Fully integrated wearable sensors are capable of dynamically, directly, and independently tracking biomarkers in raw noninvasive biofluids without any other equipment or accessories by integrating the unique on-body monitoring feature with the special complete functional implementation attribute. Sweat, saliva, and urine are three important noninvasive biofluids, and changes in their biomarkers hold great potential for revealing physiological conditions. However, it is still a challenge to design single fully integrated wearable sensor arrays (FIWSAs) that are universally able to concurrently measure electrolytes and metabolites in three of the most common noninvasive biofluids including sweat, saliva, and urine. Here, we propose the first single universal FIWSAs for wirelessly, noninvasively, and simultaneously measuring various metabolites (i.e., uric acid) and electrolytes (i.e., Na and H) in raw sweat, saliva, or urine under subjects' exercise by integrating the specifically designed microfluidic, sensing, and electronic modules in a seamless manner. We evaluate its utility for noninvasive gout management in healthy subjects and in gout patients through a purine-rich meal challenge and with a medicine-treatment control, respectively. Noninvasive monitoring of multiple electrolytes and metabolites in a variety of raw noninvasive biofluids via such single universal FIWSAs may enrich the understanding of the biomarkers' levels in the body and would also facilitate self-health management.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

OBJECTIVE:To investigate whether serum uric acid (SUA) level is associated with all-cause and cardiovascular disease (CVD) mortality among individuals with diabetes. RESEARCH DESIGN AND METHODS:In this prospective cohort study, we included patients with diabetes from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999-2018. Mortality and underlying causes of death were ascertained by linkage to national death records through 31 December 2019. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% CIs for all-cause and CVD mortality. We also performed a meta-analysis of available cohort studies to combine the association between SUA level and mortality in diabetes. RESULTS:Among the 7,101 patients with diabetes from NHANES 1999-2018, the weighted mean of SUA level was 5.7 mg/dL. During 57,926 person-years of follow-up, 1,900 deaths (n = 674 deaths from CVD) occurred. In the fully adjusted model, when compared with patients with diabetes in the lowest SUA quintile, those in the highest SUA quintile had the HRs (95% CIs) of 1.28 (1.03, 1.58) for all-cause mortality and 1.41 (1.03, 1.94) for CVD mortality. We included 13 cohort studies in the meta-analysis and found that the pooled HRs (95% CIs) were 1.08 (1.05, 1.11) for all-cause mortality and 1.05 (1.03, 1.06) for CVD mortality per 1 mg/dL increment of SUA level in patients with diabetes. CONCLUSIONS:This study indicated that higher SUA levels were associated with increased risks of all-cause and CVD mortality in diabetes. Interventional studies are needed to elucidate the health effect of treatments to lower SUA levels.

Findings on the association of sugar sweetened beverages (SSB) and fructose intakes with gout and hyperuricemia have been conflicting. We aimed to perform a systematic review and meta-analysis on studies that examined the association of SSB and fructose consumption with gout and hyperuricemia in adults. We searched PubMed, Scopus and Google Scholar up to Aug 2017 for all relevant published papers assessing SSB and fructose intakes and risk of gout and hyperuricemia. After excluding non-relevant papers, 10 studies remained in our systematic. Meta-analysis on SSB consumption and risk of gout was done on three effect sizes from cohort studies and five effect sizes from case-control studies. For risk of hyperuricemia, the meta-analysis was done on six effect sizes from cross-sectional studies. All analyses were performed on ORs or RRs. We found an overall significant positive association between SSB consumption and risk of gout in both cohort (summary effect size: 1.35; 95% CI: 1.18-1.55) and case-control studies (summary effect size: 1.33; 95% CI: 1.06-1.66). Meta-analysis on cross-sectional studies revealed that SSB consumption was associated with 35% greater odds of hyperuricemia (summary effect size: 1.35; 95% CI: 1.19-1.52). No evidence of between-study heterogeneity as well as publication bias was found. Although the studies on fructose intake and risk of gout and hyperuricemia were included in our systematic review, we did not perform met-analysis on these studies due to insufficient number of publications. We found that SSB consumption was significantly associated with increased risk of gout and hyperuricemia in adult population. Further studies are needed to examine the association between dietary fructose intake and risk of gout and hyepruricemia.

