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The association of obesity with the development of gout has been attributed to hyperuricaemia.1 ,2 However, in patients with poorly controlled gout, weight loss leads to profound suppression of gout flares, despite a relatively small reduction in urate concentrations.3 Monosodium urate (MSU) crystals are frequently identified in asymptomatic, uninflamed joints in patients with gout,4 suggesting that local or systemic factors regulate the inflammatory response to intra-articular crystals. Since weight loss is associated with reduced chronic inflammation,5 we hypothesised that weight loss influences the presentation of gout through regulation of inflammatory responses to MSU crystals.
Twenty patients with morbid obesity (body mass index ≥35 kg/m2) and type 2 diabetes, with no history of gout, were prospectively recruited from two public hospitals in Auckland, New Zealand. The Northern X Ethics Committee approved the study and all patients provided written informed consent. Ten patients underwent laparoscopic gastric bypass surgery and 10 patients underwent laparoscopic sleeve gastrectomy, according to standard institutional protocols. Fasting blood tests were obtained 3 days prior to surgery and during a follow-up postoperative study visit (mean (SD) follow-up 256 (87) days). Peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll gradient centrifugation as previously described.6 PBMCs were seeded in triplicate in 48 well plates at 2×106 cells/ml in Dulbecco's Modified Eagle Medium/10% fetal calf serum, and for interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor (TNF)α assays, pretreated for 3 h with 0.5 μM phorbol 12-myristate 13-acetate.7 PBMCs were incubated for 16 h with 0.5 mg/ml endotoxin-free MSU crystals.6 Supernatants were harvested and immediately stored at −20˚C until testing of IL-1β, IL-6, interleukin 8 (IL-8) and TNFα by ELISA (R&D). For each individual, supernatants from both time points were thawed on a single occasion and tested on the same ELISA plate. Data were analysed using Prism V.5 and SPSS V.15 by paired t tests and Spearman correlations.
The mean (SD) weight loss was 25(7) kg. Circulating urate and triglyceride concentrations reduced and high density lipoprotein (HDL) cholesterol increased during the study period (table 1). At baseline, PBMC IL-8 responses, but not other cytokine responses, correlated with weight (r=0.49, p=0.03). Neither weight nor circulating lipid concentrations correlated with PBMC cytokine responses to MSU crystals at baseline or follow-up (not shown). However, serum urate concentrations correlated with PBMC IL-1β and TNFα responses to MSU crystals at follow-up (p=0.45, p<0.05 for both). Following weight loss surgery, significant reductions were observed in PBMC IL-1β, IL-8 and IL-6 responses to MSU crystals, with a similar trend for TNFα (figure 1). Surgical procedure or gender did not influence changes in PBMC cytokine responses (not shown).
In summary, profound weight loss following bariatric surgery for morbid obesity is associated with reduced inflammatory responses to MSU crystals. The mechanisms for these observations require further investigation, but may include interactions with pro-inflammatory dietary factors such as fatty acids, urate itself, obesity-related peptides or lipid metabolism signalling pathways such as peroxisome proliferator-activated receptor γ (PPARγ).8–10 These findings provide support for the concept that, in addition to urate lowering, weight loss has the potential to reduce the risk of gout flares through suppression of inflammatory responses to MSU crystals.
Contributors ND (the guarantor) accepts full responsibility for the work and the conduct of the study, had access to the data and controlled the decision to publish. ND conceived of the study, contributed to the data interpretation and drafted the manuscript. BP did the experimental work. SY recruited participants and coordinated study visits. JC and RM conceived of the study, contributed to the data interpretation and drafted the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the Auckland Medical Research Foundation (grant number 1109014). Shelley Yip was the recipient of the Jens Henrik Jensen academic fellowship administered by the University of Auckland.
Competing interests None.
Patient consent Obtained.
Ethics approval Northern X Regional Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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