What is the approach to evaluating and managing adrenal dysfunction?

Evaluation of Adrenal Dysfunction

Initial Diagnostic Testing

The diagnosis of adrenal insufficiency begins with paired early morning (8 AM) measurement of serum cortisol and plasma ACTH, followed by cosyntropin stimulation testing when initial results are equivocal. 1, 2

First-Line Laboratory Tests

• Obtain serum cortisol and plasma ACTH simultaneously at 8 AM as the initial diagnostic approach 1, 2, 3
• Measure serum electrolytes (sodium, potassium, CO2, glucose) to assess for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of cases) 1, 4, 2
• Check DHEAS levels, which are typically low in primary adrenal insufficiency 1, 2
• Measure plasma renin activity (PRA), which is increased in primary adrenal insufficiency 1

Interpretation of Morning Cortisol and ACTH

Primary Adrenal Insufficiency:

• Serum cortisol <250 nmol/L (<9 μg/dL or <5 μg/dL) with elevated ACTH in acute illness is diagnostic 1, 4, 2, 3
• Serum cortisol <140 nmol/L with elevated ACTH confirms the diagnosis 2, 5
• Accompanied by low aldosterone, low DHEAS, and increased PRA 1

Secondary Adrenal Insufficiency:

• Serum cortisol 140-280 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 2, 3
• Low cortisol with low ACTH distinguishes secondary from primary adrenal insufficiency 2
• Mineralocorticoid function typically intact (no hyperkalemia or elevated PRA) 5

Confirmatory Testing: Cosyntropin Stimulation Test

When morning cortisol levels are equivocal (between 140-400 nmol/L), perform the cosyntropin stimulation test to confirm or exclude adrenal insufficiency. 1, 2

Test Protocol

• Administer 0.25 mg (250 μg) cosyntropin (tetracosactide) intramuscularly or intravenously 1, 4
• Obtain baseline serum cortisol and ACTH before administration 1, 4
• Measure serum cortisol at 30 and/or 60 minutes post-administration 1, 4
• The test can be performed at any time of day, though morning is preferred 4

Interpretation of Results

• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 4, 2
• Peak cortisol ≥500-550 nmol/L (≥18-20 μg/dL) indicates normal adrenal function 4, 2
• In equivocal cases with strong clinical suspicion, cortisol <400 nmol/L with elevated ACTH raises strong suspicion of primary adrenal insufficiency 1

Critical Pre-Test Considerations and Pitfalls

Medications That Confound Testing

Stop the following medications before testing to avoid false results:

• Oral glucocorticoids (prednisolone, dexamethasone) - consider at least 5 half-lives 1, 6
• Inhaled steroids (fluticasone) may confound interpretation of low cortisol levels 1, 4
• Spironolactone and estrogen-containing medications 2
• Drugs affecting pituitary or adrenocortical function 6

Common Diagnostic Pitfalls

• Never delay treatment of suspected acute adrenal crisis to perform diagnostic testing - this is potentially fatal 1, 4, 2, 6
• Do not rely solely on electrolyte abnormalities for diagnosis; hyperkalemia is absent in ~50% of primary adrenal insufficiency cases 1, 4, 2
• Between 10-20% of patients may have mild hypercalcemia or completely normal electrolytes at presentation 4
• The cosyntropin test may give false-normal results in secondary adrenal insufficiency, particularly in early or partial pituitary failure 7
• TSH levels may be mildly elevated (4-10 IU/L) in primary adrenal insufficiency due to lack of cortisol's inhibitory effect on TSH production 1

Etiologic Workup After Diagnosis Confirmation

For Primary Adrenal Insufficiency

Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of cases in Western populations. 1, 4, 2

If autoantibodies are negative:

• Obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, fungal infections, or other structural abnormalities 1, 4, 2
• In male patients, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 4
• Consider testing for APS-1 in children and young persons with hypoparathyroidism and candidiasis by measuring anti-interferon omega antibodies or AIRE gene mutation analysis 1

For Secondary Adrenal Insufficiency

• Evaluate for pituitary tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis, hemochromatosis), surgery, or radiation therapy 3
• Assess for medications that suppress corticotropin production, such as opioids 3
• Check other pituitary hormone levels to identify global pituitary insufficiency 1

For Glucocorticoid-Induced Adrenal Insufficiency

• Suspect in any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks who develops unexplained symptoms after tapering or discontinuation 4, 3
• Detailed drug history is essential, including inhaled and topical glucocorticoids 5

Special Clinical Scenarios

Distinguishing Adrenal Insufficiency from SIADH

Both conditions present with euvolemic hypo-osmolar hyponatremia, making differentiation challenging. 4

• Both show serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium 4
• The standard 0.25 mg cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia 4
• Correct diagnosis is crucial as treatment differs significantly: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction 4

Suspected Adrenal Crisis

If adrenal crisis is suspected based on unexplained collapse, hypotension, vomiting, or shock, immediately administer IV hydrocortisone 100 mg and 0.9% saline at 1 L/hour without waiting for diagnostic confirmation. 1, 4

• Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment 1, 4
• Continue hydrocortisone 100 mg IV every 6-8 hours until recovered 1
• Mortality is high if untreated 4

Patients on High-Dose Vasopressors

• Any patient with vasopressor-resistant hypotension should be evaluated for adrenal insufficiency 4
• In critically ill patients with cirrhosis and refractory shock, consider empiric hydrocortisone 50 mg IV q6h or 200-mg infusion for 7 days 4

Assessment of Adrenal Reserve Before Testing

Assess the ability of the adrenals to respond to exogenous ACTH before using metyrapone testing, as metyrapone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity. 6

• Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure during testing 6
• In the presence of hypo- or hyperthyroidism, response to testing may be subnormal 6

Alternative Testing Methods

Insulin Tolerance Test

• Considered the gold standard for secondary adrenal insufficiency when cosyntropin test is inconclusive 8, 7
• Should be performed when secondary adrenal insufficiency is strongly suspected despite normal cosyntropin test 7
• Contraindicated in patients with seizure disorders or cardiovascular disease 8

Metyrapone Test

• Alternative for diagnosing secondary adrenal insufficiency when insulin tolerance test is contraindicated 7
• Single dose of 30 mg/kg (maximum 3 grams) administered at midnight with milk/yogurt 6
• Blood sample taken at 7:30-8:00 AM for 11-desoxycortisol and ACTH measurement 6
• Normal response: 11-desoxycortisol >70 mcg/L indicates intact HPA axis 6

Salivary Cortisol Testing

• Increasingly used in conditions with abnormal cortisol-binding globulin (CBG) levels such as pregnancy 5
• Useful when serum cortisol interpretation is confounded by altered CBG 5

Pediatric Considerations

• Children require lower doses of cosyntropin for testing 5
• Hydrocortisone dosing in children should be 6-10 mg/m² of body surface area 1
• In children younger than 2 years, hypoglycemia, dehydration, and convulsions are frequently observed 7
• Circadian rhythm of cortisol is not present until after 4 months of age 7
• In young girls, virilization is suspect for congenital adrenal hyperplasia 7