Internal Medicine Board Review:

Southwest Ohio Regional Updates in Internal Medicine 2017 Endocrinology: Adrenal Disorders Sona Sharma MD Associate Professor of Clinical Medicine Division of Endocrinology, Diabetes and Metabolism University of Cincinnati College of Medicine February 2018 Adrenal Glands: Normal Anatomy and Physiology Renin-Angiotensin System Hypothalamus Pituitary

Renin CRH (Hypothalamus) ACTH (Pituitary) Zona Fasciculata Cortex Zona Reticularis Zona Glomerulosa

Medulla Glucocorticoids like cortisol Mineralocorticoids like aldosterone Catecholamines (Norepinephrine, epinephrine) Adrenal Hormones: Pathophysiology Hormones Cortex Medulla

Mineralocorticoids (Aldosterone) Glucocorticoids (Cortisol) Adrenal androgens (DHEAS, DHEA) Catecholamines (epinephrine, norepinephrine) Tumors/ Syndromes associated with overproduction Primary Aldosteronism Cushing syndrome

Virilizing or feminizing tumors Pheochromocytoma Tumors/ Syndromes associated with under production Primary Adrenal insufficiency Hypoaldosteronism Primary Adrenal insufficiency Applying normal physiology to work up of adrenal diseases Renin-Angiotensin System

Hypothalamus Pituitary Renin CRH (Hypothalamus) ACTH (Pituitary) Zona Fasciculata Cortex Zona Reticularis

Zona Glomerulosa Medulla Glucocorticoids like cortisol Mineralocorticoids like aldosterone Catecholamines (Norepinephrine, epinephrine) Tests of overproduction and underproduction Applying concepts from physiology: Using diurnal rhythm of Cortisol production Cortisol production peaks in morning and nadir at night Suspecting Cortisol deficiency > check level when it is expected

to be highest (8 am morning cortisol) Suspecting excess > check level when it is expected to be lowest (midnight cortisol) Using feedback regulation of adrenal hormone production Suspecting deficiency > stimulation tests Suspecting excess > suppression tests Cushing Syndrome/disease Definition:- large group of signs & symptoms that reflect prolonged and inappropriately high exposure of tissue to glucocorticoids (exogenous and endogenous)

Williamss Textbook of endocrinology History/Symptoms Weight gain/centripetal obesity Menstrual irregularity Osteoporosis/osteopenia Hypertension

Prediabetes or diabetes Easy bruising Acne/Hirsuitism Examination findings Purple striae Dorsocervical, Supraclavicular fat pads Moon facies Proximal myopathy Diagnostic work up for Cushing syndrome/disease Step 1: Exclude exogenous steroids intake (most common cause of Cushing syndrome) Step 2: Biochemical w/u to confirm endogenous Cushing

- Pituitary ACTH (under CRH from hypothalamus) Adrenals Cortisol (with diurnal rhythm) Low dose Dexamethasone Suppression Test (DST)

= Failure to suppress Endogenous Cortisol by 1 mg Dexamethasone Midnight salivary cortisol (MSC X2) = Loss of normal diurnal rhythm 24 hour Urinary Free Cortisol = Excessive cortisol production => 24 UFC X2 with Creatinine Step 3: Establish level/cause/source of Cushing syndrome Pituitary Ectopic Source of ACTH production ACTH ACTH

Adrenals ACTH Cortisol ACTH:- First step High Dose Dexamethasone suppression tests MRI sella CT/MRI of chest/abdomen Inferior Petrosal Sinus Sampling Adrenal Insufficiency Deficiency of glucocorticoid hormones (cortisol) with or without deficiency of mineralocorticoids (aldosterone) Clinical Presentation: Anorexia, nausea/vomiting, involuntary weight loss, generalized

weakness, volume depletion, hypotension, abdominal pain Shock: Adrenal crisis: a medical emergency Hyponatremia, hypoglycemia Hyperkalemia, hyperpigmentation (primary) Causes of Adrenal Insufficiency Primary (adrenal) Autoimmune adrenalitis (Addison's) most common cause Infections (e.g. TB, HIV, fungal) Infiltrations Adrenal hemorrhage (trauma, coagulopathy, sepsis) Drugs (e.g. mitotane, ketoconazole) Metastasis Bilateral adrenalectomy

