Advertisement

Gallstone Disease in Cirrhosis—Pathogenesis and Management

  • Bipadabhanjan Mallick
    Correspondence
    Address for correspondence:Bipadabhanjan Mallick, Assistant professor, Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India.
    Affiliations
    Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
    Search for articles by this author
  • Anil C. Anand
    Affiliations
    Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
    Search for articles by this author
Published:September 16, 2021DOI:https://doi.org/10.1016/j.jceh.2021.09.011
      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.

      Keywords

      Abbreviations:

      ACLF (acute-on-chronic liver failure), CBD (common bile duct), CTP (Child-Pugh), EPBD (Endoscopic papillary balloon dilatation), EST (endoscopic sphincterotomy), EUS (endoscopic ultrasound), FXR (farnesoid X receptors), GSs (Gallstones), HBV (hepatitis B virus), HCV (Hepatitis C virus), IR (insulin resistance), LC (laparoscopic cholecystectomy), MELD (Model for end-stage liver disease), NAFLD (non-alcoholic fatty liver disease), NS 5A (non-structural protein 5A)
      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.
      • Everhart J.E.
      • Ruhl C.E.
      Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas.
      • Aerts R.
      • Penninckx F.
      The burden of gallstone disease in Europe.
      • Unisa 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.
      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.
      • Dutta U.
      • Mallick B.
      Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.
      Pigment GSs, on the other hand, are composed of essentially calcium bilirubinate, and they contain <20% dry weight as cholesterol.
      • Dutta U.
      • Mallick B.
      Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.
      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.
      • Dutta U.
      • Mallick B.
      Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.
      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.
      • Acalovschi M.
      • Badea R.
      • Dumitrascu D.
      • Varga C.
      Prevalence of gallstones in liver cirrhosis: a sonographic survey.
      ,
      • Sheen I.S.
      • Liaw Y.F.
      The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.
      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 prevalence

      Higher prevalence of GSs in patients with liver cirrhosis has been shown (Table 1) in both postmortem series
      • Bouchier I.A.
      Postmortem study of the frequency of gallstones in patients with cirrhosis of the liver.
      ,
      • Iber F.L.
      • Caruso G.
      • Polepalle C.
      • Kuchipudi V.
      • Chinoy M.
      Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.
      and antemortem cross-sectional or longitudinal ultrasonography studies.
      • Sheen I.S.
      • Liaw Y.F.
      The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.
      ,
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      ,
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      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%.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      ,
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      The incidence of GSs in patients with cirrhosis is 3–8 times higher than that in the general population.
      • Sheen I.S.
      • Liaw Y.F.
      The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.
      ,
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      • Festi D.
      • Dormi A.
      • Capodicasa S.
      • et al.
      Incidence of gallstone disease in Italy: results from a multicenter, population-based Italian study (the MICOL project).
      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.
      • Orozco 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.
      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).
      • Maggi A.
      • Solenghi D.
      • Panzeri A.
      • et al.
      Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.
      Although these figures are comparable with noncirrhotic patients,
      • Gibney E.J.
      Asymptomatic gallstones.
      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.
      • Iber F.L.
      • Caruso G.
      • Polepalle C.
      • Kuchipudi V.
      • Chinoy M.
      Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.
      ,
      • Diehl 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.
      ,
      • Schwesinger W.H.
      • Kurtin W.E.
      • Levine B.A.
      • Page C.P.
      Cirrhosis and alcoholism as pathogenetic factors in pigment gallstone formation.
      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.
      • Coelho J.C.
      • Slongo J.
      • Dambroski Silva A.
      • et al.
      Prevalence of cholelithiasis in patients subjected to liver transplantation for cirrhosis.
      Table 1Prevalence of Asymptomatic Gallstones in Cirrhosis of the Liver.
      AuthorYearType of studyNo. of participantsPrevalence of gallstones (%)
      CirrhosisControlCirrhosisControl
      Bouchier et al.
      • Bouchier I.A.
      Postmortem study of the frequency of gallstones in patients with cirrhosis of the liver.
      1969Postmortem235446029.412.8
      Iber et al.
      • Iber F.L.
      • Caruso G.
      • Polepalle C.
      • Kuchipudi V.
      • Chinoy M.
      Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.
      1990Postmortem4603163312
      Acalovschi et al.
      • Acalovschi M.
      • Badea R.
      • Dumitrascu D.
      • Varga C.
      Prevalence of gallstones in liver cirrhosis: a sonographic survey.
      1988Ultrasonography14014029.213.6
      Fornari et al.
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      1994Ultrasonography41041431.920.7
      Del Olmo et al.
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      1997Ultrasonography31335723.316.8
      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.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      19971823.511.5%3%
      Conte et al.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      1999618522.8%5%
      Symptomatic gallstones
      Patients already harboring asymptomatic gallstones.
      Orozco et al.
      • Orozco 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.
      199434618%3%
      Maggi et al.
      • Maggi A.
      • Solenghi D.
      • Panzeri A.
      • et al.
      Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.
      1997452.54.4%<2%
      a Patients already harboring asymptomatic gallstones.

      Risk factors for GSs in cirrhosis

      Age and Sex

      Similar to the GSs in the general population, the incidence of GSs in patients with cirrhosis has female preponderance.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      ,
      • Buchner A.M.
      • Sonnenberg A.
      Factors influencing the prevalence of gallstones in liver disease: the beneficial and harmful influences of alcohol.
      ,
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      The risk of GSs becoming symptomatic is also significantly higher in women than that in men.
      • Acalovschi M.
      • Blendea D.
      • Feier C.
      • et al.
      Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.
      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.
      • Fornari F.
      • Civardi G.
      • Buscarini E.
      • et al.
      Cirrhosis of the liver. A risk factor for development of cholelithiasis in males.
      • Conte D.
      • Barisani D.
      • Mandelli C.
      • et al.
      Cholelithiasis in cirrhosis: analysis of 500 cases.
      • Elzouki 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.
      The overall prevalence of GSs in cirrhotics is increased significantly with advancing age.
      • Acalovschi M.
      • Badea R.
      • Dumitrascu D.
      • Varga C.
      Prevalence of gallstones in liver cirrhosis: a sonographic survey.
      ,
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      ,
      • Acalovschi M.
      • Blendea D.
      • Feier C.
      • et al.
      Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.

      Family History of GSs

      Similar to the general population, the incidence of GSs in cirrhotics is significantly higher in patients with family history of GSs.
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      The incidence of symptomatic GSs is also higher in patients with positive family history.
      • Acalovschi M.
      • Blendea D.
      • Feier C.
      • et al.
      Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.
      However, the role of genetic variants associated with familial GSs is yet to be proven in cirrhotics.

      Metabolic Syndrome

      Type 2 diabetes mellitus, hyperlipidemia, and high body mass index are reported to be independent risk factors for GSs in patients with liver cirrhosis.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      ,
      • Park J.H.
      • Kim T.N.
      • Lee S.H.
      The prevalence and risk factors of gallstones in Korean patients with liver cirrhosis.
      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.
      • Chang 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.

