Adrenal DisordersBraden 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

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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

aldosteronism

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

Antihypertensives with little/no effect on ARRAlpha blockers (-zosins)VerapamilHydralazine

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 metanephrineand 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 [<50 percent at 10 minutes], high signal intensity on T2-weighted magnetic resonance imaging [MRI], or cystic and hemorrhagic changes)

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

(adrenal)• Only if this imaging is not diagnostic, consider scintigraphic (nuclear

medicine) imaging• Iobenguane I-123 (also known as metaiodobenzylguanidine [MIBG])• FDG-PET• 68-Ga DOTATATE PET

Pheochromocytoma/Paraganglioma -Treatment• Alpha blockade

• Traditional answer: Phenoxybenzamine (irreversible, long-acting, nonspecific alpha blocker• Minimum $30 per pill, taken bid = $1800/month

• Practical answer: selective alpha-1-blockers (-zosins)• $0.25 per pill

• Goal: seated BP < 120/80 mmHg with standing SBP > 90 mmHg• After controlling BP with alpha blockade, can start beta blocker to decrease

heart rate if necessary (target 60-80 bpm)• Beta blocker should never be started first; blockade of vasodilatory

peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure

Pheochromocytoma/Paraganglioma -Treatment• Surgery

Adrenal nodule

• Evaluate for secretory function and evaluate for risk of malignancy• Pheochromocytoma should be excluded in all patients with adrenal

incidentalomas with unenhanced CT attenuation >10 Hounsfield units • All adrenal nodules > 1 cm in largest dimension should undergo

assessment for Cushing’s syndrome• If hypertensive or hypokalemic, assess for primary

hyperaldosteronism

Adrenal nodule

• If secretory, should be removed• If not secretory, homogeneous adrenal mass <4 cm in diameter, with a

smooth border, and an attenuation value <10 HU on unenhanced CT, and rapid contrast medium washout (eg, >50 percent at 10 minutes) is very likely to be a benign cortical adenoma• Malignant nodules will hold onto HU (high HU) and hold onto contrast

(LOW washout)• Any suspicion for adrenal malignancy à take it OUT• Only FNA nodule pt has another primary malignancy (breast, lung) and

finding an adrenal metastasis will change treatment plan (ie will go from a low stage to widely metastatic); not to diagnose primary adrenal cancer

Adrenal nodule

• If appears to be a benign, nonsecretory nodule, follow-up is debated• Follow-up imaging? Follow-up labs? How often? How long?

• Remove if it grows > 1 cm, or if becomes secretory