Elevated Serum Uric Acid and Hypertension

September 30, 2011

Outline

• Primary care case

• Risk factors for gout

• Hyperuricemia as an independent risk factor for hypertension?

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!

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

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

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

The history of uric acid and cardiovascular disease

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

• “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 SUAHypertension

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

Elevated SUA and Cardiovascular Disease

Chen, 2009 Arth Care ResElevated 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

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 asymptomaticadults without CVD

0-9% risk >10% risk

Higher serumUric acid!

Nam, 2011 Clin Chem Lab Med

Uric Acid and HypertensionFeig, 2008 NEJM (review)

16 studies:

Asymptomatic, normotensivePatients with elevatedSerum uric acid

Higher relative riskFor hypertensionIn 4-13 years

Renalfellow.blogspot.org

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:Allopurinol Placebo

86% normotensive 3% normotensive

Feig, 2008 JAMA

Elevated SUA in Rats

+ uricase inhibitor

Increased blood pressure

By allopurinol

Khosla, 2005 Kidney Int

Hyperuricemia

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)

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.

• 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 aboutme?

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.