      Severity of Liver Disease

      The 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.
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      • Conte D.
      • Fraquelli M.
      • Fornari F.
      • Lodi L.
      • Bodini P.
      • Buscarini L.
      Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      ,
      • Elzouki 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.
      ,
      • Park J.H.
      • Kim T.N.
      • Lee S.H.
      The prevalence and risk factors of gallstones in Korean patients with liver cirrhosis.
      This high prevalence of GSs in advanced liver disease could be probably due to longer duration of underlying disease.
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      However, reduced hepatic synthesis and transport of bile salts with high estrogen levels in patients with decompensated cirrhosis can lead to development of GSs.
      • Alvaro D.
      • Angelico M.
      • Gandin C.
      • Ginanni Corradini S.
      • Capocaccia L.
      Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis.
      ,
      • De 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.
      A further explanation for increased prevalence of GSs in advanced liver disease can be associated with gallbladder hypo-motility.
      • Acalovschi 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.
      ,
      • Li C.P.
      • Hwang S.J.
      • Lee F.Y.
      • et al.
      Evaluation of gallbladder motility in patients with liver cirrhosis: relationship to gallstone formation.

      GSs in relation to etiology of liver cirrhosis

      The etiology of cirrhosis may directly influence GS formation. The evidence for an association is conflicting. Some studies support it,
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      ,
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      ,
      • Conte D.
      • Barisani D.
      • Mandelli C.
      • et al.
      Cholelithiasis in cirrhosis: analysis of 500 cases.
      whereas others negate it.
      • Acalovschi M.
      • Badea R.
      • Dumitrascu D.
      • Varga C.
      Prevalence of gallstones in liver cirrhosis: a sonographic survey.
      ,
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      ,
      • Sarin S.K.
      • Guptan R.C.
      • Malhotra S.
      Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.
      ,
      • Genzini 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).

      Chronic Alcoholism

      Fornari 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.
      • Fornari F.
      • Imberti D.
      • Squillante M.M.
      • et al.
      Incidence of gallstones in a population of patients with cirrhosis.
      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%).
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      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.
      • Conte D.
      • Barisani D.
      • Mandelli C.
      • et al.
      Cholelithiasis in cirrhosis: analysis of 500 cases.
      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.
      • Del Olmo J.A.
      • Garcia F.
      • Serra M.A.
      • Maldonado L.
      • Rodrigo J.M.
      Prevalence and incidence of gallstones in liver cirrhosis.
      Another study by Sarin et al did not find any significant difference in prevalence of GSs in alcoholic and nonalcoholic cirrhotics.
      • Sarin S.K.
      • Guptan R.C.
      • Malhotra S.
      Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.
      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.
      • Genzini 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).
      Thus, there is no agreement regarding the role of alcohol in directly affecting the risk of GS formation.

      Hepatitis B and C

      The association of hepatitis B and C infection with development of GSs has been evaluated in several studies.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      ,
      • Elzouki 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.
      ,
      • Stroffolini T.
      • Sagnelli E.
      • Mele A.
      • Cottone C.
      • Almasio P.L.
      Italian Hospitals' Collaborating G
      HCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.
      ,
      • Chang T.S.
      • Lo S.K.
      • Shyr H.Y.
      • et al.
      Hepatitis C virus infection facilitates gallstone formation.
      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.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      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.
      • Benvegnu L.
      • Noventa F.
      • Chemello L.
      • Fattovich G.
      • Alberti A.
      Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease.
      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.
      • Stroffolini T.
      • Sagnelli E.
      • Mele A.
      • Cottone C.
      • Almasio P.L.
      Italian Hospitals' Collaborating G
      HCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.
      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.
      • Chang T.S.
      • Lo S.K.
      • Shyr H.Y.
      • et al.
      Hepatitis C virus infection facilitates gallstone formation.
      Elzouki et al also reported that HCV-related cirrhosis has an increased risk of developing GSs in comparison with other etiology of cirrhosis.
      • Elzouki 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.
      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.
      • Acalovschi 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.
      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.
      • Alter H.J.
      • Seeff L.B.
      Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome.

      Nonalcoholic Fatty Liver Disease

      Most 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.
      • Loria P.
      • Lonardo A.
      • Lombardini S.
      • et al.
      Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors.
      • Fracanzani 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.
      • Chen 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.
      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.
      • Fracanzani 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.
      Two recent meta-analyses have shown that the prevalence of GSs is higher in patients with NAFLD than that in the general population.
      • Jaruvongvanich V.
      • Sanguankeo A.
      • Upala S.
      Significant association between gallstone disease and nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      ,
      • Shen 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.
      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 patients

      Multiple mechanisms in cirrhosis such as chronic hemolysis due to hypersplenism,
      • Acalovschi M.
      • Badea R.
      • Dumitrascu D.
      • Varga C.
      Prevalence of gallstones in liver cirrhosis: a sonographic survey.
      ,
      • Diehl 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.
      reduced bile acid synthesis and transport,
      • Alvaro D.
      • Angelico M.
      • Gandin C.
      • Ginanni Corradini S.
      • Capocaccia L.
      Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis.
      reduced cholesterol secretion, decreased apolipoprotein (apo) A-I and A-II secretion,
      • Poynard T.
      • Lonjon I.
      • Mathurin P.
      • et al.
      Prevalence of cholelithiasis according to alcoholic liver disease: a possible role of apolipoproteins AI and AII.
      gallbladder hypo-motility,
      • Acalovschi 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.
      ,
      • Li C.P.
      • Hwang S.J.
      • Lee F.Y.
      • et al.
      Evaluation of gallbladder motility in patients with liver cirrhosis: relationship to gallstone formation.
      autonomic dysfunction,
      • Chawla A.
      • Puthumana L.
      • Thuluvath P.J.
      Autonomic dysfunction and cholelithiasis in patients with cirrhosis.
      and portal hypertension
      • Sarin S.K.
      • Guptan R.C.
      • Malhotra S.
      Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.
      jointly lead to the formation of GSs (Figure 1). All these mechanisms can affect any one of the major steps in the pathogenesis of GSs such as the change in bile composition, enhanced crystal nucleation, and impaired gallbladder emptying.
      • Dutta U.
      • Mallick B.
      Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.
      Figure 1
      Figure 1Overview of pathogenesis and management of gallstones in patients with cirrhosis of the liver. Factors contributing to pathogenesis are summarized in the blue balloons, whereas the approach to management is shown in green balloons below the cartoon.

