What are the initial steps for investigating adrenal disorders?

Initial Steps for Investigating Adrenal Disorders

The initial diagnostic approach for adrenal disorders should include hormone testing specific to the suspected condition, with paired measurements of serum cortisol and plasma ACTH serving as the cornerstone test for primary adrenal insufficiency, and the 1 mg dexamethasone suppression test (DST) as the preferred screening test for autonomous cortisol secretion in adrenal incidentalomas. 1

Clinical Presentations That Warrant Investigation

• Consider adrenal insufficiency in patients presenting with unexplained collapse, hypotension, vomiting, diarrhea, hyperpigmentation, hyponatremia, hyperkalemia, acidosis, or hypoglycemia 1
• Suspect Cushing's syndrome with proximal muscle weakness, fatigue, depression, central obesity, supraclavicular fat accumulation, dorsocervical fat pad, facial plethora, thinned skin, purple striae, and ecchymoses 1
• Evaluate for primary aldosteronism in patients with hypertension, hypokalemia, muscle cramping, weakness, headaches, or intermittent paralysis 1
• Consider pheochromocytoma in patients with headaches, anxiety attacks, sweating, palpitations, severe hypertension, tachycardia, arrhythmias, or family history of related genetic syndromes 1
• Investigate for adrenocortical carcinoma when patients present with flank pain, abdominal discomfort, hypercortisolism, virilization, feminization, weight loss, or hirsutism 1

Diagnostic Algorithm for Adrenal Insufficiency

1. Initial Testing:

   • Paired measurement of serum cortisol and plasma ACTH (preferably in the morning) 1
   • Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 1
   • Serum cortisol <400 nmol/L with elevated ACTH during acute illness raises strong suspicion 1

2. Confirmatory Testing (if initial results are equivocal):

   • Synacthen (cosyntropin) stimulation test (0.25 mg IM or IV) with peak serum cortisol <500 nmol/L confirming primary adrenal insufficiency 1, 2
   • Measure plasma renin activity (typically increased), serum aldosterone (typically low), and DHEAS (typically low) 1

3. Etiological Investigation:

   • Measure 21-hydroxylase (anti-adrenal) autoantibodies to check for autoimmune adrenal insufficiency 1
   • If antibodies are negative, proceed with CT imaging of adrenal glands 1
   • In male patients, test very long-chain fatty acids to check for adrenoleukodystrophy 1

Diagnostic Algorithm for Adrenal Incidentalomas

1. Hormonal Evaluation:

   • Cortisol secretion: 1 mg overnight dexamethasone suppression test for all adrenal incidentalomas 1

     • <50 nmol/L (1.8 μg/dL): excludes cortisol hypersecretion
     • 51-138 nmol/L (1.9-5.0 μg/dL): possible autonomous cortisol secretion

     • 138 nmol/L (>5.0 μg/dL): evidence of cortisol hypersecretion

   • Aldosterone production: Aldosterone/renin ratio (ARR) for patients with hypertension and/or hypokalemia 1

     • Test in the morning after patient has been out of bed for 2 hours and seated for 5-15 minutes
     • ARR >20 ng/dL per ng/mL/hr has >90% sensitivity and specificity for hyperaldosteronism

   • Catecholamine excess: Plasma free metanephrines or 24-hour urinary metanephrines for patients with adrenal masses ≥10 HU on non-contrast CT or with symptoms of catecholamine excess 1

     • 2x upper limit of normal is diagnostic

   • Androgen production: DHEAS and testosterone for suspected adrenocortical carcinoma or virilization 1

2. Imaging Characteristics:

   • Non-contrast CT to determine Hounsfield units (HU) 1
   • Size measurement (masses >4 cm have higher risk of malignancy) 1
   • Consider MRI for pregnant women, children, and individuals under 40 years 1

Important Caveats and Pitfalls

• Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 1
• Exogenous steroid use (oral, inhaled) may confound interpretation of cortisol levels 1
• TSH levels may be mildly elevated (4-10 IU/L) in primary adrenal insufficiency due to lack of inhibitory effect of cortisol on TSH production 1
• For aldosterone testing, patients should be potassium-replete and off interfering medications 1
• Adrenal vein sampling may be necessary to lateralize aldosterone production in primary aldosteronism before surgical intervention 1
• Bilateral adrenal masses should be evaluated individually, with special consideration for congenital adrenal hyperplasia (measure 17-hydroxyprogesterone) 1

By following this systematic approach to adrenal investigation, clinicians can efficiently diagnose adrenal disorders and initiate appropriate management to improve patient outcomes.