of adrenocortical insufficiency 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 insufficiencyEpidemiology • Predominant age: All ages; usually 3rd–5th decade; mean age at diagnosis in adults is 40 years • Predominant sex: Females > Males (slight)Incidence0.6:100,000Prevalence4:100,000Risk Factors • ∼40% of patients have a 1st- or 2nd-degree relative with associated disorders. • Chronic steroid use, then experiencing severe infection, trauma, or surgical proceduresGenetics
• Autoimmune polyglandular syndrome (APS) type 2 genetics are complex. Associated with adrenal insufficiency, type 1 diabetes, and Hashimoto disease. More common than APS type 1. • APS type 1 caused by mutations of the autoimmune regulator gene. Nearly all have the following triad: Adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis before adulthood • Adrenoleukodystrophy is an X-linked recessive disorder resulting in toxic accumulation of unoxidized long-chain fatty acids • Frequent association with other autoimmune disorders • Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA- 4)General Prevention • No preventive measures known for Addison disease; focus on prevention of complications: o Anticipate adrenal crisis and treat before symptoms begin. • Elective surgical procedures require upward adjustment in steroid dose.PathophysiologyDestruction of the adrenal cortex resulting in deficiencies incortisol, aldosterone, and androgensEtiology • Autoimmune adrenal insufficiency (80% of cases in the US) • Infectious causes: TB (most common infectious cause worldwide), HIV (most common infectious cause in the US), Waterhouse-Fredrickson syndrome, fungal disease • Bilateral adrenal hemorrhage and infarction (for patients on anticoagulants, 50% are in the therapeutic range) • Antiphospholipid syndrome • Lymphoma, Kaposi sarcoma, metastasis (lung, breast, kidney, colon, melanoma); tumor must destroy 90% of gland to produce hypofunction • Drugs (ketoconazole, 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
• Basal plasma cortisol and adrenocorticotropic hormone (ACTH) (low cortisol and high ACTH indicative of Addison disease) • 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 blood urea nitrogen, creatinine, calcium, thyroid- stimulating hormone (TSH) • Low serum aldosterone • Hypoglycemia when fasted • Metabolic acidosis • Moderate neutropenia • Eosinophilia • Relative lymphocytosis • Anemia, normochromic, normocyticFollow-Up & Special Considerations • Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring of replacement therapy (1)[C]. • TSH: Repeat when condition has stabilized: o Thyroid hormone levels may normalize with the treatment of Addison disease. • Drugs that may alter lab results: Digitalis • Disorders that may alter lab results: DiabetesImagingInitial approach • Abdominal computed tomography (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. • Magnetic resonance imaging of pituitary and hypothalamus if secondary or tertiary cause of adrenocortical insufficiency is suspected.Diagnostic Procedures/SurgeryCT-guided fine-needle biopsy of adrenal masses may identifydiagnoses (2)[C].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): o Withdrawal of long-term corticosteroid use o Sheehan syndrome (postpartum necrosis of pituitary) o Empty sella syndrome o Radiation to pituitary o Pituitary adenomas, craniopharyngiomas o Infiltrative disorders of pituitary (sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X) • Tertiary adrenocortical insufficiency (hypothalamic failure): o Pituitary stalk transection o Trauma o Disruption of production of corticotropic-releasing factor o Hypothalamic tumors • Other: o Myopathies o Syndrome of inappropriate antidiuretic hormone o Heavy-metal ingestion o Severe nutritional deficiencies o Sprue syndrome o Hyperparathyroidism o Neurofibromatosis o Peutz-Jeghers syndrome o Porphyria cutanea tarda o Salt-losing nephritis o Bronchogenic carcinoma o Anorexia nervosa Treatment
MedicationFirst Line • Chronic adrenal insufficiency: o Glucocorticoid supplementation: Dosing: Hydrocortisone 15–20 mg (or therapeutic equivalent) p.o. each morning upon rising and 10 mg at 4–5 p.m. each afternoon (3) [C]; 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 o Mineralocorticoid supplementation: Dosing: Fludrocortisone 0.05–0.2 mg p.o. per day o May require salt supplementation • Addisonian crisis: o Hydrocortisone 100 mg IV followed by 10 mg/h infusion, or hydrocortisone 100 mg IV bolus q.6–8 h. o IV glucose, saline, and plasma expanders o Fludrocortisone 0.05 mg/d p.o. (may not be required; high-dose hydrocortisone is an effective mineralcorticoid) • Acute illnesses (fever, stress, minor trauma): o Double the patients usual steroid dose, taper the dose gradually over a week or more, and monitor vital signs and serum sodium. • Supplementation for surgical procedures: o Administer hydrocortisone 25–150 mg or methylprednisolone 5–30 mg IV on the day of the procedure in addition to maintenance therapy; taper gradually to the usual dose over 1–2 days.Second LineAddition of androgen therapy: • Dehydroepiandrosterone (DHEA) 25–50 mg p.o. once daily may be considered in women to improve well-being and sexuality (4)[B].
