Association between dietary vitamin C intake and gout among American adults.

Introduction: Gout is a common type of inflammatory arthritis. Vitamin C is a potent antioxidant that neutralizes reactive oxygen species. However, the association between dietary vitamin C levels and gout remains unclear. This study evaluated the relationship between dietary vitamin C intake and gout. Methods: Cross-sectional data from individuals aged > 20 years who participated in the National Health and Nutrition Examination Survey between 2013 and 2018 were collected. Details on gout, dietary vitamin C intake, and several other essential variables were recorded. Results: There were 12589 participants, 5% (652/12589) of whom experienced gout. Compared with individuals with lower vitamin C consumption in the Q1 group (≤19.9 mg/day), the adjusted odds ratio(OR)values for dietary vitamin C intake and gout in the Q2 group (19.9-49.7 mg/day), Q3 group (49.7-110.375 mg/day), and Q4 group (≥110.375 mg/day) were 0.87 (95% confidence interval (CI): 0.69-1.1, P = 0.237), 0.81 (95% CI: 0.64-1.02, P = 0.076), and 0.77 (95% CI: 0.6-0.99, P= 0.042), respectively. Accordingly, the association between dietary vitamin C intake and gout exhibited an L-shaped curve (nonlinear, P = 0.245) in a restricted cubic spline. Subgroup analysis revealed significant interactions between vitamin C levels and gout according to sex (P < 0.05). When we used data on dietary vitamin C from the second survey, we observed a similar inverse association between vitamin C intake and gout. The vitamin C was also negatively associated with hyperuricemia (OR, 0.94; 95% CI, 0.9-0.98, P=0.005). Compared with Q1, the adjusted OR values for dietary vitamin C and hyperuricemia in Q2, Q3, and Q4 were 0.77 (95% CI: 0.69-0.86, P = 0.65), 0.81 (95% CI: 0.72-0.91, P = 0.014), and 0.72 (95% CI: 0.64-0.81, P < 0.001), respectively. No association was observed between vitamin C supplementation and gout. Conclusion: The population-based data indicate that dietary vitamin C intake is inversely associated with gout. These findings support the potential role of vitamin C in preventing gout.

Exercise and hyperuricemia: an opinion article.

Hyperuricaemia (HUA) is an abnormally high concentration of serum urate caused by either an excess of uric acid production or decreased excretion capacity in the body. Serum urate concentration forms sodium salts that deposit in the soft tissues of the joints, ultimately leading to gout. Additionally, HUA is strongly associated with several acute and chronic illnesses. In various clinical guidelines and practices, xanthine oxidase inhibitors, such as allopurinol and febuxostat, are commonly used as the initial medication for treating HUA. However, extended usage of urate-lowering drugs may have risks, including cardiovascular thrombotic events and hepatic impairment. Implementing a scientifically informed fitness diet in conjunction with appropriate exercise may decrease HUA. Unfortunately, there is currently a shortfall in exercise intervention trials for individuals suffering from HUA. Most of the previous evidence suggesting that exercise improves serum urate levels comes from intervention trials in other populations, and serum urate is only one of the outcomes observed. This opinion article analyses the causes of HUA, offers dietary and exercise guidance with the aim of furnishing a point of reference for individuals with HUA or fitness enthusiasts.

Consumption of Total and Specific Alcoholic Beverages and Long-Term Risk of Gout Among Men and Women.

