Keywords
cholesterol gallstones, gallbladder, bile, pathogenesis, primary prevention
cholesterol gallstones, gallbladder, bile, pathogenesis, primary prevention
Gallstone disease is highly predominant in Western countries, where it has a prevalence of up to 15% in adults1 and is one of the most common causes of hospital admission for gastrointestinal disease in European countries2. Also, gallstone disease has high health costs, especially in the presence of gallstones that become symptomatic or cause complications1,3,4. The presence of gallstones also generates concerns when occurring in children5 and adolescents (<20 years of age)6. Though less frequent than in adults, the prevalence of cholelithiasis in childhood is increasing. In England, an increased incidence of cholecystectomy (from 0.78 in 1997 to 2.7 per 100,000 in 2012) has been reported in children not more than 16 years old7. In a Canadian population-based, retrospective cohort, the crude incidence of cholecystectomy in subjects under 18 years of age increased from 8.8 per 100,000 person-years in 1993 to 13.0 per 100,000 person-years in 20128, and a retrospective study in the US over a nine-year period ending in 2012 registered an increment of cholecystectomies due to pediatric non-hemolytic (cholesterol) gallstones of 216%9. It has been suggested that this epidemiologic increment during childhood could be due to the increasing prevalence of obesity6,10–16, physical inactivity, diabetes, and early pregnancy6.
Cholesterol gallstones are found in more than 80% of patients with gallstone, and the pathogenesis involves both local (that is, gallbladder and bile) and systemic factors17.
Elevated levels of pro-inflammatory proteins such as interleukin-6 (IL-6), IL-10, IL-12(p70), and IL-13 appear to be associated with the risk of gallstones18. Data from epidemiologic studies suggest an association between gallstone disease and higher risk of incident ischemic heart disease19,20 and total mortality and disease-specific mortality (cardiovascular disease and cancer). These links were statistically confirmed after adjustment for potential confounders, including traditional risk factors (such as body weight, cigarette smoking, physical activity, diabetes, hypertension, and hypercholesterolemia)19–22. Thus, complex systemic pathways might link the development of gallstones to other metabolic abnormalities (that is, insulin resistance, obesity, type 2 diabetes, non-alcoholic fatty liver disease, and metabolic syndrome itself)23–32. The association might also involve extra-gallbladder tumors33,34 in the liver35, stomach36, and colon37. In this scenario, cholesterol gallstone disease becomes the expression of systemic metabolic and non-metabolic abnormalities38.
Critical factors contributing to the formation of cholesterol gallstones are defective gallbladder motility, hypersecretion and accumulation of mucin gel in the gallbladder lumen with ongoing local immune-mediated inflammation, rapid phase transition of cholesterol from supersaturated hepatic bile, and precipitation of solid cholesterol crystals17,39. Additional features include gene polymorphism, increased hepatic cholesterol secretion, increased absorption of biliary and dietary cholesterol, sluggish intestinal motility, and qualitative, quantitative, or topographic changes of gut microbiota17,40. The complex and variable interactions of such pathogenic factors contributing to cholesterol cholelithiasis require a comprehensive discussion to correctly address the management of the disease.
The relevance of a genetic background in the pathogenesis of cholesterol gallstones is disclosed by studies addressing the family history of cholelithiasis41,42, evaluating selected ethnic groups43,44, and confirming the presence of specific gene polymorphisms45–61. The simple existence of predisposing genetic conditions, however, is not sufficient to promote cholesterol gallstone formation. This concept is supported by studies on twin pairs, where genetic factors play a role in no more than 25 to 30% of subjects with symptomatic gallstones62,63. Indeed, genes provide an increased risk of forming gallstones, but several environmental factors such as diet and physical activity58,64–66 but also exposure to chemicals as heavy metals67,68 or pesticides69,70 (which also involve epigenetic mechanisms17,71) must play a crucial additional role in determining how many subjects will effectively develop gallstones. This aspect is particularly relevant for primary prevention by acting on environmental factors.
