Consistent with previous studies, we found that WC, IR, MetS, and cholecystectomy independently contributed to the risk of NAFLD [6, 13]. This study further revealed that the magnitude of the risk contributed by central obesity was similar to that by cholecystectomy. We also observed that the magnitude of the association with IR or MetS was greater than with cholecystectomy in combined analyses. This study also revealed gallstones were a risk factor for NAFLD only in the presence of central obesity, IR or MetS. In this study, comparative and joint analyses broaden our understanding of risk factors’ relative influence on NAFLD.
In the present study, those with gallstones but without central obesity, IR or MetS did not have increased risk of NAFLD. However, cholecystectomy was associated with increased risk of NAFLD, regardless of central obesity, IR or MetS status, supporting the notion that cholecystectomy may itself represent a risk factor for NAFLD . Our findings suggested that the effects of gallstones on NAFLD were mediated primarily by the presence of central obesity, IR or MetS. These results are consistent with previous reports in which gallstones were unrelated to NAFLD after correction for central obesity or metabolic risk factors [6, 14]. It is not unexpected that different relationships were observed between NAFLD and gallstones and cholecystectomy, as the latter measures different aspects of hepatic lipid metabolism and biliary lipid secretion, and represents the loss of the metabolic functions in the absence of a gallbladder [15, 16]. Ablation of the gallbladder eliminates the formation of cholesterol solid-plate crystals, which form in the gallbladder and is not able to be absorbed by the intestine . Therefore, cholecystectomy can increase the proportion of cholesterol that is reabsorbed and delivered to the liver, facilitating an increase in hepatic triglycerides concentration. The gallbladder is critical to regulating the daily cycling of bile acids (BAs) within the enterohepatic circulation. The rhythm and intensity of BAs secretion from a healthy functional gallbladder are in synchrony with food intake. Cholecystectomy may alter the rhythm of BAs flux and its receptor activation, although the basal BAs output is higher than normal, the release of BAs is not enough to balance the sharp fluctuation of lipid and glucose levels after food intake . Following the removal of the gallbladder, BAs are continuously secreted into the small intestine, and the BAs pool circulates faster, inducing increased cycling of the BA pool and thus expose the liver to a greater flux of BAs and the occurrence of metabolic derangements. Emerging evidence suggested that in addition to their well-established roles in absorption of dietary lipids, BAs are also signaling molecules that act as ligands of the nuclear receptor farnesoid X receptor and the G-protein-coupled BA receptor TGR5, which modulate complex enterohepatic and systemic lipid and glucose metabolism [19, 20]. Moreover, ablation of the gallbladder could remove the protective metabolic activity of the gallbladder mucosa, which can secret fibroblast growth factor 19 that has a role in the negative feedback regulation of BA synthesis and can inhibit hepatic fatty acid synthesis [21, 22]. The loss of this metabolic activity and changes in following cholecystectomy renders patients prone to an increased NAFLD risk.
One study using the same data have reported that the odds of NAFLD did not differ based on time since cholecystectomy . There are two longitudinal studies assessed the risk of liver steatosis after cholecystectomy [23, 24]. One study reported that hepatic steatosis developed 3 months after cholecystectomy . Another study noted that hepatic fat content was significantly increased 24 months after cholecystectomy . Hence, changes in lipid metabolism and bile acids secretion after cholecystectomy can affect the structure of the liver. However, the exact time it takes to develop NAFLD remains to be determined.
Data on the relative influence of central obesity and cholecystectomy on NAFLD risk are sparse. The present study indicated that the increased NAFLD risk was similar between non-central-obese individuals with cholecystectomy and centrally obese individuals without cholecystectomy, suggesting that the clinical evaluation of cholecystectomy play similar important role to the diagnosis of central obesity in NAFLD risk stratification. Our data also showed additive effects of cholecystectomy above central obesity for NAFLD risk. Although there are many theories, the mechanism by which central obesity affects cholecystectomy remains poorly understood. One possible explanation may be that WC and cholecystectomy are 2 independent variables, they interact with each other and contribute to some different pathogenesis leading to NAFLD. This is suggested by the no attenuation of the effects of cholecystectomy on NAFLD risk by adjusting for WC in our analyses. Since adipose tissue lipolysis supplies the majority of free fatty acids that subsequently are esterified to form hepatic triglycerides , obesity has been well recognized for its strong association with fat accumulation in the liver . Increased cycling of the BA pool after cholecystectomy could favor even a greater increase of body cholesterol synthesis and hypersecretion of biliary cholesterol observed in obesity, increasing the exposure of the liver to a higher flux of triglycerides and thus exacerbating hepatic steatosis. Therefore, cholecystectomy can exaggerate the adverse effects of central obesity on NAFLD risk.
Since symptoms are believed to be uncommon and transitory after removal of gallbladder, cholecystectomy has become one of the most frequently performed surgical procedures for treatment for gallstone disease. We observed that the magnitude of the association with NAFLD risk was similar for WC and cholecystectomy. Hence, cholecystectomy may not be innocuous.
The present study indicated that cholecystectomy had relatively small effects on NAFLD risk than IR or MetS. Alterations in gut microbiota have been linked to host insulin resistance, and diabetes [27, 28]. Emerging evidence reported that altered composition of gut microbiota was noted in patients who underwent cholecystectomy; the community diversity of intestinal microbiota in cholecystectomized patients was decreased and Bacteroidetes were increased compared with healthy population [29, 30]. A human study found that low richness of gut microbiome plays a role in insulin resistance . Taken together, alterations in gut microbiota after cholecystectomy may contribute to the involvement of insulin resistance and metabolic abnormalities. Moreover, due to the cross-sectional nature of the data, any temporal effect of cholecystectomy versus IR or MetS on risk of NAFLD could not be determined.
According to guideline, people with asymptomatic gallbladder stones found in a normal gallbladder and normal biliary tree do not need treatment unless they develop symptoms. Symptomatic gallbladder stones whether symptomatic or asymptomatic should be offered cholecystectomy . Hence, for patients with gallstones together with other risk factors such as obesity, hyperlipidemia, insulin resistance, and T2DM, which are predisposed to confer an increased NAFLD risk, comprehensive treatment including lifestyle interventions, BP, and glucose control should be take into consideration to keep body weight, BP and glucose in optimal levels and thus to avoid the occurrence of a symptomatic gallbladder.
Limitations of our study include the use of ultrasound to detect NAFLD. Although ultrasonography is a reasonably accurate technique for detecting modest amounts of liver fat (> 30% liver fat infiltration), participants with minor amounts of fatty infiltration might not have been captured. Furthermore, lack of information on residual confounding variables such as body fat percent prevented us from being able to assess these variables as potential confounders; however, major confounding factors have been controlled for in our multivariate models. These limitations are balanced by the benefits of using a nationally representative sample of US adults, particularly the ability to generalize the results to a national population. On the other hand, this study is the first human study to compare the importance of cholecystectomy and obesity on NAFLD risk.