What is the next step in managing a patient with hypocortisolism (low cortisol), undetectable Dehydroepiandrosterone sulfate (DHEAS), elevated Adrenocorticotropic hormone (ACTH), and normal electrolyte levels, including normal sodium and potassium levels?

Primary Adrenal Insufficiency: Immediate Diagnostic Confirmation Required

The next step is to perform an ACTH stimulation test (cosyntropin 0.25 mg) to definitively confirm primary adrenal insufficiency, followed by measurement of 21-hydroxylase autoantibodies to determine the underlying cause. 1, 2

Understanding the Clinical Picture

Your patient presents with the classic biochemical pattern of primary adrenal insufficiency (Addison's disease):

• Low cortisol with elevated ACTH indicates the adrenal glands are failing to respond to pituitary stimulation 1, 2
• Undetectable DHEAS further confirms adrenal destruction, as DHEA is produced exclusively by the adrenal cortex 3, 4
• Normal electrolytes do not rule out primary adrenal insufficiency—hyperkalemia occurs in only ~50% of cases and hyponatremia in 90%, but some patients present with normal values 2

Immediate Diagnostic Steps

1. ACTH Stimulation Test (Cosyntropin Test)

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 2
• Measure serum cortisol at baseline and 30 minutes post-administration 2
• Diagnostic criteria: Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and excludes the diagnosis 2

Critical caveat: If the patient is clinically unstable with symptoms suggesting adrenal crisis (hypotension, severe weakness, nausea/vomiting, abdominal pain), do not delay treatment to perform this test—give IV hydrocortisone 100 mg immediately and draw cortisol/ACTH before the first dose if possible 1, 2

2. Etiologic Workup

Once primary adrenal insufficiency is confirmed:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies as the first-line test, since autoimmune adrenalitis accounts for ~85% of cases in Western populations 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tuberculosis, fungal infections, metastases, or adrenoleukodystrophy 2
• In males with negative antibodies, consider assaying very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 2

Initiating Treatment

Glucocorticoid Replacement

• Start hydrocortisone 15-20 mg daily in divided doses (typically 10 mg morning, 5 mg early afternoon to mimic diurnal rhythm) 1, 4
• Alternative: Prednisone 5 mg daily (equivalent to hydrocortisone 20 mg), though hydrocortisone is preferred for physiologic replacement 1

Mineralocorticoid Replacement

• Add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement, as primary adrenal insufficiency affects both glucocorticoid and mineralocorticoid production 1, 5
• Titrate fludrocortisone dose to maintain blood pressure, normal potassium, and plasma renin activity in the upper half of the reference range 1, 5

DHEA Replacement Consideration

• Consider DHEA replacement (25-50 mg daily) in women with persistent low libido and/or energy despite adequate cortisol replacement 1, 3
• DHEA deficiency can be tested, and replacement remains somewhat controversial but may improve quality of life 1

Critical Patient Education (Non-Negotiable)

All patients with confirmed adrenal insufficiency require immediate education on:

• Stress dosing protocols: Double or triple maintenance dose during febrile illness, injury, or significant stress 1, 4
• Emergency injectable hydrocortisone: Prescribe and teach patient/family how to administer 100 mg IM in case of vomiting or severe illness 1
• Medical alert bracelet or necklace: Essential to trigger stress-dose corticosteroids by emergency medical personnel 1, 2
• When to seek emergency care: Persistent vomiting, severe diarrhea, high fever, or any signs of adrenal crisis 1

Important Pitfalls to Avoid

• Never rely on electrolyte abnormalities alone to make or exclude the diagnosis—10-20% of patients have normal electrolytes at presentation 2
• Do not delay treatment if the patient is clinically unstable—mortality is high if adrenal crisis goes untreated 2
• Always start corticosteroids before thyroid hormone if concurrent hypothyroidism is present, as thyroid hormone accelerates cortisol clearance and can precipitate adrenal crisis 1
• ACTH stimulation testing can give false-negative results early in evolving adrenal insufficiency, as adrenal reserve declines slowly—if clinical suspicion remains high despite normal testing, consider repeat testing in 3 months 1

Follow-Up and Monitoring

• Arrange endocrine consultation for ongoing management and optimization of replacement therapy 1
• Monitor for signs of under-replacement (fatigue, nausea, weight loss, salt craving, postural dizziness) or over-replacement (weight gain, hypertension, hyperglycemia) 6, 5
• Annual screening for associated autoimmune conditions (thyroid disease, type 1 diabetes, celiac disease, pernicious anemia) is recommended 2