Next Steps for Low Cortisol
Immediately measure morning (8 AM) serum cortisol and plasma ACTH simultaneously to distinguish primary from secondary adrenal insufficiency, then proceed with ACTH stimulation testing if cortisol is 140-500 nmol/L (5-18 mcg/dL), as this indeterminate range requires definitive confirmation. 1, 2
Initial Diagnostic Workup
First-Line Laboratory Tests
Obtain morning (8 AM) cortisol and ACTH levels together to determine the type of adrenal insufficiency 1, 2
Order basic metabolic panel (sodium, potassium, CO2, glucose) to assess for characteristic electrolyte abnormalities 1, 2
Interpreting Initial Cortisol Results
Cortisol <250 nmol/L (<9 mcg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency—no further testing needed 1, 2
Cortisol 140-500 nmol/L (5-18 mcg/dL) requires ACTH stimulation testing to definitively confirm or exclude adrenal insufficiency 2, 3, 4
Cortisol >550 nmol/L (>18-20 mcg/dL) effectively excludes adrenal insufficiency in most clinical contexts 2
ACTH Stimulation Test Protocol
When to Perform
Proceed with stimulation testing when morning cortisol falls in the indeterminate range (140-500 nmol/L or 5-18 mcg/dL) 2, 3
Standard Protocol
Administer 0.25 mg (250 mcg) cosyntropin (Synacthen) intramuscularly or intravenously 1, 2
Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 2
Peak cortisol <500 nmol/L (<18 mcg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 2
Peak cortisol >550 nmol/L (>18-20 mcg/dL) is normal and excludes adrenal insufficiency 2
Critical Considerations Before Testing
If the patient is clinically unstable with suspected adrenal crisis, NEVER delay treatment for diagnostic testing—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion 1, 2
If you need to treat emergently but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1, 2
Exogenous steroids (prednisone, prednisolone, inhaled fluticasone) suppress the HPA axis and confound results—testing should not be attempted until corticosteroid treatment is discontinued with adequate washout time 1, 2
Etiologic Workup After Diagnosis
For Primary Adrenal Insufficiency (High ACTH, Low Cortisol)
Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations 2
If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, or other structural causes 1, 2
Measure renin and aldosterone levels to assess mineralocorticoid deficiency 1, 2
For Secondary Adrenal Insufficiency (Low ACTH, Low Cortisol)
Evaluate other pituitary hormones: TSH, free T4, LH, FSH, testosterone (males) or estradiol (premenopausal females) 1
Consider MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present or if the patient has new severe headaches or vision changes 1
Treatment Based on Severity
Grade 1: Asymptomatic or Mild Symptoms
Initiate hydrocortisone 15-20 mg daily in divided doses (typically 10 mg morning, 5-10 mg early afternoon) 1
For primary adrenal insufficiency, add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement 1, 2
Titrate hydrocortisone up to maximum 30 mg daily for residual symptoms of adrenal insufficiency 1
Grade 2: Moderate Symptoms, Able to Perform Activities of Daily Living
Initiate outpatient treatment at 2-3 times maintenance dose (hydrocortisone 30-50 mg total daily or prednisone 20 mg daily) 1, 2
Decrease stress-dose corticosteroids down to maintenance doses after 2 days 1
Add fludrocortisone 0.05-0.1 mg daily for primary adrenal insufficiency 1
Grade 3-4: Severe Symptoms, Life-Threatening, Unable to Perform Activities of Daily Living
Hospitalize for IV hydrocortisone 50-100 mg every 6-8 hours 1
Administer at least 2 liters of 0.9% normal saline 1
Taper stress-dose corticosteroids down to oral maintenance doses over 5-7 days 1
Critical Pitfalls to Avoid
Diagnostic Pitfalls
Do not rely on electrolyte abnormalities alone—hyponatremia may be only marginally reduced and hyperkalemia is absent in ~50% of cases 2
Do not attempt cortisol testing in patients actively taking corticosteroids—the assay measures both endogenous and therapeutic steroids, yielding uninterpretable results 2
Do not confuse adrenal insufficiency with SIADH—both present with euvolemic hypo-osmolar hyponatremia, making ACTH stimulation testing medically necessary to distinguish them 2
Treatment Pitfalls
When treating concurrent hypothyroidism and adrenal insufficiency, ALWAYS start corticosteroids several days before initiating thyroid hormone to prevent precipitating adrenal crisis 1, 2
Long-acting steroids like prednisone carry higher risk of over-replacement compared to hydrocortisone—use hydrocortisone preferentially to recreate diurnal cortisol rhythm 1, 2
Secondary adrenal insufficiency does NOT require mineralocorticoid replacement (fludrocortisone), as the renin-angiotensin-aldosterone system remains intact 1, 3
Mandatory Patient Education
Stress Dosing
Teach patients to double or triple their usual dose during illness, fever, injury, or significant physical stress 1, 2
Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 2
Safety Measures
All patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency medical personnel 1, 2
Educate on warning signs of impending adrenal crisis: severe weakness, confusion, severe vomiting/diarrhea, hypotension, and when to seek emergency care 2