What tests to run for adrenal insufficiency (Addison's disease) with hypoglycemia (low blood sugar)?

From the Guidelines

To evaluate adrenal insufficiency with hypoglycemia, the most important tests are a morning cortisol level and an ACTH stimulation test, as well as measuring glucose, cortisol, ACTH, insulin, and growth hormone simultaneously during a hypoglycemic episode. According to the consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency 1, the diagnosis of primary adrenal insufficiency (PAI) should be considered in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea, and hyperpigmentation, hyponatremia, hyperkalemia, acidosis, and hypoglycemia increase clinical suspicion of PAI.

Diagnostic Tests

The diagnostic test for primary PAI should be paired measurement of serum cortisol and plasma ACTH 1. In equivocal cases, a synacthen (tetracosactide) stimulated (0.25 mg im or iv) peak serum cortisol <500 nmol L1 is diagnostic of PAI 1.

• Measure baseline serum cortisol and ACTH levels early in the morning (6-8 AM) when cortisol is naturally highest
• Perform an ACTH stimulation test by administering 250 mcg of synthetic ACTH (cosyntropin) intravenously and measuring cortisol levels at 30 and 60 minutes post-injection
• Collect a critical sample measuring glucose, cortisol, ACTH, insulin, and growth hormone simultaneously during a hypoglycemic episode
• Additional helpful tests include serum electrolytes (looking for hyponatremia and hyperkalemia), plasma renin activity, and aldosterone levels

Aetiology and Further Testing

For suspected primary adrenal insufficiency, check adrenal antibodies and consider adrenal imaging with CT or MRI 1. The aetiology of PAI should be ascertained starting with the measurement of serum 21-hydroxylase (anti-adrenal) autoantibodies 1. If antibodies are negative, CT imaging is recommended 1. In male patients, assay very long-chain fatty acids to check for adrenoleukodystrophy 1.

Clinical Considerations

It is crucial to note that treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 1. If there is a clinical suspicion of impending acute adrenal crisis, the patient should be given intravenous hydrocortisone (HC) immediately and a physiologic (0.9%) saline infusion 1.

From the FDA Drug Label

COSYNTROPIN for injection is an adrenocorticotropin hormone indicated, in combination with other diagnostic tests, for use as a diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients. Obtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after cosyntropin for injection administration.

To diagnose adrenal insufficiency with hypoglycemia, the following tests should be run:

• Serum cortisol level at baseline, 30 minutes, and 60 minutes after cosyntropin administration 2 It is also recommended to stop certain medications, such as glucocorticoids and spironolactone, on the day of testing, and estrogen containing drugs 4 to 6 weeks before testing, as they may affect the accuracy of the test results 2

From the Research

Diagnostic Tests for Adrenal Insufficiency with Hypoglycemia

To diagnose adrenal insufficiency with hypoglycemia, the following tests can be run:

• Cosyntropin stimulation test: This test is used to confirm the diagnosis of adrenal insufficiency 3, 4, 5.
• Insulin tolerance test: This test is considered the gold standard for diagnosing secondary adrenal insufficiency 4.
• Baseline cortisol level: A low baseline cortisol level (<100 nmol/L) alongside raised adrenocorticotropic hormone (ACTH) can be enough to diagnose primary adrenal insufficiency 4.
• Serum cortisol assays: Newer specific cortisol assays may have lower thresholds for a normal response, and new cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation have been recommended 5.
• Laboratory analysis and imaging: Initial evaluation includes assessment for the underlying etiology or concomitant condition, laboratory analysis, and imaging, when clinically indicated 3.

Interpretation of Test Results

When interpreting the results of these tests, it is essential to consider the following:

• A cortisol level of ≥18 μg/dL (500 nmol/L) is considered a normal response to cosyntropin stimulation, but newer specific cortisol assays may have lower thresholds 5.
• A baseline cortisol level <2 μg/dL is predictive of subnormal stimulated cortisol values 5.
• The diagnosis of adrenal insufficiency should be confirmed by specific testing, such as the cosyntropin stimulation test, and should be based on clinical suspicion and laboratory results 3, 4.

Clinical Considerations

In patients with suspected adrenal insufficiency and hypoglycemia, it is crucial to:

• Recognize the clinical features of hypoglycemia, such as drowsiness, collapse, jitteriness, hypothermia, and seizures 6.
• Be aware of the risk of adrenal crisis, which can be life-threatening if not treated promptly 3, 4, 6.
• Educate patients on the importance of self-management and recognition of hypoglycemic events 4, 6.