Importance: Previous studies on alcohol consumption and incident gout have mostly included men or combined both sexes, and the sex-specific associations between alcohol consumption and gout are poorly understood. Objective: To evaluate the consumption of total and specific alcoholic beverages in association with incident gout in men and women. Design, Setting, and Participants: This prospective cohort study included 401 128 participants in the UK Biobank aged 37 to 73 years who were free of gout at baseline (2006-2010). Participants were followed up through December 31, 2021, and data were analyzed between August 2023 and June 2024. Exposure: Questionnaire-based consumption of total alcohol and specific alcoholic beverages. Main Outcomes and Measures: The outcome was incident gout, identified using hospital records. Multivariable Cox proportional hazards regression models were used to estimate sex-specific hazard ratios (HRs) and 95% CIs of incident gout associated with alcohol consumption, with a particular consideration of reverse causation bias. Results: The main analysis included 179 828 men (mean [SD] age, 56.0 [8.2] years) and 221 300 women (mean [SD] age, 56.0 [8.0] years). Current drinkers showed a higher risk of gout than never drinkers among men (HR, 1.69; 95% CI, 1.30-2.18) but not among women (HR, 0.83; 95% CI, 0.67-1.03). Among current drinkers, higher total alcohol consumption was associated with a higher risk of gout among both sexes and more strongly among men than women (men: HR, 2.05 [95% CI, 1.84-2.30]; women: HR, 1.34 [95% CI, 1.12-1.61]). The most evident sex difference in the consumption of specific alcoholic beverages was observed for beer or cider (men: mean [SD], 4.2 [4.8] pints per week; women: mean [SD], 0.4 [1.1] pints per week). Consumption of champagne or white wine, beer or cider, and spirits each was associated with a higher risk of gout among both sexes, with beer or cider showing the strongest association per 1 pint per day (men: HR, 1.60 [95% CI, 1.53-1.67]; women: HR, 1.62 [95% CI, 1.02-2.57]). Some inverse associations between light to moderate consumption of specific alcoholic beverages and gout were eliminated after adjusting for other alcoholic beverages and excluding individuals who had reduced alcohol consumption for health reasons, self-reported poor health, or had cardiovascular disease, cancer, or kidney failure at baseline, or developed gout within the first 2 years of follow-up. Conclusions and Relevance: In this cohort study, higher consumption of several specific alcoholic beverages was associated with a higher risk of gout among both sexes. The sex-specific associations for total alcohol consumption may be associated with differences between men and women in the types of alcohol consumed.

Risk of new onset hyperuricemia and chronic kidney disease after living kidney donation through propensity score matching analysis.

Living kidney donors have been regarded as those people having earned the healthiest status level after having undergone scrutiny. Although one's post-donation GFR is expected to fall to 50% of their pre-donation value, it is well documented that there is a compensatory increase in GFR which subsequently reaches approximately 60-70% of the donor's pre-donation value. Data regarding gout/hyperuricemia in living kidney donors has remained scarce until now. This study involved kidney donors enrolled within the years 2000 to 2017, where those who were selected to be matched to those in group of case cohort by age, year of index date, gender and co-morbidity were considered as the control cohort. During the 17-year study period 2,716 participants were enrolled. Results revealed that kidney donors experienced a risk of new onset gout/ hyperuricemia (adjusted HR = 1.73; 95%CI = 1.27, 2.36), and new onset CKD (adjusted HR = 6.7; 95% CI = 4.4, 10.21) were found to be higher in kidney donors. Our findings suggest that people after kidney donation are significantly associated with a higher risk of new onset gout/hyperuricemia. Clinical professionals therefore need to be cautious of new onset gouy/hyperuricemia after donation surgery.

Controversies and practical management of patients with gout and chronic kidney disease.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk of cardiovascular mortality. As many as one-third of all patients with chronic kidney disease have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dl. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated and others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of chronic kidney disease, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of chronic kidney disease and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists for a team approach to gout management that includes the nephrologist.

Dose-Response Relationship Between Alcohol Consumption and Gout Risk: Do Subtypes of Alcoholic Beverages Make a Difference?

