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Concept: Hyperuricemia

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Objective To prospectively examine the relation between the Dietary Approaches to Stop Hypertension (DASH) and Western diets and risk of gout (ie, the clinical endpoint of hyperuricemia) in men.Design Prospective cohort study.Setting The Health Professionals Follow-up Study.Participants 44 444 men with no history of gout at baseline. Using validated food frequency questionnaires, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts).Main outcome measure Risk of incident gout meeting the preliminary American College of Rheumatology survey criteria for gout, adjusting for potential confounders, including age, body mass index, hypertension, diuretic use, and alcohol intake.Results During 26 years of follow-up, 1731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P=0.005).Conclusion The DASH diet is associated with a lower risk of gout, suggesting that its effect of lowering uric acid levels in individuals with hyperuricemia translates to a lower risk of gout. Conversely, the Western diet is associated with a higher risk of gout. The DASH diet may provide an attractive preventive dietary approach for men at risk of gout.

Concepts: Nutrition, Metabolic syndrome, Gout, Diuretic, Uric acid, Hyperuricemia, Diets, Fast food

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Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans.

Concepts: Metabolism, Enzyme, Triglyceride, Gout, Fructose, Uric acid, Hyperuricemia, Xanthine oxidase

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We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.

Concepts: Critical thinking, The Canon of Medicine, Evidence-based medicine, Systematic review, Cochrane Library, Rheumatology, Gout, Hyperuricemia

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BACKGROUND: While several studies have reported a link between the presence of gout and adverse cardiovascular (CV) events in the general population, none has addressed the question of whether the mortality risk of patients with gout is influenced by disease severity. METHODS: We applied survival analysis methodology to prospectively collected data on clinical and radiographic measures of disease severity and mortality in a specialty clinic based cohort of 706 patients with gout (1992-2008). Standardised mortality ratios (SMR) were calculated to assess the magnitude of excess mortality among patients with gout compared with the underlying general population. RESULTS: Mean follow-up was 47 months. Tophaceous deposition was present in 30.5% of patients; >4 joints were involved in 34.6% of cases. Mean annual flare rate was 3.4. Arterial hypertension (41.2%), hyperlipidaemia (42.2%), diabetes mellitus (20.1%), renal function impairment (26.6%) and a previous CV event (25.3%) were recorded. 64 (9.1%) patients died, death being attributed to vascular causes in 38 (59%) patients. SMR for gout patients was 2.37 (95% CI 1.82 to 3.03), 1.57 (1.18 to 2.05) and 4.50 (2.06 to 8.54) overall, and in men and women, respectively. The presence of tophi and the highest baseline serum urate (SU) levels were independently associated with a higher risk of mortality, in addition to age, loop diuretic use and a history of a previous vascular event. In the multivariable survival regression models, with time varying covariates, the presence of tophi remained a significant mortality risk after adjustment for baseline SU levels (1.98; 1.24 to 3.20). CONCLUSIONS: High baseline SU level and the presence of subcutaneous tophi were both associated with an increased risk of mortality in patients with gout, in most cases attributed to a CV cause. This suggests a plausible pathophysiological link between greater total body urate load and CV disease.

Concepts: Renal failure, Hypertension, Diabetes mellitus, Obesity, Metabolic syndrome, Diuretic, Uric acid, Hyperuricemia

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We report the case of a 36-year-old man with psoriatic arthritis and miliary tuberculosis, whose serum uric acid (SUA) level increased after the initiation of antituberculosis treatment, which included pyrazinamide. Most strikingly and paradoxically, the patient’s SUA level increased after treatment with allopurinol. On cessation of allopurinol, his SUA level decreased substantially, and complete normalisation was observed following the discontinuation of pyrazinamide treatment.