BACKGROUND:Hyperuricemia and gout have become public health concerns; many important guidelines have recommended xanthine oxidase inhibitors (XOIs) as the first-line urate-lowering therapies (ULTs) to treat chronic gout with hyperuricemia. However, whether treating hyperuricemia and gout with ULTs modifies cardiovascular risks remains controversial. The aim of this study was to assess the incident risk of cardiovascular (CV) events (CVE) in hyperuricemia population, assess the cardiovascular benefit-risk of ULTs in hyperuricemia patients with or without gout in diverse cardiovascular risk sub-groups, and specify the safety of different ULTs. METHODS:We searched PubMed, Embase, the Cochrane Library, Wanfang, Chongqing VIP (CQVIP, en.cqvip.com), and China National Knowledge Infrastructure Database for prospective cohort studies and randomized controlled trials (RCTs) in English and Chinese. Potential medications included XOIs, and uricosurics. RCTs were divided into sub-groups analysis based on blinding status and patients' history of CV diseases. Risk ratios (RRs) were calculated and were reported with corresponding 95% confidence intervals (CIs) by fixed-effects or random-effects model. RESULTS:Seven prospective cohort studies and 17 RCT studies were included. The risks of both major adverse cardiovascular events (MACE) (RR = 1.72, 95% CI 1.28-2.33) and CVE (RR = 1.35, 95% CI 1.12-1.62) were higher in the hyperuricemia population than non-hyperuricemia one. In seven RCT studies where XOIs were compared with no-treatment or placebo, the results of five low CV risk studies showed that XOIs lowered the risks of both MACE (RR = 0.35, 95% CI 0.20-0.62) and CVE (RR = 0.61, 95% CI 0.44-0.85); whereas two high CV risk studies showed that XOIs lowered the risk of CVE (RR = 0.69, 95% CI 0.54-0.88) rather than MACE (RR = 0.62, 95% CI 0.29-1.35). In nine RCT studies where the cardiovascular safety between febuxostat and allopurinol were compared, no statistical difference was found in the risk of MACE or CVE. CONCLUSIONS:The hyperuricemia population does have a higher incidence of CVE, and the results suggested that XOIs might reduce the incidence of MACE and total CVE. In addition, from the perspective of cardiovascular safety, febuxostat equaled allopurinol in our meta-analysis.

BACKGROUND:Hyperuricemia (HUA) is becoming a global public health problem and associated with multiple diseases. OBJECTIVE:We conducted a systematic review to synthesize the pooled prevalence of HUA in mainland China and delineate its demographic, regional, and temporal trends over the past two decades. METHODS:Systematic literature searches of PubMed, SCOPUS, Web of Science, the China National Knowledge Infrastructure (CNKI), and the Wanfang digital database were conducted to screen studies published from 1 January 2000 to 31 August 2019, reporting the prevalence of HUA in mainland China. The search strings were ('hyperuricemia' OR 'hyperuricaemia' OR 'uric acid') AND ('prevalence' OR 'epidemiology') AND 'China'. Article quality was appraised quantitatively from 11 items. Before formal meta-analysis, age-standardized prevalence was transformed. The random-effects model was applied to synthesize the pooled prevalence due to its high heterogeneity. Then we stratified the prevalence estimates by age, gender, area, nationality, and publication year for subgroup analysis. RESULTS:Totally 177 eligible studies with a whole population of 2,277,712 were included in the present meta-analysis. The pooled prevalence in mainland China was estimated at 16.4% (95% CI: 15.3%~17.6%). In studies with the onset age at 20 ~ 29 years old, males had a twice times higher HUA prevalence than females (21.5% vs. 8.9%). The prevalence of HUA was 13.7% (11.8%~15.7%) in people aged 15~ years old, 16.5% in 30~ (14.8%~18.4%), 17.9% in 40~ (16.4%~19.5%), 19.4% in 50~ (17.8%~21.0%), 20.5% in 60~ (18.8%~22.3%), and 24.9% in over 70 (22.9%~27.1%). Stratified by regions, southern (25.5%) and southwestern (21.2%) China shared the highest prevalence, and the lowest prevalence was observed in the northwest (12.6%). From 2001 to 2017, the prevalence estimates of HUA steadily climbed from 8.5% to 18.4% with minor fluctuations. Multiple regression revealed that HUA prevalence was positively correlated to the larger sample size, area, advanced onset age, and published year. CONCLUSIONS:The last two decades witnessed the rapid growth prevalence of HUA in China. Early screening and personalized health education for HUA need to be given enough attention.

BACKGROUND:The prognostic significance of elevated circulating uric acid level in patients with acute coronary syndrome (ACS) is conflicting. This meta-analysis aimed to assess the prognostic value of hyperuricemia in patients with ACS. METHODS:A comprehensive literature search was performed in Pubmed, Embase, VIP, CNKI and WanFang databases up to 16 June 2018. All observational studies that investigated the prognostic value of hyperuricemia in ACS patients were selected. Outcome of interests was major adverse cardiovascular events (MACEs), all-cause mortality or cardiovascular mortality. RESULTS:A total of nine studies enrolling 8776 ACS patients were included and analysed. ACS patients with hyperuricemia had an increased risk of MACEs (risk ratio [RR]: 1.86; 95% confidence intervals [CI]: 1.47-2.35), all-cause mortality (RR 1.86; 95% CI: 1.49-2.32) and cardiovascular mortality (RR: 1.74; 95% CI: 1.36-2.22) after adjustment for the conventional risk factors. Stratified analysis showed that the prognostic significance of hyperuricemia was consistently observed in each subgroups. CONCLUSIONS:This meta-analysis suggests that hyperuricemia independently predicts MACEs and death in ACS patients. Determination of uric acid level has potential to improve risk stratification of adverse outcomes in ACS patients.

