Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse
Higher body mass index (BMI) appears to be a causal risk factor for gallstones, particularly for women, Danish researchers found.
In a large population study, increasing BMI was associated with a significantly increased risk of gallstones (HR 2.84, 95% CI 2.32 to 3.46, P<0.001), Anne Tybjaerg-Hansen, MD, of Copenhagen University Hospital, and colleagues reported online in Hepatology.
With regard to causality, they also found a higher risk of gallstones among patients who had more genetic variants tied to obesity (HR 1.43, 95% CI 0.99 to 2.05, P=0.007).
"The concordance between the observational and genetic risk estimates supports that increased BMI per se is a causal risk factor for symptomatic gallstone disease," they wrote.
Elevated BMI has been associated with an increased risk of gallstones, but it's been unclear if the relationship is causal, since it may be that another factor simultaneously raises BMI and causes gallstones, such as a high-fat diet or physical inactivity.
The researchers hypothesized that if BMI caused symptomatic gallstones, an increased BMI due to certain genetic variants should confer a similar increased risk of gallstones.
To test that hypothesis, Tybjaerg-Hansen and colleagues applied the Mendelian randomization approach, which uses genetic variants that are associated with BMI but not with potential confounding factors, to 77,679 patients from the general population.
During a mean follow-up of 5.3 years, 4,106 patients developed symptomatic gallstone disease.
Patients were also genotyped for three common variants associated with BMI -- FTO, MC4R, and TMEM18.
Overall, the researchers found that increasing BMI was associated with an increased risk of gallstones (aHR 2.84, 95% CI 2.32 to 3.46, P<0.001).
That association was significant for both men and women, although it was stronger for women:
Women: HR 3.36, 95% CI 2.62 to 4.31
Men: HR 1.51, 95% CI 1.09 to 2.11
In genetic analyses, patients carrying six BMI-increasing alleles compared with none or just one had a 5.2% increase in BMI overall, with increases of 4.3% in women and 6.1% in men (P<0.001 for all).
The researchers also found a significant interaction between gallstone disease and increasing obesity alleles, with a higher risk of gallstones among patients with six BMI-increasing alleles compared with none or just one (HR 1.43, 95% CI 0.99 to 2.05, P=0.007).
However, that relationship was significant for women but not for men, they reported.
Mechanisms by which obesity may cause gallstone disease include the fact that obesity may increase hepatic de novo cholesterol synthesis and hepatobiliary cholesterol efflux, a key event in the development of cholesterol gallstones, the researchers wrote.
They also noted that increased abdominal fat mass may cause gallbladder hypomotility and bile stasis, another risk factor for gallstone formation, and factors secreted or metabolized by adipocytes may promote the formation of gallstones.
The study was limited by its reliance on hospital ICD codes to determine gallstone disease, and potentially by ascertainment bias since clinicians may be more suspect of gallbladder disease in obese patients, which could lead to overestimation of the association in the study.
The findings also may not be generalizable outside of the Danish population.
Still, the researchers concluded that BMI is likely a causal risk factor for gallstone disease, particularly in women, and the data "provide additional impetus for lifestyle interventions aimed at weight loss among overweight and obese individuals in the general population."
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