Figure 1 depicts pathways of cholesterol metabolism in the hepatocyte in humans. Cholesterol gallstones grow in the gallbladder and are made of aggregated solid cholesterol crystals originating from bile supersaturated with cholesterol, which is no longer solubilized by micelles and vesicles40. During the process of cholesterol cholelithiasis, the homeostasis of cholesterol is highly disrupted, and events involve cholesterol intake, metabolism, and synthesis. Defects involve the cholesterol transporters ABCG5 and ABCG8 (which pump sterols out of hepatocytes into the biliary ducts and from enterocytes into the intestinal lumen72), hormones (that is, estrogen73,74, insulin30, and thyroid hormones75), nuclear receptors23,76–78, and factors governing the entero-hepatic recirculation of cholesterol79–81.
Women display an increased prevalence of gallstones compared with men because of the influence of estrogen on cholesterol metabolism73. This effect involves the enhanced synthesis of cholesterol and decreased synthesis of bile acids (BAs), which are sterols synthesized from cholesterol, and represents the main catabolic pathway of cholesterol metabolism in humans. The step involves the upregulation of estrogen receptor 1 and G protein–coupled receptor 3082,83. A recent meta-analysis also confirmed a positive association between the intake of exogenous estrogen and the risk of cholelithiasis74.
The pathogenesis of cholesterol gallstones is closely linked with frequent metabolic abnormalities involving insulin resistance30, obesity, dyslipidemia (hypertrigliceridemia), type 2 diabetes44,84, and metabolic syndrome per se85–90. Insulin resistance produces several lithogenic effects; that is, it increases the activity of the rate-limiting step in cholesterol synthesis, hydroxyl-methyl-glutaryl coenzyme A reductase91; modulates the expression of the ABCG5 and ABCG8 genes involved in the expression of cholesterol transporters (governing biliary cholesterol secretion); and dysregulates the liver transcription factor forkhead box protein O1 (FOXO1)94, which modulates cholesterol homeostasis and high-density lipoprotein (HDL)-mediated reverse cholesterol transport to the liver98. In the liver, insulin resistance influences the level and activity of the BA sensor nuclear receptor farnesoid X receptor (FXR)23,76,77, which is involved in crucial pathways of cholesterol and BA metabolism. FXR also upregulates the hepatic expression of the ABCG5 and ABCG8 genes by activating the other BA sensor, liver X receptor (LXR)78. Thus, FXR plays a protective role against the development of cholesterol gallstones and pharmacologic agents as 6-α-ethyl-ursodeoxycholic acid (6EUDCA) modulating the activity of this nuclear receptor could be a useful therapeutic tool99. Also, results from animal models suggest that piperine (a potential cholesterol-lowering agent) could be useful in preventing cholesterol gallstone formation by inhibiting the expression of the cholesterol transporters ABCG5/8 and LXR100.
The systemic homeostasis of cholesterol is influenced by the small intestine; here, dietary cholesterol is absorbed (Figure 2), and biliary cholesterol is reabsorbed during the entero-hepatic circulation of BA101, with variable efficiency levels102,103. The step is co-regulated by genes determining the balance between influx of intraluminal cholesterol molecules crossing the enterocyte brush border membrane—via the Niemann-Pick C1-like 1 (NPC1L1) pathway—and efflux of enterocyte cholesterol into the intestinal lumen (via the ABCG5/ABCG8 pathway)101. A large observational study showed that genetic variations in ABCG5/8 associated with decreased levels of plasma low-density lipoprotein (LDL) cholesterol are protective against myocardial infarction but increase the risk of symptomatic gallstone disease, suggesting that there is an intrinsic link between these two diseases and that this link is based on the activity of ABCG5/8106. The coding variant rs11887534 (D19H) in ABCG8 is associated with a more efficient transport of cholesterol into bile45. Of note, despite the presence of D19H polymorphism107,108, patients with gallstones have significantly lower cholesterol absorption107,108 and higher or unchanged108 de novo synthesis of cholesterol107. This peculiar metabolic feature could precede gallstone formation in groups at risk107. Independently from the presence of obesity, cholesterol absorption by the small intestine can be reduced by the presence of insulin resistance, which is also able to increase cholesterol synthesis109,110.
