Upon completion, participants should be able to:

Learning Objectives Upon completion, participants should be able to: Describe the causes of secondary hypertension and the prevalence of primary aldosteronism Discuss the diagnostic approach to primary aldosteronism Compare medical and surgical approaches in patients with primary aldosteronism 1

Prevalence and Impact of HTN 1 in 3 adults have HTN (~70 million people in the US) 95% of hypertensive patients have essential HTN, 5% have secondary HTN (renal parenchymal/vascular disease or endocrine causes) HTN is a risk factor for coronary disease, heart failure, stroke, dementia, and renal failure Nwankwo T, et al. NCHS Data Brief. 2013;133:1-8; Carretero OA, et al. Circulation. 2000;101:329-35; CDC. High Blood Pressure Facts. www.cdc.gov. Blood Pressure Levels Vary by Age and Ethnicity Age-Specified and Age-Adjusted Prevalence of HTN Among Adults 18 Years and Older: US, 2011-2012 Overall 29.1 Men 29.7 Women 28.5 Overall Sex Age a (years) Race and Hispanic origin 18-39 years 7.3 40-59 years 32.4 60 years and older 65.0 Non-Hispanic White 28.0 Non-Hispanic Black b 42.1 Non-Hispanic Asian c 24.7 Hispanic c 26.0 0 10 20 30 40 50 60 70 Percent a Significant linear trend. b Significantly different from non-hispanic white. c Significantly different from non-hispanic black. NOTE: Estimates were age-adjusted by the direct method to the Census 2000 population, using the age groups 18-39, 40-59, and 60 years and older. CDC/NCHS. National Health and Nutrition Examination Survey, 2011-2012. Nwankwo T, et al. NCHS Data Brief. 2013;133:1-8. 2

Most Common Causes of Secondary HTN by Age a Age Groups Children (birth to 12 years) Adolescents (12 to 18 years) Young adults (19 to 39 years) Middle-aged adults (40 to 64 years) Older adults (65 years and older) Percentage of HTN With an Underlying Cause Most Common Etiologies b 70%-85% Renal parenchymal disease Coarctation of the aorta 10%-15% Renal parenchymal disease Coarctation of the aorta 5% Thyroid dysfunction Fibromuscular dysplasia Renal parenchymal disease 8%-12% Primary aldosteronism Thyroid dysfunction Obstructive sleep apnea Cushing syndrome Pheochromocytoma 17% Atherosclerotic renal artery stenosis Renal failure Hypothyroidism a Excluding dietary and drug causes and the risk factor of obesity. b Listed in approximate order of frequency within groups. Viera AJ, et al. Am Fam Physician. 2010;82:1471-8. HTN Due to Excess Adrenal Steroids Mineralocorticoids IHA: 60% APA: 35% Primary UAH: 2% Glucocorticoids (rare) ACTH dependent: 85% ACTH independent: 15% CAH/DOC (very rare) Young WF. Clin Endocrinol. 2007;66:607-18; Melmed S, et al. Williams Textbook of Endocrinology. 12th ed. Philadelphia: Elsevier/Saunders, 2011. 3

Aldosterone Signaling and HTN Aldosterone Vascular Tissues Endothelial dysfunction Vascular remodeling Oxidative stress Increased vascular tone Kidneys Sodium retention Water retention Potassium depletion Fibrosis Nervous System Increased sympathetic activity Reduced baroreceptor sensitivity HTN Stas S, et al. J Clin Hypertens. 2008;10:94-6. PA and Secondary HTN PA is the most common cause of secondary HTN (5%-13% of adults with secondary HTN) and often presents in patients with resistant or difficult-tocontrol HTN Hypokalemia is present in a minority (9%-37%) of patients and is usually associated with more severe cases Duan K, et al. Arch Pathol Lab Med. 2015;139:948-54; Mulatero P, et al. J Clin Endocrinol Metab. 2004;89:1045-50; Young WF. Clin Endocrinol. 2007;66:607-18; Funder JW, et al. J Clin Endocrinol Metab. 2016. [Epub ahead of print]. 4

Testing for PA When to consider testing for PA: HTN and hypokalemia Resistant HTN Adrenal incidentaloma and HTN Onset of HTN at a young age (< 20 years) Severe HTN ( 160 mm Hg systolic or 100 mm Hg diastolic) Whenever considering secondary HTN Morning blood sample in seated ambulant patient PAC PRA or PRC PAC ( 15 ng/dl) PRA (< 1.0 ng/ml/h) or PRC (< lower limit of detection for the assay) AND PAC/PRA ratio 20 ng/dl per ng/ml/h Investigate for PA Young WF. Clin Endocrinol. 2007;66:607-18. Diagnostic Algorithm for Patients With Suspected PA Step 1 Screening test: Plasma ARR Step 2 Confirmatory tests: Aldosterone suppression Step 3 Determination of PA subtype: AVS Step 4 The decision to operate Duan K, et al. Arch Pathol Lab Med. 2015;139:948-54. 5

