How should primary adrenal insufficiency be diagnosed and managed?

Primary Adrenal Insufficiency: Diagnosis and Management

Diagnostic Approach

Obtain paired early-morning (8 AM) serum cortisol and plasma ACTH as your first-line diagnostic test—this single measurement can often establish the diagnosis without further testing. 1, 2

Initial Laboratory Interpretation

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency and requires no further confirmatory testing 1, 2, 3
• Morning cortisol 140-400 nmol/L (5-14.5 μg/dL) with elevated ACTH requires cosyntropin stimulation testing to confirm the diagnosis 1, 2
• Morning cortisol >550 nmol/L (>18-20 μg/dL) effectively excludes adrenal insufficiency 1

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol is intermediate, proceed with the standard protocol: 1, 2

• 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 timepoint confirms adrenal insufficiency 1, 2, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes the diagnosis 1, 2

Supporting Laboratory Findings

• Hyponatremia is present in 90% of newly diagnosed cases and is the most common electrolyte abnormality 1, 2
• Hyperkalemia occurs in only ~50% of cases—its absence does NOT rule out primary adrenal insufficiency 1, 2
• Additional findings may include hypoglycemia, mild hypercalcemia, increased creatinine from prerenal azotemia, mild anemia, lymphocytosis, and eosinophilia 1, 4

Etiologic Workup After Biochemical Confirmation

Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of primary adrenal insufficiency cases in Western populations. 1, 2

If autoantibodies are negative: 1, 2

• Order CT imaging of the adrenals to evaluate for hemorrhage, tumors, metastatic disease, tuberculosis, or other structural abnormalities 1, 2
• In male patients, assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

Critical Pitfalls to Avoid

Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—mortality is high if untreated. 1, 2, 3

Emergency Management Protocol

If the patient presents with unexplained collapse, hypotension, shock, altered mental status, severe vomiting, or profound weakness: 1, 2

• Immediately administer IV hydrocortisone 100 mg bolus 1, 2, 3
• Start 0.9% saline infusion at 1 L/hour (minimum 2L total) 1, 2
• Continue hydrocortisone 100 mg IV every 6-8 hours 2
• Draw blood for cortisol and ACTH before treatment if possible, but do NOT wait for results 1

Alternative Emergency Approach

If you need to treat suspected adrenal crisis but want to preserve the ability to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays 1, 2

Medication Interference with Testing

Hold all exogenous steroids before diagnostic testing: 1, 5

• Hydrocortisone must be held for 24 hours 1, 5
• Prednisone, prednisolone, and dexamethasone require longer washout periods 1, 5
• Inhaled steroids (e.g., fluticasone) can suppress the HPA axis and confound results 1, 5
• Do NOT attempt diagnostic testing in patients actively taking corticosteroids—the assay measures both endogenous and therapeutic steroids, yielding false results 1

Maintenance Treatment

Glucocorticoid Replacement

All patients with confirmed primary adrenal insufficiency require lifelong glucocorticoid replacement therapy—this is NOT a temporary treatment. 1, 3

Standard regimen: 1, 3

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM) 1, 3
• Alternative: Prednisone 3-5 mg daily 1, 3
• Alternative: Cortisone acetate 25-37.5 mg daily in divided doses 1

Mineralocorticoid Replacement

Primary adrenal insufficiency requires both glucocorticoid AND mineralocorticoid replacement, unlike secondary adrenal insufficiency. 1, 3

• Fludrocortisone 50-200 µg daily (may require up to 500 µg daily in younger adults) 1, 3
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 1
• Encourage unrestricted sodium salt intake 1

Monitoring Replacement Adequacy

Use clinical assessment rather than serum cortisol or ACTH measurements to guide dosing. 1

Signs of under-replacement requiring dose increase: 1

• Lethargy, fatigue, morning nausea
• Poor appetite, weight loss
• Orthostatic hypotension, salt craving
• Increased pigmentation with uneven distribution

Signs of over-replacement requiring dose reduction: 1

• Weight gain, insomnia
• Peripheral edema
• Cushingoid features

Drug Interactions Affecting Dosing

Medications that increase hydrocortisone requirements (CYP3A4 inducers): 1, 5

• Anticonvulsants (phenytoin, carbamazepine, phenobarbital)
• Rifampin and other antituberculosis drugs
• Barbiturates, etomidate, topiramate

Substances that decrease hydrocortisone requirements (CYP3A4 inhibitors): 1, 5

• Grapefruit juice
• Liquorice (should be avoided)

Patient Education and Safety Measures

Stress Dosing Protocol

All patients must be instructed to double or triple their usual dose during illness, fever, or physical stress. 1, 3

Stress dosing guidelines: 1

• Minor stress: Double usual daily dose for 1-2 days
• Moderate stress: Hydrocortisone 50-75 mg daily or prednisone 20 mg daily
• Major stress/surgery: Hydrocortisone 100-150 mg daily

Emergency Preparedness

Every patient must have: 1, 3

• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 3
• Medical alert bracelet or necklace indicating adrenal insufficiency 1, 3
• Steroid emergency card carried at all times 1

Annual Monitoring and Screening

Patients should be reviewed at least annually with: 1

• Assessment of health, well-being, weight, blood pressure
• Serum electrolytes (sodium, potassium)
• Screening for associated autoimmune conditions: thyroid function, plasma glucose, complete blood count, vitamin B12 levels, tissue transglutaminase antibodies (for celiac disease) 1, 2
• Bone mineral density every 3-5 years to assess for glucocorticoid-related complications 1

Special Clinical Scenarios

Concurrent Hypothyroidism

If treating both adrenal insufficiency and hypothyroidism, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1, 5

High-Risk Populations

Suspect adrenal insufficiency in: 1, 2

• Any patient taking ≥20 mg/day prednisone (or equivalent) for ≥3 weeks who develops unexplained hypotension 1
• Patients with autoimmune hypothyroidism presenting with unexplained symptoms (increased risk of coexisting autoimmune adrenal insufficiency) 5
• Patients with systemic lupus erythematosus or antiphospholipid syndrome presenting with shock and altered mental status 6

Distinguishing from SIADH

Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings. 1

The standard 0.25 mg cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia 1