An elevated body mass index is not just associated with symptomatic gallstone disease, it appears to cause the disease, according to a report published in Hepatology (doi:10.1002/hep.26563).
Many epidemiologic and observational studies have noted a clear association between a high BMI and an increased risk for gallstones, but have not been able to pin down a causal effect. It was impossible to rule out confounding by some other factor, such as a high-fat diet, that simultaneously caused both the elevation in BMI and the elevation in risk for gallstones. Similarly, it was impossible to rule out reverse causation, such as the colicky pain of gallstone disease caused the physical inactivity that then led to a high BMI.
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According to a new study, an increasing BMI is associated with a stepwise increase in the risk of developing symptomatic gallstone disease.
A new epidemiologic statistical approach known as Mendelian randomization is thought to avert both confounding and reverse causation by pinpointing the genetic variants that are linked to a high BMI (which are a constant throughout the lifespan) but that are not related to confounding factors, then determining whether they are also linked to gallstone disease. "If raised BMI truly is a causal factor in the development of gallstone disease, genetic variants that increase BMI would be expected to also increase risk of gallstone disease," said Dr. Stefan Stender of the department of clinical biochemistry, Rigshospitalet, University of Copenhagen, and his associates.
They studied 77,679 Danish adults from the general population who participated in two large prospective studies: the Copenhagen General Population Study (67,314 subjects) and the Copenhagen City Heart Study (10,365 subjects). All the participants had donated blood samples that could be used for DNA extraction and genotyping.
A total of 4,106 of these subjects developed symptomatic gallstone disease during follow-up of up to 34 years.
The researchers used genotyping to identify study subjects who carried any of the three polymorphisms that have the largest known effect sizes for association with BMI in European populations: FTO (rs9939609), MC4R (rs17782313), or TMEM18 (rs6548238). Each of these can be carried on two possible alleles, so any given subject could carry one to six affected alleles. The number of BMI-increasing alleles, from one to six, was determined for each study subject.
In an initial analysis of the data, the mean baseline BMI was 55% higher (11 kg/m2) in subjects carrying the most alleles compared with those carrying the fewest.
Increasing BMI was associated with a stepwise increase in the risk of developing symptomatic gallstone disease.
In the overall cohort, the risk of symptomatic gallstone disease was increased 7% for every 1-kg/m2 increase in BMI. In the Mendelian randomization cohort, the risk of gallstone disease increased 17% with every 1-kg/m2 increase in BMI. The concordance between these two estimates indicates that BMI itself is a causal risk factor for symptomatic gallstone disease, Dr. Stender and his associates said.
This study did not include data on gallstone composition and was not designed to examine the pathophysiologic mechanisms by which a high BMI causes gallstone formation. However, numerous other studies have proposed several possible mechanisms, they noted.
Obesity may raise cholesterol synthesis and hepatobiliary cholesterol efflux, "a key event in the development of cholesterol gallstones." High abdominal fat mass may induce gallbladder hypomotility and bile stasis, "another risk factor for gallstone formation."
In addition, substances secreted by or metabolized by adipocytes could influence gallstone formation. For example, estrogen is produced by adipocytes and may promote gallstone formation by raising the rate of hepatobiliary cholesterol efflux. And leptin, which is also secreted by adipocytes, may have lithogenic effects.
Adinopectin, another hormone secreted by adipocytes, has been linked to gallstones in both animal and human studies. And obesity-associated hyperinsulinemia may induce gallstone formation by causing the secretion of more lithogenic bile.
This study was limited in that it included only white people of Danish descent. "Because ethnic differences in gallstone prevalence are well known, the results reported here may not necessarily translate to other ethnicities," Dr. Stender and his colleagues said.
This study was supported by the Danish Medical Research Council, the Rigshospitalet at Copenhagen University, and the Odd Fellow Order. No financial conflicts of interest were reported.