Step 1: Screening Test ARR ARR normalizes fluctuations in either plasma aldosterone or PRA ARR Cut-Off Values, Depending on Assay and Based on Whether PAC, PRA, and DRC Are Measured in Conventional or SI Units PAC (ng/dl) PAC (pmol/l) PRA (ng/ml/h) 20 30 b 40 750 b 1,000 PRA (pmol/l/min) 1.6 2.5 3.1 60 80 DRC a (mu/l) 2.4 3.7 4.9 91 122 DRC b (ng/l) 3.8 5.7 7.7 144 192 a Values shown are on the basis of a conversion factor of PRA (ng/ml/h) to DRC (mu/l) of 8.2. DRC assays are still in evolution, and in a recently introduced and already commonly used automated DRC assay, the conversion factor is 12. b The most commonly adopted cut-off values are shown in bold: 30 for PAC and PRA in conventional units (equivalent to 830 when PAC is in SI units) and 750 when PAC is expressed in SI units (equivalent to 27 in conventional units). Doi SA, et al. J Hum Hypertens. 2006;20:482-9; Tiu SC, et al. J Clin Endocrinol Metab. 2005;90:72-8; Funder JW, et al. J Clin Endocrinol Metab. 2016. [Epub ahead of print]. PAC/PRA Ratio in HTN and Hypokalemia HTN and Hypokalemia PRA PAC PRA PAC PAC/PRA Ratio < 10 Investigate for causes of secondary hyperaldosteronism PRA PAC PAC/PRA Ratio 20 AND PAC 15 ng/dl ( 416 pmol/l) Investigate for PRA PAC Investigate for Renovascular HTN Diuretic use Renin-secreting tumor Malignant HTN Coarctation of the aorta PA CAH Exogenous mineralocorticoid DOC-producing tumor Cushing syndrome 11-beta-OHSD deficiency Altered aldosterone metabolism Liddle syndrome Glucocorticoid resistance Young WF. Clin Endocrinol. 2007;66:607-18; Gupta V. Indian J Endocrinol Metab. 2011;15:S298-312. 6

Step 2: Confirmatory Tests Aldosterone Suppression 1. 24-hour urine aldosterone Oral salt loading 3 days Check 24-hour urine for Na +, K +, and aldosterone on day 3 2. Saline infusion test 2 L 0.9% saline over 4 hours Check blood renin, aldosterone, cortisol, and K + at time 0 and 4 hours 3. Fludrocortisone suppression test 0.1 mg oral fludrocortisone every 6 hours 4 days Check plasma aldosterone and PRA at 10:00 AM on day 4 and plasma cortisol at 7:00 AM and 10:00 AM on day 4 4. Captopril challenge test 25-50 mg captopril given PO PRA, aldosterone, and cortisol plasma levels drawn at time 0 and 1 or 2 hours after challenge Funder JW, et al. J Clin Endocrinol Metab. 2016. [Epub ahead of print]. Clinical Correlation Saline suppression test: 2 L NS given over 4 hours with the following laboratory results Renin Aldosterone Cortisol Potassium Baseline < 0.6 32 8.6 3.6 4 hours < 0.6 16 5.9 3.5 CT not performed given renal function MRI without contrast indicated mild hyperplasia vs adenoma of left adrenal gland Plan for AVS with minimal contrast use 7

Algorithm for Using ARR as a Case-Finding Tool and for Subtype Evaluation of PA Positive Case-Finding Test PAC/PRA > 20 ng/dl per ng/ml/h (555 pmol/l per ng/ml/h) PLUS PAC 15 ng/dl (416 pmol/l) Confirmatory Testing Sodium loading (oral, intravenous, or fludrocortisone) Adrenal CT AVS not required if patient is aged 40 years AND nodule size is 1 cm AND nodule 10 HU Unilateral Nodule Surgery Nodule size < 1 cm Adrenal Venous Sampling Lateralization No Lateralization Normal, Multinodular, Unilateral, or Bilateral Enlargement AVS not required if patient is not a suitable candidate for, or does not wish to undergo, surgery Mineralocorticoid Receptor Antagonist Mattsson C, et al. Nat Clin Pract Nephrol. 2006;2:198-208. Step 3: Determination of PA Subtype AVS Sensitivity of 95% and specificity of 100% 3 protocols 1. Unstimulated sequential or simultaneous bilateral AVS 2. Unstimulated sequential or simultaneous bilateral AVS followed by bolus cosyntropin-stimulated sequential or simultaneous bilateral AVS 3. Continuous cosyntropin infusion with sequential bilateral AVS Young WF, et al. Surgery. 2004;136:1227-35; Funder JW, et al. J Clin Endocrinol Metab. 2016. [Epub ahead of print]. 8

