What is the diagnosis and appropriate acute and chronic management for a patient with low serum cortisol and elevated plasma adrenocorticotropic hormone (ACTH)?

Primary Adrenal Insufficiency: Diagnosis and Management

Low cortisol with elevated ACTH is diagnostic of primary adrenal insufficiency (Addison's disease), requiring immediate confirmatory testing with a cosyntropin stimulation test and lifelong glucocorticoid plus mineralocorticoid replacement therapy. 1, 2

Diagnostic Confirmation

Immediate Laboratory Workup

• Obtain paired morning (8 AM) serum cortisol and plasma ACTH measurements—this is your first-line diagnostic approach 1, 2
• Check basic metabolic panel for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of cases, so its absence does NOT rule out the diagnosis) 1, 2
• Critical threshold: Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Basal cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion and mandates confirmatory testing 1, 2

Cosyntropin Stimulation Test (Gold Standard)

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes confirms adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes the diagnosis 1

Important caveat: Approximately 10% of patients with confirmed primary adrenal insufficiency present with normal basal cortisol concentrations but clearly elevated ACTH—do not dismiss the diagnosis based on a single normal cortisol if ACTH is markedly elevated and clinical suspicion is high 3

Etiologic Workup

Determine the Underlying Cause

• First step: Measure 21-hydroxylase (anti-adrenal) autoantibodies—autoimmune adrenalitis accounts for ~80-85% of primary adrenal insufficiency in Western populations 1, 2, 4
• If autoantibodies are negative: Obtain CT imaging of the adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or other structural abnormalities 1, 2
• In male patients with negative antibodies, consider assaying very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

Acute Management (If Adrenal Crisis Suspected)

Emergency Treatment Protocol

• Never delay treatment for diagnostic procedures if the patient is clinically unstable 1, 2
• Administer 100 mg IV hydrocortisone bolus immediately 1, 2
• Start 0.9% saline infusion at 1 L/hour (at least 2 L total) 1, 2
• Draw blood for cortisol and ACTH before treatment if possible, but do NOT wait for results 1, 2
• If diagnosis is uncertain and you still need to perform confirmatory testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays 1

Clinical Features of Adrenal Crisis

• Unexplained collapse, hypotension, or shock 1
• Severe vomiting and/or diarrhea 1
• Altered mental status, confusion, or loss of consciousness 1
• Severe weakness and abdominal pain 1

Chronic Maintenance Therapy

Glucocorticoid Replacement

• Standard regimen: Hydrocortisone 15-25 mg daily in divided doses 1, 2
  • Typical schedule: 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM 1
  • Alternative effective regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg 1
• Alternative options: Cortisone acetate 25-37.5 mg daily or prednisone 4-5 mg daily 1, 2
• Avoid dexamethasone for chronic replacement 1

Mineralocorticoid Replacement (Essential in Primary AI)

• Fludrocortisone 50-200 µg daily (may require up to 500 µg daily in younger adults) 1, 2
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 1, 2
• Encourage unrestricted sodium salt intake 1, 2

Monitoring and Dose Adjustments

• Base adjustments on clinical assessment, NOT serum cortisol or ACTH levels 1
• Signs of under-replacement: Lethargy, nausea, poor appetite, weight loss, morning symptoms 1
• Signs of over-replacement: Weight gain, insomnia, peripheral edema 1
• Consider waking earlier to take the first hydrocortisone dose and returning to sleep if morning nausea is prominent 1

Drug Interactions Requiring Dose Adjustment

• Increase hydrocortisone dose with CYP3A4 inducers: phenytoin, carbamazepine, rifampin, barbiturates 1
• Decrease hydrocortisone dose with CYP3A4 inhibitors: grapefruit juice, licorice 1
• Medications interfering with fludrocortisone: diuretics, acetazolamide, NSAIDs 1

Critical Patient Education and Safety Measures

Stress Dosing Protocol

• Double or triple the usual daily dose during illness, fever, or physical stress 1
• For minor stress: Double usual dose for 1-2 days 1
• For moderate stress: Hydrocortisone 50-75 mg daily 1
• For major stress/surgery: Hydrocortisone 100-150 mg daily 1

Emergency Preparedness

• Mandatory: Prescribe hydrocortisone 100 mg IM injection kit with self-injection training 1, 2
• Mandatory: Patient must wear medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Mandatory: Carry steroid emergency card at all times 1, 2
• Inadequate stress-dosing education is a frequent contributor to recurrent adrenal crises 1

Long-Term Monitoring

• Review at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes 1
• Screen annually for thyroid function, diabetes, vitamin B12 deficiency, and celiac disease (tissue transglutaminase antibodies) 1
• Monitor bone mineral density every 3-5 years 1

Critical Pitfalls to Avoid

• Never attempt to discontinue hydrocortisone in confirmed primary adrenal insufficiency—this is a permanent, lifelong condition and stopping replacement will precipitate life-threatening adrenal crisis 1
• Do not rely solely on electrolyte abnormalities for diagnosis—10-20% of patients have mild or no electrolyte disturbances at presentation 1
• Do not assume hyperkalemia must be present—it occurs in only ~50% of cases 1, 2
• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1
• Exogenous steroids (prednisolone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing—do not attempt diagnostic confirmation until adequate washout time has elapsed 1