Dermatologic Aspects of Addison Disease Workup
- Author: Elizabeth A Liotta, MD; Chief Editor: William D James, MD more...
The evaluation of patients with suspected Addison disease involves the diagnosis of adrenal insufficiency and then the identification of the site of the defect in the hypothalamic-pituitary axis. Addison disease is a primary adrenal insufficiency with the defect in the adrenal gland. Once the adrenal insufficiency is identified, the etiology of the adrenal insufficiency may be determined.
Initially, serum electrolytes should be checked but a normal potassium level does not rule out Addison disease. Because aldosterone is absent, hyponatremia, with low chloride and hyperkalemia are often present. Hyponatremia is the most common finding and occurs in 90% of patients (see Serum Sodium). Hyperkalemia is found in 60-70% of patients. Hypercalcemia is uncommon and found in approximately 5-10% of patients (see Serum Calcium).
The preliminary test for adrenal insufficiency is the measurement of serum cortisol levels from a sample of blood obtained in the morning, although some prefer to order a corticotropin level. This is an insensitive screening test. Because of variations in cortisol levels due to the circadian rhythm, blood should be drawn when the levels are highest, usually between 6:00 and 8:00 am. Morning cortisol levels greater than 19 mcg/dL (reference range, 5-25 mcg/dL) are considered normal, and no further workup is required. Values less than 3 mcg/dL are diagnostic of Addison disease. Values in the range of 3-19 mcg/dL are indeterminate, and further workup is needed.
The hypothalamic-pituitary axis can be evaluated by using 3 tests: the corticotropin (Cortrosyn) stimulation test, the insulin tolerance test, and the metyrapone test. Synthetic adrenocorticotropin 1-24 at a dose of 250 mcg works as a dynamic test. The elevated levels of renin and adrenocorticotropin verify the presence of the disease.
Cortrosyn is a synthetic corticotropin, which is intravenously administered with a dose of 350 mg. Serum cortisol levels are measured from blood samples drawn after 30 and 60 minutes. Peak serum cortisol levels greater than 18 mcg/dL exclude the diagnosis of adrenal insufficiency because the response to stimulation is considered adequate at this level. Cortisol levels of 13-17 mcg/dL are indeterminate. Cortisol levels of less than 13 mcg/dL suggest adrenal insufficiency.
The insulin tolerance test is sensitive for adrenal insufficiency. This test involves hypoglycemic stress to induce cortisol production. The test requires close monitoring of the patient and is contraindicated in patients with a history of seizures or cardiovascular disease. The peak serum cortisol response is measured after an insulin challenge of 0.1-0.15 U/kg. A cortisol level of less than 18 mcg/dL and a serum glucose level of less than 40 mg/dL suggest adrenal insufficiency.
The metyrapone test involves disruption of the cortisol production pathway by inhibiting 11 B-hydroxylase, the enzyme that converts 11-deoxycortisol (11-s) to cortisol. Metyrapone (30 mg/kg) is intravenously injected at midnight, and cortisol and 11-s levels are measured 8 hours afterward. A normal response is an increase in serum 11-s levels to more than 7 mg/dL. Levels of 11-s that are less than 7 mg/dL are diagnostic of adrenal insufficiency.
Once the diagnosis of adrenal insufficiency is confirmed, the site of the defect in the hypothalamic-pituitary axis should be determined by using corticotropin sampling, corticotropin provocative testing, or corticotrophin-releasing hormone (CRH) provocative testing.
A serum corticotropin level of greater than 100 pg/mL is diagnostic of primary adrenal insufficiency.
A corticotropin infusion can help in differentiating primary insufficiency from a hypothalamic-mediated or pituitary-mediated adrenal insufficiency. An 8-hour intravenous infusion of 250 mg/d for 3-5 days is administered, and daily urine samples are checked for 17-hydroxysteroid levels. By day 5, a 3- to 5-fold increase in the urine 17-hydroxysteroid level is diagnostic of a secondary or tertiary insufficiency; in primary adrenal insufficiency, the urine 17-hydroxysteroid level does not increase.
The CRH test involves stimulation of the pituitary gland and measurement of serum cortisol and corticotropin levels. The CRH test can be used to differentiate primary, secondary, and tertiary adrenal insufficiencies.
After adrenal insufficiency is diagnosed and the defect in the hypothalamic-pituitary-adrenal axis is identified, the cause of the adrenal insufficiency can be evaluated. Because primary adrenal insufficiency has numerous causes, the workup must be directed at the clinical findings.
Autoimmune disease and infectious etiologies are the 2 predominant causes; therefore, a workup for adrenal antibodies and tuberculosis should be part of the initial diagnostic evaluation.
Autoantibodies against 21-hydroxylase may be detected in patients with autoimmune polyglandular syndrome. These patients may also have type 1 diabetes mellitus, autoimmune thyroid disease, autoimmune gastritis, celiac disease, and/or vitiligo.
Both computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate a diminished adrenal gland in patients with autoimmune destruction and an enlarged adrenal gland in patients with infection. CT adequately shows the calcification that occurs in adrenal failure caused by tuberculosis. The calcification may be apparent in the acute phase of infection, but it is usually recognized in the chronic phase of infection.
Both CT and MRI reveal adrenal hemorrhages. MRI is superior to CT in differentiating adrenal masses, but MRI cannot distinguish a tumor from an inflammatory process.
Tissue cultures in patients with tuberculosis reveal acid-fast bacilli.
Histopathologic findings vary with the mechanism of destruction. Autoimmune destruction is characterized by a lymphocytic infiltrate. Surviving cortical cells show increased cytoplasm and nuclear atypia, which is believed to result from prolonged stimulation by corticotropin. Noncaseating granulomas are found when adrenal destruction is the result of sarcoidosis or a malignancy. Caseating granulomas are seen in patients with tuberculosis.
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