Concepts: Tuberculosis, Gout, Arthritis, Uric acid, Hyperuricemia, Miliary tuberculosis, Psoriatic arthritis

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BACKGROUND: Chronic drug interactions that exist between symptomatic congestive heart failure (CHF) therapy and pharmacologic agents used for hyperuricemia and gout are a challenging problem in clinical practice. Recent observational studies showed that prednisone can induce a potent diuresis and lower serum uric acid concentration (SUA) in CHF. We therefore designed a randomized study to compare the effect of prednisone with allopurinol on SUA in symptomatic CHF patients with hyperuricemia. METHODS: Thirty-four symptomatic CHF participants with hyperuricemia (≥ 565 μmol/L) were randomized to receive prednisone (1 mg/kg/d, orally) or allopurinol (100 mg, thrice daily, orally) for 4 weeks. The primary outcome measure was change from baseline in SUA. The secondary outcome measures were change from baseline in serum creatinine levels, estimated glomerular filtration rate, daily urine output, body weight, N-terminal pro-B-type natriuretic peptide levels, physician-assessed global clinical status, and New York Heart Association functional class. RESULTS: Both prednisone and allopurinol greatly lowered SUA rapidly. The overall SUA-lowering effect did not differ between treatment groups during the study period (P = 0.48, 2-way repeated measures analysis of variance). However, prednisone increased estimated glomerular filtration rate and daily urine output, and lowered body weights and N-terminal pro-B-type natriuretic peptide. Consequently, participants treated with prednisone had an improvement in clinical status. CONCLUSIONS: The study showed that the SUA-lowering effect of prednisone and allopurinol is similar in symptomatic CHF patients. Prednisone might be useful for short-term SUA-lowering in CHF patients with hyperuricemia.

Concepts: Heart failure, Blood urea nitrogen, Creatinine, Gout, Urea, Uric acid, Hyperuricemia, Hyperuricosuria

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Objective. The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout.Methods. This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 1-21, lesinurad 400 mg/day was added on days 8-14 and then lesinurad was increased to 600 mg/day on days 15-21. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations.Results. Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level <6 mg/dl. Febuxostat 40 or 80 mg/day plus lesinurad 400 or 600 mg/day resulted in 100% of subjects achieving sUA <6 mg/dl and up to 100% achieving sUA <5 mg/dl. No clinically relevant changes in the PKs of either drug were noted. The combination was well tolerated.Conclusion. The clinically important targets of sUA <6 mg/dl and <5 mg/dl are achievable in 100% of patients when combining lesinurad and febuxostat.

Concepts: Gout, Pharmacokinetics, Xanthine oxidase inhibitor, Uric acid, Hyperuricemia, Pharmacodynamics, Xanthine oxidase, Xanthine

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Febuxostat is a selective inhibitor of xanthine oxidase, which is used to manage hyperuricemia in patients with gout. The objective of the study was to compare the pharmacokinetics of two different strength of febuxostat formulations (80 mg and 40 mg).

Concepts: Gout, Xanthine oxidase inhibitor, Uric acid, Hyperuricemia, Hypouricemia, Xanthine oxidase, Xanthine

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Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in converting highly insoluble uric acid into 5-hydroxyisourate. Of particular interest is the observation that apes, including humans, cannot oxidize uric acid, and it appears that multiple, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes. Various arguments have been made to suggest why natural selection would allow the accumulation of uric acid despite the physiological consequences of crystallized monosodium urate acutely causing liver/kidney damage or chronically causing gout. We have applied evolutionary models to understand the history of primate uricases by resurrecting ancestral mammalian intermediates before the pseudogenization events of this gene family. Resurrected proteins reveal that ancestral uricases have steadily decreased in activity since the last common ancestor of mammals gave rise to descendent primate lineages. We were also able to determine the 3D distribution of amino acid replacements as they accumulated during evolutionary history by crystallizing a mammalian uricase protein. Further, ancient and modern uricases were stably transfected into HepG2 liver cells to test one hypothesis that uricase pseudogenization allowed ancient frugivorous apes to rapidly convert fructose into fat. Finally, pharmacokinetics of an ancient uricase injected in rodents suggest that our integrated approach provides the foundation for an evolutionarily-engineered enzyme capable of treating gout and preventing tumor lysis syndrome in human patients.

Concepts: Protein, Gene, Bacteria, Amino acid, Ammonia, Metabolism, Uric acid, Hyperuricemia

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Since uric acid is associated with cardiovascular and renal disease, a treatment to maintain blood uric acid level may be required in patients with hyperuricemia. This study aims to evaluate preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to conventional treatment.

Concepts: Urine, Gout, Xanthine oxidase inhibitor, Uric acid, Hyperuricemia, Kidney stone, Xanthine oxidase, Xanthine