What are the implications of an elevated fasting cortisol level?

Elevated Fasting Cortisol: Diagnostic Implications and Management

Immediate Clinical Assessment

A fasting cortisol of 201 nmol/L (approximately 7.3 μg/dL) falls in an indeterminate range that requires systematic evaluation to distinguish between normal variation, adrenal insufficiency, and Cushing's syndrome. This level is neither clearly normal nor diagnostic of either condition, necessitating additional testing based on clinical context 1, 2.

Critical Context-Dependent Interpretation

If Measured in the Morning (0800h)

• This level is concerning for possible adrenal insufficiency and warrants ACTH stimulation testing, as morning cortisol <275 nmol/L (<10 μg/dL) requires further investigation 2.
• Obtain paired morning cortisol and ACTH measurements to distinguish primary from secondary adrenal insufficiency 1, 3.
• A morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 1, 3.
• Proceed with cosyntropin stimulation test: administer 0.25 mg (250 mcg) IV or IM, measure cortisol at 30 and 60 minutes—peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1, 2.

If Measured in the Evening/Late Night (2300h-0100h)

• This level is highly concerning for Cushing's syndrome, as midnight cortisol ≥50 nmol/L (≥1.8 μg/dL) indicates loss of normal circadian rhythm and has 100% sensitivity for Cushing's syndrome 2.
• Normal individuals should have cortisol nadir well below 50 nmol/L by late evening 2.
• Proceed immediately with formal Cushing's screening: obtain at least two of the following—24-hour urinary free cortisol, late-night salivary cortisol on 2-3 occasions, or overnight 1-mg dexamethasone suppression test 4, 2.

Essential Clinical Features to Assess

For Adrenal Insufficiency

• Hypotension, unexplained weight loss, daily fatigue, nausea, salt craving, and orthostatic symptoms are classic features that cannot be ignored 1.
• Hyponatremia is present in 90% of newly diagnosed cases, but absence of hyperkalemia (present in only ~50%) cannot rule out the diagnosis 1, 2.
• Check basic metabolic panel for sodium, potassium, and glucose abnormalities 1.

For Cushing's Syndrome

• Central obesity, facial plethora, proximal muscle weakness, wide purple striae, and easy bruising suggest hypercortisolism 4.
• Associated conditions include hypertension, diabetes, osteoporosis, and increased susceptibility to infections 4, 5.
• Elevated cortisol is independently associated with increased mortality risk in older populations 5.

Critical Confounding Factors to Exclude

Medications and Substances

• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound all cortisol testing—do not attempt diagnostic testing until adequate washout period 1, 2.
• CYP3A4 inducers (phenobarbital, carbamazepine, rifampin) accelerate dexamethasone metabolism and cause false-positive suppression tests 4, 2.
• Oral estrogens, pregnancy, and chronic hepatitis increase cortisol-binding globulin and falsely elevate total cortisol 4, 2.

Physiologic States

• Fasting itself can acutely elevate cortisol levels, particularly in severe caloric restriction, though this effect is transient 6, 7.
• Stress, depression, alcoholism, and severe obesity can cause physiologic hypercortisolism mimicking Cushing's syndrome (pseudo-Cushing's) 4, 2.
• Night-shift workers should not use late-night cortisol testing due to disrupted circadian rhythm 2.

Definitive Diagnostic Algorithm

Step 1: Determine Timing and Clinical Context

• If morning sample with symptoms of adrenal insufficiency → proceed to Step 2A
• If evening/midnight sample → proceed to Step 2B
• If patient on corticosteroids → defer testing until adequate washout 1

Step 2A: Adrenal Insufficiency Workup

• Obtain paired morning (0800h) cortisol and ACTH levels 1, 3
• Perform cosyntropin stimulation test: 0.25 mg IV/IM, measure cortisol at 30 and 60 minutes 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) = adrenal insufficiency confirmed 1, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) = adrenal insufficiency excluded 2

Step 2B: Cushing's Syndrome Workup

• Obtain at least two of three screening tests: 24-hour urinary free cortisol (2-3 collections), late-night salivary cortisol (2-3 measurements), or overnight 1-mg dexamethasone suppression test 4, 2
• Post-dexamethasone cortisol >50 nmol/L (>1.8 μg/dL) is diagnostic of Cushing's syndrome 4, 2
• Measure 0900h plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes once hypercortisolism confirmed 2

Emergency Management Considerations

Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—if patient presents with unexplained hypotension, collapse, or severe gastrointestinal symptoms, immediately administer IV hydrocortisone 100 mg plus 0.9% saline infusion at 1 L/hour 1, 2, 3.

For suspected Cushing's syndrome with severe hypercortisolism causing life-threatening complications, rapid normalization with medical therapy (osilodrostat or metyrapone) is the primary goal 2.

Common Pitfalls to Avoid

• Do not rely on a single cortisol measurement to make or exclude either diagnosis—cortisol exhibits significant circadian variation and day-to-day variability 4, 8.
• Do not assume normal electrolytes exclude adrenal insufficiency—10-20% of patients have normal electrolytes at presentation 1.
• Do not interpret cortisol levels in patients actively taking corticosteroids—the assay measures both endogenous and therapeutic steroids with variable cross-reactivity 1.
• Do not use morning cortisol alone to screen for Cushing's syndrome—morning levels show significant overlap between normal and affected individuals 9.