1. Elevated Serum Uric Acid and Hypertension September 30, 2011

2. Outline Primary care case Risk factors for gout Hyperuricemia as an independent risk factor for hypertension?

3. At the primary care clinic… Sudden onset of severe pain of the 1st metatarsal phalangeal joint. Physical exam: tumor, rubor, calor, dolor White blood count: 6.5 x 10^9 cells/L Serum uric acid (sUA) = 8.4mg/dL Synovial fluid aspiration? Sudden onset of severe pain of the 1st metatarsal phalangeal joint. Physical exam: tumor, rubor, calor, dolor White blood count: 6.5 x 10^9 cells/L Serum uric acid (sUA) = 8.4mg/dL Synovial fluid aspiration? Please don’t put a needle in me!

4. Gout - Diagnosis Clinical Prediction Rule: 3.5 (Points) - serum uric acid > 5.88 mg/dL (350 mmol/L) 2.5 - first metatarsophalangeal joint (MTP1) involvement 2 - male sex 2 - previous patient-reported attack 1.5 - hypertension or presence of ≥ 1 cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease) 1 - joint redness 0.5 - onset within 1 day prevalence of gout by score 2.8% for score ≤ 4 27% for score > 4 to < 8 points 80.4% for score ≥ 8 points

5. Gout Risk Factors: #1 = Hyperuricemia Uric acid >6.5 mg/dL in women and >7.0 mg/dL in men Overproduction Dietary purine Excess fructose consumption Alcohol Underexcretion Renal impairment Hypertension Obesity Diuretics, ASA, and other Medications Genetics Hypothyroidism hopkins-arthritis.org

6. Elevated serum uric acid (SUA): Beyond Gout Elevated Uric Acid can cause… Uric acid nephrolithiasis –10-42% prevalence Tophaceous gout Chronic uric acid nephropathy Hypertension? Cardiovascular disease (CVD)? Metabolic syndrome? www.assh.org

7. The history of uric acid and cardiovascular disease 1874: The circulating toxin 1909: Lead, uric acid, and fatty foods 1966: “Hyperuricemia in primary and renal hypertension” 1874: The circulating toxin 1909: Lead, uric acid, and fatty foods 1966: “Hyperuricemia in primary and renal hypertension” Mazzali, 2010 Curr Rheum Res

8. “Serum Uric Acid and Risk for Cardiovascular Disease and Death: The Framingham Heart Study” (Culleton, 1999 Ann Int Med) –An association was seen, but significance went away when adjusted for CVD risk factors “Serum Uric Acid and Risk for Cardiovascular Disease and Death: The Framingham Heart Study” (Culleton, 1999 Ann Int Med) –An association was seen, but significance went away when adjusted for CVD risk factors Elevated SUA Hypertension www.guardian.co.uk Up to date: –the ability to account for elevated SUA in hypertensive patients –plus the lack of evidence for a causative effect –means that uric acid has no independent effect

9. Elevated SUA and Cardiovascular Disease Chen, 2009 Arth Care Res Elevated SUA Higher risk for all-cause mortality Cardiovascular disease ischemic stroke when adjusted for age, sex, body mass index, cholesterol, triglycerides, diabetes, hypertension, cigarette smoking and alcohol consumption

10. Elevated SUA in asymptomatic patients Framingham Risk Assessment Tool is based on: –Age –Gender –total cholesterol –HDL –Smoking –systolic blood pressure –and medications for hypertension. 8035 asymptomatic adults without CVD 0-9% risk >10% risk Higher serum Uric acid! Nam, 2011 Clin Chem Lab Med

11. Uric Acid and Hypertension Feig, 2008 NEJM (review) 16 studies: Asymptomatic, normotensive Patients with elevated Serum uric acid Higher relative risk For hypertension In 4-13 years Renalfellow.blogspot.org

12. Elevated SUA in adolescents Elevated uric acid was found in 90% of adolescents with primary hypertension. Secondary hypertension -> normal serum uric acid Patients with primary hypertension: AllopurinolPlacebo 86% normotensive3% normotensive Feig, 2008 JAMA

13. Elevated SUA in Rats + uricase inhibitor Increased blood pressure By allopurinol Khosla, 2005 Kidney Int Hyperuricemia

14. Why does this happen? Proposed mechanisms –Hyperuricemia causes renal vasoconstriction correlated with plasma renin activity in hypertensive patients. –Uric acid induced cellular proliferation, inflammation, oxidative stress, and the increase in angiotensin I and II receptors in cultured vascular smooth muscle cells. Feig, 2008 NEJM (review)

15. Summary The incidence of elevated SUA is increasing –Renal disease, hypertension, diuretic use, longevity –Increase in fructose consumption and obesity Elevated serum uric acid –predicts development of hypertension –is present in 90% adolescents with recent onset hypertension, treated with allopurinol. –causes hypertension in rats, treated with allopurinol.

16. Our patient: –Elevated SUA as a marker for future CVD? –Control his serum uric acid to prevent hypertension? Asymptomatic patients: –An inexpensive cardiac marker? –Predicting future hypertension in young patients? But what about me?

17. References Cannon PJ, Stason WB, Demartini FE, et al.: Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966; 275:457– 64. Chen J, Chuang S, Chen H, Yeh W, Pan W. Serum Uric Acid Level as an Independent Risk Factor for All-Cause, Cardiovascular, and Ischemic Stroke Mortality: A Chinese Cohort Study. Arth Rheum. 2009; 61(2): 225-232. Culleton BF, Larson, MG, Kannel, WB, and Levy, D. Serum Uric Acid and Risk for Cardiovascular Disease and Death: The Framingham Heart Study. Ann Intern Med. 1999;131:7-13. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008; 359 (17): 1811-21. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on the blood pressure of adolescents with newly diagnosed essential hypertension. JAMA. 2008; 300: 924-32. Khosla UM, Zarikov S, Finch JL, et al. Hyperuricemia induces endotherlial dysfunction. Kidney Int. 2005; 67: 1739-42. Krishnan E, Pandya BJ, Chung L, Dabbous O. Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study. Arthritis Research & Therapy. 2011; 13:R66 Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalai D, Feig DI, Johnson RJ. Uric acid and hypertension: Cause or Effect? Curr Rheumatology Rep. 2010; 12: 108-117. Merriman TR, Dalbeth N. The genetic basis of hyperuricaemia and gout. Joint Bone Spine. 2011; 78(1): 35-40 Nam GE, Lee KS, Park YG, Cho KH, Lee SH, Ko BJ, Kim DH. An increase in serum uric acid concentrations is associated with an increase in the Framingham risk score in Korean adults. Clin Chem Lab Med. 2011; 49(5): 909-14.