In a 22-year-old patient who presented with hypoglycemia, received glucose and is now hemodynamically stable, a random cortisol measured during the event was 8 µg/dL. What is the appropriate next step in evaluation and management?

Evaluation and Management of Hypoglycemia with Low Random Cortisol

In a 22-year-old patient who presented with hypoglycemia (now stable after glucose administration) and had a random cortisol of 8 µg/dL during the event, the next step is to perform a cosyntropin (ACTH) stimulation test to definitively evaluate for adrenal insufficiency, as a random cortisol below 18 µg/dL during hypoglycemia is inappropriately low and suggestive of impaired counterregulation. 1

Understanding the Clinical Context

The cortisol level of 8 µg/dL during documented hypoglycemia is concerning because:

• Normal cortisol response to hypoglycemia should exceed 18 µg/dL at 30-60 minutes post-stimulus, and levels below this threshold are suggestive of adrenocortical insufficiency 1
• Cortisol is a critical counterregulatory hormone that antagonizes insulin effects and directly influences glucose metabolism; failure to mount an adequate cortisol response during hypoglycemia indicates compromised glucose counterregulation 2, 3
• In healthy individuals experiencing hypoglycemia, cortisol concentrations should rise substantially above baseline, typically reaching 200-250 nmol/L (approximately 7-9 µg/dL increase from baseline) within 10-50 minutes 3

Immediate Next Step: Cosyntropin Stimulation Test

Perform a standard cosyntropin (ACTH) stimulation test to assess adrenal reserve:

• Administer 0.25 mg cosyntropin intravenously or intramuscularly 1
• Obtain baseline serum cortisol immediately before administration 1
• Obtain serum cortisol levels at exactly 30 minutes and 60 minutes after cosyntropin administration 1
• Interpretation: Stimulated plasma cortisol levels less than 18 µg/dL at 30 or 60 minutes post-cosyntropin are diagnostic of adrenocortical insufficiency 1

Critical Testing Considerations

Before performing the cosyntropin stimulation test, ensure:

• Stop glucocorticoids and spironolactone on the day of testing, as these may falsely elevate plasma cortisol levels; long-acting glucocorticoids may need to be stopped for a longer period 1
• Stop estrogen-containing medications 4-6 weeks before testing to allow cortisol binding globulin levels to normalize, as elevated cortisol binding globulin can falsely elevate total cortisol levels 1
• Alternatively, measure cortisol binding globulin concurrently if estrogen cannot be stopped; if cortisol binding globulin is elevated, plasma total cortisol levels are considered inaccurate 1

Additional Diagnostic Evaluation

While awaiting cosyntropin test results, complete the hypoglycemia workup:

• Obtain insulin, C-peptide, proinsulin, and beta-hydroxybutyrate levels during a documented hypoglycemic episode (ideally <55 mg/dL) to differentiate insulin-mediated from non-insulin-mediated hypoglycemia 4
• Plasma and urine sulfonylurea screen to exclude factitious hypoglycemia from oral hypoglycemic agents 4
• If the patient has predominantly postprandial symptoms, consider a mixed meal test rather than a 72-hour fast 4
• Evaluate for other causes of spontaneous hypoglycemia including insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome, insulin autoimmune syndrome, non-islet cell tumor hypoglycemia, and critical illness 4

Management Pending Diagnosis

Until adrenal insufficiency is confirmed or excluded:

• Educate the patient to carry fast-acting glucose sources (15-20 g glucose tablets) at all times and instruct on immediate treatment of hypoglycemia 5
• Prescribe glucagon for emergency use and train family members on administration, as all patients at risk of severe hypoglycemia should have access to glucagon 5, 6
• Instruct the patient to avoid fasting, ensure regular meals, and monitor for situations that increase hypoglycemia risk including delayed meals, intense exercise, and alcohol consumption 5
• Schedule close follow-up to review cosyntropin test results and adjust management accordingly 4

Common Pitfalls to Avoid

• Do not dismiss a cortisol of 8 µg/dL as "adequate" simply because it is within the normal resting range; during hypoglycemic stress, cortisol should be substantially elevated, and failure to do so indicates impaired counterregulation 3
• Do not perform the cosyntropin test while the patient is on glucocorticoids or estrogen, as this will yield inaccurate results 1
• Do not assume diabetes-related hypoglycemia in a 22-year-old without first excluding endocrine causes of hypoglycemia, particularly adrenal insufficiency and insulinoma 4
• Recognize that prior hypoglycemia can reduce basal ACTH and cortisol levels, but the adrenal response to exogenous ACTH should remain intact if the adrenal glands are functioning normally 7

If Adrenal Insufficiency is Confirmed

If the cosyntropin stimulation test confirms adrenal insufficiency (peak cortisol <18 µg/dL):

• Initiate physiologic glucocorticoid replacement therapy 1
• Investigate the etiology: primary adrenal insufficiency (Addison's disease) versus secondary/tertiary adrenal insufficiency (hypopituitarism) 4
• Provide stress-dose steroid education and medical alert identification 6
• Arrange endocrinology follow-up for long-term management 4