Testing for / diagnosing adrenal insufficiency

Initial testing for adrenal insufficiency is simple and labs can be ordered by any physician.

However, the endocrine system is complex and testing procedures are often misunderstood. Diagnostic recommendations for adrenal insufficiency evolved as different testing methods became available. At one point, the ACTH stimulation test was in use, but there was no way to measure pituitary ACTH production. Without the ACTH level to assess the pituitary, diagnosing secondary adrenal insufficiency was very difficult. This led to the discussion among professionals about whether the high or low dose ACTH stimulation test was better to diagnose secondary adrenal insufficiency. Those discussions are still in the literature used today.

Even more, we now have the ACTH baseline measurement available to help differentiate between primary (PAI) and secondary adrenal insufficiency (SAI). Physicians who see the older discussions on the ACTH stimulation test often miss the importance of the ACTH baseline test.

This said, confirmation of the clinical diagnosis of adrenal insufficiency is a three-stage process:

1. Demonstrating inappropriately low cortisol secretion.

The morning serum cortisol checks baseline adrenal cortisol production. It should be drawn between 8 and 9am.

2. Evaluation of the HPA axis

These tests determine whether the cortisol deficiency is dependent on or independent of corticotropin (ACTH) production and evaluate mineralocorticoid secretion in patients without ACTH deficiency.

The baseline ACTH test evaluates pituitary corticotropin (ACTH) production. It should be drawn simultaneously with the morning cortisol sample.

NOTE: The morning cortisol and the baseline ACTH are sampled and interpreted together and should indicate the direction for further testing and/or referral to a specialist.

The ACTH stimulation test evaluates stimulated adrenal cortisol response. This test is used to confirm or exclude PAI if the baseline cortisol result is indeterminate. Lack of appropriate response may indicate adrenal atrophy in chronic SAI patients. Adequate response to the ACTH stimulation test does not eliminate the possibility of secondary or tertiary AI.

NOTE: Wrongly, the ACTH stimulation test is often ordered first. It is important to request that the baseline ACTH is sampled BEFORE the injection for the ACTH stimulation test. If the problem originates in the pituitary or hypothalamus, it can go undetected by the ACTH stimulation test alone, leading to misdiagnosis.

The Metyrapone and the Insulin Tolerance Test (ITT), are used to measure stimulated pituitary ACTH production if SAI or TAI is suspected. Choice of which test to use is based on patient profile. Current recommendations favor the Metyrapone test. It is more accurate, less expensive, and easier to administer than the ITT.

3. Confirming / excluding a cause of the primary disorder

Imaging tests such as a CT Scan or MRI are used to confirm / exclude any infiltrative process of the adrenals or a pituitary that would compromise normal hormone production.

Additional note: Pre-testing considerations

The following hormones or drugs may interfere with accurate test results.

• Glucocorticoids or corticosteroids in any form, including topical, inhaled, injected, and oral tablets/capsules.
• Birth control or other estrogens, including soybean food products and menopause formulas.
• Drugs that inhibit cortisol biosynthesis, such as etomidate, ketoconazole, fluconazole, metyrapone, and suramin.
• Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, mitotane, and rifampin.
• High dose progestins or chronic administration of opiates.

Recommended times for discontinuing steroids before testing are 12 hours for Hydrocortisone, 24 hours for Prednisone.

Dexamethasone is commonly prescribed for patients suspected of adrenal insufficiency who require testing to confirm the diagnosis. It is not read by radioimmunoassay, the most common type of lab test for cortisol. This is an accurate way to assess HPA axis function provided that testing is done within the first two weeks of treatment. After this time period Dexamethasone will begin to suppress HPA axis function.

Additional note: Electrolytes

Electrolyte balance is an important part of managing adrenal insufficiency. Primary adrenal insufficiency patients usually have an aldosterone deficiency.  Florinef or Fludrocort, mineralocorticoid steroids, are prescribed to help regulate sodium and potassium. Secondary and tertiary patients often have their own unique electrolyte issues to address, although there is no typical pattern. Because electrolyte imbalances can be life-threatening, it’s important to discuss them with your doctor and have them tested. Aldosterone/plasma renin activity (PRA) is the correct test to evaluate mineralocorticoid deficiency. A standard Comprehensive metabolic profile, (CMP) will show potassium and sodium levels, and the RBC magnesium test is used to assess magnesium.