      Change in Bile Composition

      Pigment Stones

      Pigment stones develop when the bile is supersaturated with calcium bilirubinate, and the super-saturation occurs in the presence of an increased concentration of unconjugated bilirubin or free ionized calcium in the bile.
      • Cahalane M.J.
      • Neubrand M.W.
      • Carey M.C.
      Physical-chemical pathogenesis of pigment gallstones.
      ,
      • Carey M.C.
      Pathogenesis of gallstones.
      Increased hemolysis in patients with cirrhosis leads to increased concentration of unconjugated bilirubin and bilirubin monoconjugates in bile which are more easily deconjugated by either nonenzymatic hydrolysis or β-glucuronidase secreted by hepatocytes and biliary epithelial cells.
      • Alvaro D.
      • Angelico M.
      • Gandin C.
      • Ginanni Corradini S.
      • Capocaccia L.
      Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis.
      ,
      • Whiting J.F.
      • Narciso J.P.
      • Chapman V.
      • Ransil B.J.
      • Swank R.T.
      • Gollan J.L.
      Deconjugation of bilirubin-IX alpha glucuronides: a physiologic role of hepatic microsomal beta-glucuronidase.
      There is marked reduction of bile acid pools in patients with cirrhosis because of impaired synthesis and reduced secretion of phospholipids, especially cholesterol in bile.
      • Vlahcevic Z.R.
      • Juttijudata P.
      • Bell Jr., C.C.
      • Swell L.
      Bile acid metabolism in patients with cirrhosis. II. Cholic and chenodeoxycholic acid metabolism.
      • Vlahcevic Z.R.
      • Yoshida T.
      • Juttijudata P.
      • Bell Jr., C.C.
      • Swell L.
      Bile acid metabolism in cirrhosis. 3. Biliary lipid secretion in patients with cirrhosis and its relevance to gallstone formation.
      • Schwartz C.C.
      • Almond H.R.
      • Vlahcevic Z.R.
      • Swell L.
      Bile acid metabolism in cirrhosis. V. Determination of biliary lipid secretion rates in patients with advanced cirrhosis.
      Combined effect of all these pathophysiological factors will enhance the risk of pigment stone formation in patients with cirrhosis.

      Cholesterol Stones

      Cholesterol stones occur mainly in patients with HCV and NAFLD-related cirrhosis because of super-saturation of cholesterol in bile as both are associated with IR.
      • Allison M.E.
      • Wreghitt T.
      • Palmer C.R.
      • Alexander G.J.
      Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population.
      • Hui J.M.
      • Sud A.
      • Farrell G.C.
      • et al.
      Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected].
      • Marchesini G.
      • Brizi M.
      • Bianchi G.
      • et al.
      Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.
      • Bugianesi E.
      • Gastaldelli A.
      • Vanni E.
      • et al.
      Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.
      Hepatic IR has been proved to play a major role in the formation of cholesterol stones by producing cholesterol supersaturated bile and impairing gallbladder function.
      • Chang 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.
      ,
      • Nervi F.
      • Miquel J.F.
      • Alvarez M.
      • et al.
      Gallbladder disease is associated with insulin resistance in a high risk Hispanic population.
      IR also decreases the bile acid synthesis by enzyme inhibition and produces resistance to the farnesoid X receptors, leading to increased lithogenesis.
      • Biddinger S.B.
      • Haas J.T.
      • Yu B.B.
      • et al.
      Hepatic insulin resistance directly promotes formation of cholesterol gallstones.

      Enhanced Crystal Nucleation

      Both pigment and cholesterol stones develop on a matrix of mucin glycoproteins secreted by biliary epithelial cells. Cirrhosis of the liver is associated with reduced secretion of apo A-I and A-II which enhance the crystal nucleation as they act as antinucleating factors.
      • Poynard T.
      • Lonjon I.
      • Mathurin P.
      • et al.
      Prevalence of cholelithiasis according to alcoholic liver disease: a possible role of apolipoproteins AI and AII.
      ,
      • Mathurin P.
      • Vidaud D.
      • Vidaud M.
      • et al.
      Quantification of apolipoprotein A-I and B messenger RNA in heavy drinkers according to liver disease.
      HBV infection can modulate the function of apo A-I through HBx protein, resulting in decreased self-association and lipid binding ability.
      • Zhang T.
      • Xie N.
      • He W.
      • et al.
      An integrated proteomics and bioinformatics analyses of hepatitis B virus X interacting proteins and identification of a novel interactor apoA-I.
      Similarly, nonstructural protein 5A of the HCV binds with apo A-I and potentially increases the risk of lithogenesis.
      • Shi S.T.
      • Polyak S.J.
      • Tu H.
      • Taylor D.R.
      • Gretch D.R.
      • Lai M.M.
      Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins.

      Impaired Gallbladder Emptying

      Impaired gallbladder emptying in cirrhosis has been proved by both ultrasonography and radionuclide hepatobiliary scintigraphy,
      • Acalovschi 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.
      ,
      • Li C.P.
      • Hwang S.J.
      • Lee F.Y.
      • et al.
      Evaluation of gallbladder motility in patients with liver cirrhosis: relationship to gallstone formation.
      ,
      • Kao C.H.
      • Hsieh J.F.
      • Tsai S.C.
      • Ho Y.J.
      • Chen S.D.
      Evidence of impaired gallbladder function in patients with liver cirrhosis by quantitative radionuclide cholescintigraphy.
      ,
      • Koruk M.
      • Ozkilic S.
      • Savas M.C.
      • Celen Z.
      • Kadayifci A.
      • Ozkilic C.
      Evaluation of hepatic functions and biliary dynamics in patients with liver cirrhosis by quantitative scintigraphy.
      and the degree of impairment is proportional to the severity of liver disease.
      • Acalovschi M.
      • Dumitrascu D.L.
      • Nicoara C.D.
      Gallbladder contractility in liver cirrhosis: comparative study in patients with and without gallbladder stones.
      Autonomic neuropathy associated with liver cirrhosis can contribute to the formation of GSs, perhaps by impairing gallbladder and sphincter of Oddi motility.
      • Chawla A.
      • Puthumana L.
      • Thuluvath P.J.
      Autonomic dysfunction and cholelithiasis in patients with cirrhosis.
      Cirrhosis is a state of hyper-estrogenization, and a high serum level of estrogen can lead to development of GSs by impairment of gallbladder emptying, especially in men.
      • Fornari F.
      • Civardi G.
      • Buscarini E.
      • et al.
      Cirrhosis of the liver. A risk factor for development of cholelithiasis in males.
      However, a subsequent study did not find any effect of the plasma estrogen level on gallbladder emptying.
      • Li C.P.
      • Hwang S.J.
      • Lee F.Y.
      • et al.
      Evaluation of gallbladder motility in patients with liver cirrhosis: relationship to gallstone formation.
      ,
      • Pompili M.
      • Rapaccini G.L.
      • Caturelli E.
      • et al.
      Gallbladder emptying, plasma levels of estradiol and progesterone, and cholecystokinin secretion in liver cirrhosis.
      In addition to these abovementioned mechanisms, some people believe that the HCV impairs gallbladder mucosal function and contributes to the development of GSs by directly infecting gallbladder epithelial cells.
      • Stroffolini T.
      • Sagnelli E.
      • Mele A.
      • Cottone C.
      • Almasio P.L.
      Italian Hospitals' Collaborating G
      HCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.
      ,
      • Loriot M.A.
      • Bronowicki J.P.
      • Lagorce D.
      • et al.
      Permissiveness of human biliary epithelial cells to infection by hepatitis C virus.
      Sarin et al reported that the incidence of GSs is two times higher in people with noncirrhotic portal hypertension than that in the general population, and it is similar in comparison with cirrhotic portal hypertension, indicating a role of portal hypertension per se in pathogenesis of GSs.
      • Sarin S.K.
      • Guptan R.C.
      • Malhotra S.
      Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.

