Gout and Metabolic Disease Go Hand in Hand
October 27, 2009
* Explain to interested patients that gout is a painful inflammatory condition resulting from crystals of uric acid that accumulate in joints and other areas of the body. Explain, too, that high levels of uric acid in the blood are indirectly responsible.
* Explain that known risk factors for gout include overweight and obesity, high blood pressure, and heavy alcohol use.
* Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
PHILADELPHIA -- Gout and hyperuricemia may represent another facet of metabolic syndrome, so closely tied are they to obesity, high cholesterol, and type 2 diabetes, suggested several studies presented here.
In particular, elevated serum urate in young adulthood appears to predict metabolic diseases later on, researchers told attendees at the American College of Rheumatology meeting, while early metabolic abnormalities are a risk factor for gout in later life.
One study, meanwhile, suggested that the risk for gout can be modified by targeting metabolic risk factors for intervention.
Hyperuricemia predicts type 2 diabetes
In a prospective cohort study of some 5,000 young adults, those with serum urate levels of 7.0 mg/dL or higher were twice as likely to develop type 2 diabetes during 15 years of follow-up, reported Eswar Krishnan, MD, of Stanford University in Stanford, Calif.
This increase in risk applied even in individuals who did not have metabolic syndrome during baseline evaluations, conducted when the participants were 18 to 30 years old, Krishnan said.
He said the finding confirmed results from earlier, cross-sectional studies linking hyperuricemia to diabetes.
The study participants underwent physical exams every two to three years for 15 years following enrollment. About half the sample was African-American.
Participants were considered to have developed type 2 diabetes if they met American Diabetes Association diagnostic criteria or received antihyperglycemic medication.
Compared with individuals with serum urate below 5.0 mg/dL, those with levels of 7.0 mg/dL and higher at baseline, but not metabolic syndrome, had an adjusted relative risk of 1.99 (95% CI 1.18 to 3.26) for developing type 2 diabetes.
Each 1-mg/dL increase in serum urate increased the odds of developing diabetes overall by 18% (95% CI 4% to 35%), Krishnan reported.
In those without metabolic syndrome at baseline, the incremental risk increase was 22% (95% CI 7% to 38%).
These figures reflected adjustments for numerous risk factors for diabetes: age, gender, ethnicity, body mass index, systolic blood pressure, smoking, fasting blood glucose, family history of diabetes, and baseline physical activity level.
High cholesterol in youth, later gout
A doubling of risk was also found in the opposite direction -- young men with high total cholesterol had about twice the incidence of gout before reaching age 60 relative to those with normal or low cholesterol when they were young, said Allan C. Gelber, MD, PhD, MPH, of Johns Hopkins University.
After adjusting for hypertension and weight at baseline, total cholesterol levels higher than 217 mg/dL in a cohort of first-year medical students were associated with a relative risk of 2.2 (95% CI 1.3 to 3.7) for developing gout before age 60, he reported.
The 1,040 participants were recruited from 1948 to 1964 and followed for a median of 45 years to identify incident diseases, Gelber said.
A total of 139 participants -- about 20% of those with enough follow-up for analysis -- reported having developed gout. Of those, 60 were sent a questionnaire based on the ACR's gout classification criteria; 42 responded, with 34 fulfilling the ACR criteria. The other eight were also determined to have gout on the basis of their medical records.
For those developing gout, the median age at onset was 58.
The highest quintile of baseline total cholesterol, greater than 217 mg/dL, had a significantly elevated risk of developing gout at any age, as well as developing it before age 60.
The unadjusted all-age relative risk for gout with high baseline cholesterol was 1.7 (95% CI 1.1 to 2.5). Adjusting for body mass index at age 35 and the development of hypertension with age did not affect the risk associated with high cholesterol very much (RR 1.6, 95% CI 1.1 to 2.4), Gelber reported.
Nevertheless, both body mass index and time-dependent hypertension were independent risk factors for gout:
* BMI at 35 (adjusted for cholesterol): RR 1.1 (95% CI 1.0 to 1.2)
* Hypertension (adjusted for cholesterol): RR 1.9 (95% CI 1.2 to 2.9)
Gelber said the findings suggest that routine cholesterol screening in young adulthood can identify men with increased risk for gout later on.
Risk factors for gout in women
Gelber's study was restricted to men, reflecting a tradition in which gout was assumed to be primarily a male disease.
But, as Vidula Bhole, MD, of the Arthritis Research Centre of Canada in Vancouver, B.C., pointed out, the prevalence of gout in women has doubled in recent years. Whether the risk factors in women are the same as for men is largely unknown, she said.
She reported a study, based on Framingham Heart Study data, showing that, in fact, the risk factors are largely the same.
On the other hand, the most prominent known risk factor -- baseline levels of serum urate -- appeared to be a weaker predictor of gout in women than in men.
