Uric Acid
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Hyperuricemia, a high level of uric acid in the blood, is a problem that affects at least 4% of American adults at any one time.  Even high normal levels have been found to increase the risk of developing high blood pressure, heart disease, stroke, kidney failure, peripheral vascular disease, and death.  High levels of uric acid also cause a type of arthritis called gout, which affects especially the thumb and large toes joints.  Hyperuricemia and gout effect men 3-4 times more often than women.

Treating asymptomatic hyperuricemia with allopurinol is widely discouraged because of the very small, but potentially fatal risk of the allopurinol hypersensitivity syndrome.  It can be helped by avoiding meat, since it comes primarily from the breakdown of red blood cells.  Also, alcohol intake should be limited to a maximum of one drink per day and preferably wine (4-6 oz.) rather than beer or liquor.  Some medicines can cause hyperuricemia including theophylline (0.4% of patients-Respir Med. 2004 Oct;98(10):1016-24), diuretics (the increase is harmful: J Hypertens. 2004 Jul;22(7):1415-7), and cyclosporine.  Atorvastatin lowers uric acid, but simvastatin does not (Am Heart J. 2004 Oct;148(4):635-40).

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Beer and Liguor Increase Uric Acid, But Wine Doesn't: Using data from 14,809 adults in The Third National Health and Nutrition Examination Survey (1988-1994), uric acid levels increased with increasing beer or liquor intake but not with increasing wine intake (p <0.001), but the association was inverse with increasing wine intake (P for trend <0.001). After adjusting mutually for these alcoholic beverages and for other risk factors for hyperuricemia, including dietary risk factors, the associations were attenuated but remained significant for beer or liquor (multivariate difference per serving per day 0.46 mg/dl and 0.29 mg/dl (p <0.01), but not for wine (0.04 mg/dl). Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey. Choi HK, et al. MGH-Harvard. . Arthritis Rheum. 2004 Dec 15;51(6):1023-9

Gout Developed in 19% of Asymptomatic Hyperuricemic Men in 5 Years: In a 5-year follow-up of 223 asymptomatic hyperuricemic men gout developed in 19%. The risk factors for gout based on the analysis of repeated relationships were uric acid level, alcohol consumption, use of diuretics, and obesity. The only predictor of gout at baseline was uric acid level. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. Lin KC, et al. National Yang-Ming University, Taipei, Taiwan. J Rheumatol. 2000 Jun;27(6):1501-5.; Similar in Am J Med. 1987 Mar;82(3):421-6 with 2,038 followed for 15 years and 22% developing gout in five years if uric acid over 9.0 mg/dL.

Heart Disease: Uric Acid Elevation Big Risk Factor: In a study of 316 angiography patients with coronary artery disease followed for 5 years, uric acid >/=5.2 mg/dl independently imparted a 3.5-fold increased risk (OR 3.5) for cardiovascular death and major clinical events over a 5-year period. Uric acid may be a contributing factor to the progression of atherosclerosis and its complications. Am J Nephrol. 2005 Feb 21;25(1):36-44

Heart Disease: Uric Acid Elevation After Heart Attack Predicts Heart Failure and Death: Serum uric acid (UA) levels reflect circulating xanthine oxidase activity and oxidative stress production. Hyperuricemia has been identified in patients who have congestive heart failure and is a marker of poor prognosis in such patients. Using the Japanese Acute Coronary Syndrome Study database of 1,124 patients hospitalized within 48 hours of a heart attack, there was a close relation between serum UA concentration and Killip's classification. Patients who developed short-term adverse events had high UA concentrations. The risk of death in the highest quartile of UA was 270% higher (HR = 3.7) compared with those in the lowest quartile after adjustment for independent factors that were related to mortality. The best UA cutoff for predicting survival is 447 micromol/L. Hyperuricemia after AMI is associated with the development of heart failure and death. Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese Acute Coronary Syndrome Study). Kojima S, et al. Kumamoto University, Japan. . Am J Cardiol. 2005 Aug 15;96(4):489-95

Heart: Uric Acid Elevation Worsens Heart Failure: Hyperuricemia is a constant finding in CHF. The xanthine oxidase metabolic pathway increasingly is appreciated as an important contributor to both symptoms of CHF as well as progression of the disease. Recent data suggest hyperuricemia to be an independent marker of impaired prognosis in CHF. Uric acid in chronic heart failure. Doehner W, Anker SD. Humboldt University, Berlin, Germany. . Semin Nephrol. 2005 Jan;25(1):61-6. Survival in mice with heart failure was doubled by allopurinol. Circ Res. 2004 Nov 12;95(10):1005-11.

