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Gallstone Disease in Cirrhosis—Pathogenesis and Management

2021; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês

10.1016/j.jceh.2021.09.011

2213-3453

Bipadabhanjan Mallick, Anil C. Anand,

Liver Disease and Transplantation

Gallstones are more common in patients with cirrhosis of the liver, and the incidence increases with severity of liver disease. Pigment stones are the most frequent type of gallstones (GSs) in cirrhotics, and majority remain asymptomatic. Hepatitis C virus infection and nonalcoholic fatty liver disease are the underlying etiologies of liver diseases that most often associated with GSs. Multiple altered mechanisms in cirrhosis such as chronic hemolysis due to hypersplenism, reduced bile acid synthesis and transport, decreased cholesterol secretion, decreased apolipoprotein A-I and A-II secretion, gallbladder hypo-motility, autonomic dysfunction, and portal hypertension collectively lead to increased risk of lithogenesis. Asymptomatic GSs should be followed up closely and offered laparoscopic cholecystectomy once symptomatic in Child-Pugh class A and B patients. The model for the end-stage liver disease score is the best predictor of the outcome after cholecystectomy. In patients of Child-Pugh class C, conservative or minimally invasive approaches should be used to treat complications of GSs. Gallstones are more common in patients with cirrhosis of the liver, and the incidence increases with severity of liver disease. Pigment stones are the most frequent type of gallstones (GSs) in cirrhotics, and majority remain asymptomatic. Hepatitis C virus infection and nonalcoholic fatty liver disease are the underlying etiologies of liver diseases that most often associated with GSs. Multiple altered mechanisms in cirrhosis such as chronic hemolysis due to hypersplenism, reduced bile acid synthesis and transport, decreased cholesterol secretion, decreased apolipoprotein A-I and A-II secretion, gallbladder hypo-motility, autonomic dysfunction, and portal hypertension collectively lead to increased risk of lithogenesis. Asymptomatic GSs should be followed up closely and offered laparoscopic cholecystectomy once symptomatic in Child-Pugh class A and B patients. The model for the end-stage liver disease score is the best predictor of the outcome after cholecystectomy. In patients of Child-Pugh class C, conservative or minimally invasive approaches should be used to treat complications of GSs. The incidence of gallstones (GSs) is rising globally because of increasing incidence of metabolic diseases, sedentary life styles, and dietary changes in the society. The prevalence of GSs is 10–15% in the United States and Europe and 5–6% in India.1Everhart J.E. Ruhl C.E. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas.Gastroenterology. 2009; 136: 1134-1144Google Scholar, 2Aerts R. Penninckx F. The burden of gallstone disease in Europe.Aliment Pharmacol Ther. 2003; 18: 49-53Google Scholar, 3Unisa S. Jagannath P. Dhir V. Khandelwal C. Sarangi L. Roy T.K. Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural Gangetic basin of North India.HPB (Oxford). 2011; 13: 117-125Google Scholar GSs are essentially of two types: cholesterol stones (80%) and pigment stones (20%). The cholesterol stones are either pure cholesterol stones or mixed stones which contain >50% of their dry weight as cholesterol.4Dutta U. Mallick B. Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.11th ed. Association of Physicians India, 2019: 1846Google Scholar Pigment GSs, on the other hand, are composed of essentially calcium bilirubinate, and they contain <20% dry weight as cholesterol.4Dutta U. Mallick B. Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.11th ed. Association of Physicians India, 2019: 1846Google Scholar The prevalence of GSs is higher among women and increases with increasing age and parity. The risk factors for development of GSs are obesity, diabetes mellitus, dyslipidemia, total parenteral nutrition, rapid weight loss, ileal disease or resection, and chronic hemolysis.4Dutta U. Mallick B. Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.11th ed. Association of Physicians India, 2019: 1846Google Scholar The reported prevalence of GS disease in patients with liver cirrhosis ranges between 25% and 30%, which is higher than that of the general population.5Acalovschi M. Badea R. Dumitrascu D. Varga C. Prevalence of gallstones in liver cirrhosis: a sonographic survey.Am J Gastroenterol. 1988; 83: 954-956Google Scholar,6Sheen I.S. Liaw Y.F. The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.Hepatology. 1989; 9: 538-540Google Scholar In this review, we discuss the mechanisms responsible for the development of GSs as well as the clinical and therapeutic aspects of GSs formed in patients with cirrhosis of the liver.Incidence and prevalenceHigher prevalence of GSs in patients with liver cirrhosis has been shown (Table 1) in both postmortem series7Bouchier I.A. Postmortem study of the frequency of gallstones in patients with cirrhosis of the liver.Gut. 1969; 10: 705-710Google Scholar,8Iber F.L. Caruso G. Polepalle C. Kuchipudi V. Chinoy M. Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.Am J Gastroenterol. 1990; 85: 1593-1596Google Scholar and antemortem cross-sectional or longitudinal ultrasonography studies.6Sheen I.S. Liaw Y.F. The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.Hepatology. 1989; 9: 538-540Google Scholar,9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar,10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar In a longitudinal study of 618 patients with cirrhosis over a mean follow-up period of about 5 years, 22.8% developed GSs, and in another study of 182 patients with cirrhosis on a median follow-up period of 3.5 years, 11.5% developed GSs with an annual incidence rate of about 3–5%.10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar,11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar The incidence of GSs in patients with cirrhosis is 3–8 times higher than that in the general population.6Sheen I.S. Liaw Y.F. The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.Hepatology. 1989; 9: 538-540Google Scholar,9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar, 10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar, 11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar, 12Festi D. Dormi A. Capodicasa S. et al.Incidence of gallstone disease in Italy: results from a multicenter, population-based Italian study (the MICOL project).World J Gastroenterol. 2008; 14: 5282-5289Google Scholar These studies have reported the incidence and prevalence of asymptomatic GSs. The prevalence of symptomatic GSs in patients with cirrhosis of the liver is largely unknown. In a longitudinal cohort study of 34 patients with asymptomatic GSs and cirrhosis, 6 (18%) patients developed symptoms for GSs over 6 years.13Orozco H. Takahashi T. Mercado M.A. Prado E. Borunda D. Long-term evolution of asymptomatic cholelithiasis diagnosed during abdominal operations for variceal bleeding in patients with cirrhosis.Am J Surg. 1994; 168: 232-234Google Scholar In another study of 45 patients with a mean follow-up period of about 2.5 years, only 4.4% patients developed either symptoms or complication with an estimated annual rate of less than 2% (Table 2).14Maggi A. Solenghi D. Panzeri A. et al.Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.Ital J Gastroenterol Hepatol. 1997; 29: 330-335Google Scholar Although these figures are comparable with noncirrhotic patients,15Gibney E.J. Asymptomatic gallstones.Br J Surg. 1990; 77: 368-372Google Scholar the number of patients in the studies was small and the duration of follow-up was short, so there is no clear evidence whether asymptomatic GSs behave similarly in cirrhotic and noncirrhotic patients. Most of the GSs in patients with liver cirrhosis are pigment stones although a small proportion of patients harbor cholesterol stones.8Iber F.L. Caruso G. Polepalle C. Kuchipudi V. Chinoy M. Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.Am J Gastroenterol. 1990; 85: 1593-1596Google Scholar,16Diehl A.K. Schwesinger W.H. Holleman Jr., D.R. Chapman J.B. Kurtin W.E. Clinical correlates of gallstone composition: distinguishing pigment from cholesterol stones.Am J Gastroenterol. 