What are the diagnostic criteria for adrenal insufficiency (Addison's disease)?

From the Guidelines

The diagnosis of adrenal insufficiency should be considered in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea, and should be confirmed by paired measurement of serum cortisol and plasma ACTH, with a synacthen stimulated peak serum cortisol <500 nmol L-1 being diagnostic of primary adrenal insufficiency. The diagnostic criteria for adrenal insufficiency, also known as Addison's disease, involve a combination of clinical assessment and laboratory testing. According to the consensus statement on the diagnosis, treatment, and follow-up of patients with primary adrenal insufficiency 1, the initial step involves measuring serum cortisol and plasma ACTH levels.

Key Diagnostic Criteria

• The diagnosis of primary adrenal insufficiency (PAI) should be considered in all patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea, and should be confirmed by paired measurement of serum cortisol and plasma ACTH.
• A synacthen stimulated (0.25 mg im or iv) peak serum cortisol <500 nmol L-1 is diagnostic of PAI.
• In cases of suspected acute adrenal insufficiency, a serum cortisol <250 nmol L-1 and increased ACTH is diagnostic of primary PAI, while a serum cortisol <400 nmol L-1 and increased ACTH raises a strong suspicion of PAI.
• Additional tests may include electrolytes, blood glucose, and in cases of suspected primary adrenal insufficiency, testing for adrenal antibodies and adrenal imaging.

Laboratory Testing

• The gold standard diagnostic test is the ACTH stimulation test (also called cosyntropin or Synacthen test), where synthetic ACTH is administered intravenously or intramuscularly, and cortisol levels are measured at baseline, 30 minutes, and 60 minutes after administration.
• Plasma ACTH levels should be measured to distinguish between primary and secondary adrenal insufficiency; elevated ACTH indicates primary adrenal insufficiency (Addison's disease), while normal or low ACTH suggests secondary adrenal insufficiency due to pituitary or hypothalamic dysfunction.

Clinical Considerations

• Patients with suspected adrenal crisis require immediate treatment with hydrocortisone 100 mg IV before completing diagnostic workup, as this is a life-threatening condition 1.
• The diagnostic work-up for patients in whom adrenal insufficiency is suspected should include evaluation of ACTH, cortisol level, and basic metabolic panel, with consideration of an ACTH stimulation test for indeterminate results 1.

From the FDA Drug Label

An intact HPA axis function is generally indicated by an increase in 11‑desoxycortisol to over 70 mcg/L. The diagnostic criteria for adrenal insufficiency (Addison's disease) include an increase in 11-desoxycortisol to over 70 mcg/L after metyrapone administration, indicating an intact HPA axis function. Key points:

• 11-desoxycortisol levels are used to diagnose adrenal insufficiency
• An increase in 11-desoxycortisol to over 70 mcg/L indicates an intact HPA axis function
• The ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency 2

From the Research

Diagnostic Criteria for Adrenal Insufficiency

The diagnostic criteria for adrenal insufficiency, also known as Addison's disease, involve a combination of clinical presentation, laboratory tests, and dynamic testing. The following are some key points to consider:

• Adrenal insufficiency is characterized by cortisol deficiency, and its evaluation can be challenging due to the rarity of the disease and limitations in biochemical assessment 3.
• The adrenocorticotropic hormone (ACTH) stimulation test is commonly used to diagnose adrenal insufficiency, but its interpretation can be affected by technical aspects such as time of day, type of assay, and sample source used for cortisol measurement 3, 4.
• The current cut-offs for diagnosing adrenal insufficiency have been established using outdated immunoassays, and the use of more specific cortisol assays can result in lower cortisol concentrations, leading to potential misdiagnosis and overtreatment 4.
• A low baseline cortisol level (often <100 nmol/L) alongside raised ACTH can be enough to diagnose primary adrenal insufficiency, while confirmatory testing can be done using the cosyntropin stimulation test or the insulin tolerance test 5.
• Baseline measurements of serum cortisol are helpful only when they are very low (≤ 5 μg/dL) or clearly elevated, whereas baseline plasma ACTH levels are helpful only when primary adrenal insufficiency is suspected 6.
• Measurements of baseline serum dehydroepiandrosterone sulfate (DHEA-S) levels are valuable in patients suspected of having adrenal insufficiency, and a normal age- and sex-adjusted serum DHEA-S level practically rules out the diagnosis of adrenal insufficiency 6.
• The corticotropin-releasing hormone test and basal serum cortisol have been evaluated in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease, and basal cortisol levels of 285 nmol/liter or more can be used to diagnose adrenal insufficiency with high sensitivity and specificity 7.

Key Diagnostic Tests

Some key diagnostic tests for adrenal insufficiency include:

• ACTH stimulation test
• Cosyntropin stimulation test
• Insulin tolerance test
• Basal serum cortisol measurement
• Basal serum DHEA-S measurement
• Corticotropin-releasing hormone test

Interpretation of Test Results

The interpretation of test results for adrenal insufficiency can be complex and requires consideration of various factors, including:

• Clinical presentation and likelihood of adrenal insufficiency
• Technical aspects of testing, such as time of day and type of assay used
• Comparison to established cut-offs and normal ranges
• Correlation with other test results and clinical findings 3, 4, 5, 6, 7