What is the appropriate management for a patient with low serum cortisol, potentially indicating adrenal insufficiency?

Management of Low Serum Cortisol

Immediately measure morning (8 AM) serum cortisol and plasma ACTH simultaneously, then perform a cosyntropin stimulation test if cortisol is <18 μg/dL (500 nmol/L) to confirm adrenal insufficiency before initiating glucocorticoid replacement therapy. 1

Initial Diagnostic Workup

Critical first steps:

• Obtain paired early morning (8 AM) serum cortisol and plasma ACTH levels as the first-line diagnostic tests 1, 2
• Order basic metabolic panel to assess for hyponatremia (present in 90% of newly diagnosed cases) and hyperkalemia (present in only ~50% of primary AI cases) 1
• Measure dehydroepiandrosterone sulfate (DHEAS) to help distinguish primary from secondary adrenal insufficiency 2

Interpreting initial cortisol values:

• Morning cortisol <5 μg/dL (<140 nmol/L) with elevated ACTH is diagnostic of primary adrenal insufficiency 1, 2
• Morning cortisol 5-10 μg/dL (140-275 nmol/L) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency 1, 2
• Morning cortisol >18 μg/dL (>500 nmol/L) effectively rules out adrenal insufficiency 1
• Critical pitfall: Approximately 10% of patients with confirmed primary adrenal insufficiency present with normal cortisol concentrations but have clearly elevated ACTH—do not dismiss the diagnosis based on cortisol alone if clinical suspicion is high 3

Cosyntropin Stimulation Test Protocol

When to perform:

• Morning cortisol is indeterminate (5-18 μg/dL or 140-500 nmol/L) 1, 2
• Clinical suspicion remains high despite normal morning cortisol but elevated ACTH 3

Test administration:

• Administer 250 μg (0.25 mg) cosyntropin intramuscularly or intravenously 1
• Measure serum cortisol at baseline and 30 and/or 60 minutes post-administration 1
• Peak cortisol <18 μg/dL (<500 nmol/L) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >18-20 μg/dL (>500-550 nmol/L) is considered normal 1

Important precautions:

• Do NOT perform this test in patients currently taking hydrocortisone (requires 24-hour washout), prednisone, or other exogenous steroids that suppress the HPA axis 1
• Dexamethasone 4 mg IV can be used for emergent treatment if you need to preserve diagnostic testing capability, as it does not interfere with cortisol assays 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern:

• Low cortisol with high ACTH (>300 pg/mL) 1
• Hyponatremia PLUS hyperkalemia (though hyperkalemia absent in ~50% of cases) 1, 4
• Low DHEAS 2
• Both glucocorticoid and mineralocorticoid deficiency 1

Secondary adrenal insufficiency pattern:

• Low cortisol with low or inappropriately normal ACTH 1, 4, 2
• Hyponatremia WITHOUT hyperkalemia (aldosterone secretion remains intact) 4
• Low or low-normal DHEAS 2
• Glucocorticoid deficiency only; mineralocorticoid function preserved 1, 4

Critical diagnostic consideration:

• Adrenal insufficiency can present identically to SIADH with euvolemic hypo-osmolar hyponatremia—never diagnose SIADH without first excluding adrenal insufficiency via cosyntropin stimulation test 1, 4

Etiologic Workup After Confirming Diagnosis

For primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of cases in Western populations 1
• If autoantibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or other structural causes 1
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

For secondary adrenal insufficiency:

• Obtain pituitary MRI to evaluate for tumors, hemorrhage, hypophysitis, sarcoidosis, or hemochromatosis 2
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, growth hormone) 1
• Review medication history for opioids or other drugs that suppress corticotropin production 2

Treatment Based on Clinical Severity

SEVERE SYMPTOMS (adrenal crisis with hypotension, altered mental status, or shock):

• DO NOT DELAY TREATMENT FOR DIAGNOSTIC TESTING 1, 2
• Administer hydrocortisone 100 mg IV bolus immediately 1, 2
• Infuse 0.9% saline at 1 L/hour (minimum 2L total) 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1
• Continue hydrocortisone 50 mg IV every 6 hours or 200 mg/day continuous infusion 5

MODERATE SYMPTOMS (significant fatigue, nausea, orthostatic hypotension):

• Initiate outpatient treatment at 2-3 times maintenance dose 1, 6
• Hydrocortisone 30-50 mg total daily dose (e.g., 20 mg morning, 10-15 mg afternoon) or prednisone 20 mg daily 1, 6
• Taper to maintenance dose over 5-10 days as symptoms improve 6

MILD SYMPTOMS (fatigue, mild nausea, no hypotension):

• Start maintenance glucocorticoid replacement therapy 1, 2
• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) 1, 2
• Alternative: Prednisone 3-5 mg daily 1, 2

For primary adrenal insufficiency, ADD mineralocorticoid replacement:

• Fludrocortisone 0.05-0.1 mg daily initially, titrate up to 0.05-0.3 mg daily based on blood pressure, sodium, potassium, and renin levels 1, 7, 2
• Monitor for adequacy by assessing salt cravings, orthostatic blood pressure, and peripheral edema 1

For secondary adrenal insufficiency:

• Glucocorticoid replacement only; mineralocorticoid NOT needed 1, 4

Critical Management Pitfalls to Avoid

When treating concurrent hypothyroidism and adrenal insufficiency:

• ALWAYS start corticosteroids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1, 6

Drug interactions that increase hydrocortisone requirements:

• Anti-epileptics, antituberculosis drugs, antifungal medications, etomidate, topiramate 1
• Avoid grapefruit juice and liquorice, which decrease hydrocortisone requirements 1

Medications that interfere with fludrocortisone:

• Diuretics, acetazolamide, NSAIDs 1

Exogenous steroid considerations:

• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency 1, 8
• Exogenous steroids suppress the HPA axis and confound diagnostic testing—wait until patient has been weaned off corticosteroids before performing definitive testing, or use dexamethasone for acute treatment if testing still needed 1, 8

Mandatory Patient Education and Follow-Up

All patients with adrenal insufficiency require:

• Education on stress dosing: double or triple dose during illness, fever, or physical stress 1, 2
• Prescription for hydrocortisone 100 mg IM injection kit with self-injection training 1, 2
• Medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Written instructions on warning signs of impending adrenal crisis 1

Stress-dose guidelines:

• Minor stress: double usual daily dose for 1-2 days 1
• Moderate stress: hydrocortisone 50-75 mg daily 1
• Major stress (surgery, severe illness): hydrocortisone 100-150 mg daily 1

Follow-up monitoring:

• Schedule follow-up in 2-4 weeks to reassess symptoms and adjust medication 6
• Annual screening for associated autoimmune conditions (thyroid disease, diabetes, pernicious anemia, celiac disease) 1
• Endocrine consultation mandatory for newly diagnosed patients, pre-operative planning, and recurrent adrenal crises 1