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Explore This IssueAugust 2014
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A recent prospective longitudinal study has reported that bariatric surgery lowered serum urate levels in morbidly obese patients with diabetes, with most of the study participants who had previously been treated for gout able to discontinue the therapy after surgery.
Published in May 2014 Annals of the Rheumatic Diseases, the research by Nicola Dalbeth, MD, and colleagues in New Zealand detected clinically relevant reductions in serum urate levels following bariatric surgery in patients who had diabetes and were morbidly obese. The mean BMI of patients in the study was 47.9 kg/m2. According to the researchers, the study shows that for patients with gout, morbid obesity and diabetes “bariatric surgery allows achievement of therapeutic target [serum urate] concentrations and may enable cessation of urate-lowering therapy.”
Although bariatric surgery is not a recommended treatment for gout, the study results can serve as a reminder that gout is closely tied to metabolic syndrome, that a patient’s comorbidities and gout should be treated aggressively, and that medications for other conditions can play a significant role in its development and worsening.
According to John FitzGerald, MD, PhD, who was not involved in the study but commented on its implications, “The research should remind rheumatologists and generalists to treat gout as part of hypercholesterolemia, hypertension and obesity. It reminds us that weight loss can influence the comorbidities and can help improve gout.”
Dr. FitzGerald, principal investigator on the ACR’s gout management guidelines published in 2012 and associate clinical professor of medicine at the University of California, Los Angeles, says the trial “reinforces the need to treat gout as part of the metabolic syndrome. You can’t just focus on the gout. You need to encourage patients to try and improve their lifestyle.”
The ACR guidelines make clear that gout is mediated by comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes and chronic kidney disease, and the guidelines underlined the importance of treating and managing those comorbidities to effect improvement in hyperuricemia.
Monitoring a patient’s medications for these comorbidities is important, Dr. FitzGerald says, noting that 42% of the patients with gout in the study were taking diuretics, which can aggravate hyperuricemia. “It’s entirely possible that if the group had been switched from diuretics to other blood pressure medications, there would have been similar results in serum urate lowering [as were achieved with bariatric surgery].”
Sixty patients were included in the single-center trial. Inclusion criteria included age between 20 and 60, diagnosis of type 2 diabetes, treatment with oral hypoglycemia medication or insulin, BMI of at least 35 kg/m2 and no contraindications to surgery. The average age of patients was 46. Thirty-two percent of the population was Maori, 30% was Pacific Islander, and 38% was European/other. The study authors cautioned that several of these factors may limit whether the results can be generalized to other populations.
Twenty-four of the 60 patients had serum urate above saturation concentrations (≥0.41 mmol/L) at baseline. Twelve of the 24 had been diagnosed with gout (five women), and 9 of the 12 were on urate-lowering therapy: The mean dose for eight patients was 237 mg daily of allopurinol. Five of the 12 patients with gout, and 21 of the 48 patients without gout were taking diuretics for hypertension.
After six months of nonsurgical weight loss efforts with dietary intervention, the mean weight loss was about 12.5 lbs., and there was no change in serum urate. All patients were then assigned laparoscopic sleeve gastrectomy and followed for one year. Mean weight loss was 75.3 lbs. at one year, and four of the 26 patients taking diuretics at the trial’s start were continuing that medication.
Serum urate significantly increased in the postoperative period and then started declining at three months after surgery, with the final mean at 0.30 mmol/L. According to the researchers, the data suggest that this temporary increase immediately after surgery may have occurred because of renal dysfunction associated with major surgery. They added that other contributing factors could have been fasting or rapid weight loss.
The investigators identified the factors associated with change in serum urate by the one-year follow-up: the baseline level, cessation of diuretic therapy, change in serum creatinine and female gender.
Implications of the Research
Robert Terkeltaub, MD, San Diego (Calif.) VA Medical Center rheumatology section chief and professor of medicine at University of California, San Diego, and also not involved in the study, says the research reinforces “our clinical impressions that it is hard to get people to lose weight, especially without bariatric surgery.”
The implications of the research, however, should be interpreted somewhat cautiously by physicians who do not treat a large number of Maori or Pacific Islanders, two ethnic groups that have high rates of gout and diabetes. Other caveats are that the BMI of patients was exceptionally high, only 12 patients with gout were in the study, and gout was not part of the inclusion criteria in the study, he says.
Some news reports about the study have suggested that bariatric surgery could be a new treatment for gout, but the trial was not designed to study the disease, he says. Dr. Terkeltaub, who was co-principal investigator and senior and corresponding author for the ACR 2012 gout guidelines, says the study “does not prove that bariatric surgery is a frontline procedure for treating people with gout. In fact, the patients with gout had not been treated prior to surgery with the maximum appropriate oral medication regimen, instead receiving a mean of only 237 mg of allopurinol daily. Patients with gout should be treated to uric acid target,” he says.
Gout is known to be undertreated, especially in primary care. The target for serum urate is <6 mg/dL at a minimum, and often <5 mg/dL. Many physicians, however, don’t titrate upward from the starting dose of a first-line pharmacologic therapy with a xanthine oxidase inhibitor (XOI) therapy. The maintenance dose of allopurinol can exceed 300 mg daily, even in patients with chronic kidney disease. If the target is not reached with appropriately dosed XOI monotherapy, adding uricosuric therapy onto an XOI inhibitor is recommended by the ACR 2012 guidelines as the potential next step, depending on appropriateness for the patient.
Ongoing research has suggested that uric acid and xanthine oxidase in abdominal fat are mediating inflammation and obesity, contributing to the metabolic syndrome (see figure, left). Xanthine oxidase acts partly on adipose tissue by regulating PPARgamma and adipogenesis. All of these associations highlight the importance of comprehensive management of gout and associated comorbidities, including obesity, Dr. Terkeltaub says.
Kathy L. Holliman, MEd, is a medical writer based in Beverly, Mass.
> ↑ Body mass index (BMI), associated with hyperuricemia & increased incident gout risk (>3-fold OR: BMI 30–34.9)3
> Mechanisms by which obesity promotes both hyperuricemia and gout:
— ••Insulin resistance decreased renal uric acid excretion systemic inflammatory state
— ••? ↑ Leptin (decreased renal uric acid excretion)4
— ••↑ Adipocyte xanthine oxidase (XO) and urate generation, secretion5
— ••Too much or too little XO–> fat tissue inflammation5,6
— ••XO–>PPARg –> adipogenesis5,6
— ••(?) Soluble uric acid in fat –> promotes fat tissue inflammation, obesity, metabolic syndrome7
Table source: Chart created by Robert Terkeltaub, MD, and used with permission.
- Dalbeth N, Chen P, White M, et al. Impact of bariatric surgery on serum urate targets in people with morbid obesity and diabetes: A prospective longitudinal study. Ann Rheum Dis. 2014;73:797–802.
- Khanna D, FitzGerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part I: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1447–1461.
- Choi HK, Ford ES, Li C, et al. Prevalence of the metabolic syndrome in patients with gout: The Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007 Feb 15;57(1):109–115.
- de Oliveira EP, Burini RC. High plasma uric acid concentration: Causes and consequences. Diabetol Metab Syndr. 2012 Apr 4;4:12.
- Tsushima Y, Nishizawa H, Tochino Y, et al. Uric acid secretion from adipose tissue and its increase in obesity. J Biol Chem. 2013 Sep. 20;288(38):27138–27349.
- Murakami N, Ohtsubo T, Kansui Y, et al. Mice heterozygous for the xanthine oxidoreductase gene facilitate lipid accumulation in adipocytes. Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):44–51.
- Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes. 2011 Apr;60(4):1258–1269.