Clinical Correlation AVS performed with strong lateralization to left adrenal Vein Aldosterone, ng/dl Cortisol, μg/dl A/C Ratio IVC 53 27.7 1.9 Right adrenal 75 356.3 0.21 Left adrenal 3,800 583 6.5 > 4 unilateral secretion, < 3 bilateral secretion Patient s left/right ratio was 30, suggesting unilateral left adrenal disease Detection and Removal of APA PAC = 34 ng/dl PRA < 0.6 ng/ml/h Recommended for right adrenalectomy and found to have APA 9

Lateralization With Ambiguous Imaging CT scan shows nodularity in both right and left adrenal glands AVS indicates lateralization to the right adrenal gland Vein Aldosterone, ng/dl Cortisol, μg/dl A/C Ratio Aldosterone Ratio a IVC 13 22 0.6 Right adrenal 8,450 1,669 5.1 8.5 Left adrenal 923 1,599 0.6 Important to perform AVS if possible before sending patient to surgery a Right adrenal A/C ratio divided by left adrenal A/C ratio. Adrenal Vein Aldosterone Ratios for Patients With APA, IHA, and Primary UAH Aldosterone Lateralization Ratio 100 10 0 APA (n = 102) IHA (n = 84) UAH (n = 8) Shaded symbols: diagnosis was confirmed surgically AVS identified 56.7% of PA patients with unilateral disease (APA or UAH) CT scanning correctly identified unilateral or bilateral disease in only 53% of patients 41.4% of patients with a normal CT scan were identified with APA or UAH using AVS Based only on CT, 21.7% of patients were possibly bypassed as candidates for surgery, and 24.7% may have had unnecessary surgery Young WF, et al. Surgery. 2004;136:1227-35. 10

Treatment for PA Surgery Considered in patients with unilateral PA (APA or UAH) Consider age (younger), worse HTN, higher PAC, and lower K + HTN cured in 35%-60% of patients More cost effective than lifelong medical therapy Medication Mineralocorticoid receptor blockade Spironolactone a : starting dose 12.5-25 mg daily and titrate to max 100 mg/day Eplerenone b : starting dose 25 mg daily or BID a Adverse reactions include dizziness, diarrhea, fatigue, and flu-like symptoms. b Adverse reactions include hyperkalemia, renal impairment, and dizziness. Sywak M, et al. Br J of Surgery. 2002;89:1587-93; Funder JW, et al. J Clin Endocrinol Metab. 2016. [Epub ahead of print]; Spironolactone [package insert]. New York, NY: Pfizer Inc.; 2014; Epelerone [package insert]. New York, NY: Pfizer Inc.; 2008. Comments about today s program? Call (toll-free) 866 858 7434 E-mail info@med-iq.com To receive credit, read the introductory CME material, watch the Webcast, and complete the evaluation, attestation, and post-test, answering at least 70% of the post-test questions correctly. The evaluation, attestation, and post-test may be accessed by clicking the Get Credit tab. Please visit us online at www.med-iq.com for additional activities sponsored by Med-IQ. 11

Co-sponsored by the Duke University Health System Department of Clinical Education and Professional Development and Med-IQ. Copyright 2016 Duke University Health System and Med-IQ. All rights reserved. 12

Abbreviations and Acronyms A/C = aldosterone/cortisol ACTH = adrenocorticotropic hormone APA = aldosterone-producing adenoma ARR = aldosterone-to-renin ratio AVS = adrenal vein sampling CAH = congenital adrenal hyperplasia CT = computed tomography DOC = deoxycorticosterone DRC = direct renin concentration HTN = hypertension HU = Hounsfield units IHA = idiopathic hyperaldosteronism IVC = inferior vena cava MRI = magnetic resonance imaging NS = normal saline OHSD = hydroxysteroid dehydrogenase PA = primary aldosteronism PAC = plasma aldosterone concentration PRA = plasma renin activity PRC = plasma renin concentration UAH = unilateral adrenal hyperplasia SI = Systeme International