Heart Failure Endothelial Dysfunction Helped by Allopurinol: In a DB PC crossover study of 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo, allopurinol significantly increased the forearm blood flow response to acetylcholine (181% versus 120% allopurinol versus placebo; P=0.003). Plasma malondialdehyde was significantly reduced with allopurinol treatment (346 nmol/L versus 461 nmol/L; P=0.03), consistent with reduced oxidative stress with allopurinol therapy. Allopurinol improves endothelial dysfunction in chronic heart failure. Farquharson CA, et al. Dundee, UK. Circulation. 2002 Jul 9;106(2):221-6.

Hypertension: Uric Acid Elevation Predicts Hypertension: Several epidemiological studies have shown a positive association between serum uric acid levels and the risk of hypertension. In a prospective study with 23 years of follow-up of 4,489 adults who did not have hypertension, 289 developed hyptertension. Multivariate analysis found a 48% increased risk in men with hyperuricemia and 90% in women (OR = 1.48 and 1.90(p <0.05, respectively). Hyperuricemia as a predictor of hypertension in a screened cohort in Okinawa, Japan. Nagahama K, et al. University of the Ryukyus, Okinawa, Japan. . Hypertens Res. 2004 Nov;27(11):835-41.

Hypertension: Childhood Uric Acid May Play a Key Role as a Cause of Hypertension. In a study of 334 European- and 243 African-Americans enrolled in the Bogalusa Heart Study as children ages 5- 17 and as adults ages 18-35 with 12 years of follow-up, in a multivariate regression analysis, adjusting for age, sex, race, childhood body mass index, researchers found that childhood uric acid levels, and change in levels of uric acid were significant predictors of adult diastolic blood pressure, whereas change in uric acid was a significant predictor of adult systolic blood pressures. Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Alper AB Jr, et al. Tulane University. . Hypertension. 2005 Jan;45(1):34-8.

Uric Acid an Independent Predictor of Hypertension in Framingham Study: In a 4-year follow-up study of 3329 Framingham Study adults (mean age 48.7 years) free of hypertension, myocardial infarction, heart failure, renal failure, or gout, 458 persons (13.8%) had developed hypertension, and 1201 persons (36.1%) had experienced progression to a higher BP stage. Age- and sex-adjusted rates of hypertension incidence increased progressively from 9.8% for the lowest quartile to 15.6% for the top quartile of serum UA; BP progression rates increased from 32.8% (lowest quartile) to 39.6% (top quartile). In multivariable analyses adjusting for age, sex, body mass index, diabetes, smoking, alcohol intake, serum creatinine, proteinuria, glomerular filtration rate, baseline BP, and interim weight change, a 1 SD higher serum UA was associated with an odds ratio (OR) of 1.17 for developing hypertension, and an OR of 1.11 for BP progression. In analyses of a subsample of 3157 individuals not on antihypertensive treatment at the follow-up examination, serum UA was positively associated with changes in systolic (P=0.02) and diastolic pressure 4 years later (P=0.04).  Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Sundstrom J, et al. The Framingham Heart Study. . Hypertension. 2005 Jan;45(1):28-33.

Kidney Damage: Uric Acid: Hyperuricemia induces arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis, as well as arterial hypertension. Sanchez-Lozada LG, et al. Mexico City. Kidney Int. 2005 Jan;67(1):237-47.

Kidney Function Decreased by Hyperuricemia: In a 12-year follow-up study of 3499 employees of the Electric Generation Authority of Thailand, ages 35-55, the risk of developing decreased kidney function was increased 157% for systolic hypertension (>159 mmHg)(adjusted OR 2.57), 82% for hyperuricemia (>6.29 mg/dl)(OR = 1.82), 68% for being overweight (BMI>24.9) compared with subjects with systolic BP <140 mmHg, serum uric acid <4.5 mg/dl, and body mass index 20.8 to 22.8 kg/m(2). The rising prevalence of decreased kidney function in this population resulted mainly from the increasing prevalence of the risk factors in the population. Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study. Domrongkitchaiporn S, et al. Bangkok, Thailand. . J Am Soc Nephrol. 2005 Mar;16(3):791-9. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Semin Nephrol. 2005 Jan;25(1):43-9.

Kidney Dialysis: High Uric Acid is an Independent Predictor for End Stage Renal Disease: In a 7-year follow-up of 48,177 healthy adults, the mean serum uric acid level was 6.4 mg/dL (381 micromol/L) in men and 4.8 mg/dL in women. Prevalences of hyperuricemia (>6.0 mg/dL) were 32% in men and 14% in women. By the end of the study, 103 had entered dialysis programs. Calculated incidences of end stage renal disease (ESRD) per 1,000 adults were 1.22 for men without hyperuricemia and 4.64 for men with hyperuricemia and 0.87 for women without hyperuricemia and 9.03 for women with hyperuricemia. Adjusted hazard ratios for hyperuricemia were 2.0(P = not significant) in men and 5.8 (P = 0.0002) in women. Strategies to control serum uric acid levels in the normal range may reduce the population burden of ESRD. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Iseki, K, et al. University Hospital of The Ryukyus, Okinawa. . Am J Kidney Dis. 2004 Oct;44(4):642-50.