She and her colleagues found the following relative risks in multivariate analyses:
* BMI of 30 or more, relative to less than 25: women, 2.74 (95% CI 1.65 to 4.58); men, 2.90 (95% CI 1.89 to 4.44)
* Use of diuretics (relative to no diuretics): women, 2.39 (95% CI 1.53 to 3.74); men, 3.41 (95% CI 2.38 to 4.89)
* Heavy alcohol use (relative to light use): women, 3.10 (95% CI 1.69 to 5.68); men, 2.21 (95% CI 1.56 to 3.14)
* Hypertension diagnosis (relative to no diagnosis): women, 1.82 (95% CI 1.06 to 3.14); men, 1.59 (95% CI 1.12 to 2.24)
* Age (per five-year increment): women, 1.24 (95% CI 1.08 to 1.43); men, 1.14 (95% CI 1.03 to 1.26)
Other factors such as blood glucose and cholesterol levels, education, and menopause did not appear to affect gout incidence in study participants of either sex, Bhole reported.
The only factor that was significant in one gender and not the other was mid-range BMI. Men with values between 25 and 30 were at significantly increased risk for gout (RR 1.76, 95% CI 1.22 to 2.54) whereas moderately overweight women were not (RR 1.44, 95% CI 0.88 to 2.37).
Bhole's study involved 2,476 women and 1,951 men with a mean age of 47 at baseline.
Relatively small minorities of the sample had the risk factors at baseline: 13% were obese, 13% had hypertension, 4% used diuretics, and 14% were heavy drinkers. The proportions of women with these factors were about the same except for heavy alcohol use, which was found in only 6% of the female participants.
Median follow-up was 28 years, with 304 incident gout cases, including 104 in women.
As expected, the risk of gout in women was associated with serum urate levels at baseline, ranging from 0.8 cases per 1,000 person-years for those with urate less than 5 mg/dL up to 27.3 per 1,000 person-years for those with urate of 8 mg/dL or higher.
Nevertheless, Bhole said, this association was significantly weaker than it was in men. The incremental increase in risk per 1-mg/dL in urate was 2.01 in women compared with 2.66 in men (P<0.001).
She said this finding could explain the lower incidence rate among women -- 1.4 per 1,000 person-years, versus 4.0 in men -- which is seen even after adjusting for baseline serum urate.
Weight loss reduces hyperuricemia
An important question is whether modifying the modifiable risk factors affects the actual risk for gout. Another study presented here indicated that this is indeed the case for one such factor: overweight and obesity.
Yanyan Zhu, MSc, of Boston University, and colleagues found that individuals who lost weight -- as little as 5 kg (11 lb) -- significantly decreased the rate of hyperuricemia, defined as serum urate of 6 mg/dL or more.
Those losing at least 10 kg (22 lb) cut their risk of hyperuricemia by more than half, Zhu reported.
The study examined more than 12,000 participants in the Multiple Risk Factor Intervention Trial, a randomized study that began in the mid-1970s. The interventions included dietary modifications and other measures intended to reduce body weight and blood pressure.
Data on body weight and serum urate were collected at baseline and then annually over a six-year period, giving a total of more than 79,000 observations.
Study participants were 46 years old on average at baseline and had a mean BMI of 28. Mean serum urate was 6.79 mg/dL at baseline, with 73% of participants surpassing the 6-mg/dL threshold for hyperuricemia.
The researchers found a clear relationship between weight loss or gain and the risk of hyperuricemia at follow-up.
Compared with individuals whose weight didn't vary by more than 1 kg from baseline, Zhu and colleagues calculated the following odds ratios, in multivariate analyses that accounted for other risk factors, for the following categories of weight change:
* Loss of 1 to 4.9 kg: 0.83 (95% CI 0.79 to 0.87)
* Loss of 5 to 9.9 kg: 0.68 (95% CI 0.63 to 0.73)
* Loss of 10 kg or more: 0.44 (95% CI 0.39 to 0.49)
* Gain of 10 kg or more: 1.54 (95% CI 1.27 to 1.85)
* Gain of 5 to 9.9 kg: 1.46 (95% CI 1.33 to 1.60)
* Gain of 1 to 4.9 kg: 1.09 (95% CI 1.04 to 1.15)
Overall, each 1-kg change in weight was associated with a 5% change in the risk of hyperuricemia (P<0.0001), the researchers found.
The study by Krishnan and colleagues was funded by Takeda and the American College of Rheumatology.
The study by Gelber and colleagues was supported by the National Institutes of Health and the Donald B. and Dorothy Stabler Foundation.
The study by Bhole and colleagues had no external funding.
The National Heart, Lung and Blood Institute funded the Multiple Risk Factors Intervention Trial. No external funding was reported for the current analysis.
The study by Zhu and colleagues was supported by the National Institutes of Health.
Krishnan reported relationships with Takeda and Savient.
Gelber, Bhole, and Zhu reported no potential conflicts. Several co-authors on the study by Krishnan and colleagues were employees of Takeda.
Primary source: Arthritis & Rheumatism
Bennett M, et al "Hyperuricemia as an early marker for type 2 diabetes among young adults" Arthritis Rheum 2009; 60: S760-61.
Additional source: Arthritis & Rheumatism
Gelber A, et al "Serum cholesterol in young men and risk of incident gout" Arthritis Rheum2009; 60: S761.
Additional source: Arthritis & Rheumatism
Zhu Y, et al "Weight loss and the risk of hyperuricemia among men with a high cardiovascular risk profile" Arthritis Rheum 2009; 60: S761-62.