      Treatment

      Asymptomatic GSs

      GSs in liver cirrhosis are usually asymptomatic and have more chances to be detected incidentally by ultrasonography at periodical evaluation for liver disease. There is a paucity of data on the natural history of asymptomatic GSs in patients with liver cirrhosis. In a longitudinal follow-up study of 34 patients with asymptomatic GSs and cirrhosis, only 6 (18%) patients developed symptoms for GSs (4 patients of acute cholecystitis and 2 patients of chronic cholecystitis) and 3 (8.8%) patients died because of complications of cholecystitis.
      • Orozco 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.
      In another longitudinal follow-up study of 45 patients, only 4.4% patients developed either symptoms or complications.
      • Maggi A.
      • Solenghi D.
      • Panzeri A.
      • et al.
      Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.
      The estimated annual rate of development of symptoms or complication is less than 3% in both the studies.
      • Orozco 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.
      ,
      • Maggi A.
      • Solenghi D.
      • Panzeri A.
      • et al.
      Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.
      Earlier studies have also reported that the incidence of acute cholecystitis is less in cirrhotic patients with GSs.
      • Dunnington G.
      • Alfrey E.
      • Sampliner R.
      • Kogan F.
      • Putnam C.
      Natural history of cholelithiasis in patients with alcoholic cirrhosis (cholelithiasis in cirrhotic patients).
      • Schwartz S.I.
      Biliary tract surgery and cirrhosis: a critical combination.
      • Castaing D.
      • Houssin D.
      • Lemoine J.
      • Bismuth H.
      Surgical management of gallstones in cirrhotic patients.
      In a case–control study of 140 patients with liver cirrhosis and with GSs, the multivariate analysis showed that only advanced age and family history of GSs are independent risk factors for development of symptoms.
      • Acalovschi M.
      • Blendea D.
      • Feier C.
      • et al.
      Risk factors for symptomatic gallstones in patients with liver cirrhosis: a case-control study.
      The lower complication rate despite having higher incidence of GSs in cirrhotic patients could probably be related to a higher percentage of pigment stones. The smaller size and greater friability of pigment stones make them less likely to obstruct the cystic duct.
      • Dunnington G.
      • Alfrey E.
      • Sampliner R.
      • Kogan F.
      • Putnam C.
      Natural history of cholelithiasis in patients with alcoholic cirrhosis (cholelithiasis in cirrhotic patients).
      Given the high rate of morbidity associated with surgery in patients with cirrhosis, prophylactic cholecystectomy is not recommended in asymptomatic GSs, and they should be followed up closely.
      • Puggioni A.
      • Wong L.L.
      A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis.

      Symptomatic GSs

      Medical Management

      Bile acid dissolution therapy is not effective in resolution of symptoms or complications of GSs and is not recommended.
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones.
      A higher percentage of pigment stones and associated impaired gallbladder emptying in cirrhosis makes it more unsuitable for treatment of GSs in cirrhotic patients.

      Surgical Management

      Early elective cholecystectomy is recommended when symptoms supervene, and laparoscopic cholecystectomy (LC) is the treatment of choice for symptomatic GSs.
      • Puggioni A.
      • Wong L.L.
      A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis.
      ,
      European Association for the Study of the Liver
      EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones.
      The first study regarding the outcome of LC for symptomatic GSs in cirrhotic patients was published in 1993.
      • Yerdel M.A.
      • Tsuge H.
      • Mimura H.
      • Sakagami K.
      • Mori M.
      • Orita K.
      Laparoscopic cholecystectomy in cirrhotic patients: expanding indications.
      Subsequently, multiple meta-analyses have shown that LC has advantage of fewer postoperative and infectious complications and shorter operative time and hospital stay than open cholecystectomy (OC) in patients with cirrhosis.
      • Puggioni A.
      • Wong L.L.
      A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis.
      ,
      • Laurence J.M.
      • Tran P.D.
      • Richardson A.J.
      • Pleass H.C.
      • Lam V.W.
      Laparoscopic or open cholecystectomy in cirrhosis: a systematic review of outcomes and meta-analysis of randomized trials.
      • de Goede B.
      • Klitsie P.J.
      • Hagen S.M.
      • et al.
      Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and symptomatic cholecystolithiasis.
      • Cheng Y.
      • Xiong X.Z.
      • Wu S.J.
      • Lin Y.X.
      • Cheng N.S.
      Laparoscopic vs. open cholecystectomy for cirrhotic patients: a systematic review and meta-analysis.
      However, the mortality and postoperative hepatic decompensation rates are similar in both LC and OC groups.
      • Laurence J.M.
      • Tran P.D.
      • Richardson A.J.
      • Pleass H.C.
      • Lam V.W.
      Laparoscopic or open cholecystectomy in cirrhosis: a systematic review of outcomes and meta-analysis of randomized trials.
      ,
      • Cheng Y.
      • Xiong X.Z.
      • Wu S.J.
      • Lin Y.X.
      • Cheng N.S.
      Laparoscopic vs. open cholecystectomy for cirrhotic patients: a systematic review and meta-analysis.
      The reported conversion rate from LC to OC is 4–14%.
      • Laurence J.M.
      • Tran P.D.
      • Richardson A.J.
      • Pleass H.C.
      • Lam V.W.
      Laparoscopic or open cholecystectomy in cirrhosis: a systematic review of outcomes and meta-analysis of randomized trials.
      ,
      • Quillin 3rd, R.C.
      • Burns J.M.
      • Pineda J.A.
      • et al.
      Laparoscopic cholecystectomy in the cirrhotic patient: predictors of outcome.
      • Machado N.O.
      Laparoscopic cholecystectomy in cirrhotics.
      • Chmielecki D.K.
      • Hagopian E.J.
      • Kuo Y.H.
      • Kuo Y.L.
      • Davis J.M.
      Laparoscopic cholecystectomy is the preferred approach in cirrhosis: a nationwide, population-based study.
      A population-based study analyzing cholecystectomy in cirrhotic patients showed that patients converted from LC to OC have lower infection rate, need for blood transfusion, and hepatic decompensation rates than the OC group.
      • Chmielecki D.K.
      • Hagopian E.J.
      • Kuo Y.H.
      • Kuo Y.L.
      • Davis J.M.
      Laparoscopic cholecystectomy is the preferred approach in cirrhosis: a nationwide, population-based study.
      The model for the end-stage liver disease (MELD) score is a better predictor of the outcome after LC than the Child-Pugh (CTP) score.
      • Quillin 3rd, R.C.
      • Burns J.M.
      • Pineda J.A.
      • et al.
      Laparoscopic cholecystectomy in the cirrhotic patient: predictors of outcome.
      ,
      • Delis S.
      • Bakoyiannis A.
      • Madariaga J.
      • Bramis J.
      • Tassopoulos N.
      • Dervenis C.
      Laparoscopic cholecystectomy in cirrhotic patients: the value of MELD score and Child-Pugh classification in predicting outcome.
      ,
      • Gad E.H.
      • Kamel Y.
      • Alsebaey A.
      • Mohammed A.
      • Abdelsamee M.A.
      Laparoscopic cholecystectomy in patients with liver cirrhosis: 8 years experience in a tertiary center. A retrospective cohort study.
      Delis et al observed that patients with a preoperative MELD score above 13 have a higher postoperative complication rate.
      • Delis S.
      • Bakoyiannis A.
      • Madariaga J.
      • Bramis J.
      • Tassopoulos N.
      • Dervenis C.
      Laparoscopic cholecystectomy in cirrhotic patients: the value of MELD score and Child-Pugh classification in predicting outcome.
      All the abovementioned meta-analyses have included a majority of Child-Pugh class A and B patients and very few number of Child-Pugh class C patients. The risk of mortality and postoperative hepatic decompensation is very high in Child-Pugh class C patients.
      • Curro G.
      • Iapichino G.
      • Melita G.
      • Lorenzini C.
      • Cucinotta E.
      Laparoscopic cholecystectomy in Child-Pugh class C cirrhotic patients.
      • Curro G.
      • Cucinotta E.
      Percutaneous gall bladder aspiration as an alternative to laparoscopic cholecystectomy in Child-Pugh C cirrhotic patients with acute cholecystitis.
      • Xu Q.
      • Gu L.
      • Wu Z.Y.
      Operative treatment for patients with cholelithiasis and liver cirrhosis.
      The conservative approach would be preferable for symptomatic GSs in Child-Pugh class C patients (Figure 2).
      Figure 2
      Figure 2The flowchart for management of gallstones in cirrhosis of the liver. ∗Ascites, variceal bleed, and/or hepatic encephalopathy. ∗∗Severe acute cholecystitis.