OBJECTIVE:A systematic review and meta-analysis were conducted to investigate the associations of hyperuricemia, gout, and uric acid (UA)-lowering therapy with the risk of fractures. METHODS:Electronic searches on PubMed, the Cochrane Library, and Embase were conducted from inception to January 2, 2019. Observational studies assessing the effects of hyperuricemia, gout, and UA-lowering therapy on fractures were included in the meta-analysis. Summary risk estimates with 95% confidence intervals (CI) were calculated by a random-effects model. RESULTS:A total of 14 eligible studies with 909 803 participants and 64 047 incident fractures were included. The results suggested that hyperuricemia and gout are not associated with any type of fracture (relative risk [RR], 0.98, 95% CI 0.85-1.11; P = 0.71) or osteoporotic fractures (RR, 1.02, 95% CI 0.90-1.14; P = 0.79). Further analysis indicated that hyperuricemia is associated with a lower risk of fractures (RR, 0.80, 95% CI 0.66-0.96; P = 0.02) but not with osteoporotic fractures (RR, 0.84, 95% CI 0.68-1.03; P = 0.10). However, gout is associated with an increased risk of fractures (RR, 1.17, 95% CI 1.04-1.31; P = 0.007) as well as osteoporotic fractures (RR, 1.13, 95% CI 1.00-1.26; P = 0.045). Furthermore, no significant association of UA-lowering therapy with the risk of fractures was found compared with the placebo (RR, 0.88, 95% CI 0.76-1.03; P = 0.11). Evidence supporting a non-linear association between serum UA levels and fractures was found (P < 0.001 for non-linearity), which revealed a U-shaped curve. CONCLUSION:Our meta-analysis revealed that hyperuricemia was associated with lower risk for any type fracture but not associated with osteoporotic fractures; however, gout was associated with an increased risk of any type fracture as well as osteoporotic fractures. Notably, a U-shaped relationship may exist between the serum UA level and fractures. The associations observed in our study may be due to reasons other than causality.

BACKGROUND:Fructose plays an important role in the complex metabolism of uric acid in the human body. However, high blood uric acid concentration, known as hyperuricemia, is the main risk factor for development of gout. Therefore, we conducted an updated meta-analysis on the prevalence and geographical distribution of hyperuricemia among the general population in mainland China using systematic literature search. METHODS:Five electronic databases were used to search for relevant articles published until 2019. All calculations were conducted using the Comprehensive Meta-Analysis (CMA) software. We included 108 eligible articles (172 studies by sex, 95 studies by regions, and 107 studies by study type) and an overall sample size of > 808,505 participants. RESULTS:The pooled prevalence of hyperuricemia among the general population in mainland China was 17.4% (95% CI: 15.8-19.1%). Our subgroup analysis indicated that the pooled prevalence by regions ranged from 15.5 to 24.6%. Those living Northeast region and being males had the highest prevalence (P < 0.001). In addition, some provinces in South Central, East and Northeast regions reported a high prevalence (> 20%), particularly in males. An increasing prevalence was reported since 2005-2009 until 2015-2019. No publication of bias was observed as indicated by a symmetrical funnel plot and Begg and Mazumdar rank correlation (P = 0.392). CONCLUSION:Prevalence of hyperuricemia is increasing in China, and future studies should investigate the association between the prevalence of hyperuricemia and its risk factors in order to tackle the issue, particularly among the vulnerable groups. Also, our study was the first comprehensive study to investigate the overall prevalence of hyperuricemia in mainland China covering the six different regions.

The association between hyperuricemia or gout and cancer risk has been investigated in various published studies, but their results are conflicting. We conducted a meta-analysis to investigate whether hyperuricemia or gout was associated with the cancer incidence and mortality. Linear and nonlinear trend analyses were conducted to explore the dose-response association between them. The pooled relative risk (RR) and 95% confidence interval (CI) were used to evaluate cancer risk. A total of 24 articles (33 independent studies) were eligible for inclusion. When compared participants with the highest SUA (hyperuricemia) levels and those with the lowest SUA levels, the pooled RR was 1.08 (95% CI, 1.04-1.12), it was significantly associated among males but not among females (males, RR = 1.07; 95% CI, 1.03-1.11; females, RR = 1.06; 95% CI, 0.96-1.17). Hyperuricemia increased total cancer mortality (RR = 1.15; 95% CI, 1.05-1.26), but a significant association was observed in females rather than in males (females: RR = 1.26; 95% CI, 1.09-1.45; males, RR = 1.02; 95% CI, 0.80-1.30). Linear relationships of SUA levels with overall cancer incidence (p for nonlinearity = 0.238) and overall cancer mortality (p for nonlinearity = 0.263) were identified. However, 1 mg/dL increment in SUA levels was weakly significant in overall cancer incidence (RR = 1.01; 95% CI, 1.01-1.01) but not associated with overall cancer mortality (RR = 1.01; 95% CI, 0.99-1.03). Gout was significantly associated with increased cancer incidence (RR = 1.19; 95% CI, 1.12-1.25). In conclusion, Hyperuricemia or gout was associated with higher cancer incidence and mortality. Though a potential linear relationship between them was found, we'd better treat this result with caution.

Based on a systematic review and meta-analysis of articles published in PubMed, Embase, Cochrane, and Web of Science, we identified nine articles that provide evidence of the relationship between persistent organic pollutants and hyperuricemia. Our researchers assess the quality of the included studies and their risk of bias using the recommended method and tool. This study uses meta-analyses of the random effects of each exposure and outcome to estimate combined odds ratios (ORs) and 95% confidence intervals (CIs). We found that the risk of hyperuricemia was strongly associated with three perfluorinated compounds, PFNA, PFOA, and PFOS, with the OR(95%CI) of 1.26 (1.07-1.47), 1.44(1.15-1.79), and 1.23(1.01-1.50) respectively. We also found a weak association between two other perfluorinated compounds, PFDA and PFHxS. Other than that, the summary ORs (95% CIs) of incident hyperuricemia were 2.34 (1.79-3.08) for DDT, 3.25(2.40-4.39) for DDE, 2.57 (1.37-4.81) for PCBs and 3.05(2.22-4.19) in trans-nonanchlor. Therefore, DDT and its breakdown product, DDE, PCBs, and trans-nonanchlor have also been linked with an increased risk of hyperuricemia in humans. This study finds that persistent organic pollutant is a critical factor for hyperuricemia, and further studies in specific regions will be considered in the future.