OBJECTIVE: Although previous studies have explored the association of drinking with gout risk, we sought to explore the dose-response relationship and the evidence between subtypes of alcoholic beverages and gout risk. METHODS: The weekly alcoholic beverage consumption of patients in the UK Biobank was collected and calculated. The Cox regression model was applied to assess the effects of drinking alcohol in general and its subtypes on gout risk by calculating the hazard ratio (HR) and 95% CIs. Additionally, the restricted cubic splines were used to estimate the dose-response relationship between alcohol consumption and gout risk. To evaluate the robustness, we performed subgroup analysis across various demographic characteristics. RESULTS: During a mean follow-up period of 11.7 years, a total of 5728 new incident gout cases were diagnosed among 331,865 participants. We found that light alcohol consumption was linked to a slight decrease in gout incidence among female individuals (HR 0.78, 95% CI 0.65-0.94, P = 0.01), whereas there was no significant association in male individuals. Moreover, the dose-response relationship showed that drinking light red wine and fortified wine could reduce the gout risk, whereas beer or cider, champagne or white wine, and spirits increased the gout risk at any dose. CONCLUSION: Our study suggested a J-shaped dose-response relationship between drinking and gout risk in female individuals, but not in male individuals. For specific alcoholic beverages, light consumption of red wine and fortified wine was associated with reduced gout risk. These findings offer new insights into the roles of alcoholic beverages in gout incidence risk, although further validation is warranted.

Current updates for hyperuricemia and gout in age-related macular degeneration.

The escalating prevalence of metabolic syndrome poses a significant public health challenge, particularly among aging populations, with metabolic dysfunctions contributing to pro-inflammatory states. In this review, we delved into the less recognized association between hyperuricemia (HUA), a manifestation of metabolic syndrome and a primary risk factor for gout, and age-related macular degeneration (AMD), a sight-threatening ailment predominantly affecting the elderly. In recent years, inflammation, particularly its involvement in complement pathway dysregulation, has gained prominence in AMD pathophysiology. The contradictory role of uric acid (UA) in intercellular and intracellular environments was discussed, highlighting its antioxidant properties in plasma and its pro-oxidant effects intracellularly. Emerging evidence suggests a potential link between elevated serum uric acid levels and choroid neovascularization in AMD, providing insights into the role of HUA in retinal pathologies. Various pathways, including crystal-induced and non-crystal-induced mechanisms, were proposed to indicate the need for further research into the precise molecular interactions. The implication of HUA in AMD underscores its potential involvement in retinal pathologies, which entails interdisciplinary collaboration for a comprehensive understanding of its impact on retina and related clinical manifestations.

Uric acid en route to gout.

Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.

Spontaneous resolution of acute gout: mechanisms and therapeutic targets.

Gout is a common inflammatory arthritis that has been increasing in both prevalence and incidence. Consequently, management of refractory and chronic gout has been gaining attention. Onset of gout is related to the deposition of monosodium urate crystals under hyperuricaemia. Interestingly, acute gout attacks often resolve spontaneously within 7-10 days, and many studies have confirmed the notion that gout flares can be self-relieved. However, the underlying mechanism for spontaneous remission of gout requires further elucidation. In this article, we summarise the roles and mechanisms related to spontaneous remission of gout, which are essential for understanding its pathogenesis and developing potential targeted therapies.

Sodium-glucose cotransporter-2 inhibitors use and the risk of gout: a systematic review and meta-analysis.

Objective: To assess the relationship between use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the risk of gout among patients with type 2 diabetes mellitus (T2DM). Methods: A systemic review and meta-analysis were designed by reviewing articles published between 2000 January 1 and 2022 December 31 using PubMed system and Web of Science system based on the PRISMA 2020 guidelines. The end point of interest was gout (including gout flares, gout events, starting uric-acid lowering therapy and starting anti-gout drugs use) among patients with T2DM using SGLT2i versus not using SGLT2i. A random-effects model was utilized to measure the pooled hazard ratio (HR) with 95% confidence interval (CI) for the risk of gout associated with SGLT2i use. Results: Two prospective post-hoc analyses of randomized controlled trials and 5 retrospective electronic medical record-linkage cohort studies met the inclusion criteria. The meta-analysis demonstrated that there was a decreased risk of developing gout for SGLT2i use as comparing with non-use of SGLT2i among patients with T2DM (pooled HR=0.66 and 95%CI=0.57-0.76). Conclusions: This meta-analysis demonstrates that SGLT2i use is associated with a 34% decreased risk of developing gout among patients with T2DM. SGLT2i may be the treatment options for patients with T2DM who are at high risk of gout. More randomized controlled trials and real-world data are needed to confirm whether there is a class effect of SGLT2i for the risk reduction of gout among patients with T2DM.