Meat: Uric Acid Increased by Meat; Reduced by Dairy: Using data from 14,809 adults in the Third National Health and Nutrition Examination Survey and adjusting for age, sex, total energy intake, body mass index, use of diuretics, beta-blockers, allopurinol, and uricosuric agents, self-reported hypertension and gout, serum creatinine level, and intake of alcohol, researchers found that the serum uric acid level increased with increasing total meat or seafood intake and decreased with increasing dairy intake. After adjusting for age, the differences in uric acid levels between the extreme quintiles of intake were 0.48 mg/dl for total meat, 0.16 mg/dl for seafood, and -0.21 mg/dl for total dairy intake. After adjusting for other covariates, the differences between the extreme quintiles were attenuated but remained significant (P < 0.05). The total protein intake was not associated with the serum uric acid level in multivariate analyses (P = 0.74 for trend). Milk 1 or more times per day had a lower serum uric acid level than did those who did not drink milk (multivariate difference -0.25; P < 0.001). Yogurt at least once every other day had a multivariate difference -0.26; P < 0.001. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Choi HK, Liu S, Curhan G. MGH-Harvard. Arthritis Rheum. 2005 Jan;52(1):283-9.

Peripheral Circulation Helped by Allopurinol in Heart Failure Patients: In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow.  In 10 CHF patients with normal serum uric acid (UA) levels (315 micromol/L) and 9 patients with elevated UA (535 micromol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 microg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P<0.05). In a 1-week DB PC crossover design, allopurinol 300 mg/d reduced UA by 217 micromol/L, P<0.0001. Compared with placebo, allopurinol improved peak blood flow (in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05). Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Doehner W, et al. Imperial College School of Medicine, London, UK. Circulation. 2002 Jun 4;105(22):2619-24.

Peripheral Artery Disease: Elevated Uric Acid an Independent and Important Risk Factor: In a study of 508 Taiwanese with Type 2 diabetes, UA levels were higher in patients with peripheral artery disease (PAD) than in those without PAD (345.0 vs. 309.3 micromol/l; P < 0.0005). Prevalences of PAD for quintiles of UA levels were 6.8, 8.9, 10.2, 13.1 and 16.5%, (P-trend < 0.05). The optimal cut-off point for UA as determined by the receiver operating characteristic curve was 264.7 micromol/l. The sensitivity and specificity at this cut-off point was 82.6 and 33.3%, respectively. The multivariate-adjusted odds ratio for PAD for UA above this level was 2.7 or a 170% elevated risk (P < 0.05). The results after excluding 56 cases using diuretics were similar. Independent association of uric acid levels with peripheral arterial disease in Taiwanese patients with Type 2 diabetes. Tseng CH. National Taiwan University. . Diabet Med. 2004 Jul;21(7):724-9.

Stroke: Uric Acid Elevation Increased Stroke Risk in Taiwan: In an 11-year follow-up of 3602 adults older than 35 years, 86 develop coronary heart disease and 155 had strokes. The rate ratios of hyperuricemia ranged between 2.00 and 3.96, with higher risk ratios in women than in men. After adjustment for age effect, higher uric acid at baseline was associated with significant CHD risk in both genders (hazard risk [HR] 1.43 in men and HR 1.22 in women). But the magnitude of hazard risks decreased after adjusting more atherosclerotic risk factors for CHD. Multiple adjustment by risk factors demonstrated that uric acid was still a significant predictor for stroke in women (HR 1.32). Uric acid had significant risk only in hypertension and metabolic syndrome subgroups. Authors conclude that uric acid could predict cardiovascular events in the community of relatively low CHD but high stroke risk in Taiwan. Hyperuricemia as a risk factor on cardiovascular events in Taiwan: The Chin-Shan Community Cardiovascular Cohort Study. Chien KL, et al. National Taiwan University, Taipei, Taiwan. Atherosclerosis. 2005 Sep 7

Uric Acid Elevation May Be Harmful: Elevation of serum uric acid is related to the onset of essential hypertension in children, reduced birth weight, and endothelial dysfunction. Normalization of uric acid appears to ameliorate new onset essential hypertension. Kidney Int. 2004 Jul;66(1):281-7.

Uric acid causes endothelial dysfunction when infused into the human brachial artery. Endogenous uric acid concentrations correlate with endothelial dysfunction. In numerous population studies, uric acid has been shown to be an independent