BMI升高可能导致胆结石

《Hepatology》发表的一份研究报告显示，体重指数(BMI)升高不仅与症状性胆石病相关，还可能是这种疾病的发病原因之一(doi:10.1002/hep.26563)。

许多流行病学研究和观察性研究都表明BMI升高与胆结石风险增加之间有明确的相关性，但却没能确定两者间的因果关系。要排除其他一些因素的混杂效应很难，比如高脂饮食；高脂饮食会同时导致BMI升高和胆结石风险增加。同样，也很难排除反向因果关系，比如胆石病的绞痛使身体活动减少从而导致了BMI升高。



丹麦哥本哈根大学Rigshospitalet医院临床生化科的Stefan Stender博士及其同事说，一种名为“孟德尔随机化(Mendelian randomization)”的流行病学统计新方法可以通过先确定与BMI偏高(终身不变)相关但与混杂因素无关的遗传变异因素，然后再确定其是否也与胆石病相关，从而排除混杂效应和反向因果关系。“如果BMI升高的确是形成胆石病的病因，那么导致BMI升高的遗传变异因素也应该会增加胆石病的发病风险。”

研究者对来自一般人群的77,679例丹麦成年人进行了分析，所有受试者均来自两项大规模前瞻性研究：哥本哈根一般人群研究(67,314例受试者)和哥本哈根市心脏研究(10,365例受试者)。所有受试者均提供了可以用于DNA提取和基因分型分析的血液样本。

共有4,106例受试者在长达34年的随访期内出现了症状性胆石病。研究者采用了基因分型分析以确定哪些受试者携带了3种基因多态性中的任何一种；这是目前已知的在欧洲人群中与BMI相关的效应量最大的3种多态性，它们分别是：FTO (rs9939609)、MC4R (rs17782313)或者TMEM18 (rs6548238)。每种多态性都可能携带在2个等位基因上，因此任何一名受试者可能携带1~6个受累的等位基因。研究者确定了每名受试者携带的与高BMI相关的等位基因数量，范围是1~6个。

初始数据分析显示，携带等位基因最多的受试者的基线平均BMI比携带等位基因最少者高55% (11 kg/m²)。

BMI升高与症状性胆石病的发病风险逐步增加相关。

Stender博士及其同事报告称，在总体队列中，BMI每升高1 kg/m²，症状性胆石病的发病风险就会增加7%。在孟德尔随机化队列中，BMI每升高1 kg/m²，胆石病发病风险就会增加17%。这两个估值间的一致性提示了BMI本身就是症状性胆石病的一个致病性危险因素。

研究者指出，这项研究没有纳入有关胆结石成分的数据，研究目的也不是为了探讨BMI升高导致胆结石形成的病理生理机制。不过，其他大量研究提出了多种可能存在的机制。

肥胖可能促进胆固醇合成以及肝胆内胆固醇外流，这是“导致胆固醇结石形成的一个关键因素” 。腹内脂肪量增加可能诱导胆囊运动减少和胆汁淤积，这是“导致胆结石形成的另一个危险因素”。

此外，由脂肪细胞分泌或代谢的物质也可能影响胆结石的形成。例如，雌激素是由脂肪细胞生成的，它可以通过提高肝胆内胆固醇外流的速率来促进胆结石的形成。同样由脂肪细胞分泌的瘦素也可能产生致结石效应。脂联素是由脂肪细胞分泌的另一种激素，动物和人体研究均表明其与胆结石相关。与肥胖相关的高胰岛素血症也可能导致更多的致结石胆汁分泌从而诱导胆结石的形成。

Stender博士及其同事指出，这项研究的局限性在于只纳入了丹麦血统的白人。“由于我们已知胆结石的患病率存在种族差异，因此这里报告的研究结果可能不一定适用于其他种族的人群。”

这项研究由丹麦医学研究理事会、哥本哈根大学Rigshospitalet医院以及Odd Fellow Order共同资助。作者声明无相关经济利益冲突。

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By: MARY ANN MOON, Internal Medicine News Digital Network

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.

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.