Risk Factors for Hyperuricemia or Gout in Men and Women: The Circulatory Risk in Communities Study (CIRCS).

AIM: We aimed to examine sex-specific risk factors for hyperuricemia or gout in Japanese cohorts. METHODS: We followed up 3,188 men (mean age, 55.6 years) and 6,346 women (mean age, 54.1 years) without hyperuricemia, gout, or elevated liver enzymes at baseline from 1986 to 1990 for a median of 14.6 years. The participants were considered as having hyperuricemia or gout if their serum uric acid levels were ≥ 7.0 mg/dL or they were receiving treatment for hyperuricemia or gout during annual health checkups. The sex-specific multivariable hazard ratios (HRs) of hyperuricemia or gout incidence were calculated after adjustment for smoking and drinking status, body mass index, hypertension, diabetes, hypercholesterolemia, and hypertriglyceridemia using the Cox proportional-hazard model. RESULTS: During follow-up, 733 men and 355 women had hyperuricemia or gout. Among men, the multivariable HRs (95% confidence intervals) of hyperuricemia or gout were 1.23 (1.00-1.52) and 1.41 (1.13-1.75) for drinkers of ＜46 and ≥ 46 g ethanol/day, respectively, compared with non-drinkers; 1.00 (0.81-1.24) and 1.18 (0.93-1.50) for smokers of 1-19 and ≥ 20 cigarettes/day, respectively, compared with never smokers; and 1.41 (1.20-1.65) for hypertensive compared with non-hypertensive participants. The HRs for women were 1.02 (0.70-1.48), 1.66 (1.05-2.63), and 1.12 (0.88-1.42) for current drinkers, current smokers, and hypertensive participants, respectively. For both men and women, body mass index, diabetes, hypercholesterolemia, and hypertriglyceridemia were not associated with hyperuricemia or gout incidence. CONCLUSIONS: Hypertension and alcohol drinking are risk factors for hyperuricemia or gout among men and smoking among women.

"Dialogue Between Franklin and the Gout" Reexamined.

Benjamin Franklin, one of the founding fathers of the United States, was not just a politician and a political philosopher but an inventor with a scientific temperament. He was overweight and likely suffered from the consequences of metabolic syndrome including gout. He woke up with a gout attack on October 22, 1780 and wrote the "Dialogue Between Franklin and the Gout." His observations on the risk factors for gout are re-examined in the modern context 243 years later.

Modifiable risk factors and incidence of gout: Estimation of population attributable fraction in the US.

OBJECTIVE: The burden of gout is substantial in the United States (US). Most gout cases can be attributed to modifiable risk factors, while systematic evidence-based assessment of gout cases and incidence attributable to the risk factors in the US is limited. METHODS: The estimated cases and incidence of gout in the US was obtained from global burden of disease (GBD) study 2019. We calculated the exposure rate of risk factors from National Health and Nutrition Examination Survey (NHANES) 2009-2010, since we estimated an average induction time of 10 years for risk factors and gout. We also conducted a meta-analysis to evaluate the associations of modifiable risk factors and gout in the US population. Furthermore, the population attributable fraction (PAF) was calculated using based on the prevalence of risk factors and relative risk (RR) from the meta-analysis. RESULTS: The weighted prevalence of hypertension was 14.37%, and the average body mass index (BMI) and alcohol consumption was 28.50 kg/m2 and 7.14 g/d, respectively. Meta-analysis showed that individuals with hypertension had a higher risk of gout (2.12, 95% CI 1.88 to 2.40). For every five units of increase in BMI, the risk of gout increased by 1.48-fold (95% CI 1.26 to 1.75). The pooled RR was 1.21 (95% CI 1.13 to 1.29) for every 10 g/day increment of alcohol consumption. BMI, hypertension and alcohol consumption accounted for 53.58%, 13.85% and 12.66% of gout cases, respectively. Overall, 65.05% of gout incidence was attributable to the joint effects of these three risk factors. CONCLUSION: Hypertension, excess BMI and high alcohol consumption were responsible for approximately 65% of gout incidence in the US in 2019. Reducing the exposure to these factors can effectively reduce the incidence of gout.