1995; 90: 967-972Google Scholar,17Schwesinger W.H. Kurtin W.E. Levine B.A. Page C.P. Cirrhosis and alcoholism as pathogenetic factors in pigment gallstone formation.Ann Surg. 1985; 201: 319-322Google Scholar In a study of 369 transplant recipients with liver cirrhosis and GSs, the reported incidence of pigment stones was in 318 (86.2%) patients and cholesterol stones was in 51 (13.8%) patients.18Coelho J.C. Slongo J. Dambroski Silva A. et al.Prevalence of cholelithiasis in patients subjected to liver transplantation for cirrhosis.J Gastrointestin Liver Dis. 2010; 19: 405-408Google ScholarTable 1Prevalence of Asymptomatic Gallstones in Cirrhosis of the Liver.AuthorYearType of studyNo. of participantsPrevalence of gallstones (%)CirrhosisControlCirrhosisControlBouchier et al.7Bouchier I.A. Postmortem study of the frequency of gallstones in patients with cirrhosis of the liver.Gut. 1969; 10: 705-710Google Scholar1969Postmortem235446029.412.8Iber et al.8Iber F.L. Caruso G. Polepalle C. Kuchipudi V. Chinoy M. Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.Am J Gastroenterol. 1990; 85: 1593-1596Google Scholar1990Postmortem4603163312Acalovschi et al.5Acalovschi M. Badea R. Dumitrascu D. Varga C. Prevalence of gallstones in liver cirrhosis: a sonographic survey.Am J Gastroenterol. 1988; 83: 954-956Google Scholar1988Ultrasonography14014029.213.6Fornari et al.9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar1994Ultrasonography41041431.920.7Del Olmo et al.20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar1997Ultrasonography31335723.316.8 Open table in a new tab Table 2Incidence of Asymptomatic and Symptomatic Gallstones in Cirrhosis of the Liver.CharactersAuthorYearNo. of patientsFollow-up yearsIncidence of gallstonesAnnual incidence rate (%)Asymptomatic gallstonesBenvegnu et al.11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar19971823.511.5%3%Conte et al.10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar1999618522.8%5%Symptomatic gallstonesaPatients already harboring asymptomatic gallstones.Orozco et al.13Orozco H. Takahashi T. Mercado M.A. Prado E. Borunda D. Long-term evolution of asymptomatic cholelithiasis diagnosed during abdominal operations for variceal bleeding in patients with cirrhosis.Am J Surg. 1994; 168: 232-234Google Scholar199434618%3%Maggi et al.14Maggi A. Solenghi D. Panzeri A. et al.Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.Ital J Gastroenterol Hepatol. 1997; 29: 330-335Google Scholar1997452.54.4%<2%a Patients already harboring asymptomatic gallstones. Open table in a new tab Risk factors for GSs in cirrhosisAge and SexSimilar to the GSs in the general population, the incidence of GSs in patients with cirrhosis has female preponderance.10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar,19Buchner A.M. Sonnenberg A. Factors influencing the prevalence of gallstones in liver disease: the beneficial and harmful influences of alcohol.Am J Gastroenterol. 2002; 97: 905-909Google Scholar,20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar The risk of GSs becoming symptomatic is also significantly higher in women than that in men.21Acalovschi M. Blendea D. Feier C. et al.Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.Am J Gastroenterol. 2003; 98: 1856-1860Google Scholar However, the degree of female predominance may be less in comparison with the general population as few studies have reported equal incidence of GSs in male and female cirrhotics.22Fornari F. Civardi G. Buscarini E. et al.Cirrhosis of the liver. A risk factor for development of cholelithiasis in males.Dig Dis Sci. 1990; 35: 1403-1408Google Scholar, 23Conte D. Barisani D. Mandelli C. et al.Cholelithiasis in cirrhosis: analysis of 500 cases.Am J Gastroenterol. 1991; 86: 1629-1632Google Scholar, 24Elzouki A.N. Nilsson S. Nilsson P. Verbaan H. Simanaitis M. Lindgren S. The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction.Hepato-Gastroenterology. 1999; 46: 2946-2950Google Scholar The overall prevalence of GSs in cirrhotics is increased significantly with advancing age.5Acalovschi M. Badea R. Dumitrascu D. Varga C. Prevalence of gallstones in liver cirrhosis: a sonographic survey.Am J Gastroenterol. 1988; 83: 954-956Google Scholar,10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar,21Acalovschi M. Blendea D. Feier C. et al.Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.Am J Gastroenterol. 