Gallstone disease, towards a better understanding and clinical practice

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Among all digestive diseases, gallstone disease is the most common and costly one, with an estimated prevalence of 10–20% in the Western world. Symptomatic disease is responsible for 1.4 million visits and 750 000 cholecystectomies per year in the United States. The vast majority of gallstones (more than 75%) are of cholesterol or cholesterol-predominant type. In this issue of Current Opinion in Gastroenterology, Shabanzadeh reports on the epidemiology of gallstone disease on the basis of ultrasound screening, notably in population cohorts unaware of the presence of gallstones. These studies indicate that approximately one out of five gallstone carriers will develop symptoms, whereas the majority will remain asymptomatic. The determinants of symptomatic disease, including biliary colic and complicated disease, consist in female sex, younger age, higher BMI, awareness of gallstone presence, gallstone multiplicity and size above 10 mm. Symptomatic disease exposes the patient to a high risk of symptom recurrence and therefore justifies cholecystectomy. Lamberts has reviewed recent clinical studies, which led to major revisions in recommendations regarding the indication and timing of cholecystectomy. Whereas a significant number of unnecessary cholecystectomies have been performed in the past, it is now recommended not to delay cholecystectomy in patients with complications such as acute cholecystitis, common bile duct stones or biliary pancreatitis, so as to reduce the risk of recurrent complications in these patients. Endoscopic retrograde cholangiography with sphincterotomy and stone extraction is recommended for bile duct stones. Patients with complications should undergo same-admission (laparoscopic) cholecystectomy, as opposed to delayed cholecystectomy in previous guidelines. However, some patients with uncomplicated symptomatic gallstone disease remain at high risk of persistent symptoms after cholecystectomy and should be treated conservatively. Therefore, the selection of patients for cholecystectomy still needs to be optimized, which will require the exploration of treatment algorithms in future prospective clinical trials. Overweight, insulin resistance and nonalcoholic fatty liver disease (NAFLD) have been identified as potential targets, in the prevention of cholesterol gallstone disease. Arrese et al. herein describe the frequent association and bidirectional relationship between gallstone disease and NAFLD. Insulin resistance, a well established key event in the development and progression of NAFLD, has also been shown to cause cholesterol gallstone formation. In addition, apart from common risk factors, NAFLD has been identified as an independent risk factor of gallstone disease. Conversely gallstone disease and cholecystectomy have an impact on the development and severity of NAFLD. These observations highlight gallbladder endocrine functions and its critical role in the homeostasis of bile acids. Farnesoid X receptor, the nuclear receptor of bile acids, which regulates fat metabolism in the liver and the composition of bile, is a therapeutic target of particular interest both in NAFLD and gallstone disease. There is also evidence to indicate that the bile acid transmembrane G-protein-coupled receptor promotes cholesterol gallstone formation. Even though cholecystectomy is currently the best option in patients with gallstone disease complications, gallbladder ablation has metabolic consequences that need to be better defined in the future. The mechanisms of cholesterol gallstone formation, reviewed by Portincasa et al. primarily consist in the hypersecretion of cholesterol into bile largely through the canalicular ATP-binding cassette transporter ABCG/G8 heterodimer, but also involve the precipitation of cholesterol crystals, impaired gallbladder motility, increased gallbladder mucin secretion and increased intestinal absorption of cholesterol. Genetic factors have also been elucidated, notably on the basis of mouse models, as summarized by Wang et al. However, studies of twin pairs have suggested that genetic factors were responsible for no more than 25–30% of symptomatic gallstones.
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