OBJECTIVE:Despite the high incidence and mortality of cardiovascular events in hyperuricemia patients, the role of serum uric acid in cardiovascular diseases is still controversial. The aim of this meta-analysis was to explore the difference of carotid intima-media thickness in hyperuricemia and control groups. METHODS:We performed this meta-analysis by searching the PubMed, Cochrane Library, Embase and Web of Science databases up to July 2020. The 95% confidence intervals and standard mean differences were calculated to analyze the differences in carotid intima-media thickness in hyperuricemia groups and control groups. Sensitivity analysis, subgroup analysis and meta-regression were used to explore the sources of heterogeneity. Publication bias was evaluated by funnel plot and Begg's regression test. We used Stata 14.0 software to complete our analyses. RESULTS:A total of 8 articles were included. The results showed that there was a significant increase in carotid intima-media thickness in the hyperuricemia groups compared with the control groups [SMD = 0.264, 95% CI (0.161-0.366), P < 0.001]. Subgroup analyses showed that age, sample size, blood pressure and body mass index were not the source of heterogeneity. Meta-regression enrolled the method of CIMT measurement, location, age, smoking and diabetes mellitus as categorical variables, but none of these factors was found to be significant in the model. The Begg's test value (P = 0.174) was greater than 0.05, indicating there was no publication bias. CONCLUSION:The results showed that carotid intima-media thickness was increased in hyperuricemia patients compared with controls, which indicated that hyperuricemia patients may have a higher risk of cardiovascular diseases.

PURPOSE OF REVIEW:This review discusses the impact of recent treatment guidelines for the management of gout and the barriers to treating gout patients. RECENT FINDINGS:Multiple guidelines for both the treatment and prevention of gout have been put forth in the last decade including those from the British Rheumatism Society; the European League Against Rheumatism; the Multinational Evidence, Expertise, Exchange Initiative; the Japanese Society of Gout and Nucleic Acid Metabolism; the American College of Rheumatology. These guidelines are designed to facilitate the management of gout by providers with key recommendations for the management of hyperuricemia, which is the greatest risk factor for developing gout. However, despite the extant guidelines, overall adherence to recommendations and uptake have been slow and initiation of urate-lowering therapy, titration of dosing, and monitoring of serum urate is infrequent. Greater education in proper management as well as increased awareness of new treatment strategies appear to be the primary reasons for this gap and offer avenues for improvement in management as well as areas for further research. SUMMARY:Gout remains a treatment challenge for both acute and chronic disease. Despite the availability of management guidelines, primary care providers are struggling with appropriate management of the disease. More research tools and strategies are needed to improve overall outcomes and quality of care.

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long-term urate-lowering treatment. Urate-lowering drugs should be used during the inter-critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate-lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.

OBJECTIVES:: To examine adherence to validated quality indicators assessing the quality of allopurinol use in the treatment of gout and asymptomatic hyperuricaemia. METHODS:We determined physician adherence in the UK General Practice Research Database (GPRD) to three validated quality indicators developed to assess the quality of allopurinol prescribing practices. These indicators were developed to assess: (i) dosing in renal impairment; (ii) concomitant use with azathioprine or 6-mercaptopurine; and (iii) use in the treatment of asymptomatic hyperuricaemia. We also examined the association of patient-level factors (sociodemographics, comorbidity, follow-up duration and concomitant medicine use) with the treatment of asymptomatic hyperuricaemia using multivariable logistic regression. RESULTS:Of the 63 105 gout patients, 185 (0.3%) were eligible for Quality Indicator 1 and 52 (0.1%) were eligible for Quality Indicator 2. There were an additional 471 patients with asymptomatic hyperuricaemia eligible for Quality Indicator 3. Rates of practice deviation for the three individual quality indicators ranged from 25 to 57%. Male sex, older age, a history of chronic renal failure, and a greater number of concomitant medications were significantly associated with increased odds of inappropriate treatment for asymptomatic hyperuricaemia. Hypertension and diuretic use were associated with lower odds of this practice. CONCLUSIONS:One-quarter to one-half of all patients eligible for at least one of the validated quality of care indicators were subject to possible allopurinol prescribing error, suggesting that inappropriate prescribing practices are widespread with this agent. Future interventions aimed at reducing inappropriate allopurinol use are needed and should be targeted towards high-risk groups, including older men and those receiving multiple concomitant medications.

