What does raised serum cortisol indicate?

What Raised Serum Cortisol Indicates

Raised serum cortisol indicates either endogenous hypercortisolism (Cushing's syndrome), exogenous glucocorticoid use, physiologic stress states, or conditions that falsely elevate cortisol measurements—and the clinical context, timing of measurement, and accompanying ACTH levels are essential to distinguish between these possibilities. 1, 2

Primary Diagnostic Considerations

Endogenous Cushing's Syndrome

• Elevated cortisol with loss of normal circadian rhythm indicates pathologic hypercortisolism, which affects 2-8 per million people annually 2
• ACTH levels definitively determine whether hypercortisolism is ACTH-dependent (pituitary or ectopic source) or ACTH-independent (adrenal source) 1, 3
• ACTH >5 ng/L with elevated cortisol indicates ACTH-dependent disease, while suppressed/undetectable ACTH indicates an adrenal source 3
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing's disease (pituitary adenoma) 3

Exogenous Glucocorticoid Use

• The most frequent cause of elevated cortisol is exogenous steroid use, which must be excluded before pursuing endogenous Cushing's syndrome workup 2, 4
• Oral prednisolone, dexamethasone, and even fluticasone inhalers can confuse cortisol interpretation 1
• Topical hydrocortisone preparations can contaminate samples and falsely elevate results, particularly in salivary cortisol 1

Physiologic Hypercortisolism (Pseudo-Cushing's States)

• Depression, alcoholism, severe obesity, polycystic ovary syndrome, and uncontrolled diabetes can activate the HPA axis and cause mildly elevated cortisol that mimics true Cushing's syndrome 1, 4, 5
• Late pregnancy normally increases cortisol production 4
• Acute physical or psychological stress, strenuous exercise within 24-48 hours, and acute illness transiently elevate cortisol 1

False Elevation of Cortisol Measurements

Estrogen-Related Causes

• Oral contraceptives and estrogen therapy are the most common causes of falsely elevated total cortisol—estrogen increases cortisol-binding globulin (CBG), raising total cortisol while free cortisol remains normal 1
• Pregnancy and chronic active hepatitis also increase CBG production 1
• This is the most critical pitfall: always inquire about oral contraceptives, estrogen therapy, and pregnancy before pursuing extensive hypercortisolism workup 1

Other Interfering Factors

• CYP3A4 inducers (phenytoin, rifampin, carbamazepine) accelerate dexamethasone metabolism, causing false-positive suppression tests 1
• Night-shift workers have disrupted circadian rhythm, making standard morning measurements unreliable 1
• Blood contamination from dental work, teeth brushing, or oral trauma within 1-2 hours can falsely elevate salivary cortisol 1

Diagnostic Approach Based on Clinical Context

When Cushing's Syndrome is Suspected

• Screen with late-night salivary cortisol >3.6 nmol/L (sensitivity >90%, highest specificity), 24-hour urinary free cortisol (perform 2-3 collections due to 50% variability), or overnight 1-mg dexamethasone suppression test with cortisol ≥1.8 μg/dL at 0800h as abnormal 1, 6
• Cortisol >5 μg/dL (138 nmol/L) after dexamethasone indicates overt Cushing's syndrome 1
• At least 2-3 abnormal screening tests are recommended before confirming hypercortisolism due to test variability and cyclic disease 1

Determining the Source

• Measure morning (08:00-09:00h) plasma ACTH once hypercortisolism is confirmed 3
• For ACTH-dependent disease (ACTH >5 ng/L): obtain pituitary MRI with thin slices (3T preferred), and if inconclusive or lesion <6 mm, proceed to bilateral inferior petrosal sinus sampling (BIPSS) with central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 post-stimulation confirming pituitary source 7, 3
• For ACTH-independent disease (suppressed ACTH): obtain adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia 3

When Adrenal Insufficiency is Suspected

• Morning cortisol >14 μg/dL (>386 nmol/L) effectively rules out adrenal insufficiency 1
• Cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1
• Cortisol <400 nmol/L with elevated ACTH in acute illness generates strong suspicion requiring further evaluation 1
• Consider synacthen stimulation test (0.25 mg) if equivocal, with peak cortisol <500 nmol/L diagnostic of primary adrenal insufficiency 1

Critical Pitfalls to Avoid

• Never interpret elevated total cortisol as pathologic without considering CBG status—this is the single most important clinical error 1
• Do not delay treatment of suspected acute adrenal insufficiency for diagnostic testing 1
• Recognize that subclinical Cushing's syndrome (abnormal dexamethasone suppression without overt signs) is much more common than classic Cushing's syndrome, with prevalence of 79 per 100,000 versus 1 per 100,000 8
• Cyclic Cushing's syndrome produces weeks to months of normal cortisol interspersed with excess, requiring repeated testing over time 1
• Measuring dexamethasone levels concomitantly with cortisol during suppression testing reduces false-positive results by confirming adequate drug absorption 1
• None of the diagnostic tests reaches 100% specificity, and results may be discordant in up to one-third of patients 3

Clinical Manifestations When Hypercortisolism is Confirmed

• Classic features include facial plethora, easy bruising, wide purple striae (>1 cm), proximal muscle weakness, and central obesity 2, 5
• Associated comorbidities include hypertension, hyperglycemia/diabetes, cardiovascular disease, thromboembolic disease, psychiatric disorders, cognitive deficits, infections, and osteoporosis 2, 5
• These comorbidities significantly impact morbidity, mortality, and quality of life, making early diagnosis and treatment essential 2, 5