      Management of Acute Calculus Cholecystitis

      Antibiotics and cholecystectomy, including open and laparoscopic, are the standard of care for acute calculus cholecystitis. As mentioned previously, these procedures are quite safe in patients with Child-Pugh class A and B cirrhosis. In patients with Child-Pugh class C, cholecystectomy is associated with a higher rate of postoperative complications and mortality. The conservative approach with antibiotics should be the first line of management in these patients presenting with acute cholecystitis. Minimally invasive gallbladder drainage procedures, that is percutaneous cholecystostomy, trans-papillary or endoscopic ultrasound (EUS)–guided transmural gallbladder drainage, can be considered in case of failure of medical management. Cholecystectomy can be performed in the later stage if liver function improves. Percutaneous gallbladder aspiration has shown to be an effective alternative to LC for acute cholecystitis in Child-Pugh class C patients.
      • Curro G.
      • Cucinotta E.
      Percutaneous gall bladder aspiration as an alternative to laparoscopic cholecystectomy in Child-Pugh C cirrhotic patients with acute cholecystitis.
      Percutaneous cholecystostomy can be performed with an accepted complication rate in cirrhotic patients who are at high risk for surgery.
      • Jayadevan R.
      • Garg M.
      • Schiano T.
      • Divino C.M.
      Is cholecystostomy a safe procedure in patients with cirrhosis?.
      Endoscopic trans-papillary gallbladder stenting is also an effective option to prevent morbidity and mortality in Child-Pugh class C patients with symptomatic GSs.
      • Shrestha R.
      • Trouillot T.E.
      • Everson G.T.
      Endoscopic stenting of the gallbladder for symptomatic gallbladder disease in patients with end-stage liver disease awaiting orthotopic liver transplantation.
      ,
      • Schlenker C.
      • Trotter J.F.
      • Shah R.J.
      • et al.
      Endoscopic gallbladder stent placement for treatment of symptomatic cholelithiasis in patients with end-stage liver disease.
      Per-oral cholecystoscopy with lithotripsy can be another treatment option with added advantage of stone clearance.
      • Chen Y.K.
      • Nichols M.T.
      • Antillon M.R.
      Peroral cholecystoscopy with electrohydraulic lithotripsy for treatment of symptomatic cholelithiasis in end-stage liver disease (with videos).
      EUS-guided transmural gallbladder drainage using the self-expandable metal stent or lumen apposing metal stent has shown to be effective in treating acute cholecystitis with lower adverse events in patients who are deemed to be poor candidates for surgery.
      • Itoi T.
      • Coelho-Prabhu N.
      • Baron T.H.
      Endoscopic gallbladder drainage for management of acute cholecystitis.
      ,
      • Jain D.
      • Bhandari B.S.
      • Agrawal N.
      • Singhal S.
      Endoscopic ultrasound-guided gallbladder drainage using a lumen-apposing metal stent for acute cholecystitis: a systematic review.
      It has been already established as a safe and efficacious modality for cholecystitis in patients with Child-Pugh class A and B cirrhosis who are nonoperative candidates, but studies are needed to determine its role in patients with Child-Pugh class C cirrhosis.
      • James T.W.
      • Krafft M.
      • Croglio M.
      • Nasr J.
      • Baron T.
      EUS-guided gallbladder drainage in patients with cirrhosis: results of a multicenter retrospective study.

