WORKUP	Section 5 of 11
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Lab Studies:

• 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 because the results will most likely be abnormal.

• Because aldosterone is absent, hyponatremia and hyperkalemia are often present.

• Hyponatremia is the most common finding and occurs in 90% of patients.

• Hyperkalemia is found in 60-70% of patients.

• Hypercalcemia is uncommon and found in approximately 5-10% of patients.

• The preliminary test for adrenal insufficiency is the measurement of serum cortisol levels from a sample of blood obtained in the morning. 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 mg/dL (reference range, 9-25 mg/dL) are considered normal, and no further workup is required.

• Values less than 3 mg/dL are diagnostic of Addison disease.

• Values in the range of 3-19 mg/dL are indeterminate, and further workup is needed.

• The hypothalamic-pituitary axis can be evaluated by using 3 tests: the ACTH (Cortrosyn) stimulation test, the insulin tolerance test, and the metyrapone test.

• Cortrosyn is a synthetic ACTH, 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 mg/dL exclude the diagnosis of adrenal insufficiency because the response to stimulation is considered adequate at this level.

  • Cortisol levels of 13-17 mg/dL are indeterminate.

  • Cortisol levels of less than 13 mg/dL are diagnostic of 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 mg/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 ACTH sampling, ACTH provocative testing, or corticotrophin-releasing hormone (CRH) provocative testing.

• A serum ACTH level of greater than 100 pg/mL is diagnostic of primary adrenal insufficiency.

• An ACTH 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 ACTH 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.

Imaging Studies:

• 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.

Other Tests:

• Tissue cultures in patients with tuberculosis reveal acid-fast bacilli.

	MEDICATION	Section 7 of 11
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With optimum dosing (which is often a challenge), the glucocorticoids are adequately replaced with minimal adverse effects. Underdosing of glucocorticoids results in continued adrenal insufficiency. In children, nocturnal hypoglycemia can result in seizures. Overdosing of glucocorticoids results in weight gain, increased blood pressure, and osteoporosis. The effects of steroid replacement are assessed with clinical examination.

The resolution of symptoms and the correction of electrolyte abnormalities are the customary signals in determining the adequacy of replacement. In patients at risk for osteoporosis, monitor serum and urine cortisol levels; this method appears to be the best available assessment of steroid dosing.

The titration of mineralocorticoid replacement is achieved by monitoring electrolyte levels and plasma rennin concentrations and by evaluating clinical findings such as dizziness or weight gain. Weakness, decreased diastolic blood pressure, low serum sodium levels, and increased plasma rennin concentrations occur with an underdosing of fludrocortisone. Overdosing is difficult to determine. Decreased serum potassium levels may be seen. Increased levels of atrial natriuretic peptide have been proposed to be more accurate in determining an overdose.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Failure to diagnose and treat acute adrenal insufficiency immediately when the condition is suspected is a pitfall.

• Failure to perform diagnostic laboratory tests when acute adrenal insufficiency is suspected is a pitfall.

Special Concerns:

• Pregnancy increases the physiologic stress on the patient.

• The diagnosis of Addison disease may be delayed in pregnant women because the presenting symptoms of nausea, vomiting, and skin hyperpigmentation may be confused with symptoms of pregnancy.

• Glucocorticoid and mineralocorticoid doses may need to be adjusted in patients who are pregnant. For example, the fludrocortisone dose may need to be decreased if preeclampsia develops.

• Glucocorticoid and mineralocorticoid doses may need to be increased, especially during labor. Commonly, 1-3 doses of hydrocortisone 100 mg are intramuscularly or intravenously administered during labor.

• Pediatric patients receiving adequate hormone replacement maintain a normal growth pattern, although their growth is rarely above the 50th percentile. Pubertal development is also normal.

• The presenting symptoms of Addison disease in children are similar to those in adults, with the exception of weight loss, which is not a common finding in the pediatric population.