Congenital Adrenal Hyperplasia Adrenoleukodystrophy in males Central (Hypothalamus/Pituitary) Supraphysiologic doses of exogenous steroids is most common cause Megace, Ipilimumab Pituitary disease (e.g. tumor, trauma) After surgery for Cushing disease Diagnostic work up of Adrenal Insufficiency Step 1: Confirm diagnosis Am cortisol < 5 ug/dL suggests adrenal insufficiency

Standard 250 mcg Cosyntropin Stimulation test: Peak cortisol levels <18 g/dL at 30 or 60 minutes confirms adrenal g/dL at 30 or 60 minutes confirms adrenal insufficiency Step 2: Identify ACTHACTH is the main test Level of level defect of defect => Cortisol Aldosterone Primary Central Adrenals Secondary (pituitary)

Tertiary (hypothalamus) Low Low Step 3: Work up of underlying cause High Low or Normal Low Normal Renin High

Normal Treatment of Adrenal Insufficiency Severe adrenal insufficiency/adrenal crisis is medical emergency Start glucocorticoids (hydrocortisone) urgently without waiting for results of diagnostic tests Start intravenous fluids Chronic treatment: Primary adrenal insufficiency needs both: Glucocorticoids (hydrocortisone, dexamethasone, prednisone) Mineralocorticoids (fludrocortisone) Secondary/tertiary adrenal insufficiency need only glucocorticoids Stress dosing of steroids during illness or surgery Medic alert/Intramuscular kit for prn use at home Primary Aldosteronism (PA) Definition of PA:- excessive, inappropriate, autonomous production of

aldosterone hormone Too much aldosterone => Plasma Aldosterone Concentration (PAC) Suppressed renin => Plasma renin activity (PRA) Clinical Presentation:-Most common cause of secondary HTN. Suspect PA if: Severe or resistant HTN +/- hypokalemia (even on diuretic) Early onset of HTN HTN + adrenal tumor Family h/o early onset HTN, strokes <40 yrs, PA Diagnostic work up of Primary Aldosteronism (PA) Step 1: Biochemical Confirmation of Primary Aldosteronism (PA) Case detection/Screening tests:PAC (ng/dL) => Aldosterone to renin ratio (ARR) PRA (ng/mL/min) ARR > 30 suggestive of PA (some authors also include PAC >10-15) ARR >30, positive screening tests, need confirmatory tests in most cases Most antihypertensive meds can usually be continued except MRB, K

sparing diuretics (stop for >/= 4 weeks prior to test) Confirmatory tests:- Measure aldosterone in 24 hour urine after oral salt loading or serum after IV saline infusion Diagnostic work up of Primary Aldosteronism (PA) Step 2: Subtype Classification of Primary Aldosteronism (PA) Imaging:- Abdomen CT scan is initial imaging unless contraindicated Adrenal Vein Sampling (AVS):- to differentiate between unilateral vs bilateral aldosterone overproduction (done only in surgical candidates) Treatment of Primary Aldosteronism (PA) Treatment: Medical vs surgical Unilateral overproduction of aldosterone: Adrenalectomy (only in surgical candidates) Bilateral overproduction of aldosterone or patient not surgical candidate or declines surgery

medical treatment with mineralocorticoid receptor blockers (MRB: Spironolactone or Eplerenone) Pheochromocytoma Definition: Pheochromocytoma: tumor arising from adrenal medulla that commonly produces catecholamines Extra adrenal pheochromocytomas: Paraganglioma Clinical presentation: HTN (can be labile, resistant, severe with hypertensive crises), sweating, palpitations, headaches, orthostatic hypotension Can occur in familial conditions (MEN2, NF1, VHL, SDH mutations) Can be malignant Diagnostic work of Pheochromocytoma Lab tests: 24 hour urinary fractionated metanephrines with creatinine or Plasma free metanephrines (normetanephrine, metanephrine) Stress, meds (TCA, sympathomimetic, cocaine): false positive tests

Imaging: CT scan- Initial choice of imaging Usually large, heterogeneous, vascular, high HU, marked contrast enhancement Other modalities: MRI MIBG scan (I-Metaidodobenzylguanidine) PET Scan Pheochromocytoma Treatment:Surgery is mainstay but is high risk: Hypertensive crises/tachyarrhythmias Requires careful preoperative management: Control of HTN: Alphablockers, followed by betablockers Volume expansion: High sodium and fluid intake Careful hemodynamic monitoring Lifelong annual biochemical and clinical monitoring required