      Management of Common Bile Duct Stones

      The prevalence of common bile duct (CBD) stones is three times higher in cirrhotic patients than that in noncirrhotics patients.
      • Iber F.L.
      • Caruso G.
      • Polepalle C.
      • Kuchipudi V.
      • Chinoy M.
      Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis.
      ,
      • Acalovschi M.
      • Badea R.
      • Pascu M.
      Incidence of gallstones in liver cirrhosis.
      The reported incidence of acute cholangitis is 19% in cirrhotic patients with CBD stones.
      • Sugiyama M.
      • Atomi Y.
      • Kuroda A.
      • Muto T.
      Treatment of choledocholithiasis in patients with liver cirrhosis. Surgical treatment or endoscopic sphincterotomy?.
      There is an increased risk of morbidity and mortality with CBD exploration; endoscopic sphincterotomy (EST) is a safer option for management of choledocholithiasis in patients with cirrhosis.
      • Sugiyama M.
      • Atomi Y.
      • Kuroda A.
      • Muto T.
      Treatment of choledocholithiasis in patients with liver cirrhosis. Surgical treatment or endoscopic sphincterotomy?.
      • Isozaki H.
      • Okajima K.
      • Morita S.
      • et al.
      Surgery for cholelithiasis in cirrhotic patients.
      • Prat F.
      • Tennenbaum R.
      • Ponsot P.
      • et al.
      Endoscopic sphincterotomy in patients with liver cirrhosis.
      However, the overall risk of post-EST bleeding and pancreatitis is higher in cirrhotic patients than that in noncirrhotic patients.
      • Mashiana H.S.
      • Dhaliwal A.S.
      • Sayles H.
      • et al.
      Endoscopic retrograde cholangiopancreatography in cirrhosis - a systematic review and meta-analysis focused on adverse events.
      Endoscopic papillary balloon dilatation (EPBD) without sphincterotomy has been shown to be safe and effective treatment of CBD stones in patients with liver cirrhosis.
      • Kawabe T.
      • Komatsu Y.
      • Tada M.
      • et al.
      Endoscopic papillary balloon dilation in cirrhotic patients: removal of common bile duct stones without sphincterotomy.
      ,
      • Komatsu Y.
      • Kawabe T.
      • Toda N.
      • et al.
      Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases.
      A population-based study of cirrhotic patients has shown that EPBD is associated with lesser incidence of post-procedure bleeding than EST (1.9% vs. 3.5%).
      • Hung T.H.
      • Tseng C.W.
      • Chen Y.C.
      • Tseng K.C.
      • Hsieh Y.H.
      • Tsai C.C.
      Endoscopic papillary balloon dilation decreases the risk of bleeding in cirrhotic patients compared with endoscopic biliary sphincterotomy: a national population-based study.
      The risk of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, cholangitis, and bleeding is significantly higher in decompensated cirrhotics than that in compensated cirrhotics, and the MELD score can predict the risk of post-ERCP complication.
      • Inamdar S.
      • Berzin T.M.
      • Berkowitz J.
      • et al.
      Decompensated cirrhosis may be a risk factor for adverse events in endoscopic retrograde cholangiopancreatography.
      • Zhang J.
      • Ye L.
      • Zhang J.
      • et al.
      MELD scores and Child-Pugh classifications predict the outcomes of ERCP in cirrhotic patients with choledocholithiasis: a retrospective cohort study.
      • Leal C.
      • Prado V.
      • Colan J.
      • et al.
      Adverse events and acute chronic liver failure in patients with cirrhosis undergoing endoscopic retrograde cholangiopancreatography: a multicenter matched-cohort study.
      The incidence of acute-on-chronic liver failure (ACLF) is higher in patients who develop post-ERCP complications, especially cholangitis.
      • Leal C.
      • Prado V.
      • Colan J.
      • et al.
      Adverse events and acute chronic liver failure in patients with cirrhosis undergoing endoscopic retrograde cholangiopancreatography: a multicenter matched-cohort study.
      Patients with an MELD score ≥15 are three times more likely to develop ACLF after ERCP.
      • Leal C.
      • Prado V.
      • Colan J.
      • et al.
      Adverse events and acute chronic liver failure in patients with cirrhosis undergoing endoscopic retrograde cholangiopancreatography: a multicenter matched-cohort study.
      Thus, a thorough risk and benefit assessment should be performed before ERCP in decompensated cirrhotic patients. ERCP in patients with cirrhosis should be performed at high-volume centers and in expert hands to minimize the post-ERCP complications, which will subsequently reduce the rate of hepatic decompensation after ERCP. When the indication is strong, the benefit of ERCP still outweighs the risk among patients with cirrhosis.
      The frequency of GSs is higher in patients with cirrhosis of the liver than that in the general population, and it increases with severity of liver disease. Most of GSs in cirrhotics are pigment stones. Hepatitis C and NAFLD are strongly associated with increased lithogenesis. Asymptomatic GSs should be followed up closely and offered LC once symptomatic in Child-Pugh class A and B patients. In patients of Child-Pugh class C, conservative or minimally invasive procedures should be used to treat complications of GSs.

      Credit authorship contribution statement

      Bipadabhanjan Mallick: literature search, writing the manuscript and approval to final version. Anil C Anand: Conceptualization, editing the manuscript and approval to final version.

      Conflicts of interest

      The authors have none to declare.

      Funding

      None.

