The main risk factors for cholesterol gallstones (e.g., obesity, type-2 diabetes, dyslipidemia, and hyperinsulinemia) are the components of metabolic syndrome.²⁾ Increased body mass index is a risk factor for gallstone formation and growth²⁾ and acts as an independent risk factor for symptomatic GSD, particularly in women.¹⁵⁾ Waist circumference and triglyceridemia are correlated with GSD.¹⁶⁾ Additional obesity-related pro-lithogenic factors include gallbladder stasis,¹⁷⁾ insulin resistance, and reduced high density lipoprotein (HDL)-cholesterol.¹⁶⁾ Appropriate lifestyle interventions may influence the pathogenesis of cholesterol gallstones, and should focus on maintaining an ideal weight in people with normal weight and weight loss in overweight and obese individuals.¹⁵⁾ The key mechanisms regulating this pathogenic process seem to involve gene-environment interactions through epigenetic mechanisms that also occur during the fetal stage and involve factors such as lifestyle, toxic agents, and environmental pollutants.¹⁸⁾

People should be aware of the importance of performing regular physical activity whenever possible.¹⁹⁾ The overall beneficial effect of exercise goes beyond simple protection against gallstone formation.²⁰⁾ In the Epic-Norfolk prospective cohort study, energy expenditure and cardio-respiratory fitness²¹⁾ were investigated via questionnaires in 25,639 volunteers (range, 40 to 74 years old). Subjects were monitored over 14 years. After 5 years, 135 cases of symptomatic gallstones (70% women, 69% uncomplicated) were observed. After 14 years, 290 cases of symptomatic gallstones (68% women, 54% complicated) were recorded. The highest level of physical activity was associated with a 70% decreased risk of symptomatic gallstones in both sexes, with a likely causal effect seen after 5 years. Hyperinsulinemia promotes the hepatic uptake of cholesterol,²²⁾ with increased secretion in bile²³⁾ and decreased secretion of bile acids²⁴⁾ (leading to supersaturated lithogenic bile). Regular exercise reduces insulin levels,²⁵⁾ insulin resistance,²⁶⁾ triglyceridemia, ²⁷⁾ and fatty acid-dependent hypersecretion of gallbladder mucin,²⁸⁾ and increases serum HDL-cholesterol.²⁹⁾ HDL-cholesterol is the precursor of bile acids³⁰⁾ and is inversely related to gallstone prevalence.³¹⁾ Finally, physical activity promotes cholecystokinin-dependent gallbladder contraction.³²⁾

Long-term population-based prospective studies have highlighted difficulties in estimating the quantity and ingestion patterns of nutrients. High-fiber and high-calcium diets reduce biliary hydrophobic bile acids, while a regular eating pattern decreases gallbladder stasis by promoting regular emptying.¹⁹⁾ Both aspects play a preventive role against GSD. The likelihood of GSD is increased by westernized diets, including meat intake.³³⁾ Fruit and vegetables³⁴⁾ might be protective against GSD, but the data remain controversial. Unsaturated fats³⁵⁾ might protect against GSD. Coffee has been reported to be protective in some,^36,37) but not all, epidemiological studies.³⁸⁾ Although prospective epidemiological studies reported protective effects of alcohol consumption on gallstone formation,¹⁶⁾ and a Danish Mendelian randomization study indicated that patients with symptomatic gallstones consumed less alcohol compared to those with asymptomatic stones,¹⁵⁾ the findings are controversial,³⁹⁾ and alcohol consumption cannot be recommended for the prevention of gallstones. Vitamin C supplementation may have a protective effect against GSD. Cholesterol conversion to bile acids requires 7α-hydroxylation and appropriate hepatocyte content of vitamin C.⁴⁰⁾ Vitamin C deficiency might therefore increase the risk of cholesterol gallstone formation.⁴¹⁾ Vitamin C supplementation (500 mg, 4 times/d) was shown to change biliary bile acid composition, increase phospholipids, and prolong the cholesterol crystallization time.⁴²⁾ Observational studies have identified an association between low vitamin C consumption and GSD risk.⁴¹⁾ In the EMIL observational population-based study (n=2,129 subjects; range, 18 to 65 years old), gallstone prevalence was 4.7% vs. 8.2% in patients reporting regular use of vitamin C (n=232) compared to those who did not report using vitamin C regularly (n=1,897).⁴³⁾