Adrenal Incidentaloma Definition:- adrenal mass discovered incidentally on imaging done for reasons other than adrenal disease Clinical significance:- can be malignant or hormonally overproducing tumors. Most are benign and nonfunctional Radiological exam is most helpful diagnostic test Imaging features suggestive of benignity on CT scan Size:- < 4 cm Imaging characteristics:- <10 HU on noncontrast CT scan, homogeneous, smooth bordered Absence of these features: suspicious or indeterminate Other diagnostic modalities:- MRI/PET Scan Biopsy is only RARELY indicated Adrenal Incidentaloma Recommend hormonal evaluation on initial presentation in: All patients for pheochromocytoma (24 hour urinary fractionated

metanephrines or plasma free metanephrines) All patients for Cushing by 1 mg (low dose) DST Only patients with HTN for aldosteronism (PRA, PAC) Only patients with symptoms of virilization in women or feminization in men for androgen secreting tumors (DHEAS, estradiol) Adrenal Incidentaloma Indications for surgery: Most tumors > 4 cm in size (except adrenomyelolipoma) All pheochromocytoma Cushing and aldosteronoma in some people Tumors that enlarge on follow up imaging Need clinical, biochemical or imaging monitoring Question 1

46 year old lady History:- resistant hypertension X 3 years + hypokalemia X 2 years No palpitations, headaches or sweating Periods are regular. No hirsuitism. No h/o CAD or PVD Meds: Lisinopril 40 mg/day, Metoprolol 25 mg X 2/day, Amlodipine 10 mg/day, HCTZ 25 mg/day, KCL 40 meq X 2/day Exam: BMI 25 kg/m2, BP 160/100 mm Hg, pulse 80/minute. No centripetal obesity or purple striae Labs:- Na 143 meq/L, K 3.3 meq/L. No worsening of Cr after starting Lisinopril Question 1 What would be the next step to diagnose her condition? A. Plasma metanephrines B. CT scan to look at adrenal

glands C. Duplex ultrasound for renal arteries D. Plasma renin activity (PRA) and aldosterone E. Dexamethasone suppression test (DST) Answers She probably has primary aldosteronism (high BP+ hypokalemia) A-Plasma metanephrines: Incorrect No signs or symptoms of pheochromocytoma B-CT scan to look at adrenal glands: Incorrect Biochemical diagnosis should precede imaging C-Duplex ultrasound for renal arteries: Incorrect Duplex ultrasound is done to r/o renal artery stenosis (RAS) but she has no

suggestive features of RAS D-Plasma renin activity (PRA) and aldosterone: Correct Check PRA & aldosterone (for primary hyperaldosteronism) E-Dexamethasone suppression test (DST): Incorrect DST is done to r/o Cushing but she has no signs or symptoms of Cushing Question 2 65 year old man History:- referred after his colonoscopy got cancelled because BP rose to > 200/110 mm Hg prior to getting procedure Also c/o episodes of sudden rise in BP, sweating, palpitations, headaches in past few months Current meds: Losartan 50 mg, HCTZ 25 mg Exam: BP 156/96 mm Hg, pulse 104/min, BMI 27 kg/m2 Labs: normal serum K, PRA, PAC, elevated plasma metanephrines and normetanephrines

CAT scan abdo: 4.5 cm right adrenal mass with marked contrast enhancement Question 2 What is the best next step in his management? A. Monitor him since BP is already getting better B. Refer to surgeon for urgent adrenalectomy C. Start alphablocker like phenoxybenzamine D. Start betablockers like metoprolol E. Increase hydrochlorothiazide to 50 mg daily Answers

He has pheochromocytoma: clinical symptoms + elevated plasma metanephrines + adrenal mass on CT Scan A- Monitor him since BP is already getting better: Incorrect Pheochromocytoma should be removed since it can be fatal. He is also symptomatic. B- Refer to surgeon for urgent adrenalectomy: Incorrect Adrenalectomy is a high risk surgery and requires preoperative and perioperative medical preparation C- Start alphablocker like phenoxybenzamine: Correct Start alphablocker before sending him for surgery D- Start betablockers like metoprolol: Incorrect Starting betablockers before alpha blockers can precipitate hypertensive crisis because of unopposed alpha adrenergic action E- Increase hydrochlorothiazide to 50 mg daily: Incorrect: HCTZ not enough to control HTN in him. May cause orthostasis

