What is the appropriate workup and treatment for an adult patient with no known history of adrenal disease and a low morning cortisol level, specifically 4.1, suggestive of adrenal insufficiency?

Workup and Treatment for Morning Cortisol of 4.1

A morning cortisol of 4.1 µg/dL (113 nmol/L) is highly suggestive of adrenal insufficiency and requires immediate confirmatory testing with an ACTH stimulation test while simultaneously measuring ACTH to distinguish primary from secondary causes. 1, 2, 3

Immediate Diagnostic Workup

Confirm the Diagnosis

• Obtain simultaneous morning ACTH and cortisol levels if not already done—the relationship between these two values determines whether this is primary (high ACTH, low cortisol) or secondary (low/normal ACTH, low cortisol) adrenal insufficiency 2, 4, 3
• Perform a cosyntropin stimulation test: Administer 0.25 mg (250 mcg) cosyntropin IV or IM, measure cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 2
• A peak cortisol <500 nmol/L (<18 µg/dL) at either 30 or 60 minutes confirms adrenal insufficiency 1, 2
• A peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 2

Critical caveat: If the patient is clinically unstable with hypotension, unexplained collapse, severe nausea/vomiting, or altered mental status, do not delay treatment for diagnostic testing—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour, and draw blood for cortisol and ACTH before administering hydrocortisone if possible 1, 2

Obtain Supporting Laboratory Tests

• Basic metabolic panel: Check for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of primary AI cases, so absence does not exclude diagnosis) 1, 2
• Morning glucose: Hypoglycemia may occur, particularly in children 2
• Serum creatinine: Prerenal azotemia is common 2

Determine the Etiology

If ACTH is Elevated (Primary Adrenal Insufficiency)

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first—autoimmune destruction accounts for ~85% of primary AI in Western populations 1, 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, fungal infections, or other structural causes 1, 2
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

If ACTH is Low or Inappropriately Normal (Secondary Adrenal Insufficiency)

• Assess for other pituitary hormone deficiencies: TSH, free T4, LH, FSH, testosterone/estradiol 4
• Consider MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present or if there are new severe headaches 4
• Review medication history: Look for recent or current use of glucocorticoids (prednisone ≥20 mg/day for ≥3 weeks), opioids, or immune checkpoint inhibitors 2, 4, 3

Important pitfall: Approximately 10% of patients with primary adrenal insufficiency may present with normal cortisol concentrations but clearly elevated ACTH—this represents early Addison's disease and should not be dismissed 5

Treatment Algorithm

For Stable Outpatients with Mild Symptoms

• Initiate hydrocortisone 15-25 mg daily in divided doses: Typical regimen is 10 mg upon waking, 5 mg at noon, and 2.5-5 mg at 4 PM to mimic physiological cortisol secretion 1, 2, 3
• Alternative: Prednisone 3-5 mg daily or cortisone acetate 18.75-31.25 mg daily 1, 3
• For primary AI, add fludrocortisone 50-200 µg daily as a single morning dose for mineralocorticoid replacement 1, 2, 3
• Secondary AI does not require mineralocorticoid replacement 4

For Moderately Symptomatic Patients

• Start with 2-3 times maintenance dosing: Hydrocortisone 20-30 mg in the morning and 10-20 mg in early afternoon 2, 4
• Taper to maintenance doses over 5-10 days as symptoms improve 4

For Severe Symptoms or Adrenal Crisis

• Administer IV hydrocortisone 100 mg bolus immediately, followed by 100 mg every 6-8 hours until recovered 1, 2
• Infuse 0.9% saline at 1 L/hour until hemodynamic improvement (at least 2L total) 1, 2
• Seek and treat the underlying precipitant (infection, trauma, surgery) once treatment has been initiated 1
• Taper stress-dose corticosteroids down to maintenance over 7-14 days after discharge 4

Critical warning: If treating concurrent hypothyroidism and adrenal insufficiency, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 2, 4

Essential Patient Education and Safety Measures

Mandatory Components

• Provide medical alert identification (bracelet or necklace) indicating adrenal insufficiency 1, 2, 3
• Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training 2, 3
• Educate on stress dosing: Double or triple usual dose during illness, fever, or physical stress 2, 3
• Advise unrestricted salt intake and to avoid liquorice and grapefruit juice (which affect cortisol metabolism) 1, 2

Medication Interactions to Monitor

• CYP3A4 inducers (anticonvulsants, rifampin, barbiturates) increase cortisol clearance and may require higher replacement doses 2
• CYP3A4 inhibitors (grapefruit juice, liquorice) decrease cortisol clearance and may require lower doses 2

Long-Term Follow-Up

• Review patients at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes 1
• Screen periodically for new autoimmune disorders, particularly hypothyroidism, diabetes, pernicious anemia, and celiac disease 1, 2
• Monitor bone mineral density every 3-5 years to assess for complications of glucocorticoid therapy 1
• Endocrine consultation is mandatory for newly diagnosed patients, pre-operative planning, and any patient with recurrent adrenal crises 2

This is lifelong replacement therapy—never attempt to discontinue hydrocortisone in patients with confirmed primary or secondary adrenal insufficiency from non-iatrogenic causes, as stopping replacement therapy will precipitate life-threatening adrenal crisis 2