Additional TreatmentGeneral MeasuresConsider the 5 Ss for the management of adrenal crisis: • Salt, sugar, steroids, support, search for a precipitating illness (usually infection, trauma, recent surgery, or not taking prescribed replacement therapy)In-Patient ConsiderationsInitial StabilizationAddisonian crisis: • Airway, breathing, and circulation management • Establish IV access; 5% dextrose and normal saline • Administer hydrocortisone 100 mg IV bolus q.6–8h.; replacement with fludrocortisone is not necessary (high-dose hydrocortisone is an effective mineralcorticoid) • Correct electrolyte abnormalities. • Blood pressure (BP) support for hypotension • Antibiotics if infection suspectedAdmission Criteria • Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia • Intensive care unit admission for unstable casesIV FluidsIntravenous saline containing 5% dextrose and plasma expandersDischarge CriteriaNormal laboratory and stable vital signs Ongoing Care Follow-Up RecommendationsPatient Monitoring • 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 overdoseDietMaintain water, sodium, and potassium balance.Patient Education • For patient education materials, contact: National Adrenal Disease Foundation, 505 Northern Blvd., Suite 200, Great
Neck, NY 11021, (516) 487–4992 (http://www.medhelp.org/nadf) • 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.PrognosisRequires lifetime treatment: Life expectancy approximates normalwith adequate replacement therapy; without treatment, the diseaseis 100% lethal.Complications • Hyperpyrexia • Psychotic reactions • Complications from underlying disease • Over- or underuse of steroid treatment • Hyperkalemic paralysis (rare) • Addisonian crisisReferences1. Nieman LK, Chanco Turner ML. Addisons disease. ClinDermatol. 2006 Jul-Aug;24:276–802. Oelkers W. Adrenal insufficiency. N Engl J Med.1996;335:1206–123. Coursin DB, Wood KE. Corticosteroid supplementation foradrenal insufficiency. JAMA. 2002;287:236–404. Arlt W, Callies F, van Vlijmen JC et al. Dehydroepiandrosteronereplacement in women with adrenal insufficiency. N Engl J Med.1999;341:1013–20Additional Reading See Also (Topic, Algorithm, Electronic Media Element) Algorithm: Adrenocortical Insufficiency Codes ICD9 • 255.41 Glucocorticoid deficiency • 017.60 Tuberculosis of adrenal glands, unspecified examinationSnomed • 363732003 Addison disease (disorder) • 186270000 Tuberculous Addison disease (disorder)Clinical Pearls
• 80% of cases are caused by an autoimmune process, and the average age of diagnosis in adults is 40 years.• Consider the 5 Ss for the management of Addison disease: Salt, sugar, steroids, support, and search for an underlying cause.• The goal of steroid replacement therapy should be to use the lowest dose that alleviates patient symptoms while preventing adverse drug events.• Plasma ACTH levels do not correlate with treatment and should not be used for routine monitoring for efficacy of replacement therapy.• Long-term use of steroids predisposes patients to the development of osteoporosis; screen annually and encourage calcium and vitamin D supplementation. Thank you