What do we know about the pathogenesis of gallstones?

Gallstone disease represents one of the most common hepatobiliary conditions worldwide among adults,¹ with an increasing prevalence among children.² Major risk factors include age, female sex, pregnancy, diabetes, obesity, and sedentary lifestyle. Additionally, inherited predisposition can significantly influence the likelihood of developing gallstones.³ Common genetic variants have only a modest impact on gallstone disease but in rare conditions, such as low phospholipid–associated cholelithiasis (LPAC) syndrome, specific genetic mutations play a central role.⁴

Gallstones are broadly classified into 2 major types: cholesterol stones and pigment stones, with the former type being the most common.⁵ They can develop either in the gallbladder or in the bile ducts. Bile mainly consists of water and 3 main lipids as solutes, that is, bile acids, cholesterol, and phospholipids. Maintaining the physiological concentrations of each of these compounds is necessary for undisturbed bile flow in the fasting / postprandial period, and for prevention of cholestatic conditions or gallstone formation. Gallstones may develop due to increased cholesterol secretion into bile leading to biliary cholesterol supersaturation or, in the case of LPAC, due to decreased concentrations of biliary phospholipids in bile, a predisposing factor to cholesterol precipitation / crystallization in bile.⁶ Additionally, bile stasis in the gallbladder, often caused by hypomotility, further increases the risk of both cholesterol and pigment gallstone formation.

Are there known methods for primary prevention of gallbladder stones? Are there evidence‑based strategies for secondary prevention of bile duct stones?

Cholesterol gallstones constitute 90%–95% of all gallstones in the Western populations. Black pigment stones are predominantly associated with chronic hemolytic disorders and liver cirrhosis. Cholesterol and black pigment stones are primarily formed within the gallbladder, whereas brown pigment stones generally develop within the obstructed common bile duct. The etiology of cholesterol and pigment gallstones involves a complex interplay of genetic, environmental, local, and metabolic factors.⁷

To mitigate nongenetic risk factors, various general and specific primary preventive strategies are available.⁸ Increased body mass index (BMI) and waist circumference as well as dyslipidemia are established risk factors for cholesterol gallstones and symptomatic gallstone disease.^9,10 Regular physical activity has been found to reduce the risk of gallstone formation and symptomatic gallstones by 30%–70%,¹¹ underscoring the importance of physical activity and weight maintenance as primary preventive measures. Additionally, a Western diet, characterized by frequent consumption of meat and saturated fat and high caloric intake, is associated with an increased risk of gallstone disease.¹² Diets rich in vegetables and fruits may provide some protective effects against gallstone disease.¹³ The intake of polyunsaturated and monounsaturated fats, particularly from nuts, has been associated with a reduced risk of gallstone disease, potentially as part of an overall healthy dietary pattern.¹⁴

Recurrent bile duct stones following endoscopic sphincterotomy occur in 4%–24% of patients.¹⁵ Currently, no evidence‑based secondary prophylactic measures exist, and data on the potential benefits of ursodeoxycholic acid (UDCA) remain unconfirmed by randomized controlled trials.¹⁶ However, patients with a monogenic predisposition for LPAC may benefit from long‑term prophylaxis or medical therapy with UDCA (15 mg/kg body weight per day) to prevent stone formation or recurrence as well as related complications.¹⁷

Rapid weight loss (eg, after bariatric surgery) increases the risk of developing cholesterol gallstones. What is the mechanism in this setting? Can gallstones be prevented, and if so, how?

Increased BMI is a significant risk factor for both gallstone formation¹⁸ and symptomatic gallstone disease.⁹ However, rapid weight loss has also been associated with an elevated risk of cholesterol gallstone formation.¹⁹ In contrast, gradual weight loss at a moderate pace (up to 1.5 kg per week) has been shown to reduce the risk of gallstone development.²⁰

