What if a patient's morning cortisol level is low, how to diagnose and manage suspected Addison's disease?

Diagnosing Addison's Disease from Cortisol Test Results

If morning cortisol is <250 nmol/L (<9 μg/dL) with elevated ACTH, this is diagnostic of primary adrenal insufficiency (Addison's disease) and requires immediate glucocorticoid and mineralocorticoid replacement. 1

Initial Diagnostic Workup

When evaluating suspected Addison's disease, obtain the following tests simultaneously:

• Morning (8 AM) serum cortisol and plasma ACTH - this paired measurement is the first-line diagnostic approach 1
• Basic metabolic panel to assess for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of cases) 1
• Renin and aldosterone levels to evaluate mineralocorticoid deficiency 2

Interpreting Cortisol and ACTH Results

Diagnostic Patterns:

Primary Adrenal Insufficiency (Addison's Disease):

• Morning cortisol <250 nmol/L (<9 μg/dL) with high ACTH is diagnostic 1
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness raises strong suspicion 1
• Important caveat: Approximately 10% of Addison's patients present with normal cortisol concentrations but clearly elevated ACTH (>300 pg/mL), representing early disease 3

Secondary Adrenal Insufficiency:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 4

Critical Pitfall to Avoid:

Do not rely on electrolyte abnormalities alone - hyperkalemia is absent in 50% of Addison's cases, and some patients may have completely normal electrolytes 1. The absence of hyperkalemia cannot rule out the diagnosis 1.

When to Perform ACTH Stimulation Testing

The cosyntropin (Synacthen) stimulation test is indicated when initial results are indeterminate (morning cortisol between 250-400 nmol/L or 9-14.5 μg/dL) 1.

Test Protocol:

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

Testing Precautions:

• Hold hydrocortisone for 24 hours before testing 1
• Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound results 1
• If you must treat suspected adrenal crisis but still need diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1

Determining the Etiology of Addison's Disease

Once primary adrenal insufficiency is confirmed:

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies - autoimmunity accounts for ~85% of Addison's cases in Western populations 1

2. If autoantibodies are negative, obtain adrenal CT imaging to evaluate for:

   • Adrenal hemorrhage 2
   • Metastatic disease 2
   • Tuberculosis or fungal infections 1
   • Other structural abnormalities 1

3. In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

Emergency Management: Never Delay Treatment

If a patient is clinically unstable with suspected adrenal crisis, treatment must NEVER be delayed for diagnostic procedures 1. Immediate management includes:

• IV hydrocortisone 100 mg bolus immediately 1
• 0.9% saline infusion at 1 L/hour (at least 2L total) 2, 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1

Clinical Red Flags for Adrenal Crisis:

• Unexplained collapse or hypotension 1
• Gastrointestinal symptoms (vomiting, diarrhea, nausea) 1
• Vasopressor-resistant hypotension 1
• Any patient on ≥20 mg/day prednisone for ≥3 weeks who develops unexplained hypotension 1

Maintenance Treatment After Diagnosis

For Primary Adrenal Insufficiency (Addison's Disease):

Glucocorticoid Replacement:

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) 1, 5
• Alternative regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg 1
• Hydrocortisone is preferred over long-acting steroids as it recreates the diurnal cortisol rhythm 5

Mineralocorticoid Replacement:

• Fludrocortisone 0.05-0.1 mg daily (may require up to 0.2 mg daily) 2, 5
• Adjust based on volume status, sodium levels, and renin response (target upper half of reference range) 2
• Monitor for adequacy by assessing salt cravings, orthostatic blood pressure, and peripheral edema 1

Monitoring for Over-Replacement:

Reduce dosing if signs of iatrogenic Cushing's syndrome develop: bruising, thin skin, edema, weight gain, hypertension, hyperglycemia 2, 5

Essential Patient Education

All patients with Addison's disease require:

• Stress dosing education: double or triple doses during illness, fever, or physical stress 1, 5
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1
• Medical alert bracelet or necklace indicating adrenal insufficiency 2, 1, 5
• Mandatory endocrine consultation for optimization and long-term management 2, 1

Critical Warning:

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