In animal studies, cholesterol gallstone formation can be prevented by ezetimibe, the selective inhibitor of the intestinal NPC1L1. The mechanism involves reduced amounts of absorbed cholesterol reaching the liver through the entero-hepatic circulation and, in turn, decreased biliary cholesterol saturation79–81. Additionally, deficiency of osteopontin (OPN) (a soluble cytokine and a matrix-associated protein detectable in the majority of tissues and body fluids) in OPN−/− mice on lithogenic diet reduces the intestinal absorption of cholesterol through a suppressed expression of NPC1L1, preventing cholesterol gallstone formation111.
The potential effects of the intestinal microbiota on the pathogenesis of cholesterol gallstones should not be neglected. Gut bacterial communities collected from patients with gallstones exhibit increased phylum Proteobacteria and a decrement of genera Faecalibacterium, Lachnospira, and Roseburia112. The cecum of patients with gallstones contains increased amounts of Gram-positive anaerobic bacteria with elevated 7α-dehydroxylation activity, a finding linked with increased concentrations of the more hydrophobic and lithogenic secondary BA deoxycholate113. Increased concentrations of secondary BA could also depend on enrichment with the genus Oscillospira, negatively correlated with primary BA formation. An opposite trend exists for the phylum Bacteroidetes114. A reduced richness and alpha diversity of microbiota, with lower levels of Firmicutes and decreased ratio of the phyla Firmicutes to Bacteroidetes, have been reported in mice fed a lithogenic diet and forming gallstones115.
A number of studies have examined the role of defective gallbladder motility (that is, increased fasting and postprandial gallbladder volumes and slower postprandial emptying in response to meal) as a major risk factor for cholesterol gallstone formation44,116–119. Indeed, intraluminal gallbladder stasis provides a sufficiently prolonged time for nucleation of excess biliary cholesterol and gallstone growth120–122. A sluggish motility function of the gallbladder also predisposes to gallstone recurrence after successful extracorporeal shock-wave lithotripsy or oral BA litholysis or both123,124. Abnormal gallbladder motor function is found in about one third of patients, independently of the physical presence of (small) stones125–130, and is a feature before gallstone occurrence120,125,131,132. Alterations in the gallbladder contractility are secondary, at least in part, to a direct toxic effect of unesterified biliary cholesterol on the gallbladder smooth muscle plasma membranes133–135. The steps involve the migration of intraluminal cholesterol into the muscularis propria, inhibition of action potentials, currents of Ca2+136, decreased density of cholecystokinin-1R (CCK-1R) on the smooth muscle137 and signal-transduction decoupling of the CCK-1R122,138–140 (mainly due to CCK binding to cell receptors not followed by G-protein activation138,141–143), and smooth muscle cell proliferation and inflammation in the gallbladder mucosa and lamina propria119,144.
A defective intrinsic innervation of the gallbladder has also been described with marked reduction of neurons, enteric glial cells, mast cells, and interstitial cells of Cajal in patients with gallstones145. These alterations lead not only to altered postprandial contraction but also to defective interprandial relaxation146,147.
Of note, extra-gallbladder (that is, systemic) factors play a relevant role also in the modulation of fasting and postprandial gallbladder motility. Besides the existence of polymorphisms in the CCK-1R gene that might be associated with gallstone formation in humans148, insulin resistance has been linked with defective gallbladder motility in lean, non-diabetic, and gallstone-free subjects149. The gallbladder dysmotility is also described in women with polycystic ovary syndrome, a condition often linked with insulin resistance150. Notably, the anti-diabetic agent metformin ameliorates the gallbladder motility defect151, and prolonged therapy with this drug has been linked with reduced risk of gallstones in patients with diabetes152.