      References

        • Everhart J.E.
        • Ruhl C.E.
        Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas.
        Gastroenterology. 2009; 136: 1134-1144
        • Aerts R.
        • Penninckx F.
        The burden of gallstone disease in Europe.
        Aliment Pharmacol Ther. 2003; 18: 49-53
        • Unisa 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: 117-125
        • Dutta U.
        • Mallick B.
        Diseases of the Gall Bladder and Biliary Tract. API Textbook of Medicine.
        11th ed. Association of Physicians India, 2019: 1846
        • Acalovschi M.
        • Badea R.
        • Dumitrascu D.
        • Varga C.
        Prevalence of gallstones in liver cirrhosis: a sonographic survey.
        Am J Gastroenterol. 1988; 83: 954-956
        • Sheen I.S.
        • Liaw Y.F.
        The prevalence and incidence of cholecystolithiasis in patients with chronic liver diseases: a prospective study.
        Hepatology. 1989; 9: 538-540
        • Bouchier I.A.
        Postmortem study of the frequency of gallstones in patients with cirrhosis of the liver.
        Gut. 1969; 10: 705-710
        • Iber 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: 1593-1596
        • Fornari F.
        • Imberti D.
        • Squillante M.M.
        • et al.
        Incidence of gallstones in a population of patients with cirrhosis.
        J Hepatol. 1994; 20: 797-801
        • Conte 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: 49-52
        • Benvegnu 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: 293-298
        • Festi 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: 5282-5289
        • Orozco 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: 232-234
        • Maggi A.
        • Solenghi D.
        • Panzeri A.
        • et al.
        Prevalence and incidence of cholelithiasis in patients with liver cirrhosis.
        Ital J Gastroenterol Hepatol. 1997; 29: 330-335
        • Gibney E.J.
        Asymptomatic gallstones.
        Br J Surg. 1990; 77: 368-372
        • Diehl 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: 967-972
        • Schwesinger 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: 319-322
        • Coelho 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: 405-408
        • Buchner 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: 905-909
        • Del 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: 1061-1065
        • Acalovschi 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: 1856-1860
        • Fornari 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: 1403-1408
        • Conte D.
        • Barisani D.
        • Mandelli C.
        • et al.
        Cholelithiasis in cirrhosis: analysis of 500 cases.
        Am J Gastroenterol. 1991; 86: 1629-1632
        • Elzouki 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: 2946-2950
        • Park 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: 461-465
        • Chang 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: 644-650
        • Alvaro 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: 228-234
        • De 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: 271-276
        • Acalovschi 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: 412-417
        • Li 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: 1109-1114
        • Sarin S.K.
        • Guptan R.C.
        • Malhotra S.
        Increased frequency of gallstones in cirrhotic and non-cirrhotic portal hypertension.
        J Assoc Physicians India. 2002; 50: 518-522
        • Genzini 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: 52-59
        • Stroffolini T.
        • Sagnelli E.
        • Mele A.
        • Cottone C.
        • Almasio P.L.
        • Italian Hospitals' Collaborating G
        HCV infection is a risk factor for gallstone disease in liver cirrhosis: an Italian epidemiological survey.
        J Viral Hepat. 2007; 14: 618-623
        • Chang T.S.
        • Lo S.K.
        • Shyr H.Y.
        • et al.
        Hepatitis C virus infection facilitates gallstone formation.
        J Gastroenterol Hepatol. 2005; 20: 1416-1421
        • Acalovschi 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: 860-866
        • Alter 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: 17-35
        • Loria P.
        • Lonardo A.
        • Lombardini S.
        • et al.
        Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors.
        J Gastroenterol Hepatol. 2005; 20: 1176-1184
        • Fracanzani 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; 7e41183
        • Chen 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: 1737-1743
        • Jaruvongvanich 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: 2389-2396
        • Shen 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: 31-39
        • Poynard T.
        • Lonjon I.
        • Mathurin P.
        • et al.
        Prevalence of cholelithiasis according to alcoholic liver disease: a possible role of apolipoproteins AI and AII.
        Alcohol Clin Exp Res. 1995; 19: 75-80
        • Chawla A.
        • Puthumana L.
        • Thuluvath P.J.
        Autonomic dysfunction and cholelithiasis in patients with cirrhosis.
        Dig Dis Sci. 2001; 46: 495-498
        • Cahalane M.J.
        • Neubrand M.W.
        • Carey M.C.
        Physical-chemical pathogenesis of pigment gallstones.
        Semin Liver Dis. 1988; 8: 317-328
        • Carey M.C.
        Pathogenesis of gallstones.
        Am J Surg. 1993; 165: 410-419
        • Whiting J.F.
        • Narciso J.P.
        • Chapman V.
        • Ransil B.J.
        • Swank R.T.
        • Gollan J.L.
        Deconjugation of bilirubin-IX alpha glucuronides: a physiologic role of hepatic microsomal beta-glucuronidase.
        J Biol Chem. 1993; 268: 23197-23201
        • Vlahcevic Z.R.
        • Juttijudata P.
        • Bell Jr., C.C.
        • Swell L.
        Bile acid metabolism in patients with cirrhosis. II. Cholic and chenodeoxycholic acid metabolism.
        Gastroenterology. 1972; 62: 1174-1181
        • Vlahcevic Z.R.
        • Yoshida T.
        • Juttijudata P.
        • Bell Jr., C.C.
        • Swell L.
        Bile acid metabolism in cirrhosis. 3. Biliary lipid secretion in patients with cirrhosis and its relevance to gallstone formation.
        Gastroenterology. 1973; 64: 298-303
        • Schwartz C.C.
        • Almond H.R.
        • Vlahcevic Z.R.
        • Swell L.
        Bile acid metabolism in cirrhosis. V. Determination of biliary lipid secretion rates in patients with advanced cirrhosis.
        Gastroenterology. 1979; 77: 1177-1182
        • Allison M.E.
        • Wreghitt T.
        • Palmer C.R.
        • Alexander G.J.
        Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population.
        J Hepatol. 1994; 21: 1135-1139
        • Hui J.M.
        • Sud A.
        • Farrell G.C.
        • et al.
        Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected].
        Gastroenterology. 2003; 125: 1695-1704
        • Marchesini G.
        • Brizi M.
        • Bianchi G.
        • et al.
        Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.
        Diabetes. 2001; 50: 1844-1850
        • Bugianesi E.
        • Gastaldelli A.
        • Vanni E.
        • et al.
        Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.
        Diabetologia. 2005; 48: 634-642
        • Nervi F.
        • Miquel J.F.
        • Alvarez M.
        • et al.
        Gallbladder disease is associated with insulin resistance in a high risk Hispanic population.
        J Hepatol. 2006; 45: 299-305
        • Biddinger S.B.
        • Haas J.T.
        • Yu B.B.
        • et al.
        Hepatic insulin resistance directly promotes formation of cholesterol gallstones.
        Nat Med. 2008; 14: 778-782
        • Mathurin P.
        • Vidaud D.
        • Vidaud M.
        • et al.
        Quantification of apolipoprotein A-I and B messenger RNA in heavy drinkers according to liver disease.
        Hepatology. 1996; 23: 44-51
        • Zhang T.
        • Xie N.
        • He W.
        • et al.
        An integrated proteomics and bioinformatics analyses of hepatitis B virus X interacting proteins and identification of a novel interactor apoA-I.
        J Proteomics. 2013; 84: 92-105
        • Shi S.T.
        • Polyak S.J.
        • Tu H.
        • Taylor D.R.
        • Gretch D.R.
        • Lai M.M.
        Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins.
        Virology. 2002; 292: 198-210
        • Kao C.H.
        • Hsieh J.F.
        • Tsai S.C.
        • Ho Y.J.
        • Chen S.D.
        Evidence of impaired gallbladder function in patients with liver cirrhosis by quantitative radionuclide cholescintigraphy.
        Am J Gastroenterol. 2000; 95: 1301-1304
        • Koruk M.
        • Ozkilic S.
        • Savas M.C.
        • Celen Z.
        • Kadayifci A.
        • Ozkilic C.
