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  • Adrenal Disorders Braden Barnett, MD

  • Adrenal Disorders

    • Cushing’s disease • Primary hyperaldosteronism • Adrenal insufficiency • Pheochromocytoma/paraganglioma • Adrenal nodules

  • Adrenal Hormone Synthesis

    Things to note:

    Cortisone = inactive form of cortisol

    DHEA/DHEAS are inactive precursors of androgens (no major androgenic activity)

  • Adrenal function







  • Cortisol Action

  • Cushing’s Syndrome

    • Defined: end result of chronic exposure to pathologically high levels of glucocorticoids; could be endogenous hypercortisolism, or exogenous • Cushing’s Disease is Cushing’s Syndrome that is caused by a pituitary tumor secreting ACTH

    • Pseudo-Cushing’s Syndrome • Physiologic hypercortisolism • The appropriate secretion of high

    amounts of endogenous cortisol in response to a stressor • Lack of Cushingoid

    signs/symptoms • Causes: uncontrolled DM, chronic

    alcoholism, caloric mismatch (weight loss), anorexia, stress, depression, pregnancy

  • Dexamethasone vs other synthetic GCs

    • Dexamethasone is not measured in cortisol assays, but does provide glucocorticoid action • All other synthetic glucocorticoids (hydrocortisone, prednisone,

    prednisolone, methylprednisolone, triamcinolone, betamethasone) will be at least partially measured in cortisol assays

  • Diagnosis

    • Screening tests and diagnostic/confirmatory tests are the same, which makes diagnosis challenging • 24 hour urine collection for free

    cortisol (3x ULN) • Late night (11pm-12am) salivary

    cortisol (anything above RR)

    • 1 mg (low dose) overnight dexamethasone suppression test • 1 mg dex given at 11pm-12am • Cortisol measured the next

    morning • A normal response should

    suppress the cortisol below 1.8 mcg/dL • Order a serum dexamethasone

    level, if available, to ensure absorption

  • Diagnosis

    • Low dose dexamethasone suppression test • 0.5 mg q6h x 8 doses starting in the early morning, then measure cortisol 6

    hours after the final dose (should be in the early morning) • Normal response should suppress below 1.8 mcg/dL

    • “Paired PM cortisol and ACTH” – Both cortisol and ACTH should be low in the late afternoon • No validated cutoffs

    • Do not do a dexamethasone suppression test during your 24 hour urine collection for free cortisol!

  • Workup

    • If you diagnose Cushing’s syndrome, then get an ACTH level to establish the level of defect • ACTH level is appropriately low à

    ACTH independent, look at the adrenal glands • ACTH level is inappropriately

    high/“normal” à ACTH dependent, look in the pituitary gland • 8 mg (high dose) dex suppression test

    (pituitary will suppress, ectopic will not) • Inferior petrosal sinus sampling (pituitary

    will lateralize to one side, ectopic will not)

  • Treatment

    • Preferred treatment is surgical removal of causative tumor

    • Medical therapy: ketoconazole, metyrapone • Etomidate potently blocks 11β-hydroxylase and aldosterone synthase,

    administered by continuous IV infusion in low, nonanesthetic doses

  • Adrenal Function

    Primary Hyperaldosteronism

  • Who should be tested?

    • Sustained blood pressure (BP) above 150/100 mm Hg on each of three measurements obtained on different days, with hypertension (BP 140/90 mm Hg) resistant to three conventional antihypertensive drugs (including a diuretic), or controlled BP (140/90 mm Hg) on four or more antihypertensive drugs; • hypertension and spontaneous or diuretic-induced hypokalemia; • hypertension and adrenal incidentaloma; • hypertension and sleep apnea; • hypertension and a family history of early onset hypertension or

    cerebrovascular accident at a young age (40 years); • and all hypertensive first-degree relatives of patients with primary


  • D = “Down” (decreases) U = “Up” (increases) R = “Right arrow” (no change) FP = False Positive FN = False Negative

    Antihypertensives with little/no effect on ARR Alpha blockers (-zosins) Verapamil Hydralazine

  • Confirmatory Testing

    • Oral sodium loading test • Saline infusion test • Fludrocortisone suppression test • Captopril challenge test

    • All of these should suppress aldosterone in a normal individual without primary hyperaldosteronism