OBJECTIVES:Despite the publication of hundreds of trials on gout and hyperuricemia, management of these conditions remains suboptimal. We aimed to assess the quality and consistency of guidance documents for gout and hyperuricemia. DESIGN:Systematic review and quality assessment using the appraisal of guidelines for research and evaluation (AGREE) II methodology. DATA SOURCES:PubMed and EMBASE (27 October 2016), two Chinese academic databases, eight guideline databases, and Google and Google scholar (July 2017). ELIGIBILITY CRITERIA:We included the latest version of international and national/regional clinical practice guidelines and consensus statements for diagnosis and/or treatment of hyperuricemia and gout, published in English or Chinese. DATA EXTRACTION AND SYNTHESIS:Two reviewers independently screened searched items and extracted data. Four reviewers independently scored documents using AGREE II. Recommendations from all documents were tabulated and visualised in a coloured grid. RESULTS:Twenty-four guidance documents (16 clinical practice guidelines and 8 consensus statements) published between 2003 and 2017 were included. Included documents performed well in the domains of scope and purpose (median 85.4%, range 66.7%-100.0%) and clarity of presentation (median 79.2%, range 48.6%-98.6%), but unsatisfactory in applicability (median 10.9%, range 0.0%-66.7%) and editorial independence (median 28.1%, range 0.0%-83.3%). The 2017 British Society of Rheumatology guideline received the highest scores. Recommendations were concordant on the target serum uric acid level for long-term control, on some indications for urate-lowering therapy (ULT), and on the first-line drugs for ULT and for acute attack. Substantially inconsistent recommendations were provided for many items, especially for the timing of initiation of ULT and for treatment for asymptomatic hyperuricemia. CONCLUSIONS:Methodological quality needs improvement in guidance documents on gout and hyperuricemia. Evidence for certain clinical questions is lacking, despite numerous trials in this field. Promoting standard guidance development methods and synthesising high-quality clinical evidence are potential approaches to reduce recommendation inconsistencies. PROSPERO REGISTRATION NUMBER:CRD42016046104.

OBJECTIVE:In vitro and clinical studies suggest that urate may contribute to osteoarthritis (OA) risk. We tested the associations between hyperuricemia and knee OA, and examined the role of obesity, using a cross-sectional, nationally representative dataset. METHOD:National Health and Nutrition Examination Survey (NHANES) III used a multistage, stratified probability cluster design to select USA civilians from 1988 to 1994. Using NHANES III we studied adults >60 years, with or without hyperuricemia (serum urate > 6.8 mg/dL), excluding individuals with gout (i.e., limiting to asymptomatic hyperuricemia (AH)). Radiographic knee OA (RKOA) was defined as Kellgren-Lawrence grade ≥ 2 in any knee, and symptomatic radiographic knee osteoarthritis (RKOA) (sRKOA) was defined as RKOA plus knee pain (most days for 6 weeks) in the same knee. RESULTS:AH prevalence was 17.9% (confidence interval (CI) 15.3-20.5). RKOA prevalence was 37.7% overall (CI 35.0-40.3), and was 44.0% for AH vs 36.3% for normouricemic adults (p = 0.056). symptomatic radiographic knee osteoarthritis (sRKOA) was more prevalent in AH vs normouricemic adults (17.4% vs 10.9%, p = 0.046). In multivariate models adjusting for obesity, model-based associations between AH and knee OA were attenuated (for RKOA, prevalence ratio (PR) = 1.14, 95% CI 0.95, 1.36; for sRKOA, PR = 1.40, 95% CI 0.98, 2.01). In stratified multivariate analyses, AH was associated with sRKOA in adults without obesity (PR = 1.66, 95% CI 1.02, 2.71) but not adults with obesity (PR = 1.21, 95% CI 0.66, 2.23). CONCLUSIONS:Among adults aged 60 or older, AH is associated with knee OA risk that is more apparent in adults without obesity.

Whether asymptomatic hyperuricemia in the absence of comorbidities increases the risk for cardiometabolic disorders and chronic kidney disease remains controversial. This study was conducted to clarify the association between asymptomatic hyperuricemia and cardiometabolic conditions. Subjects consisting of Japanese adults between 30 and 85 years of age were enrolled in the study at Center for Preventive Medicine, St Luke's International Hospital, Tokyo, and were available at enrollment (2004) and at 5-year follow-up (2009). Subjects were excluded if they were overweight or obese, hypertensive, diabetic, and dyslipidemic, had a history of gout or hyperuricemia on medications, or had chronic kidney disease as estimated glomerular filtration rate <60 mL/min per 1.73 m Linear and logistic regression analyses were used to examine the relationship between hyperuricemia and development of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, and overweight/obesity (unadjusted and adjusted for age, sex, smoking, drinking habits, baseline estimated glomerular filtration rate, and body mass index). Five thousand eight hundred and ninety-nine subjects without comorbidities (mean age of 47±10 years, 1864 men) were followed for 5 years. Hyperuricemia (defined as >7 mg/dL in men and ≥6 mg/dL in women) was associated with increased cumulative incidence of hypertension (14.9% versus 6.1%; <0.001), dyslipidemia (23.1% versus 15.5%; <0.001), chronic kidney disease (19.0% versus 10.7%; <0.001), and overweight/obesity (8.9% versus 3.0%; <0.001), while diabetes mellitus (1.7% versus 0.9%; =0.087) showed a trend but did not reach statistical significance. In conclusion, asymptomatic hyperuricemia carries a significant risk for developing cardiometabolic conditions in Japanese individual without comorbidities.

With the deepening of the researches on uric acid, especially in the study of metabolic diseases, uric acid has been found to be closely related to obesity, metabolic syndrome, nonalcoholic fatty liver disease, diabetes, and other metabolic diseases. Uric acid causes a series of pathophysiological changes through inflammation, oxidative stress, vascular endothelial injury, and so on and thus subsequently promotes the occurrence and development of diseases. This review confirmed the positive correlation between uric acid and diabetes mellitus and its chronic complications through the pathogenesis and clinical studies aspects.

