Workup for Suspected Increased Mineralocorticoid Precursors with Elevated Overnight 1 mg Dexamethasone Suppression Test
In a patient with suspected increased mineralocorticoid precursors (congenital adrenal hyperplasia) and an abnormal overnight 1 mg dexamethasone suppression test, you should immediately confirm autonomous cortisol secretion with 24-hour urinary free cortisol (preferably multiple collections) and/or midnight salivary cortisol, then measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes, followed by measurement of specific steroid precursors including deoxycorticosterone (DOC), 11-deoxycortisol, and androgens to confirm the specific enzyme deficiency. 1
Initial Confirmation of Hypercortisolism
The elevated overnight 1 mg dexamethasone suppression test requires confirmation before proceeding with extensive workup, as this test has significant limitations in mild or episodic hypercortisolism:
- Repeat screening tests are essential: Perform at least 2-3 additional screening tests including 24-hour urinary free cortisol (preferably multiple collections) and midnight salivary cortisol to confirm true hypercortisolism 2, 3
- Interpret the dexamethasone suppression test carefully: A serum cortisol >1.8 μg/dL (50 nmol/L) at 8 AM suggests autonomous cortisol secretion, though cortisol >5.0 μg/dL (138 nmol/L) provides stronger evidence 2
- Be aware of false positives: The 1 mg overnight dexamethasone test has poor sensitivity (18-41%) in patients with mild or episodic Cushing's syndrome, meaning many patients with true disease will suppress inappropriately 4, 5
Critical Pitfall: Rule Out Confounding Factors
Before interpreting any abnormal dexamethasone suppression test, you must exclude factors that cause false results:
- CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerate dexamethasone metabolism, causing falsely elevated cortisol levels 2, 6
- CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) slow dexamethasone metabolism, potentially causing false-negative results 2, 6
- Oral estrogens increase corticosteroid-binding globulin, elevating total cortisol measurements 6
- Malabsorption conditions (celiac disease, chronic diarrhea) affect dexamethasone absorption 6
- Consider measuring dexamethasone levels concomitantly with cortisol (threshold ≥4.5 nmol/L indicates adequate absorption) to identify false positives from inadequate drug levels 2, 6
Measure Plasma ACTH: The Pivotal Differentiating Test
Once hypercortisolism is confirmed, plasma ACTH determines the diagnostic pathway:
- Morning plasma ACTH measurement (ideally 8 AM) differentiates ACTH-dependent from ACTH-independent causes 3
- ACTH >5 ng/L indicates ACTH-dependent disease, which includes Cushing's disease, ectopic ACTH syndrome, and congenital adrenal hyperplasia 3
- ACTH <5 ng/L suggests ACTH-independent disease, pointing toward primary adrenal pathology like adenoma or carcinoma 3
- In congenital adrenal hyperplasia, ACTH is typically elevated due to impaired cortisol synthesis and loss of negative feedback 1
Specific Testing for Congenital Adrenal Hyperplasia
When congenital adrenal hyperplasia is suspected (early-onset hypertension, resistant hypertension, hypokalemia, virilization signs, or incomplete masculinization), proceed with:
Biochemical Confirmation
- Measure aldosterone and renin levels: Both should be low or normal in mineralocorticoid excess syndromes from CAH, distinguishing this from primary aldosteronism 1
- Check serum electrolytes: Hypokalemia is common with 11-beta-hydroxylase deficiency; hyperkalemia may occur with other enzyme defects 1
Steroid Precursor Measurement
- For 11-beta-hydroxylase deficiency: Measure elevated deoxycorticosterone (DOC), 11-deoxycortisol, and androgens 1
- For 17-alpha-hydroxylase deficiency: Measure decreased androgens and estrogen, with elevated deoxycorticosterone and corticosterone 1
- Urinary cortisol metabolites provide additional diagnostic information 1
- Genetic testing confirms the specific enzyme deficiency and guides family counseling 1
Concurrent Evaluation for Primary Aldosteronism
Given the clinical overlap between CAH and primary aldosteronism in patients with hypertension and hypokalemia:
- Measure aldosterone-to-renin ratio in the morning after 2 hours upright and 5-15 minutes seated if hypertension or hypokalemia is present 3
- A ratio >20 ng/dL per ng/mL/hr has >90% sensitivity and specificity for hyperaldosteronism 3
- In CAH, both aldosterone and renin should be low or normal, distinguishing it from primary aldosteronism where aldosterone is elevated 1
Adrenal Imaging
After biochemical confirmation:
- Adrenal CT scan (non-contrast initially) characterizes adrenal morphology 3
- <10 Hounsfield units suggests benign adenoma; higher values or bilateral hyperplasia support CAH diagnosis 3
- Look for bilateral adrenal hyperplasia, which is characteristic of ACTH-dependent conditions including CAH 1
Clinical Examination Clues
Physical examination findings guide the specific enzyme deficiency suspected:
- 11-beta-hydroxylase deficiency: Signs of virilization (hirsutism, acne, clitoromegaly in females, precocious puberty in males) 1
- 17-alpha-hydroxylase deficiency: Incomplete masculinization in males, primary amenorrhea in females, absence of secondary sexual characteristics 1
- Check blood pressure in all extremities: Elevated BP with hypokalemia is the hallmark presentation 1
Important Caveat About Dexamethasone Testing in CAH
The overnight 1 mg dexamethasone suppression test is designed to screen for Cushing's syndrome, not CAH. In CAH patients:
- Cortisol levels may be normal or low despite elevated ACTH, as the enzyme deficiency impairs cortisol synthesis 1
- An "abnormal" dexamethasone test in CAH may reflect the underlying cortisol deficiency rather than autonomous cortisol excess 1
- The test may be misleading if interpreted solely for Cushing's syndrome without considering the broader differential 4, 5