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

From the Guidelines

Investigation for adrenal insufficiency should begin with paired measurement of serum cortisol and plasma ACTH, and in equivocal cases, a synacthen stimulated peak serum cortisol <500 nmol L-1 is diagnostic of primary adrenal insufficiency. The diagnostic approach to adrenal insufficiency involves a combination of clinical suspicion and laboratory testing. 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 Approach

The following steps should be taken:

• Measure serum cortisol and plasma ACTH levels to differentiate between primary and secondary adrenal insufficiency.
• In cases where the results are equivocal, perform a synacthen stimulation test to assess the adrenal gland's response to ACTH.
• If primary adrenal insufficiency is suspected, evaluate for precipitating causes of crisis, such as infection, and consider adrenal CT for metastasis or hemorrhage 1.
• Additional testing, such as measuring electrolyte levels and checking for adrenal antibodies, may be necessary to confirm the diagnosis and identify the underlying cause.

Importance of Prompt Diagnosis

Prompt diagnosis and treatment of adrenal insufficiency are crucial to prevent life-threatening adrenal crisis, characterized by severe hypotension, electrolyte abnormalities, and shock, especially during physiological stress. As noted in the management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy 1, emergent therapy for suspected adrenal insufficiency can be done with dexamethasone, allowing for subsequent stimulation testing if needed.

Key Considerations

• Treatment should not be delayed by diagnostic procedures in cases of suspected acute adrenal insufficiency 1.
• Patients with adrenal insufficiency should receive education on managing daily medications and situations of minor to moderate concurrent illnesses, and should be provided with supplies to allow self-injection of parenteral hydrocortisone 1.

From the FDA Drug Label

Cosyntropin for injection is indicated, in combination with other diagnostic tests, for use as a diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients.

Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post cosyntropin for injection are suggestive of adrenocortical insufficiency.

The investigation for adrenal insufficiency using cosyntropin involves administering the drug and measuring plasma cortisol levels at baseline and 30 and 60 minutes after administration. Adrenocortical insufficiency is suggested if stimulated plasma cortisol levels are less than 18 mcg/dL at 30 or 60 minutes post-administration.

• Key steps in the investigation include:
  • Administering cosyntropin by intravenous or intramuscular injection
  • Obtaining blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after cosyntropin administration
  • Interpreting cortisol levels to determine the presence of adrenocortical insufficiency 2, 2, 2

From the Research

Investigation for Adrenal Insufficiency

• Adrenal insufficiency is characterized by inadequate glucocorticoid production due to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation 3.
• The diagnosis of adrenal insufficiency is made by demonstrating low basal and/or stimulated serum cortisol, and should be followed by appropriate investigations to establish the underlying aetiology 3.
• A low baseline cortisol (often <100 nmol/L) alongside raised adrenocorticotropic hormone (ACTH) can be enough to diagnose primary adrenal insufficiency 4.
• Confirmatory testing can be done using the cosyntropin (Synacthen®) stimulation test or the insulin tolerance test, which is the gold standard for secondary adrenal insufficiency 4.

Diagnostic Criteria

• A morning serum cortisol of <275 nmol/L identified subnormal-stimulated cortisol with 96.2% sensitivity, while for afternoon samples, a cut-off of <250 nmol/L achieved 96.1% sensitivity 5.
• The optimized threshold for cortisol using the Abbott Architect assay was 14.6 μg/dL at 60 minutes after stimulation (sensitivity, 92%; specificity, 96%) and 13.2 μg/dL at 30 minutes after stimulation (sensitivity, 100%; specificity, 89%) 6.
• Basal cortisol levels ≤100 and ≥450 nmol/L were found in almost half of patients tested for possible adrenal insufficiency and had high diagnostic accuracy, abolishing the need for formal ACTH testing 7.

Testing Protocols

• The cosyntropin stimulation test is the current standard for assessing primary and secondary adrenal insufficiency (AI) 7.
• The use of assay-specific cutoffs will be essential for reducing misclassification and overtreatment in patients with suspected adrenal insufficiency 6.
• A single measurement of serum cortisol carries the potential to significantly reduce the need for dynamic testing in the investigation of adrenal insufficiency 5.