What interventions are indicated for a patient with a random cortisol of 5 µg/dL?

Management of Low Cortisol (5.0 µg/dL)

A random cortisol of 5.0 µg/dL requires immediate clinical assessment for symptoms of adrenal insufficiency, followed by confirmatory testing with an ACTH stimulation test and measurement of morning ACTH to distinguish primary from secondary adrenal insufficiency—if the patient is symptomatic or clinically unstable, initiate glucocorticoid replacement immediately without waiting for test results. 1, 2, 3

Immediate Clinical Assessment

Evaluate for symptoms and signs of adrenal crisis that mandate immediate treatment:

• Severe symptoms requiring emergency treatment: Unexplained hypotension (especially vasopressor-dependent), altered mental status, severe weakness, collapse, persistent nausea/vomiting, or gastrointestinal symptoms suggestive of acute decompensation 2, 3
• If adrenal crisis is suspected: Administer IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour—never delay treatment for diagnostic testing 1, 2, 4
• Moderate symptoms (able to perform activities of daily living): Fatigue, nausea, poor appetite, weight loss, orthostatic symptoms—these patients can be evaluated as outpatients but require prompt testing 1, 3

Diagnostic Workup

For stable patients, proceed with systematic evaluation:

Initial Laboratory Testing

• Morning (8 AM) cortisol and plasma ACTH: Obtain paired measurements to distinguish primary from secondary adrenal insufficiency 1, 2, 3
  • Primary AI pattern: Low cortisol (<5 µg/dL) with elevated ACTH (>2× upper limit of normal) 1, 2
  • Secondary AI pattern: Low cortisol with low or inappropriately normal ACTH 1, 2
• Basic metabolic panel: Check sodium, potassium, CO2, and glucose 1
  • Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 2, 4
  • Hyperkalemia occurs in only ~50% of primary AI cases, so its absence does not rule out the diagnosis 2, 4

Confirmatory Testing: ACTH Stimulation Test

The cosyntropin stimulation test is the gold standard for confirming adrenal insufficiency when initial cortisol is indeterminate (5-18 µg/dL): 1, 3

• Protocol: Administer 0.25 mg (250 µg) cosyntropin IV or IM, measure serum cortisol at baseline, 30 minutes, and 60 minutes 1, 4
• Interpretation:
  • Peak cortisol <500 nmol/L (<18 µg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 4
  • Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 4, 3
• Important caveat: The high-dose (250 µg) test is preferred over low-dose (1 µg) due to easier administration, FDA approval, and comparable diagnostic accuracy 4, 5

Etiologic Workup (After Diagnosis Confirmed)

For primary adrenal insufficiency:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies: Autoimmunity accounts for ~85% of primary AI in Western populations 4
• If autoantibodies negative: Obtain adrenal CT imaging to evaluate for hemorrhage, metastases, tuberculosis, fungal infections, or other structural causes 4

For secondary adrenal insufficiency:

• Pituitary MRI: Evaluate for pituitary tumors, hemorrhage, hypophysitis, or other structural lesions 1, 5
• Assess other pituitary hormone axes: Check thyroid function, gonadal function, and growth hormone status 1

Treatment Initiation

Glucocorticoid Replacement

Maintenance therapy for confirmed adrenal insufficiency:

• Preferred regimen: 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) to mimic physiologic diurnal rhythm 1, 4, 3
• Alternative regimens: Prednisone 3-5 mg daily or cortisone acetate 25-37.5 mg daily 1, 4, 3
• Avoid dexamethasone for chronic replacement therapy 4

Stress dosing for moderate symptoms (outpatient):

• Initiate hydrocortisone 30-50 mg total daily dose or prednisone 20 mg daily (2-3× maintenance dose) 1
• Taper to maintenance doses after 2 days once symptoms improve 1

Emergency treatment for severe symptoms:

• IV hydrocortisone 50-100 mg every 6-8 hours initially 1
• Taper stress-dose corticosteroids down to oral maintenance over 5-7 days 1
• Aggressive IV saline resuscitation (at least 2 liters) 1, 4

Mineralocorticoid Replacement (Primary AI Only)

Primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid replacement:

• Fludrocortisone 0.05-0.1 mg daily as starting dose 1, 4, 3
• Adjust based on volume status, sodium levels, blood pressure (supine and standing), salt cravings, and plasma renin activity (target upper half of reference range) 1, 4
• Typical range 50-200 µg daily, but doses up to 500 µg daily may be needed in younger adults 4
• Unrestricted sodium salt intake is essential 4

Secondary adrenal insufficiency does NOT require mineralocorticoid replacement because the renin-angiotensin-aldosterone system remains intact 4, 5

Critical Pitfalls to Avoid

• Never delay treatment in suspected adrenal crisis for diagnostic testing—mortality is high if untreated 1, 2, 4
• Do not rely solely on electrolyte abnormalities for diagnosis—hyponatremia may be mild and hyperkalemia is absent in 50% of cases 2, 4
• When treating concurrent hypothyroidism and adrenal insufficiency, always start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 1, 4
• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing—if diagnosis is uncertain and you need to treat emergently while preserving ability to test later, use dexamethasone 4 mg IV (does not interfere with cortisol assays) 4
• If patient is on corticosteroids, wait until they have been discontinued with adequate washout time before performing definitive HPA axis testing 4

Mandatory Patient Education and Safety Measures

All patients with confirmed adrenal insufficiency require:

• Stress-dose education: Double or triple usual dose during illness, fever, or physical stress 4, 3
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 4, 3
• Medical alert bracelet or necklace indicating adrenal insufficiency to trigger emergency stress-dose administration 1, 4, 3
• Steroid emergency card carried at all times 4
• Early endocrinology consultation for ongoing management, pre-operative planning, and education 1, 4

Follow-Up and Monitoring

• Annual review with assessment of health, well-being, weight, blood pressure, and serum electrolytes 4
• Screen periodically for new autoimmune disorders (thyroid function, diabetes, pernicious anemia, celiac disease) in patients with autoimmune primary AI 4
• Monitor bone mineral density every 3-5 years to assess for glucocorticoid-related complications 4
• Adjust glucocorticoid dosing based on clinical symptoms rather than cortisol levels—signs of over-replacement (weight gain, insomnia, edema) warrant dose reduction; signs of under-replacement (fatigue, nausea, weight loss) require dose increase 4