2003; 98: 1856-1860Google ScholarFamily History of GSsSimilar to the general population, the incidence of GSs in cirrhotics is significantly higher in patients with family history of GSs.20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar The incidence of symptomatic GSs is also higher in patients with positive family history.21Acalovschi M. Blendea D. Feier C. et al.Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.Am J Gastroenterol. 2003; 98: 1856-1860Google Scholar However, the role of genetic variants associated with familial GSs is yet to be proven in cirrhotics.Metabolic SyndromeType 2 diabetes mellitus, hyperlipidemia, and high body mass index are reported to be independent risk factors for GSs in patients with liver cirrhosis.10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar,25Park J.H. Kim T.N. Lee S.H. The prevalence and risk factors of gallstones in Korean patients with liver cirrhosis.Hepato-Gastroenterology. 2013; 60: 461-465Google Scholar Increased insulin resistance (IR) associated with these disorders is the main culprit, as clinical studies have shown that IR could play a major role in the lithogenesis by favoring the production of cholesterol supersaturated bile and impaired gallbladder function.26Chang Y. Sung E. Ryu S. Park Y.W. Jang Y.M. Park M. Insulin resistance is associated with gallstones even in non-obese, non-diabetic Korean men.J Kor Med Sci. 2008; 23: 644-650Google ScholarSeverity of Liver DiseaseThe severity of liver disease is an independent risk factor for development of GSs. Most studies have shown that prevalence of GSs is higher in Child B or C cirrhosis than that in Child A cirrhosis and in decompensated cirrhosis than that in patients with compensated cirrhosis.9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar, 10Conte D. Fraquelli M. Fornari F. Lodi L. Bodini P. Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.Arch Intern Med. 1999; 159: 49-52Google Scholar, 11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar,24Elzouki A.N. Nilsson S. Nilsson P. Verbaan H. Simanaitis M. Lindgren S. The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction.Hepato-Gastroenterology. 1999; 46: 2946-2950Google Scholar,25Park J.H. Kim T.N. Lee S.H. The prevalence and risk factors of gallstones in Korean patients with liver cirrhosis.Hepato-Gastroenterology. 2013; 60: 461-465Google Scholar This high prevalence of GSs in advanced liver disease could be probably due to longer duration of underlying disease.20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar However, reduced hepatic synthesis and transport of bile salts with high estrogen levels in patients with decompensated cirrhosis can lead to development of GSs.27Alvaro D. Angelico M. Gandin C. Ginanni Corradini S. Capocaccia L. Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis.J Hepatol. 1990; 10: 228-234Google Scholar,28De Besi L. Zucchetta P. Zotti S. Mastrogiacomo I. Sex hormones and sex hormone binding globulin in males with compensated and decompensated cirrhosis of the liver.Acta Endocrinol (Copenh). 1989; 120: 271-276Google Scholar A further explanation for increased prevalence of GSs in advanced liver disease can be associated with gallbladder hypo-motility.29Acalovschi M. Dumitrascu D.L. Csakany I. Gastric and gall bladder emptying of a mixed meal are not coordinated in liver cirrhosis--a simultaneous sonographic study.Gut. 1997; 40: 412-417Google Scholar,30Li C.P. Hwang S.J. Lee F.Y. et al.Evaluation of gallbladder motility in patients with liver cirrhosis: relationship to gallstone formation.Dig Dis Sci. 2000; 45: 1109-1114Google ScholarGSs in relation to etiology of liver cirrhosisThe etiology of cirrhosis may directly influence GS formation. The evidence for an association is conflicting. Some studies support it,9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar,11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar,23Conte D. Barisani D. Mandelli C. et al.Cholelithiasis in cirrhosis: analysis of 500 cases.Am J Gastroenterol. 1991; 86: 1629-1632Google Scholar whereas others negate it.5Acalovschi M. Badea R. Dumitrascu D. Varga C. Prevalence of gallstones in liver cirrhosis: a sonographic survey.Am J Gastroenterol. 1988; 83: 954-956Google Scholar,20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar,31Sarin S.K. Guptan R.C. Malhotra S. Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.J Assoc Physicians India. 2002; 50: 518-522Google Scholar,32Genzini T. de Miranda M.P. de Oliveira e Silva A. et al.Cholelithiasis in cirrhotic patients. (Analysis of cholelithiasis among patients with liver cirrhosis in Sao Paulo, Brazil).Arq Gastroenterol. 1996; 33: 52-59Google ScholarChronic AlcoholismFornari et al reported that previous alcohol abuse is an independent risk factor for development of GSs on prospective follow-up of patients with cirrhosis, and the risk ratio for GSs in alcoholic cirrhosis is 14 times higher than virus-associated cirrhosis.9Fornari F. Imberti D. Squillante M.M. et al.Incidence of gallstones in a population of patients with cirrhosis.J Hepatol. 1994; 20: 797-801Google Scholar Benvegnu et al observed a higher rate of GS development in cirrhotic patients with prior history of alcohol abuse than in those without history of alcohol abuse (20.9% vs. 8.6%).11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar Another study comparing the prevalence of GSs in alcoholic and viral etiology of cirrhosis reported that the frequency of GSs is higher in the alcohol etiology of cirrhosis.23Conte D. Barisani D. Mandelli C. et al.Cholelithiasis in cirrhosis: analysis of 500 cases.Am J Gastroenterol. 1991; 86: 1629-1632Google Scholar However, in a study of 313 cirrhotic patients, the etiology of cirrhosis did not seem to be important as a risk factor for GS formation.20Del Olmo J.A. Garcia F. Serra M.A. Maldonado L. Rodrigo J.M. Prevalence and incidence of gallstones in liver cirrhosis.Scand J Gastroenterol. 1997; 32: 1061-1065Google Scholar Another study by Sarin et al did not find any significant difference in prevalence of GSs in alcoholic and nonalcoholic cirrhotics.31Sarin S.K. Guptan R.C. Malhotra S. Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.J Assoc Physicians India. 2002; 50: 518-522Google Scholar Genzini et al also did not find any evidence that the etiology of liver cirrhosis affects the prevalence of GSs in this group of patients.32Genzini T. de Miranda M.P. de Oliveira e Silva A. et al.Cholelithiasis in cirrhotic patients. (Analysis of cholelithiasis among patients with liver cirrhosis in Sao Paulo, Brazil).Arq Gastroenterol. 1996; 33: 52-59Google Scholar Thus, there is no agreement regarding the role of alcohol in directly affecting the risk of GS formation.Hepatitis B and CThe association of hepatitis B and C infection with development of GSs has been evaluated in several studies.11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar,24Elzouki A.N. Nilsson S. Nilsson P. Verbaan H. Simanaitis M. Lindgren S. The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction.Hepato-Gastroenterology. 1999; 46: 2946-2950Google Scholar,33Stroffolini T. Sagnelli E. Mele A. Cottone C. Almasio P.L. Italian Hospitals' Collaborating GHCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.J Viral Hepat. 2007; 14: 618-623Google Scholar,34Chang T.S. Lo S.K. Shyr H.Y. et al.Hepatitis C virus infection facilitates gallstone formation.J Gastroenterol Hepatol. 2005; 20: 1416-1421Google Scholar Benvegnu et al reported that the prevalence of GSs is higher in hepatitis B surface antigen (HBsAg)–negative cirrhotics than that in HBsAg-positive cirrhotics, and no difference was noted in relation to hepatitis C virus (HCV) infection.11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar On follow-up of 182 patients with cirrhosis and without GSs for 40 months, the rate of development of new GSs is significantly lower in HBsAg-positive patients than that in HBsAg-negative patients, and there is no relevant difference in relation to anti-HCV positivity.11Benvegnu L. Noventa F. Chemello L. Fattovich G. Alberti A. Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.Digestion. 1997; 58: 293-298Google Scholar Stroffolini et al observed that patients with HCV-related cirrhosis have higher prevalence of GSs than patients with hepatitis B virus (HBV) and alcohol-related cirrhosis.33Stroffolini T. Sagnelli E. Mele A. Cottone C. Almasio P.L. Italian Hospitals' Collaborating GHCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.J Viral Hepat. 