        Evaluation of hepatic functions and biliary dynamics in patients with liver cirrhosis by quantitative scintigraphy.
        Hepato-Gastroenterology. 2003; 50: 1803-1805
        • Acalovschi M.
        • Dumitrascu D.L.
        • Nicoara C.D.
        Gallbladder contractility in liver cirrhosis: comparative study in patients with and without gallbladder stones.
        Dig Dis Sci. 2004; 49: 17-24
        • Pompili M.
        • Rapaccini G.L.
        • Caturelli E.
        • et al.
        Gallbladder emptying, plasma levels of estradiol and progesterone, and cholecystokinin secretion in liver cirrhosis.
        Dig Dis Sci. 1995; 40: 428-434
        • Loriot M.A.
        • Bronowicki J.P.
        • Lagorce D.
        • et al.
        Permissiveness of human biliary epithelial cells to infection by hepatitis C virus.
        Hepatology. 1999; 29: 1587-1595
        • Dunnington G.
        • Alfrey E.
        • Sampliner R.
        • Kogan F.
        • Putnam C.
        Natural history of cholelithiasis in patients with alcoholic cirrhosis (cholelithiasis in cirrhotic patients).
        Ann Surg. 1987; 205: 226-229
        • Schwartz S.I.
        Biliary tract surgery and cirrhosis: a critical combination.
        Surgery. 1981; 90: 577-583
        • Castaing D.
        • Houssin D.
        • Lemoine J.
        • Bismuth H.
        Surgical management of gallstones in cirrhotic patients.
        Am J Surg. 1983; 146: 310-313
        • Puggioni A.
        • Wong L.L.
        A metaanalysis of laparoscopic cholecystectomy in patients with cirrhosis.
        J Am Coll Surg. 2003; 197: 921-926
        • European Association for the Study of the Liver
        EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones.
        J Hepatol. 2016; 65 (Electronic address eee): 146-181
        • Yerdel M.A.
        • Tsuge H.
        • Mimura H.
        • Sakagami K.
        • Mori M.
        • Orita K.
        Laparoscopic cholecystectomy in cirrhotic patients: expanding indications.
        Surg Laparosc Endosc. 1993; 3: 180-183
        • Laurence J.M.
        • Tran P.D.
        • Richardson A.J.
        • Pleass H.C.
        • Lam V.W.
        Laparoscopic or open cholecystectomy in cirrhosis: a systematic review of outcomes and meta-analysis of randomized trials.
        HPB (Oxford). 2012; 14: 153-161
        • de Goede B.
        • Klitsie P.J.
        • Hagen S.M.
        • et al.
        Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and symptomatic cholecystolithiasis.
        Br J Surg. 2013; 100: 209-216
        • Cheng Y.
        • Xiong X.Z.
        • Wu S.J.
        • Lin Y.X.
        • Cheng N.S.
        Laparoscopic vs. open cholecystectomy for cirrhotic patients: a systematic review and meta-analysis.
        Hepato-Gastroenterology. 2012; 59: 1727-1734
        • Quillin 3rd, R.C.
        • Burns J.M.
        • Pineda J.A.
        • et al.
        Laparoscopic cholecystectomy in the cirrhotic patient: predictors of outcome.
        Surgery. 2013; 153: 634-640
        • Machado N.O.
        Laparoscopic cholecystectomy in cirrhotics.
        J Soc Laparoendosc Surg. 2012; 16: 392-400
        • Chmielecki D.K.
        • Hagopian E.J.
        • Kuo Y.H.
        • Kuo Y.L.
        • Davis J.M.
        Laparoscopic cholecystectomy is the preferred approach in cirrhosis: a nationwide, population-based study.
        HPB (Oxford). 2012; 14: 848-853
        • Delis S.
        • Bakoyiannis A.
        • Madariaga J.
        • Bramis J.
        • Tassopoulos N.
        • Dervenis C.
        Laparoscopic cholecystectomy in cirrhotic patients: the value of MELD score and Child-Pugh classification in predicting outcome.
        Surg Endosc. 2010; 24: 407-412
        • Gad E.H.
        • Kamel Y.
        • Alsebaey A.
        • Mohammed A.
        • Abdelsamee M.A.
        Laparoscopic cholecystectomy in patients with liver cirrhosis: 8 years experience in a tertiary center. A retrospective cohort study.
        Ann Med Surg (Lond). 2020; 51: 1-10
        • Curro G.
        • Iapichino G.
        • Melita G.
        • Lorenzini C.
        • Cucinotta E.
        Laparoscopic cholecystectomy in Child-Pugh class C cirrhotic patients.
        J Soc Laparoendosc Surg. 2005; 9: 311-315
        • Curro G.
        • Cucinotta E.
        Percutaneous gall bladder aspiration as an alternative to laparoscopic cholecystectomy in Child-Pugh C cirrhotic patients with acute cholecystitis.
        Gut. 2006; 55: 898-899
        • Xu Q.
        • Gu L.
        • Wu Z.Y.
        Operative treatment for patients with cholelithiasis and liver cirrhosis.
        Hepatobiliary Pancreat Dis Int. 2007; 6: 479-482
        • Jayadevan R.
        • Garg M.
        • Schiano T.
        • Divino C.M.
        Is cholecystostomy a safe procedure in patients with cirrhosis?.
        Am Surg. 2014; 80: 1169-1171
        • Shrestha R.
        • Trouillot T.E.
        • Everson G.T.
        Endoscopic stenting of the gallbladder for symptomatic gallbladder disease in patients with end-stage liver disease awaiting orthotopic liver transplantation.
        Liver Transpl Surg. 1999; 5: 275-281
        • Schlenker C.
        • Trotter J.F.
        • Shah R.J.
        • et al.
        Endoscopic gallbladder stent placement for treatment of symptomatic cholelithiasis in patients with end-stage liver disease.
        Am J Gastroenterol. 2006; 101: 278-283
        • Chen Y.K.
        • Nichols M.T.
        • Antillon M.R.
        Peroral cholecystoscopy with electrohydraulic lithotripsy for treatment of symptomatic cholelithiasis in end-stage liver disease (with videos).
        Gastrointest Endosc. 2008; 67: 132-135
        • Itoi T.
        • Coelho-Prabhu N.
        • Baron T.H.
        Endoscopic gallbladder drainage for management of acute cholecystitis.
        Gastrointest Endosc. 2010; 71: 1038-1045
        • Jain D.
        • Bhandari B.S.
        • Agrawal N.
        • Singhal S.
        Endoscopic ultrasound-guided gallbladder drainage using a lumen-apposing metal stent for acute cholecystitis: a systematic review.
        Clin Endosc. 2018; 51: 450-462
        • James T.W.
        • Krafft M.
        • Croglio M.
        • Nasr J.
        • Baron T.
        EUS-guided gallbladder drainage in patients with cirrhosis: results of a multicenter retrospective study.
        Endosc Int Open. 2019; 7: E1099-E1104
        • Acalovschi M.
        • Badea R.
        • Pascu M.
        Incidence of gallstones in liver cirrhosis.
        Am J Gastroenterol. 1991; 86: 1179-1181
        • Sugiyama M.
        • Atomi Y.
        • Kuroda A.
        • Muto T.
        Treatment of choledocholithiasis in patients with liver cirrhosis. Surgical treatment or endoscopic sphincterotomy?.
        Ann Surg. 1993; 218: 68-73
        • Isozaki H.
        • Okajima K.
        • Morita S.
        • et al.
        Surgery for cholelithiasis in cirrhotic patients.
        Surg Today. 1993; 23: 504-508
        • Prat F.
        • Tennenbaum R.
        • Ponsot P.
        • et al.
        Endoscopic sphincterotomy in patients with liver cirrhosis.
        Gastrointest Endosc. 1996; 43: 127-131
        • Mashiana H.S.
        • Dhaliwal A.S.
        • Sayles H.
        • et al.
        Endoscopic retrograde cholangiopancreatography in cirrhosis - a systematic review and meta-analysis focused on adverse events.
        World J Gastrointest Endosc. 2018; 10: 354-366
        • Kawabe T.
        • Komatsu Y.
        • Tada M.
        • et al.
        Endoscopic papillary balloon dilation in cirrhotic patients: removal of common bile duct stones without sphincterotomy.
        Endoscopy. 1996; 28: 694-698
        • Komatsu Y.
        • Kawabe T.
        • Toda N.
        • et al.
        Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases.
        Endoscopy. 1998; 30: 12-17
        • Hung T.H.
        • Tseng C.W.
        • Chen Y.C.
        • Tseng K.C.
        • Hsieh Y.H.
        • Tsai C.C.
        Endoscopic papillary balloon dilation decreases the risk of bleeding in cirrhotic patients compared with endoscopic biliary sphincterotomy: a national population-based study.
        Medicine (Baltimore). 2019; 98e16529
        • Inamdar S.
        • Berzin T.M.
        • Berkowitz J.
        • et al.
        Decompensated cirrhosis may be a risk factor for adverse events in endoscopic retrograde cholangiopancreatography.
        Liver Int. 2016; 36: 1457-1463
        • Zhang J.
        • Ye L.
        • Zhang J.
        • et al.
        MELD scores and Child-Pugh classifications predict the outcomes of ERCP in cirrhotic patients with choledocholithiasis: a retrospective cohort study.
        Medicine (Baltimore). 2015; 94: e433
        • Leal C.
        • Prado V.
        • Colan J.
        • et al.
        Adverse events and acute chronic liver failure in patients with cirrhosis undergoing endoscopic retrograde cholangiopancreatography: a multicenter matched-cohort study.
        Am J Gastroenterol. 2019; 114: 89-97