Characteristic dysbiosis in gout and the impact of a uric acid-lowering treatment,febuxostat on the gut microbiota

Gut dysbiosis is suggested to play a critical role in the pathogenesis of gout. The aim of our study was to identify the characteristic dysbiosis of the gut microbiota in gout patients and the impact of a commonly used uric acid-lowering treatment, febuxostat on gut microbiota in gout. 16S ribosomal RNA sequencing and metagenomic shotgun sequencing was performed on fecal DNA isolated from 38 untreated gout patients, 38 gout patients treated with febuxostat, and 26 healthy controls. A restriction of gut microbiota biodiversity was detected in the untreated gout patients, and the alteration was partly restored by febuxostat. Biochemical metabolic indexes involved in liver and kidney metabolism were significantly associated with the gut microbiota composition in gout patients. Functional analysis revealed that the gut microbiome of gout patients had an enriched function on carbohydrate metabolism but a lower potential for purine metabolism, which was comparatively enhanced in the febuxostat treated gout patients. A classification microbial model obtained a high mean area under the curve up to 0.973. Therefore, gut dysbiosis characterizings gout could potentially serve as a noninvasive diagnostic tool for gout and may be a promising target of future preventive interventions.     

高尿酸血症和痛风的流行病学及其危险因素的研究进展

高尿酸血症和痛风是由于长期嘌呤代谢紊乱所引起的一种代谢性疾病,随着各国经济的发展,其患病率在全球范围呈逐年升高的趋势,因此相关研究也日益增多.本文就近年来有关高尿酸血症与痛风的流行病学及其危险因素的研究作一综述,并着重阐述高尿酸血症与糖尿病关系的相关研究进展.     

Comorbidities in patients with gout

Gout is one of the most important diseases associated with hyperuricemia. Gout is characterized by acute monoarthritis with frequent flares. Some patients with gout have gouty tophi that are composed of monosodium urate crystals and inflammatory cells. In addition to tophi, gout is associated with various comorbidities such as obesity, hypertension, abnormal lipid metabolism, renal dysfunction, and urolithiasis. We examined the associations of the presence of tophi and comorbidities with demographic and disease characteristic data of gout patients. Subjects were 422 male patients with gout who visited our outpatient clinic. The patients' background data and laboratory data at the first visit were collected from patient records. We investigated the relationship between comorbidities and characteristics of patients using multiple regression models. The age of gout onset was 44 ± 13 years. The duration of gout at the first visit was 6 ± 8 years. Five percent of subjects had tophi. The presence of tophi was significantly associated with the duration of gout and maximum serum uric acid (SUA), indicating a close association of tophi with urate deposition. Reduced estimated glomerular filtration rate was associated with older age of onset, longer duration of gout, and higher levels of maximum SUA, indicating that sustained hyperuricemia relates with renal impairment of gout. Urolithiasis did not associate with gout duration and maximum SUA. The increased frequency of hypertension was associated with the duration of gout, suggesting that poor control of gout is one of the causes of hypertension. This study provides useful information for gout management and patient education.     

Epidemiology,risk factors,and lifestyle modifications for gout

Gout affects more than 1% of adults in the USA, and it is the most common form of inflammatory arthritis among men. Accumulating data support an increase in the prevalence of gout that is potentially attributable to recent shifts in diet and lifestyle, improved medical care, and increased longevity. There are both nonmodifiable and modifiable risk factors for hyperuricemia and gout. Nonmodifiable risk factors include age and sex. Gout prevalence increases in direct association with age; the increased longevity of populations in industrialized nations may contribute to a higher prevalence of gout through the disorder's association with aging-related diseases such as metabolic syndrome and hypertension, and treatments for these diseases such as thiazide diuretics for hypertension. Although gout is considered to be primarily a male disease, there is a more equal sex distribution among elderly patients. Modifiable risk factors for gout include obesity, the use of certain medications, high purine intake, and consumption of purine-rich alcoholic beverages. The increasing prevalence of gout worldwide indicates that there is an urgent need for improved efforts to identify patients with hyperuricemia early in the disease process, before the clinical manifestations of gout become apparent.     

The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets

Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.     

