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Adrenal Insufficiency and Addison Disease

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Signs and symptoms such as darkened patches of skin on the face, neck, and back of the hands (hyperpigmentation), weakness, low blood pressure, and salt cravings may lead a healthcare practitioner to suspect adrenal insufficiency, especially if these appear to worsen during periods of physical stress, such as an illness or trauma. Laboratory tests can determine if adrenal insufficiency is present, distinguish between primary and secondary insufficiencies, and help determine the underlying cause of the condition.

Laboratory Tests

  • Cortisol. Levels normally vary in the blood, peaking in the early morning. If the adrenal gland is either not functioning normally or not being stimulated by ACTH, then cortisol levels will be consistently low. Cortisol tests, with blood samples usually collected in the morning, may be used in combination with morning ACTH tests and/or ACTH stimulation tests, to help diagnose adrenal insufficiency.
  • ACTH. ACTH is a pituitary hormone that signals the adrenal glands to produce cortisol. This test is primarily ordered as a baseline test to evaluate if the pituitary is producing appropriate amounts of ACTH. In someone with adrenal insufficiency, low ACTH levels indicate secondary adrenal insufficiency, while high levels indicate primary adrenal insufficiency (Addison disease).
  • ACTH stimulation test. This is the optimal test for diagnosing primary adrenal insufficiency, according to guidelines from the Endocrine Society. It involves measuring the level of cortisol in a person's blood before and after an injection of synthetic ACTH. If the adrenal glands are functional, cortisol blood levels will rise in response to the ACTH stimulation. If they are damaged or non-functional, then their response to ACTH will be minimal. This rapid screening test may be ordered along with a baseline ACTH test and, if abnormal, may be followed with a 1 to 3 day prolonged ACTH stimulation test to help differentiate between primary and secondary adrenal insufficiency.
  • Aldosterone. Levels are measured to help diagnose Addison disease, to determine whether the adrenal gland is producing aldosterone. If the levels are low, it is another indication that an individual may have a primary adrenal insufficiency.
  • Renin. Renin activity is elevated in primary adrenal insufficiency because a lack of aldosterone causes increased renal sodium losses. This lowers blood sodium levels and decreases the amount of fluid in the blood (which lowers blood volume and pressure), which in turn stimulates renin production by the kidney.
  • Electrolytes. Sodium, potassium, chloride and carbon dioxide are measured to help detect and evaluate the severity of an existing electrolyte imbalance and to monitor the effectiveness of treatment. Electrolytes may be affected by many conditions. With Addison disease, the sodium, chloride, and carbon dioxide levels are often low, while the potassium level may be very high.
  • BUN and Creatinine are tests done to monitor kidney function.
  • Glucose levels may be very low during an adrenal crisis. Glucose testing may be used in order to help monitor an individual during a crisis.
  • Corticotropin-releasing hormone (CRH) stimulation test. Currently, this test is not available in the United States. In other countries, it may be used when the ACTH test is abnormal to help determine the cause of adrenal insufficiency. CRH is a hormone released by the hypothalamus that stimulates ACTH production by the pituitary gland, which in turn stimulates cortisol production by the adrenal glands. For this test, synthetic CRH is injected intravenously and blood cortisol and ACTH levels are measured at timed intervals after the injection, for example, at 30 and 60 minutes. The normal response is a peak in ACTH levels followed by a peak in cortisol levels.
    • People with Addison disease (underactive or damaged adrenal glands) produce a high level of ACTH but no cortisol.
    • People with secondary adrenal insufficiency have absent or delayed ACTH responses. If someone has a damaged pituitary, CRH will not stimulate ACTH secretion and an absent ACTH response indicates the pituitary is the cause. If ACTH response is delayed, that indicates the hypothalamus is the cause.

Examples of tests to identify the underlying cause

  • Insulin-induced hypoglycemia test. Occasionally, a healthcare practitioner will order this test to learn if pituitary disease (secondary adrenal insufficiency) is the cause of adrenal insufficiency. Glucose and cortisol levels are measured at predetermined intervals after an injection of insulin is used to stress the pituitary gland. In healthy people, blood glucose levels fall and cortisol concentrations increase. In those with adrenal insufficiency, cortisol levels will remain low and glucose levels will fall, then recover slowly. This test should be performed in a specialized facility where there are people experienced in the procedure and where the person tested can be monitored closely.
  • 21-hydroxylase autoantibodies are sometimes ordered as part of the diagnostic process when autoimmune Addison disease is suspected. The test is considered a good indicator of autoimmune Addison disease.
  • 17-hydroxyprogesterone or other adrenal androgens may be used to help diagnose congenital adrenal hyperplasia (CAH), which can cause low cortisol and aldosterone.
  • Very long chain fatty acids (VLCFA) will be assessed in males with adrenal insufficiency of unknown cause to evaluate for adrenoleukodystrophy. (To learn more about this, see the resources listed in the Related Pages section.)
  • A TB screening test (skin test or blood test) may be done to detect tuberculosis (TB).
  • Other autoimmune markers and hormonal assays may be done to assess conditions that affect multiple endocrine glands (autoimmune polyglandular syndromes).

Non-Laboratory Tests

  • X-rays may be used to look for calcification on the adrenal cortex that may be due to a tuberculosis infection.
  • CT (computerized tomography) or MRI (magnetic resonance imaging) scans are sometimes used to look at the size and shape of the adrenal glands and the pituitary. The adrenal glands can be enlarged with infections and cancers. With autoimmune diseases and secondary adrenal insufficiency, the adrenal glands are often normal or small.

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