AIMS:To explore the association between serum uric acid (SUA) level and the risk of cardiovascular complications and all-cause mortality rates among individuals with type 2 diabetes. METHODS:Web of Science and PubMed database were searched for studies reported associations between SUA level and cardiovascular complications and all-cause mortality among individuals with type 2 diabetes. Hazard ratios (HRs) were independently extracted by two investigators and synthesized through meta-analysis across selected studies. RESULTS:6 (n = 11,750 patients), 4 (n = 3044 patients) and 2 studies (n = 7792 patients) were identified reporting associations between SUA level and all-cause mortality, coronary heart disease (CHD) and stroke respectively. HR for all-cause mortality, CHD, and stroke per 59 μmol/l increase was 1.06 (95% CI: 1.03, 1.09), 1.09 (95% CI: 0.94, 1.26) and 1.19 (95% CI: 1.08, 1.31), respectively. CONCLUSIONS:Overall, the SUA level was associated with a higher risk of all-cause mortality and stroke. We found no significant association between SUA level and CHD among type 2 diabetes population.

 To map the diverse health outcomes associated with serum uric acid (SUA) levels. Umbrella review. Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references. Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes. 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies. Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

If hyperuricemia is an independent risk factor in blood-pressure control, urate-lowering therapy should be used to reduce cardiovascular risk. It may also act as a prognostic marker of other abnormalities. This review presents current evidence on the relationship between hyperuricemia and hypertension.

Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.

AIM:To investigate the association of urinary glucose excretion with levels of serum uric acid in adults with newly diagnosed diabetes. METHODS:A total of 597 people with newly diagnosed diabetes, confirmed in an oral glucose tolerance test, were included in the present study. The participants were divided into two groups: 142 participants with low urinary glucose excretion and 455 with high urinary glucose excretion. Demographic characteristics and clinical variables were evaluated. The association of urinary glucose excretion with uric acid was analysed using multivariable regression analysis. RESULTS:The low urinary glucose excretion group had a significantly higher prevalence of hyperuricaemia than the high urinary glucose excretion group. Moreover, urinary glucose excretion was negatively associated with uric acid level. The correlation remained significant after adjusting for potential confounders, including gender, age, fasting plasma glucose, 2-h plasma glucose and BMI. The results also showed that participants with high urinary glucose excretion were at decreased risk of hyperuricaemia (odds ratio 0.47, 95% CI 0.27-0.80; P = 0.006). CONCLUSION:Urinary glucose excretion was independently associated with uric acid level in participants with newly diagnosed diabetes. In addition to lowering blood glucose, promoting urinary glucose excretion may also be an effective approach to reducing serum uric acid levels, especially for people with diabetes complicated with hyperuricaemia.

BACKGROUND:The association between hyperuricaemia and nonalcoholic fatty liver disease (NAFLD), one of the leading causes of cirrhosis worldwide, has been demonstrated in recent epidemiological studies. This meta-analysis was conducted to summarize all available data and to estimate the risk of NAFLD among subjects with hyperuricaemia. METHODS:Comprehensive literature review was conducted using MEDLINE and EMBASE database through August 2016 to identify studies that compared the risk of NAFLD among subjects with hyperuricaemia vs those with normal uric acid level. Effect estimates from individual study were extracted and combined together using random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS:Twenty-five studies met the eligibility criteria and were included in the meta-analysis. The risk of NAFLD in subjects with hyperuricaemia was significantly higher than subjects with normal uric acid level with the pooled odds ratio (OR) of 1.97 (95% confidence interval (CI), 1.69-2.29). The heterogeneity between studies of the overall analysis was high with an I of 87%. Subgroup analysis based on 11 studies that provided data on males subgroup and nine studies that provided data on females subgroup showed that the risk was significantly increased for both sexes with pooled OR of 1.64 (95% CI, 1.40-1.93) among males and pooled OR of 2.21 (95% CI, 1.85-2.64) among females. CONCLUSIONS:A significantly increased risk of NAFLD among patients with hyperuricaemia was demonstrated in this meta-analysis. Further studies are required to establish the role of uric acid in the pathogenesis of NAFLD.

OBJECTIVE:There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS:A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS:The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION:Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

OBJECTIVE:To examine the associations between dietary zinc intake and hyperuricaemia. DESIGN:Cross-sectional study. SETTING:This study was conducted in a health examination centre of China. PARTICIPANTS:A total of 5168 middle-aged and older participants (aged 40 years or above) (2697 men and 2471 women) were included. OUTCOME MEASURES:Dietary zinc intake was assessed using a validated semiquantitative food frequency questionnaire. Hyperuricaemia was defined as uric acid ≥416 µmol/L for males and ≥360 µmol/L for females. RESULTS:For males, the prevalence of hyperuricaemia was 22.9%. After adjusting for age, body mass index (BMI) and energy intake, the ORs were 0.68 (95% CI 0.45 to 0.92) in the second quintile, 0.63 (95% CI 0.45 to 0.89) in the third quintile, 0.68 (95% CI 0.46 to 1.00) in the fourth quintile and 0.55 (95% CI 0.35 to 0.87) in the fifth quintile comparing the lowest quintile of Zn intake, respectively (p for trend=0.03). In the multivariable adjusted model, the relative odds of hyperuricaemia were significantly decreased by 0.71 times in the second quintile of zinc intake (OR 0.71, 95% CI 0.52 to 0.98), 0.64 times in the third quintile (OR 0.65, 95% CI 0.44 to 0.94) and 0.55 times in the fifth quintile (OR 0.56, 95% CI 0.32 to 0.97) compared with those in the lowest quintile, and p for trend was 0.064. For females, the prevalence of hyperuricaemia was 10.0%, and unadjusted, minimally adjusted as well as multivariable adjusted ORs all suggested no significant association between dietary zinc intake and hyperuricaemia. CONCLUSIONS:The findings of this cross-sectional study indicated that dietary zinc intake was inversely associated with hyperuricaemia in middle-aged and older males, but not in females. The association was significant after considering the influence of age, BMI and energy intake, and after that, minimum adjustment remained independent of further confounding factors such as vitamin C intake, alcohol drinking status and nutrient supplementation.