If weight loss is rapid (i.e., over 1.5 kg/wk),⁵²⁾ the risk of gallstones increases significantly, although they tend to be asymptomatic in such cases. This is the case in patients starting very-low-calorie diets (i.e., <800 kcal/d)⁵³⁾ or undergoing bariatric surgery (up to 48% of patients for weight loss exceeding 25% of their original weight).^53,54) The overall risk decreases when body weight stabilizes after approximately 24 months.⁵³⁾ Weight cycling also represents an independent risk factor for gallstones.⁵⁵⁾ Excessive de novo biosynthesis of cholesterol and biliary cholesterol excretion are the two main pathogenic factors.⁵⁶⁾ Some preventive measures are possible during weight-reducing programs.

It is advisable to keep the rate of weight loss to <1.5 kg/wk.^52,57) The risk of developing symptomatic gallstones decreases if gallbladder motility is improved by appropriate fat content in the diet (at least 7 g/d).⁵³⁾ UDCA, which is litholytic and hydrophilic, greatly decreases the risk of cholesterol gallstone formation (<10%) and of gallstones becoming symptomatic,⁵⁸⁾ following rapid weight loss.^58,59) A meta-analysis of 5 randomized controlled trials including 521 patients (322 taking UDCA and 199 taking a placebo) concluded that UDCA 300–1,200 mg/d effectively prevents gallstone formation after bariatric surgery,⁵⁹⁾ reducing the incidence from 32% to 2%,⁶⁰⁾ with no severe side effects. The beneficial effect of (n-3) polyunsaturated fatty acids (11.3 g/d) on biliary cholesterol nucleation time and crystallization and the prevention of gallstone formation was confirmed in a randomized, doubleblind placebo-UDCA (1,200 mg/d)-controlled trial in obese women on hypocaloric diets (1,200 kcal/d, 20% energy from fat).⁴⁸⁾ The protective mechanism is probably mediated by the replacement of biliary arachidonate by (n-3) polyunsaturated fatty acids,⁶¹⁾ increasing biliary phospholipids,⁶²⁾ and changing intrahepatic cholesterol transportation and the hypersecretion of biliary cholesterol.⁶³⁾ Concurrent prophylactic cholecystectomy has previously been recommended based on the assumption that almost 19% of patients might require a cholecystectomy following bariatric surgery.⁶⁴⁾ The data on this are inconclusive, since up to 97% of patients remain asymptomatic as confirmed by a recent decision analysis model.⁶⁵⁾

These patients exhibit biliary lithogenic changes and gastrointestinal motility changes, including delayed intestinal transit and gallbladder stasis.^66,67) Prophylactic therapy with UDCA has been suggested for these patients.^67,68,69)

Gallbladder stasis and changes in biliary composition are typical in pregnancy⁷⁰⁾ or during prolonged fasting such as during total parenteral nutrition (TPN). Both sludge and small gallstones might disappear spontaneously in the postpartum period⁷⁰⁾ and when the oral diet is resumed following TPN.⁷¹⁾ Therefore, there is no indication for oral litholysis in either of these conditions.

A metanalysis⁷²⁾ showed a significantly increased risk of GSD in women under hormone replacement therapy for the control of menopause symptoms or the prevention of osteoporosis.⁷³⁾ The possibility of any pharmacological preventive approach has not been addressed, and therefore has no rationale as yet.

The dissolution rate of cholesterol gallstones is 37% to 60%⁷⁴⁾ after 2 years of treatment with UDCA. Recurrence is high following dissolution (15% by 1 year and 45% by 5 years).^75,76,77) The pharmacological prophylaxis of gallstone recurrence should be restricted to very high-risk subgroups or to patients not fitting the criteria of subsequent cholecystectomy.

There are no evidence-based prophylactic measures able to prevent the recurrence of bile duct stones.

Heterozygous mutation of the gene 'ABCB4,' encoding the phospholipid-flippase, is a rare form of monogenic predisposition for cholelithiasis associated with low biliary phospholipids and bile salt-mediated damage of the canalicular membrane. In patients with this mutation, gallstones, intrahepatic sludge, and microlithiasis develop before the age of 40, while biliary symptoms recur after cholecystectomy.^78,79) A few studies have suggested that long-term prophylactic therapy with UDCA should be initiated as early as possible.^78,79)