2007; 14: 618-623Google Scholar Chang et al observed that the prevalence of GSs in anti–HCV-positive patients, HBsAg-positive patients, and both marker–negative patients to be 11.7%, 5.4%, and 6%, respectively.34Chang T.S. Lo S.K. Shyr H.Y. et al.Hepatitis C virus infection facilitates gallstone formation.J Gastroenterol Hepatol. 2005; 20: 1416-1421Google Scholar Elzouki et al also reported that HCV-related cirrhosis has an increased risk of developing GSs in comparison with other etiology of cirrhosis.24Elzouki A.N. Nilsson S. Nilsson P. Verbaan H. Simanaitis M. Lindgren S. The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction.Hepato-Gastroenterology. 1999; 46: 2946-2950Google Scholar Acalovschi et al observed that the prevalence of GSs is higher in all age groups up to 60 years in patients with HCV-related chronic hepatitis without cirrhosis than that in the general population, indicating GSs occur earlier in patients with HCV infection.35Acalovschi M. Buzas C. Radu C. Grigorescu M. Hepatitis C virus infection is a risk factor for gallstone disease: a prospective hospital-based study of patients with chronic viral C hepatitis.J Viral Hepat. 2009; 16: 860-866Google Scholar Thus, the evidence for the role of HBV infection in development of GSs is lacking. On the other hand, the association of HCV infection and GSs appears more solid, probably due to associated chronic hepatic inflammation in HCV infection.36Alter H.J. Seeff L.B. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome.Semin Liver Dis. 2000; 20: 17-35Google ScholarNonalcoholic Fatty Liver DiseaseMost of the epidemiological studies of GSs in cirrhosis were carried out before the concept of nonalcoholic fatty liver disease (NAFLD). The prevalence of both the conditions in the general population is high. One may think that an association between them is likely to be incidental as they share common risk factors. Interestingly, several studies have shown that the prevalence of GSs is higher in patients with NAFLD than that in the general population.37Loria P. Lonardo A. Lombardini S. et al.Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors.J Gastroenterol Hepatol. 2005; 20: 1176-1184Google Scholar, 38Fracanzani A.L. Valenti L. Russello M. et al.Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease.PLoS One. 2012; 7e41183Google Scholar, 39Chen C.H. Huang M.H. Yang J.C. et al.Prevalence and risk factors of gallstone disease in an adult population of Taiwan: an epidemiological survey.J Gastroenterol Hepatol. 2006; 21: 1737-1743Google Scholar Fracanzani et al reported that the prevalence of GSs progressively increases with advancing fibrosis stages, 15% in the F0-2 stage to 29% in the F3 stage and 56% in the F4 stage, and the prevalence of GSs increases with severity of necroinflammatory activity without differences in the severity of steatosis.38Fracanzani A.L. Valenti L. Russello M. et al.Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease.PLoS One. 2012; 7e41183Google Scholar Two recent meta-analyses have shown that the prevalence of GSs is higher in patients with NAFLD than that in the general population.40Jaruvongvanich V. Sanguankeo A. Upala S. Significant association between gallstone disease and nonalcoholic fatty liver disease: a systematic review and meta-analysis.Dig Dis Sci. 2016; 61: 2389-2396Google Scholar,41Shen S.S. Gong J.J. Wang X.W. et al.Promotional effect of nonalcoholic fatty liver disease on Gallstone disease: a systematic review and meta-analysis.Turk J Gastroenterol. 2017; 28: 31-39Google Scholar In nutshell, NAFLD is an independent risk factor for GS disease, and the risk increases with advancing fibrosis of the liver.Pathogenesis: how it is different from noncirrhotic patientsMultiple mechanisms in cirrhosis such as chronic hemolysis due to hypersplenism,5Acalovschi M. Badea R. Dumitrascu D. Varga C. Prevalence of gallstones in liver cirrhosis: a sonographic survey.Am J Gastroenterol. 1988; 83: 954-956Google Scholar,16Diehl A.K. Schwesinger W.H. Holleman Jr., D.R. Chapman J.B. Kurtin W.E. Clinical correlates of gallstone composition: distinguishing pigment from cholesterol stones.Am J Gastroenterol. 1995; 90: 967-972Google Scholar reduced bile acid synthesis and transport,27Alvaro D. Angelico M. Gandin C. Ginanni Corradini S.