Environmental factors and risk of gout.

Gout is a chronic disease with inflammatory arthritis caused by monosodium urate (MSU) crystals deposition, an elevated serum urate level (hyperuricaemia) is the critical factor leading to MSU crystals deposition and promoting the progression of gout. The onset and development of gout is generally the result of multiple factors, such as diet, heredity and environmental factors. Although genetics and diet are thought to play as major factors, a growing body of research evidence has highlighted that environmental factors also play a significant role in the onset and exacerbation of gout. Recent studies have shown that air pollutants such as particulate matter, sulfur dioxide (SO2) and carbon monoxide (CO) may increase the risk of hospitalizations for gout, and that the changes in temperature and humidity may affect uric acid (UA) levels. There is also seasonal trend in gout. It has been demonstrated that environmental factors may induce or accelerate the production and release of pro-inflammatory mediators, causing an unbalance oxidative stress and systemic inflammation, and then participating in the overall process or a certain link of gout. Moreover, several environmental factors have shown the ability to induce the production urate and regulate the innate immune pathways, involving in the pathogenesis of gout. Nevertheless, the role of environmental factors in the etiology of gout remains unclear. In this review, we summarized the recent literatures and aimed to discuss the relationship between environmental factors (such as microclimate, season, ambient/indoor air pollution and extreme weather) and gout. We further discussed the inflammatory mechanisms of environmental factors and gout and the comprehensive effects of environmental factors on gout. We also made a prospect of the management and treatment of gout, with special consideration to environmental factors associated with gout.

The Role of the Intestine in the Development of Hyperuricemia.

Gout is a common inflammatory arthritis caused by the deposition of sodium urate crystals in the joints. Hyperuricemia is the fundamental factor of gout. The onset of hyperuricemia is related to purine metabolism disorders or uric acid excretion disorders. Current studies have shown that the intestine is an important potential organ for the excretion of uric acid outside the kidneys. The excretion of uric acid of gut is mainly achieved through the action of uric acid transporters and the catabolism of intestinal flora, which plays an important role in the body's uric acid balance. Here we reviewed the effects of intestinal uric acid transporters and intestinal flora on uric acid excretion, and provide new ideas for the treatment of hyperuricemia and gout.

Tetrahedral-Framework Nucleic Acids Carry Small Interfering RNA to Downregulate Toll-Like Receptor 2 Gene Expression for the Treatment of Sepsis.

Sepsis is caused by the invasion of pathogenic microorganisms, which can lead to excessive expression of toll-like receptors (TLRs) in cells and uncontrollable amplification of the inflammatory response. TLR2, as an essential part of the TLR family, has a significant feature in the identification of innate immune responses. Therefore, blocking the expression and activation of TLR2 can inhibit the synthesis and release of inflammatory factors and avoid the occurrence of excessive inflammatory reactions. Small interfering RNA (siRNA) can selectively target the silencing or downregulation of pathogenic genes and has the advantages of high specificity, a strong effect, and fewer adverse reactions. However, the application of siRNA is limited by its high molecular weight, poor biostability, and difficulty in passive uptake into cells. Tetrahedral-framework nucleic acid (tFNA) is a new kind of three-dimensional nucleic acid nanomaterial, which has the advantages of good biocompatibility, stable structure, and editability. In this study, we used tFNA as carriers to deliver siRNA-targeting downregulation of TLR2 expression for anti-inflammatory therapy. We show that siRNA can specifically reduce lipopolysaccharide (LPS)-induced TLR2 elevation and reduce release of inflammatory factors in LPS-induced experimental sepsis, which provides a new idea for the prevention and treatment of sepsis.