Soft drinks,fructose consumption,and the risk of gout in men: prospective cohort study

Objective To examine the relation between intake of sugar sweetened soft drinks and fructose and the risk of incident gout in men.Design Prospective cohort over 12 years.Setting Health professionals follow-up study.Participants 46 393 men with no history of gout at baseline who provided information on intake of soft drinks and fructose through validated food frequency questionnaires.Main outcome measure Incident cases of gout meeting the American College of Rheumatology survey criteria for gout.Results During the 12 years of follow-up 755 confirmed incident cases of gout were reported. Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout. Compared with consumption of less than one serving of sugar sweetened soft drinks a month the multivariate relative risk of gout for 5-6 servings a week was 1.29 (95% confidence interval 1.00 to 1.68), for one serving a day was 1.45 (1.02 to 2.08), and for two or more servings a day was 1.85 (1.08 to 3.16; P for trend=0.002). Diet soft drinks were not associated with risk of gout (P for trend=0.99). The multivariate relative risk of gout according to increasing fifths of fructose intake were 1.00, 1.29, 1.41, 1.84, and 2.02 (1.49 to 2.75; P for trend <0.001). Other major contributors to fructose intake such as total fruit juice or fructose rich fruits (apples and oranges) were also associated with a higher risk of gout (P values for trend <0.05).Conclusions Prospective data suggest that consumption of sugar sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men. Furthermore, fructose rich fruits and fruit juices may also increase the risk. Diet soft drinks were not associated with the risk of gout.     

痛风及高尿酸血症动物模型的研究现状和评价

痛风是一种以血尿酸增高为特征的代谢性疾病 ,近年来随着我国人民生活水平的提高 ,高尿酸血症和痛风的发病率逐年上升 ,因而研制防治痛风和高尿酸血症的药物已成为当前医药界研究的热点 ,但实验动物模型的困难严重地影响着研究工作的开展。本文对目前常见的痛风和高尿酸血症实验动物模型进行了较系统的简介 ,并根据笔者的研究经验进行了简要评价 ,供致力于该方面研究的学者参考。     

Anemia and the onset of gout in a population-based cohort of adults: Atherosclerosis Risk in Communities study

Introduction

There is a growing prevalence of gout in the US and worldwide. Gout is a recognized risk factor for cardiovascular disease (CVD). It is unclear whether other risk factors for CVD are also associated with increased risk of gout. Anemia is one such CVD risk factor. No studies have evaluated the relationship between anemia and gout. We tested whether anemia was associated with incident gout independent of comorbid conditions in Atherosclerosis Risk in the Communities.

Methods

This population-based cohort recruited 15,792 individuals in 1987 to 1989 from four US communities and contained nine years of follow-up. Anemia was defined as hemoglobin <13.5 g/dL for men and <12 g/dL for women. Using a Cox Proportional Hazards model, we estimated the hazard ratio (HR) and confidence intervals (CI) of incident gout by baseline anemia, adjusted for confounders (sex, race, estimated glomerular filtration rate, body mass index and alcohol intake) and clinical factors (coronary heart disease, congestive heart failure, diabetes, hypertension, diuretic use and serum urate level).

Results

Among the 10,791 participants, 10% had anemia at baseline. There were 271 cases of incident gout. Patients with anemia had a two-fold increased risk of developing gout over nine years (HR = 2.01, 95% CI: 1.46, 2.76). Anemia was associated with incident gout independent of known gout risk factors, confounders and clinical risk factors (HR = 1.73, 95% CI: 1.24, 2.41). This association persisted after additionally adjusting for serum urate level (HR = 1.83, 95% CI: 1.30, 2.57).

Conclusion

We identified anemia as a novel risk factor for gout. Anemia was associated with an approximately two-fold increased risk of gout-independent kidney function and serum urate. These findings suggest that anemia is a risk factor for gout on par with other chronic conditions such as obesity and diabetes. The biological mechanism linking anemia to gout remains unclear.     