Question 3 42 year old woman History: Unexplained weight gain of 20 lbs Worsening of DM over past 6 months Irregular periods, facial hair Exam: BMI 35 kg/m2, BP 158/86 mm Hg Centripetal obesity, dorsocervical fat pads, purple striae Labs: blood glucose 230 mg/dl, K 3.9 meq/L, am cortisol 16.7 mcg/dL, ACTH 5 pg/mL Question 3 What is the next best test to confirm the diagnosis? A. 250 mcg cosyntropin test B. Low dose dexamethasone test

(DST) C. High dose dexamethasone suppression test (DST) D. Abdominal CT scan to look at adrenal glands E. Sellar MRI to look at pituitary gland Answers She has clinical signs/symptoms suggestive of Cushing. Needs biochemical confirmation of diagnosis A- 250 mcg cosyntropin test: Incorrect Cosyntropin test is to diagnosis adrenal insufficiency B- Low dose dexamethasone test (DST): Correct Low dose DST is an appropriate test to confirm diagnosis of Cushing disease/syndrome

C- High dose dexamethasone suppression test (DST): Incorrect High dose DST is done to differentiate between pituitary vs ectopic source and is done after diagnosis of Cushing has been confirmed D- Abdominal CT and E Sellar MRI: Incorrect Imaging tests are done after biochemical confirmation of Cushing Question 4 39 year old man seen for the first time History: T1DM since age 12 years and hypothyroidism C/o increased, unexplained hypoglycemia for past few months C/o some n/v, dizziness, weight loss of 6 lbs in last 3 months Exam: BP 90/56 mm Hg, pulse104 beats/min. Increased pigmentation in his hands Current meds: glargine and aspart insulin, levothyroxine Labs: Na 132 meq/L, K 5.6 meq/L, Tsh 5.5 U/mL (ULN 5.2), 8 am cortisol

2.6 mcg/dL with ACTH 670 pg/mL Question 4 In addition to decreasing his insulin dose, what is the next best step in his management? A. Order an urgent brain MRI to rule out pituitary tumor B. Increase dose of levothyroxine to normalize tsh C. Start hydrocortisone as soon as possible D. Check for celiac disease E. Order insulin induced hypoglycemia test to confirm adrenal insufficiency Answers

A Order an urgent brain MRI to rule out pituitary tumor: wrong Even though ACTH is high, since his corresponding cortisol is low, he has adrenal insufficiency and not an ACTH producing tumor B Increase dose of levothyroxine to normalize tsh: Incorrect Borderline high tsh can not explain his clinical picture/lab abnormalities. Glucocorticoids should be replaced before replacing/increasing Levothyroxine C Start hydrocortisone as soon as possible: Correct High likelihood of primary adrenal insufficiency based on his symptoms and labs. Glucocorticoids should be started as soon as possible D Check for celiac disease: Incorrect Celiac disease cannot explain low cortisol E Do insulin induced hypoglycemia test to confirm adrenal insufficiency: Incorrect In a stable patient, test of choice to confirm adrenal insufficiency is Cosyntropin test Question 5

62 year old man History: presented to ER for abdominal pain Abdominal CT scan revealed a round, 2.2 cm adrenal mass, HU 9 No h/o HTN or hypokalemia No sweating or palpitations Exam: BMI 32 kg/m2, BP 132/80 mmHg. No purple striae, dorsocervical fat pad Question 5 What should be included in the diagnosis work up of this adrenal tumor? A. Biopsy of adrenal tumor B. No further tests needed since tumor looks benign on CT scan C. PRA and PAC

D. 8 mg (high dose) DST E. Plasma or 24 hour urine metanephrines Answers A Biopsy of adrenal tumor: Incorrect Biopsy is rarely indicated and only in specific situations. Always r/o pheochromocytoma before performing biopsy B No further tests needed since tumor looks benign on CT scan: Incorrect All patients with adrenal incidentaloma should be tested for Cushing and pheochromocytoma C PRA and PAC: Incorrect In setting of adrenal tumor only hypertensive patients need to be tested for PA D 8 mg (high dose) DST: Incorrect 1 mg or low dose DST (not high dose DST), is the test of choice for adrenal incidentaloma to r/o cushing

E Plasma or 24 hour urine metanephrines: Correct Do Plasma or 24 hour urine metanephrines to rule out pheochromocytoma References The Management of Primary Aldosteronism: Case detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline (2016) Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guidelines (2014) Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2015) The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline (2008) American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentaloma (2009) Management of adrenal incidentalomas: European Society of Endocrinology

Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors (2016)

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