What lab tests are used to diagnose adrenal problems in patients?

Laboratory Testing for Adrenal Problems

All patients with suspected adrenal problems should undergo morning (8 AM) serum cortisol and plasma ACTH measurements as the initial diagnostic tests, followed by targeted hormonal screening based on the clinical presentation and imaging characteristics. 1, 2

Initial Diagnostic Laboratory Panel

For All Patients with Suspected Adrenal Insufficiency

• Morning serum cortisol (<5 µg/dL or <140 nmol/L) with elevated ACTH is diagnostic of primary adrenal insufficiency, while low cortisol with low or inappropriately normal ACTH indicates secondary adrenal insufficiency. 1, 2, 3

• Basic metabolic panel (sodium, potassium, CO2, glucose) reveals hyponatremia in 90% of newly diagnosed cases and hyperkalemia in approximately 50% of primary adrenal insufficiency cases. 4, 2

• Dehydroepiandrosterone sulfate (DHEAS) is low in both primary and secondary adrenal insufficiency; a normal age- and sex-adjusted DHEAS level practically rules out adrenal insufficiency. 2, 5

Confirmatory Testing When Initial Results Are Indeterminate

• The cosyntropin (Synacthen) stimulation test is the gold standard confirmatory test: administer 0.25 mg (250 µg) cosyntropin intramuscularly or intravenously, then measure serum cortisol at 30 and 60 minutes post-administration. 1, 4, 2

• **A peak cortisol <500-550 nmol/L (<18-20 µg/dL) is diagnostic of adrenal insufficiency**, while >550 nmol/L is considered normal. 1, 4, 6

• Morning cortisol 5-10 µg/dL (140-275 nmol/L) requires dynamic testing to definitively establish or exclude the diagnosis. 4, 2

Etiologic Workup for Primary Adrenal Insufficiency

• 21-hydroxylase (anti-adrenal) autoantibodies should be measured first, as autoimmunity accounts for approximately 85% of primary adrenal insufficiency cases in Western populations. 1, 4

• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or other structural abnormalities. 1, 4

• In male patients with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy. 1, 4

• In young patients with hypoparathyroidism or candidiasis, measure interferon omega or IL-22 autoantibodies and consider AIRE gene mutation analysis for autoimmune polyglandular syndrome type 1. 1

Hormonal Screening for Adrenal Incidentalomas

Autonomous Cortisol Secretion (Required for All)

• All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion using the 1 mg dexamethasone suppression test (administered at 11 PM with cortisol measured at 8 AM). 1

Primary Aldosteronism (Selective Screening)

• Patients with hypertension and/or hypokalemia should be screened with an aldosterone-to-renin ratio. 1

• Adrenal vein sampling is recommended prior to offering adrenalectomy in patients with confirmed primary aldosteronism. 1

Pheochromocytoma (Selective Screening)

• Patients with adrenal masses displaying >10 HU on non-contrast CT or who have signs/symptoms of catecholamine excess (hypertension, headaches, palpitations, sweating) should be screened with plasma or 24-hour urinary metanephrines. 1

• Screening for pheochromocytoma is not necessary in patients with unequivocal adrenocortical adenomas (<10 HU on unenhanced CT) and no adrenergic symptoms. 1

Androgen Excess (Selective Screening)

• In cases of suspected adrenocortical carcinoma and/or clinical signs of virilization, measure serum DHEA-S, 17-OH-progesterone, androstenedione, testosterone, and 17-beta-estradiol (in men and postmenopausal women). 1

• 24-hour urine steroid metabolite examination can help differentiate adenomas from adrenocortical carcinomas. 1

Critical Pitfalls to Avoid

• Never delay treatment of suspected acute adrenal crisis to obtain diagnostic tests—if clinically unstable, immediately administer 100 mg IV hydrocortisone and 0.9% saline infusion at 1 L/hour, securing blood samples for cortisol and ACTH before treatment if possible. 1, 4, 2

• The absence of hyperkalemia cannot rule out adrenal insufficiency, as it is present in only approximately 50% of cases. 4

• Do not attempt diagnostic testing in patients actively taking corticosteroids—exogenous steroids (including prednisone, prednisolone, dexamethasone, and inhaled fluticasone) suppress the HPA axis and confound results. Wait until treatment is discontinued with adequate washout time. 1, 4

• Morning cortisol measurements are uninterpretable in patients on corticosteroid therapy because assays measure both endogenous cortisol and therapeutic steroids with variable cross-reactivity. 4

• If you must treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 4