ABCG2基因rs2231142位点多态性与汉族女性痛风的相关性

目的：ABCG2基因第5外显子区单核苷酸多态性位点rs2231142与中国汉族男性痛风密切相关,基于痛风易感基因存在性别差异的考虑,本研究旨在探讨该单核苷酸多态性位点与中国汉族女性人群痛风易感性之间的相关性。方法：选取185例女性痛风患者和311例女性正常对照者,提取外周血基因组DNA,采用聚合酶链式反应（PCR技术）,特异性扩增ABCG2基因所需要的目的片段并测序,比较痛风组和正常对照组的基因型频率及等位基因频率分布情况。结果：rs2231142位点的CC、CA、AA基因型频率在两组间存在显著差异（x2=16.519,P〈0.001）,且痛风组中A等位基因频率显著高于正常对照组（分别为42.2%和29.3%,P〈0.001,OR 1.76[95%CI：1.35-2.31]）。结论：ABCG2基因第五外显子区rs2231142（C/A）位点的单核苷酸多态性与中国汉族女性人群痛风易感性密切相关,携带A等位基因的汉族女性人群有更高的痛风患病率。ABCG2基因首次被证实为中国汉族女性人群的痛风致病易感基因。     

A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility

Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, gout patients can be divided into those with renal overload (ROL) gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of gout as well as the physiological roles of MCT9.     

痛风与单纯性高尿酸血症人群高脂血症的对比分析

目的:对比分析痛风与单纯高尿酸血症合并高脂血症的情况。方法:收集青岛大学附属医院痛风专病门诊2009年5月至2016年1月收治的痛风患者7207例(男性6759例,女性448例),单纯高尿酸血症患者2095例(男性1852例,女性243例)。测量受试者身高、体重、腰围、臀围、血压、空腹血糖(FPG)、血甘油三酯(TG)、血胆固醇(TC)及血尿酸(UA),计算并比较两组高甘油三脂血症、高胆固醇血症的患病率,并分析其在痛风发生中的独立作用。结果:痛风组高甘油三酯血症和高胆固醇血症的患病率分别为57.8%、47.5%;单纯高尿酸血症组为51.8%、52.9%;两组率相比的比值比,高甘油三脂血症1.274[95%CI(1.155,1.404)],胆固醇血症0.805[95%CI(0.730,0.887)]。按性别分层分析,男性痛风组高甘油三脂血症、高胆固醇血症患病率分别为56.2%,46.8%;单纯高尿酸血症组分别为52.3%,52.6%。两组率相比的比值比,高甘油三脂血症1.25[95CI%(1.13,1.39)],高胆固醇血症0.80[95CI%(0.72,0.89)]。女性中痛风组高甘油三脂血症、高胆固醇血症患病率分别为52.2%,58.90%;单纯高尿酸血症组分别为46.6%,58.0%;两组差异无统计学意义。高甘油三脂血症与痛风的发生正相关OR=1.29,95%CI(1.12,1.48),高胆固醇血症与痛风的发生负相关OR=0.80,95%CI(0.73,0.89)。结论:痛风与单纯高尿酸血症患者存在不同的脂代谢状态,高甘油三酯血症可能是单纯高尿酸血症发展为痛风的危险因素。     

Association between gout and polymorphisms in GCKR in male Han Chinese

Several genome-wide association studies (GWASs) have reported associations between single nucleotide polymorphisms (SNPs) and uric acid concentrations or gout in a number of different ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of the qualitative trait gout, in the present study, the associations between two SNPs in the glucokinase (hexokinase 4) regulator (GCKR) gene and gout were assessed in a male Chinese Han population. The study population comprised 476 male gout patients and 465 male controls. Multiple PCR was performed using time-of-flight mass spectrometry (MALDI-TOF MS) to identify genotypes. Two SNPs, rs780093 and rs780094, located in intronic regions of the GCKR gene were found to be significantly associated with the development of gout. Thus, the association between the two GCKR SNPs and gout was replicated in the male Han Chinese population investigated in the present study. Furthermore, GCKR was identified as a novel candidate gene associated with gout.     

Risk of end-stage renal disease associated with gout: a nationwide population study

Introduction

We explored the risk of end-stage renal disease (ESRD) among gout patients in a representative cohort in Taiwan.