The interprandial gallbladder relaxation leading to organ refilling is stimulated by the acid-induced duodenal release of vasointestinal peptide (VIP) and is regulated by the human protein fibroblast grow factor 19 (FGF19, FGF15 in mice)153, located in the gallbladder epithelium but also in cholangiocytes154 and in the ileum155. Secreted BAs reach the terminal ileum and act as signaling factors, which activate FXR and, in turn, increase the intestinal FGF19 levels in the portal circulation. FGF19 binds to its receptor fibroblast growth factor receptor 4 (FGFR4)/co-receptor β-klotho found in the liver and also in the gallbladder156. FGF19-FGFR4/β-klotho interaction in the gallbladder accounts for relaxation of the gallbladder smooth muscle and this feedback modulates gallbladder refilling between meals119,153. Intraluminal hydrophobic BAs also act as signaling agents for the G protein – coupled bile acid receptor 1 (GPBAR-1)157, located in the gallbladder epithelium and smooth muscle156,158 and stimulating gallbladder relaxation independently of FGF19159, through the activation of KATP channels160.
The existence of impaired gallbladder refilling due to altered interprandial motility might have a role in the pathogenesis of gallstones. In the intedigestive period, fasting rhythmic fluctuations physiologically decrease the gallbladder volume by 20 to 30%161,162. An altered interprandial gallbladder motility120,163, mainly secondary to less frequent migrating myoelectric complex cycles and abnormal motilin release, has been described in patients with cholesterol gallstone as compared with healthy subjects119,125,128,163. The interprandial motility defect would be able to increase the hepatic secretion of lithogenic bile to the small intestine, with faster recycling of BAs and increased hydrophobicity of the BA pool164, a mechanism predisposing to cholesterol crystallization and stone growth165. As suggested by animal studies, CCK incretion might also have a role in the modulation of fasting gallbladder motility linked with an impaired small intestinal motility since an increment of fasting gallbladder volume, a prolonged intestinal transit time, and an increased intestinal cholesterol absorption have been detected in CCK knockout mice166.
The majority of patients with gallstone disease remain asymptomatic throughout their life167,168 and should be managed with watchful waiting40. If symptoms or complications occur or if subjects are at high clinical risk of complications, the current therapeutic approach is surgery, which remains the mainstay treatment169, by laparoscopy, small incision, or (in selected cases) laparotomy40,170. In a small (10%) subgroup of patients with small (<5 mm), pure-cholesterol radiotransparent stones in a functioning gallbladder with a patent cystic duct, litholysis with oral ursodeoxycholic acid (UDCA) (12 to 15 mg/kg per day up to 12 to 24 months) could be considered40. Nevertheless, the risk of post-dissolution gallstone recurrence is high (about 10% per year and up to 50% by five years171).
Cholecystectomy has a low risk of mortality (30-day mortality 0.15%, close to that of the general population in a Swedish study172) but is not a neutral event. About 10% of patients can develop non-specific gastrointestinal symptoms following cholecystectomy (that is, the “post-cholecystectomy syndrome”) mainly due, in the first three years, to gastric diseases, including peptic ulcer, hiatus hernia, and gastro-esophageal reflux. In these cases, however, a misdiagnosis of pre-existing clinical conditions is possible. In a longer time window, the most common cause is the presence of stones within the biliary tree173.
Although laparoscopic cholecystectomy has a low surgical risk and is the most common elective abdominal surgery performed in the US174, a series of complications is possible, ranging from conversion to open cholecystectomy (the most frequent) to bile leak, bile duct injury, and (in few cases) death175. It was recently suggested that surgical complications are more likely in patients with low socioeconomic status, who appear to be more vulnerable. In fact, patients from low-income populations show higher rates of 30-day mortality, in-hospital complications, readmission for complications, hospital costs, and length of stay in comparison with the general population176.
Increased health costs have also been described in the case of delayed cholecystectomy, as compared with early cholecystectomy177, and of emergency surgical procedure178 and laparoscopic cholecystectomy, as compared with small-incision open cholecystectomy (with similar quality of life after these last two procedures)179.
