Median And Long-term Outcome Of Cholecystocolostomy In Patients With Progressive Familial Intrahepatic Cholestasis

Background Progressive familial intrahepatic cholestasis(PFIC)is a cohort of autosomal recessive syndromes caused by bile acid secretion or excretion disorder due to gene mutation.Without treatments,patients progress to liver failure in early childhood.Biliary diversion strategies have been deployed to interrupt enterohepatic circulation to alleviate symptoms and delay progression to cirrhosis.Cholecystocolostomy has been the diversion method of choice at our institution.Purpose Aim to evaluate medium and long-term outcome for cholecystocolostomy and figure out the related risk factors and the mechanism of postoperative cholestasis.Methods Between August 2003 to May 2019,the clinical and follow-up data of 58 PFIC patients underwent cholecystocolostomy were retrospectively analyzed to evaluate the remission of postoperative cholestasis,growth,complications and survival rate.The patients were divided into three groups according to the postoperative total bile acid.Group1 was complete remission of cholestasis after operation.Group2 was recurrence after remission of cholestasis 12 months after operation.Group3 was refractory cholestasis.Chi square test was used to compare the preoperative clinical manifestations and liver fibrosis grades.Paired-t sample test was used to compare the weight standard deviation,defecation frequency and liver function indexes before and after operation.Kaplan Meier survival analysis was used to analyze survival rate of native liver.Kendall’s correlation analysis was performed on cholangitis,constipation,intrahepatic reflux from Y-loop and cystic duct stenosis to identify the risk factors for postoperative cholestasis.Chi square test and independent sample t test were used to analyze the differences between patients with end-stage liver disease and patients without end-stage liver disease in the proportion of postoperative recurrence and refractory patients,the incidence of preoperative liver fibrosis,the severity of fibrosis,the incidence of postoperative cholangitis and constipation,and the age of operation.Results The median follow-up time was 58 months(range:12-142months).Among the 58 cases,41 cases were followed up(M/F:20/21),including 20 cases(48.8%)in group 1,7 cases(17.1%)in group 2 and 14 cases(34.1%)in group 3.Thirty one cases(75.6%)gained weight to the level of normal children of the same age after operation,and moderately or severely underweight patients decreased from 60.9%to 24.4%after operation.Postoperative complications included stress ulcer(n=4),diarrhea(n=5),constipation(n=8),cholangitis(n=10,3 cases had intrahepatic reflux)and cystic duct stenosis(n=3).Kaplan Meier survival analysis showed that the 2-,5-,and 10-year survival rates of all patients were 82.9%,69%,and 69%,respectively.The 2-,5-,and 10-year survival rates of patients without liver cirrhosis were 89.2%,77.5%,and 77.5%,respectively.There was significant difference in liver fibrosis grade between group 1 and group 3(P=0.007).The postoperative weight of group 1 and group 2 were significantly increased(P<0.01),and the total bilirubin,direct bilirubin and total bile acid of group 1 and group 2 were significantly decreased postoperatively(P<0.01).In group 1 and group 2,100%and 83.3%of native liver survivors did not need drug treatment,while in group 3,all of them needed drug treatment.There were 21 cases of relapsed and refractory cholestasis,including hepatic fibrosis(n=10,24.4%,grade Ⅰ-Ⅱ:n=5;grade Ⅲ-Ⅳ,n=5),cholangitis(n=10,24.4%,single cholangitis:n=l,with constipation:n=7,with intrahepatic reflux:n=3,with cystic duct stenosis:n=1),constipation(n=8,19.5%,single constipation:n=1,with cholangitis:n=7,with intrahepatic reflux:n=1,with cystic duct stenosis:n=2),cystic duct stones(n=1,2.4%),unknown clinical causes(n=5,12.2%).Kendall’s correlation analysis showed that postoperative relapsed and refractory cholestasis were significantly correlated with preoperative fibrosis,cholangitis,constipation and cystic duct stenosis(P=0.002,P=0.000,P=0.002,P=0.42),intrahepatic reflux was significantly correlated with cholangitis and constipation(P=0.002,P=0.034),cholangitis was significantly correlated with constipation and cystic duct stenosis(P=0.000,P=0.014).Three patients(7.3%)with cystic duct stenosis were treated with enlargement of the cystic duct+cholecystocolostomy.Eleven cases progressed to end-stage liver disease after operation,and thirty cases did not progressed to end-stage liver disease.Chi square test showed that the rate of relapse and refractory cholestasis of the former was significantly higher than that of the latter(100%vs 33.3%,P=0.000),the rate of liver fibrosis of the former was significantly higher than that of the latter(54.5%vs 16.7%,P=0.041),and the former’ fibrosis was significantly severer than that of the latter(grade Ⅰ-grade Ⅱ:18.2%vs 16.7%,grade Ⅲ-Ⅳ:36.4%vs 0,P=0.003),and the operation age of the former was significantly later than that of the latter(median age:2.9 years vs 1.3 years,mean age:4.0 years vs 3.0 years,P=0.046).The proportion of end-stage liver disease in different operation age groups showed significant difference between≤1.25 years old group and>1.25 years old group(P=0.000).Conclusion The middle and long-term follow-up confirmed that cholecystocolostomy was effective in the treatment of progressive familial intrahepatic cholestasis,improving liver function,growth,survival rate of native liver and long-term drug use rate.The related factors that lead to postoperative relapsed and refractory cholestasis include preoperative liver fibrosis,constipation,cholangitis,intrahepatic reflux and postoperative cystic duct stenosis.The constipation,cholangitis,intrahepatic reflux and cystic duct stenosis influences each other.In order to improve the curative effect,patients should keep normal defecation after operation,and receive enlargement of the cystic duct+cholecystocolostomy when diagnosed cystic duct stenosis.Operation should be performed as early as possible.The best time of operation is before the occurrence of liver fibrosis and the recommended operative age is before 1.25 years old,which could improve curative effect,the rate of getting rid of drugs,and the survival rate of native liver.