Patients undergoing rapid weight reduction following treatment with glucagon‑like peptide‑1 receptor agonists or gastric bypass surgery are at a higher risk of symptomatic gallstone disease, with incidence rates between 28% and 71%,^21,22 which is higher than in individuals undergoing sleeve gastrectomy or gastric banding. UDCA has demonstrated efficacy in preventing cholesterol gallstone formation following rapid weight loss in patients with obesity, regardless of the weight loss method. In a recent multicenter, double‑blind, randomized, placebo‑controlled superiority trial, UDCA reduced the risk of new symptomatic gallstones as compared with placebo in patients undergoing Roux‑en‑Y gastric bypass.²³ UDCA treatment has shown efficacy at doses ranging from 500 to 600 mg per day, with the highest effectiveness observed during the period of active weight loss, as the risk of gallstone formation decreases once body weight stabilizes.²⁴ The European Association for the Study of the Liver clinical practice guidelines recommend temporary UDCA therapy (≥500 mg per day) until body weight stabilization is achieved.²⁵

When should prophylactic cholecystectomy be performed in asymptomatic gallstone patients?

In most cases, asymptomatic gallstones are not an indication for cholecystectomy. Exceptions are patients with porcelain gallbladder, large solitary gallstones (>3 cm) and gallbladder polyps greater than 1 cm or rapidly growing polyps, and coexistence of primary sclerosing cholangitis and gallbladder polyps. In these individuals, prophylactic cholecystectomy can reduce the risk of complications, including malignant transformation to gallbladder cancer.²⁵

Is asymptomatic gallstone disease an indication for any other treatment?

In general, it is not recommended to treat asymptomatic gallstones. However, dissolution therapy with UDCA may be considered in individual cases when the following criteria are met: mild symptoms, stones smaller than 6 mm, cholesterol‑rich, noncalcified stones, and preserved gallbladder motility with a patent cystic duct.²⁶ However, it has to be kept in mind that after pausing the therapy, the risk of gallstone recurrence is as high as 10% per year.²⁷ Additionally, small stones that dissolve might migrate through the bile ducts, increasing the risk of biliary pancreatitis.

What is the risk of complications from gallbladder stones? Can this risk be estimated for a given patient, and can cholecystectomy be performed to prevent it? Can this risk be reduced?

Approximately 70% of patients with gallstone disease are asymptomatic and often remain so. Among the individuals with asymptomatic gallstones, the cumulative risk of developing symptoms over a 10‑year period is estimated at approximately 10%–20%.^28,29 For patients who experienced an initial episode of biliary colic, the risk of complications, such as acute cholecystitis, biliary pancreatitis, or acute cholangitis, ranges between 1% and 3%, whereas for asymptomatic patients, the rate of complications is only 0.1%–0.3% per year.³⁰

In over 50% of cases, complications related to gallstones are preceded by at least 1 “warning” episode of biliary colic.³¹ The most common complication of gallstone disease is acute cholecystitis, occurring in approximately 10% of patients with symptomatic gallstones.³² Routine cholecystectomy is not recommended for patients with asymptomatic gallbladder stones, as it does not improve life expectancy; the risks associated with surgery (mortality and morbidity) outweigh the potential risk of complications from gallstones.

Laparoscopic cholecystectomy remains the treatment of choice for symptomatic cholecystolithiasis, as roughly up to 50% of patients with symptoms experience recurrent episodes of biliary colic.³³

Does gallstone disease increase the risk of gallbladder cancer? Are there cancer screening strategies for patients with gallbladder stones?

The overall prevalence of gallbladder cancer is as low as 1 or 2 cases per 100 000 individuals, with incidence higher in women than men (ie, 1.7 vs 1 cases per 100 000 individuals/year).³⁴ Ethnic variability is encountered in Southwestern Native Americans and in Mexican Americans, who have a much higher prevalence rate of gallbladder cancer.³⁵ Gallstones are a major risk factor for gallbladder cancer. In fact, up to 85% of patients with gallbladder cancer have gallstones.³⁶ However, only a small percentage of individuals with gallstones develop gallbladder cancer.³⁷ Additionally, the rising incidence of biliary tract cancer among younger individuals suggests the presence of risk factors other than long‑standing gallstones.³⁸ These additional risk factors include infections with Helicobacter bilis³⁹ or Salmonella typhi,⁴⁰ menopausal hormonal therapy,⁴¹ or exposure to aflatoxin B₁.⁴² Another risk factor accounting for the increasing burden of gallbladder cancer over the last 30 years⁴³ is the rising frequency of metabolic syndrome.