Methods

The primary database used was the Taiwan National Health Insurance Research Database. Subjects older than 20 years without ESRD, coronary heart disease, or stroke were included in the study. The case definition of gout in the present study was gout diagnosis and medical treatment for gout. An ESRD case was defined by the presence of chronic renal failure necessitating long-term renal replacement therapy. Multivariate Cox proportional hazards models were used to evaluate the risk of ESRD among gout patients.

Results

The analysis included data of 656,108 patients who were followed up for a mean of 8.0 years. Among them, 19,963 (3.0%) patients had gout. At the end of 2008, 2,377 individuals (gout, n = 276; non-gout, n = 2,101) had ESRD, and 861 individuals (gout, n = 77, 27.9%; non-gout, n = 521, 24.8%) died due to ESRD. The rates of incidence of ESRD were 1.73 and 0.41 cases per 1,000 patient-years in the gout and non-gout groups. After adjustment for age, sex, and history of diabetes mellitus and/or hypertension, gout was associated with a hazard ratio (HR) of 1.57 for ESRD (95% confidence interval [CI], 1.38-1.79; P < 0.001). In patients with ESRD, the adjusted HR for death in patients with gout was 0.95 (0.74-1.23, P = 0.71), which was similar to the HR obtained in patients without gout.

Conclusions

Gout is associated with an increased hazard for development of ESRD.     

A case-control study of alcohol consumption and drinking behaviour in patients with acute gout.

The alcohol intake and drinking behaviour of 24 patients who presented with acute gout in a family practice over a 5-year period were compared with these features of a control population matched for sex, age, weight and use of hyperuricemia-inducing diuretics. The average weekly alcohol intake of the group with gout was twice that of the control group (p less than 0.02), and a statistically significant relation was found between alcohol abuse and acute gout (p less than 0.05). About half of the patients with gout drank excessively. Acute gout should be considered a possible clinical sign of alcohol abuse.     

Bidirectional Association between Self-Reported Hypertension and Gout: The Singapore Chinese Health Study

It has been hypothesized that the association between hypertension and gout is bidirectional, however, few studies have examined this in a prospective cohort. We analyzed data from the Singapore Chinese Health Study (SCHS) follow-up I (1999–2004) and II (2006–2010) interviews, when both physician-diagnosed hypertension and gout were self-reported. We included participants with data for both follow-up interviews and who were free of heart disease, stroke and cancer at follow-up I. The analysis of hypertension and risk of gout included 31,137 participants when prevalent gout cases were excluded, while the analysis of gout and risk of hypertension included 20,369 participants when prevalent hypertension cases were excluded. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The mean age at follow-up I was 60.1 (SD 7.3) years, and the average follow-up was 6.8 (SD 1.4) years. In the analysis of hypertension and risk of gout, 682 incident cases were identified. Compared to normotensive participants, hypertensive patients had an88% increased risk of developing gout (HR 1.88; 95% CI 1.61–2.21). In the parallel analysis, 5,450 participants reported to have newly diagnosed hypertension during follow-up. Compared to participants without gout, those with gout had an18% increased risk of developing hypertension (HR 1.18; 95% CI 1.02–1.37). The bidirectional association was stronger in normal weight adults compared to overweight/obese individuals (P _interaction = 0.06 and 0.04, respectively). The hypertension to gout association was stronger in women compared to men (P _interaction = 0.04), while the gout to hypertension association was evident in women but not in men (P _interaction = 0.02). In conclusion, our results suggest that the hypertension-gout association is bidirectional in this cohort of Singapore Chinese adults. The potential interactions of the bidirectional association with obesity and sex deserve further investigations.     

痛风的相关研究

痛风是一种由高尿酸血症引起的关节炎类型。研究其流行病学,使临床对高尿酸血症及痛风性关节炎的病理生理学有了新的见解。研究表明,遗传倾向的作用越来越明显。痛风的临床表现分为无症状高尿酸血症,急性痛风性关节炎,发作间期和慢性痛风性关节炎。痛风的诊断基于实验室和放射学特征,其中偏振光显微镜发现滑液中针状或杆状的单钠尿酸盐晶体是诊断的金标准。其成像方法主要有常规放射成像、超声检查、双能CT。其中超声和双能CT应用的进步使该领域的诊断、分期、随访和临床研究有了显著的提高。深入了解痛风的发病机制,不断优化诊断方式,有助于提高痛风的临床诊疗水平。痛风的管理一直是医学史上对医学技能的挑战,当前需要不断深入了解痛风的发病机制,不断优化诊断方式,以寻求不同寻常的治疗方案。在秋水仙碱、泼尼松、别嘌醇、非布司他、雷西纳德等药物的临床应用取得不错效果的同时,存在的一些不良反应值得重视。随着精准医疗时代的到来,相信痛风的个体化诊疗有着更加乐观的未来。     