  • Hyperreninemic Hyperaldosteronism

    • Physiologic (appropriate) response to sodium restriction, hypovolemia, diuretics • Renin producing tumors – rare • Renovascular hypertension • Renal artery stenosis • Fibromuscular dysplasia • Gold standard: invasive renal artery angiography • Non-invasive options: Duplex Doppler, CT angiography, MR angiography

  • Adrenal Insufficiency - Causes

    • Secondary • Damage to the pituitary gland • Chronic corticotroph suppression from exogenous glucocorticoids, followed

    by withdrawal

    • Primary • Autoimmune adrenalitis (“Addison’s Disease”)

  • Adrenal Insufficiency - Diagnosis

    • An early morning serum cortisol concentration less than 1.8-3 mcg/dL is strongly suggestive of adrenal insufficiency; with proper clinical findings, could be diagnostic • An early morning serum cortisol concentration greater than 15-18 mcg/dL

    is strongly suggestive of adrenal sufficiency; unless strong suspicion remains, no further testing necessary • Standard high dose (250 mcg = 0.25 mg) ACTH/cosyntropin/Cortrosyn

    stimulation test • Cortisol measured at baseline, ACTH injected, cortisol measured at 30 minutes and

    60 minutes • Cortisol peak > 18-20 mcg/dL is expected response • “Delta” (change from baseline to peak) no longer used as criteria

  • Adrenal Insufficiency - Diagnosis

    • Why does the ACTH stimulation test exclude secondary adrenal insufficiency? • Problem is with the pituitary, not the adrenals, so response of the adrenals

    might be expected to be normal • In acute secondary adrenal insufficiency (eg, days/few weeks after pituitary

    surgery), response may be normal, so this test may not be ideal • In chronic secondary adrenal insufficiency, adrenal glands have atrophied and

    response will be abnormal

  • Adrenal insufficiency - Treatment

    • Treatment of choice is hydrocortisone due to short half life, ability to mimic normal diurnal variation • Any glucocorticoid will work • Lowest dose possible to relieve

    symptoms; do not use ACTH to adjust dose • 15-25 mg/day in divided doses • 10 to 12 mg/m2/day • Hydrocortisone > 50 mg/day

    provides sufficient mineralocorticoid activity

  • Adrenal Insufficiency - Mineralocorticoid

    • Fludrocortisone • Adjust dose to • Blood pressure • Serum sodium • Serum potassium • Renin levels (too low suggests overtreatment; above ref range probably not a

    problem as long as pt is asymptomatic and BP, sodium, potassium are ok)

  • Adrenal Insufficiency - Treatment

    • Stress dosing – illness, procedures • Double or triple the dose for a few days (3 x 3 rule; triple the dose for 3 days) • Need extra tablets with each prescription for possible stress dosing • Injectable glucocorticoid (hydrocortisone or dexamethasone) at home

    • Medical identification at all times

  • Adrenal Insufficiency in Critically Ill

    • Absolute adrenal insufficiency is RARE among critically ill patients • Relative adrenal insufficiency?

    “critical illness-related corticosteroid insufficiency (CIRCI)” • Poorly defined but some use • ACTH stim test < 9 mcg/dL

    increase at 60 minutes (delta) • Random cortisol < 10 mcg/dL

  • Pheochromocytoma/Paraganglioma

    • Paraganglioma = tumor of neuroendocrine cells capable of secreting catecholamines • Pheochromocytoma = intra-

    adrenal paraganglioma

  • Pheochromocytoma/Paraganglioma - Diagnosis • 24-hour urine fractionated

    metanephrines and catecholamines • 1.5-2x elevation

    • Plasma fractionated metanephrines (NOT catecholamines) • drawn supine with an indwelling

    cannula for 30 minutes – ref range • Seated – 1.5x elevation

    • Majority of the metabolism of catecholamines is intratumoral, with formation of metanephrine and normetanephrine

  • Pheochromocytoma/Paraganglioma - Diagnosis • Some say plasma testing should only be used as initial testing in “high risk

    patients” • A family history of pheochromocytoma • A genetic syndrome that predisposes to pheochromocytoma (eg, MEN2) • A past history of resected pheochromocytoma • An incidentally discovered adrenal mass that has imaging characteristics

    consistent with pheochromocytoma (eg, high CT attenuation [measure in Hounsfield units (HU)] on noncontrast CT scan, marked enhancement with intravenous [IV] contrast medium on CT with delayed contrast washout [

  • Pheochromocytoma/Paraganglioma - Evaluation • Image the adrenals first – CT abdomen (adrenal) or MRI abdome