BACKGROUND:This is the second update of this systematic review. High blood pressure represents a major public health problem. Worldwide, approximately one-fourth of the adult population has hypertension. Epidemiological and experimental studies suggest a link between hyperuricaemia and hypertension. Hyperuricaemia affects 25% to 40% of those with untreated hypertension; a much lower prevalence has been reported in those with normotension or in the general population. However, whether lowering serum uric acid (UA) might lower blood pressure (BP), is an unanswered question. OBJECTIVES:To determine whether UA-lowering agents reduce BP in people with primary hypertension or prehypertension, compared with placebo. SEARCH METHODS:The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to May 2020: the Cochrane Hypertension Specialised Register, CENTRAL 2018, Issue 12, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched LILACS (1982 to May 2020), and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language or date restrictions. SELECTION CRITERIA:To be included in this updated review, the studies had to meet the following criteria: 1) randomised or quasi-randomised, with a group assigned to receive a UA-lowering agent and another group assigned to receive placebo; 2) double-blind, single-blind, or open-label; 3) parallel or cross-over trial design; 4) cross-over trials had to have a washout period of at least two weeks; 5) minimum treatment duration of four weeks; 6) participants had to have a diagnosis of essential hypertension or prehypertension plus hyperuricaemia (serum UA greater than 6 mg/dL in women, 7 mg/dL in men, and 5.5 mg/dL in children or adolescents); 7) outcome measures included change in 24-hour ambulatory systolic or diastolic BP, or both; or clinic-measured systolic or diastolic BP, or both. DATA COLLECTION AND ANALYSIS:The two review authors independently collected the data using a data extraction form, and resolved any disagreements via discussion. We assessed risk of bias using the Cochrane 'Risk of bias' tool. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS:In this review update, we screened 722 records, selected 26 full-text reports for evaluation. We identified no ongoing studies and did not add any new studies. We included three randomised controlled trials (RCTs), enrolling 211 people with hypertension or prehypertension, plus hyperuricaemia. Low-certainty evidence from three RCTs found inconclusive results between those who received UA-lowering drugs and placebo, in 24-hour ambulatory systolic (MD -6.2 mmHg, 95% CI -12.8 to 0.5) or diastolic BP (-3.9 mmHg, 95% CI -9.2 to 1.4). Low-certainty evidence from two RCTs found that UA-lowering drugs reduced clinic-measured systolic BP (-8.43 mmHg, 95% CI -15.24 to -1.62) but results for clinic-measured diastolic BP were inconclusive (-6.45 mmHg, 95% CI -13.60 to 0.70). High-certainty evidence from three RCTs found that serum UA levels were reduced by 3.1 mg/dL (95% CI 2.4 to 3.8) in the participants that received UA-lowering drugs. Low-certainty evidence from three RCTs found inconclusive results regarding the occurrence of adverse events between those who received UA-lowering drugs and placebo (RR 1.86, 95% CI 0.43 to 8.10). AUTHORS' CONCLUSIONS:In this updated Cochrane Review, the current RCT data are insufficient to know whether UA-lowering therapy lowers BP. More studies are needed.

OBJECTIVES:Several recent observations have suggested that the prevalence of gout may be increasing worldwide, but there are no recent data from the USA. We analysed the prevalence of hyperuricaemia and gout in the US population from 2007-08 to 2015-16. METHODS:We studied adults ⩾20 years of age from the National Health and Nutrition Examination Survey from 2007-08 to 2015-16. Persons with gout were identified from the home interview question 'Has a doctor or other health professional ever told you that you had gout?' Hyperuricaemia was defined as a serum urate level >0.40 mmol/l (6.8 mg/dl) (supersaturation levels at physiological temperatures and pH). RESULTS:In 2015-16, the overall prevalence of gout among US adults was 3.9%, corresponding to a total affected population of 9.2 million. Hyperuricaemia (>0.40 mmol/l or 6.8 mg/dl) was seen in 14.6% of the US population (estimated 32.5 million individuals). No significant trends were identified in the age-adjusted prevalence of gout and hyperuricaemia. Statistical comparisons between 2007-08 and 2015-16 age-adjusted rates were not significant. CONCLUSION:While the age-adjusted prevalence of gout and hyperuricaemia has remained unchanged in the most recent decade from 2007-08 to 2015-16, the estimated total number of persons with self-reported gout has increased from 8.3 million to 9.2 million. The age-adjusted prevalence of hyperuricaemia has declined slightly, but the total number of affected individuals is virtually identical (32.5 million in 2015-16 compared with 32.1 million in 2007-08).