Currently, cholecystectomy is not routinely recommended as a preventive measure to reduce cancer risk in patients with gallstones, except in specific situations described above in the answer to the question regarding prophylactic cholecystectomy. Detailed recommendations for follow‑up and therapy in patients with gallbladder polyps can be found in the latest guidelines.⁴⁴

Is there a risk for developing bile duct stones after cholecystectomy and sphincterotomy (and in which patients)?

Common bile duct stones (CBDS) are classified as primary when detected 2 years or more after cholecystectomy, and as secondary when they originate from the gallbladder. Recurrent CBDS refer to stones detected at least 6 months after initial endoscopic retrograde cholangiography (ERC) with complete duct clearance.⁴⁵ Even after complete stone removal, CBDS recurrence remains common, with rates ranging from approximately 4% to 25%, increasing over time.^46,47 Recurrent choledocholithiasis should be managed endoscopically, as no effective pharmacological secondary preventive measures are currently available.

A subset of patients suffers from genetic predisposition, that is, LPAC due to mutations in the ABCB4 gene encoding the hepatocanalicular phosphatidylcholine floppase. This condition typically develops before the age of 40 years and is characterized by intrahepatic bile duct and gallbladder cholesterol stones, along with recurrent choledocholithiasis after cholecystectomy.⁶ Patients with LPAC benefit from long‑term treatment with UDCA (15 mg/kg body weight per day), ideally initiated in young adulthood to prevent the occurrence and recurrence of stones.¹⁷

What is the best treatment for symptomatic bile duct stones?

The European Society of Gastrointestinal Endoscopy recommends stone extraction for all patients with CBDS who are medically fit to tolerate the procedure, regardless of whether they are symptomatic.⁴⁸ According to the GallRiks study,⁴⁹ the benefits of stone removal outweigh the risks associated with the intervention—complications were observed in 25% of the patients with retained CBDS (eg, pancreatitis, biliary obstruction, cholangitis), compared with 13% of those who underwent stone removal. The choice of the therapy depends on the timing of CBDS diagnosis (before, during, or after cholecystectomy) and the local expertise.

ERC is the recommended first‑line endoscopic treatment for choledocholithiasis following cholecystectomy, or in patients with CBDS without gallbladder stones. In the case of concomitant gallbladder stones and CBDS, preoperative ERC followed by laparoscopic cholecystectomy is the preferred approach.²⁵ Laparoscopic or open cholecystectomy with transcystic stone extraction, common bile duct exploration, or intraoperative ERC (in the case of failed endoscopic therapy) are alternative strategies, demonstrating satisfactory stone clearance rates and safety comparable to that of preoperative ERC.^50,51

In high‑risk cases, T‑tube drainage remains the safest option for common bile duct exploration. For CBDS detected intraoperatively, transcystic stone extraction is a viable option, with success and safety rates dependent on the skills and experience of the local surgical team.

When should cholecystectomy be performed after symptomatic bile duct stones or gallstone‑induced acute pancreatitis?

The timing of cholecystectomy after biliary pancreatitis depends on the severity of pancreatitis. In general, cholecystectomy should be performed as soon as possible. In the case of uncomplicated or mild pancreatitis, it should be performed within 72 hours of ERC (if this was indicated by biliary obstruction) and within the same admission. This recommendation is based on the results of the PONCHO trial,⁵² in which patients with mild biliary pancreatitis (C‑reactive protein <⁠100 mg/l) were randomized either to early (within 72 hours of ERC) or interval cholecystectomy after discharge (ie, within 25–30 days of randomization). The latter group of patients was characterized by an increased risk of complications, such as readmission, cholecystitis, or pancreatitis. In patients with severe biliary pancreatitis, cholecystectomy should be performed when inflammation and necrosis have resolved. Early cholecystectomy is not recommended in these cases, as it may increase the risk of complications.⁵³