Ultrasonography in the diagnosis of asymptomatic hyperuricemia and gout

ABSTRACT

Sonography has detected urate deposits in 34%–42% of the patients with asymptomatic hyperuricemia. This may prompt reclassification of asymptomatic hyperuricemia into “asymptomatic gout” and consideration of urate lowering therapy (ULT) to resolve urate deposits. In patients with gout and no visible tophi, sonography has detected urate deposits in half of the patients. This may allow diagnosing “tophaceous gout” and influencing the serum urate target level, prophylaxis to avoid acute gout flares during ULT, and clinical follow-up. Current accessibility to sonography may better classify patients with hyperuricemia and gout and contribute to delineate therapeutic objectives and clinical guidance.     

Relationship between insulin resistance and low urinary pH in patients with gout, and effects of PPARalpha agonists on urine pH.

Patients with gout frequently have low urinary pH, though the underlying mechanism has not been identified. Recently, nephrolithiasis has been reported to be involved with renal manifestation of metabolic syndrome. The present study was conducted to clarify the mechanism of low urinary pH in gout patients. The relationships between urine pH and factors contributing to metabolic syndrome were investigated. In addition, the effects of PPAR alpha agonists on urine pH were examined. Patients with 24-hour urine samples below a level of pH 5.5 showed higher values for factors constituting metabolic syndrome, compared with those with 24-hour urine pH equal to or greater than 5.5. Multiple regression analysis demonstrated that HOMA index was the only contributing factor to low urinary pH in gout patients, except for serum uric acid. Administrations of PPAR alpha agonists significantly raised 24-hour urine pH levels in gout patients in accordance with a reduction in serum triglyceride concentration, probably through their activities to improve insulin resistance. Our results suggest that insulin resistance plays an important role in the development of low urinary pH in patients with gout and that PPAR alpha agonist is preferable for raising urinary pH of the gout patients with hypertriglyceridemia.     

Reduced Glomerular Function and Prevalence of Gout: NHANES 2009–10

Background

The renal tubule is a major route of clearance of uric acid, a product of purine metabolism. The links between reduced glomerular filtration rate (GFR), hyperuricemia, and gout in the general population are not well understood. The objective of the present study was to estimate prevalence of gout and hyperuricemia among people with impaired GFR in the US general population.

Study Design

Cross-sectional, survey-weighted analyses of data on adults (age>20 years) in the 2009–10 cycle of the US National Health and Nutrition Examination Surveys (n = 5,589). Associations between self-reported physician diagnosis of gout and degrees of renal impairment were the primary focus of the present analyses.

Results

In the 2009–2010 period, there was an estimated 7.5 million people with gout in the US. There were 1.25 million men and 0.78 million women with moderate or severe renal impairment and gout. The age standardized prevalence of gout was 2.9% among those with normal GFR compared to 24% among those with GFR<60 ml/min/1.73 m².In multivariable logistic regression analyses that adjusted for age, gender, body mass index, hypertension, diabetes, hypertension medications, including diuretics, blood lead levels, and hyperlipidemia, the odds ratios of gout and hyperuricemia were 5.9 (2.2, 15.7) and 9.58 (4.3, 22.0) respectively among those with severe renal impairment compared to those with no renal impairment. Approximately 2–3 fold increase in prevalence of gout was observed for each 30 ml/min/1.73 m² decrease in GFR, after accounting for the above factors.

Conclusions

Renal glomerular function is an important risk factor for gout. The prevalence of hyperuricemia and gout increases with decreasing glomerular function independent of other factors. This association is non-linear and an eGFR of 60 ml/min/1.73 m² appears to be a threshold for the dramatic increase in the prevalence of gout.