The definition of asymptomatic hyperuricemia remains unclear, as no consensus exists about the serum urate cutoff or the relevance of ultrasound findings. Comorbidities associated with hyperuricemia have increased in frequency over the past two decades. Hyperuricemia (and/or gout) may be a cause or a consequence of a comorbidity. Whereas epidemiological studies suggest that hyperuricemia may be linked to cardiovascular, metabolic, and renal comorbidities, Mendelian randomization studies have not provided proof that these links are causal. Discrepancies between findings from observational studies and clinical trials preclude the development of recommendations about the potential benefits of urate-lowering therapy (ULT) in individual patients with asymptomatic hyperuricemia. The risk/benefit ratio of ULT is unclear. The risk of developing gout, estimated at 50%, must be weighed against the risk of cutaneous and cardiovascular side effects of xanthine oxidase inhibitors. The need for optimal comorbidity management, in contrast, is universally accepted. Medications for comorbidities that elevate urate levels should be discontinued and replaced with medications that have the opposite effect. Therapeutic lifestyle changes, weight loss as appropriate, and sufficient physical activity are useful for improving general health. Whether ULT has beneficial effects on comorbidities will be known only when well-powered interventional trials with relevant primary endpoints are available.

PURPOSE OF REVIEW:Hyperuricemia is highly prevalent, affecting approximately 38 million individuals in the United States. However, the significance of asymptomatic hyperuricemia - hyperuricemia in the absence of gout - continues to be debated. RECENT FINDINGS:Asymptomatic hyperuricemia results in monosodium urate crystal deposition in tissues, which may promote chronic inflammation. Intracellularly, hyperuricemia inhibits the master regulator adenosine monophosphate (AMP)-associated protein kinase and may condition innate immune responses through durable epigenetic modifications. At the population level, asymptomatic hyperuricemia is associated with multiple comorbidities, including hypertension, chronic kidney disease, coronary artery disease, and diabetes; limitations of these studies include that most are retrospective and some do not rigorously distinguish between asymptomatic hyperuricemia and gout. Treatment studies suggest that urate lowering may reduce the risk of incidence or progression of some of these comorbidities; unfortunately, many of these treatment studies are small or flawed, and not all study results are consistent. SUMMARY:Accumulating evidence suggests that asymptomatic hyperuricemia contributes to the comorbidities with which it associates and that proper asymptomatic hyperuricemia treatment may reduce future risk. Additional prospective trials are needed to definitely establish causality and support decision-making as to whether, and which patients with asymptomatic hyperuricemia would warrant urate-lowering treatment.

OBJECTIVES:Ultrasound lesions of gout have been described in people with asymptomatic hyperuricemia. However, the anatomical sites and ultrasound lesions most frequently involved in asymptomatic hyperuricemia have not yet been established. This systematic review and meta-analysis aimed to determine the prevalence of the Outcome Measures in Rheumatology (OMERACT) elementary ultrasound lesions of gout (double contour, aggregates, tophus, erosion) at various sites in people with asymptomatic hyperuricemia and to determine which sites and lesions discriminate from people with normouricemia. METHODS:A systematic search of electronic databases, conference abstracts and reference lists was undertaken. Studies were included if they used ultrasound to image people with asymptomatic hyperuricemia and reported ≥1 OMERACT-defined lesion of gout. Meta-analyses were undertaken for the pooled prevalence of site-specific lesions in people with asymptomatic hyperuricemia, and the pooled odds ratios of these lesions compared to people with normouricemia. RESULTS:Twenty studies were included. The most common site scanned was the first metatarsophalangeal joint (1MTP) (n = 17 studies) and the most common lesion reported, the double contour (n = 18). Meta-analyses of pooled prevalence showed 1MTP double contour was the most frequent finding in people with asymptomatic hyperuricemia (0.31, 95% confidence interval (CI) 0.20-0.42), followed by femoral condyle double contour (0.16, 95%CI 0.08-0.24) and 1MTP tophus (0.16, 95%CI 0.03-0.29). The highest pooled odds ratios for asymptomatic hyperuricemia vs. normouricemia were 6.98 (95%CI 3.14-15.57) for 1MTP double contour, 13.67 (95%CI 5.42-34.49) for femoral condyle double contour and 6.10 (95%CI 1.55-24.04) for 1MTP tophus. CONCLUSION:In people with asymptomatic hyperuricemia, scanning of the 1MTP and femoral condyle for double contour, plus the 1MTP for tophus, has the highest prevalence and discrimination compared to those with normouricemia.

AIM:The definition and management of asymptomatic hyperuricemia has been an area of controversy for many decades. Debate persists regarding the benefit of treating all cases of asymptomatic hyperuricemia and hence, unsurprisingly there are no clear clinical practice guidelines from our country. PARTICIPANTS:Ten members consisting of eminent physicians, endocrinologists, nephrologist and a rheumatologist were selected by the Integrated Diabetes & Endocrine Academy (IDEA) for a closed meeting with the aim to come to a consensus. EVIDENCE:A literature search was performed using PubMed and Cochrane library following which published articles in indexed peer review journals were selected. CONSENSUS PROCESS:Each participant voiced their opinion after reviewing the available data and a consensus was reached after three meetings by voting. CONCLUSION:Recommendations were made on important areas such as definition, investigation and management of asymptomatic hyperuricemia.