Uric acid extrarenal excretion: the gut microbiome as an evident yet understated factor in gout development.

Humans do not produce uricase, an enzyme responsible for degrading uric acid. However, some bacteria residing in the gut can degrade one-third of the dietary and endogenous uric acid generated daily. New insights based on metagenomic and metabolomic approaches provide a new interest in exploring the involvement of gut microbiota in gout. Nevertheless, the exact mechanisms underlying this association are complex and have not been widely discussed. In this study, we aimed to review the evidence that suggests uric acid extrarenal excretion and gut microbiome are potential risk factors for developing gout. A literature search was performed in PubMed, Web of Science, and Google Scholar using several keywords, including "gut microbiome AND gout". A remarkable intestinal dysbiosis and shifts in abundance of certain bacterial taxa in gout patients have been consistently reported among different studies. Under this condition, bacteria might have developed adaptive mechanisms for de novo biosynthesis and salvage of purines, and thus, a concomitant alteration in uric acid metabolism. Moreover, gut microbiota can produce substrates that might cross the portal vein so the liver can generate de novo purinogenic amino acids, as well as uric acid. Therefore, the extrarenal excretion of uric acid needs to be considered as a factor in gout development. Nevertheless, further studies are needed to fully understand the role of gut microbiome in uric acid production and its extrarenal excretion, and to point out possible bacteria or bacterial enzymes that could be used as probiotic coadjutant treatment in gout patients.

The role of alcohol consumption in pathogenesis of gout.

Alcohol is recognized a risk factor for increased uric acid and gout flare. The aim of the study was to review the literature in order to find out what is the role of alcohol consumption in pathogenesis of gout. A search in PubMed, Google Scholar, Medline Complete database was performed in January 2021. The databases were searched with the phrases: "uric acid and alcohol," "alcoholic beverages and gout," "hyperuricemia and alcoholic beverages consumption" published between 2000 and 2021. A total of 2642 results were found. The 99 non-duplicate citations were screened. Then 81 articles were excluded after abstract screen. After that 18 articles were retrieved. Eventually 15 articles were included for systematic review. Several authors see the positive correlation between beer or distilled spirits consumption and gout. Some include wine to the list of triggers of gout. Others state that moderate wine consumption protects from gout attacks due to antioxidants and phytoestrogen content. Majority noticed the relationship between episodic alcohol consumption and gout attacks. Episodic alcohol intake triggers gout attacks, regardless of type of alcohol. Thus, individuals with established gout and pre-existing risk factors should limit all types of alcohol intake to prevent gout episodes.

Purinergic Signaling in the Regulation of Gout Flare and Resolution.

Gout flares require monosodium urate (MSU) to activate the NLRP3 inflammasome and secrete sufficient IL-1ß. However, MSU alone is not sufficient to cause a flare. This is supported by the evidence that most patients with hyperuricemia do not develop gout throughout their lives. Recent studies have shown that, besides MSU, various purine metabolites, including adenosine triphosphate, adenosine diphosphate, and adenosine bind to different purine receptors for regulating IL-1ß secretion implicated in the pathogenesis of gout flares. Purine metabolites such as adenosine triphosphate mainly activate the NLRP3 inflammasome through P2X ion channel receptors, which stimulates IL-1ß secretion and induces gout flares, while some purine metabolites such as adenosine diphosphate and adenosine mainly act on the G protein-coupled receptors exerting pro-inflammatory or anti-inflammatory effects to regulate the onset and resolution of a gout flare. Given that the purine signaling pathway exerts different regulatory effects on inflammation and that, during the inflammatory process of a gout flare, an altered expression of purine metabolites and their receptors was observed in response to the changes in the internal environment. Thus, the purine signaling pathway is involved in regulating gout flare and resolution. This study was conducted to review and elucidate the role of various purine metabolites and purinergic receptors during the process.