The robotic-assisted laparoscopic cholecystectomy appears to be an interesting and emerging technology. However, in the case of benign gallbladder diseases, this procedure does not seem to be more effective or safer than conventional laparoscopic cholecystectomy, which should be preferred because of lower costs180.
Finally, the potential metabolic consequences of cholecystectomy have recently been discussed. Cholecystectomy might disrupt trans-intestinal flow of BAs acting as signaling (hormonal) agents via FXR, GPBAR-1 intestinal receptors in the absence of their natural reservoir (the gallbladder)181. This aspect has practical implications, and cholecystectomy is suggested after adequate selection of patients on the basis of clinical and epidemiological evidence. It is mandatory that the surgical procedure be restricted to patients with specific symptoms (that is, colicky pain) or complications of cholelithiasis or to subjects at high risk requiring prophylactic cholecystectomy181.
In conclusion, given the limits, risks, and costs of the currently available therapeutic approaches, the critical role played by systemic factors in the risk of gallstone formation and in the pathogenesis of cholesterol gallstone disease might offer interesting possibilities for primary prevention64,71,105,182,183 aimed at reducing gallstone prevalence in subjects at risk and the related health costs.
A major intervention in the general population should include lifestyle changes64,184–189, including dietary models able to possibly reduce the risk of gallstones mainly acting on lipid metabolism and metabolic pathways leading to gallstone formation188 (that is, a low-carbohydrate diet with enriched vegetable proteins188, nuts190, and vegetable oils191,192 with moderate alcohol intake193), and adequate physical activity187 aimed at maintaining a normal body weight.
In fact, the risk of developing gallstones appears to increase with some dietary factors (that is, increased energy intake, low dietary fiber content, highly refined sugars, high fructose and fat intake, and low vitamin C intake) and to decrease with others (that is, olive oil consumption, ω-3 fatty acids, high intake of monounsaturated fats and fiber, vegetables, vitamin C supplementation, fruit, and moderate alcohol consumption)64. In a large French cohort, the high adherence to the Mediterranean diet was linked with a significantly lower risk of cholecystectomy185. Physical activity also positively influences several metabolic features related with the hepatobiliary–gut axis, and beneficial effects are anticipated by regular physical activity on several metabolic disorders, including cholesterol gallstone disease184.
Owing to the scarcity of strong evidence of effectiveness, pharmacological prevention of gallstones is not advisable in the general population169. In theory, however, each pathogenic factor involved in gallstone formation could be considered a potential therapeutic target for prevention or treatment of cholesterol cholelithiasis (Figure 3). In particular, a protective role is possible for the hydrophilic bile acid UDCA194–199. Other therapeutic options (alone or in combination) are promising but not yet supported by strong evidence: statins or inhibitors (or both) of the intestinal absorption of cholesterol such as ezetimibe79,95,201–207; nuclear receptor modulators99,208–212 such as 6EUDCA, a synthetic derivative of UDCA acting as FXR modulator99, or piperine, an alkaloid able to inhibit ABCG5/8 and LXR expression in the liver reducing biliary cholesterol secretion100; possible modulators of gut microbiota112; dietary/lifestyle models64,65,184,213; pharmacologic agents acting on gallbladder hypomotility121,214,215; and inflammatory cytokine modulators216–218.
Future experimental and clinical studies are certainly needed to clarify the real usefulness of these potentially innovative preventive tools in selected groups of subjects.
The author(s) declared that no grants were involved in supporting this work.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Views | Downloads | |
---|---|---|
F1000Research | - | - |
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | ||
---|---|---|
1 | 2 | |
Version 1 24 Sep 18 |
read | read |
Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
Sign up for content alerts and receive a weekly or monthly email with all newly published articles
Already registered? Sign in
The email address should be the one you originally registered with F1000.
You registered with F1000 via Google, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Google account password, please click here.
You registered with F1000 via Facebook, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Facebook account password, please click here.
If your email address is registered with us, we will email you instructions to reset your password.
If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance.
Comments on this article Comments (0)