Outcome in adulthood of biliary atresia: A study of 63 patients who survived for over 20 years with their native liver

Authors


  • See Editorial on Page 231

  • Conflict of interest: Nothing to report.

Abstract

To define the long-term prognosis of children undergoing the Kasai operation for biliary atresia, a retrospective study was undertaken comprising 271 patients operated between 1968 and 1983. Twenty years after surgery, 63 (23%) were alive with their native liver. Serum bilirubin was normal in 21 of these patients, 12 also had normal serum aminotransferase and γ-glutamyltransferase activities, all but 2 had signs of cirrhosis, 44 had signs of portal hypertension, 19 had late bacterial cholangitis, and 6 had gallstones. Seven female patients gave birth to 9 children, and 3 male patients fathered 6 children. After age 20, 2 patients died of liver failure and 14 underwent or are awaiting liver transplantation. Twenty-year survival with native liver was significantly better in children with biliary atresia restricted to the hepatic ducts or with cysts at the porta hepatis. In conclusion, in the long term, less than 18% of infants with biliary atresia who are treated with corrective surgery may avoid liver transplantation, but even these patients require assiduous lifelong care. (HEPATOLOGY 2005;41:366–371.)

Congenital biliary atresia is characterized by complete obstruction of all or part of the extrahepatic bile duct and is always associated with abnormalities of the intrahepatic bile ducts.1, 2 Its cause is unknown, and its incidence ranges from 1 in 3,400 to 1 in 20,000 births.3 It results in death if left untreated. The Kasai operation or its variants constitute the first step in the surgical treatment of infants with biliary atresia4; liver transplantation is performed secondarily when bile flow is not restored or when complications of biliary cirrhosis occur. Many authors have reported the short-term results and prognostic factors of the Kasai operation, but few data are available regarding its results in adulthood. The present study was therefore undertaken to evaluate the liver status and general condition of patients with biliary atresia who underwent the Kasai operation and survived with their native liver for at least 20 years.

Patients and Methods

From 1968 to 1983, 271 infants were investigated and operated on for biliary atresia by the same medical and surgical teams. In all cases the diagnosis of biliary atresia was confirmed by examination during surgery and by histological study of the liver and biliary remnants.5 In 14 children, biliary atresia was associated with malformations described in the polysplenia syndrome. In 208 children, atresia involved the entire extrahepatic biliary tree, and all of these patients underwent hepatic portoenterostomy. In 43 children, the gallbladder, cystic duct, and common bile duct were patent, and all of these patients underwent hepatic portocholecystostomy (which had to be changed to hepatic portoenterostomy in 3 patients). In 19 children, a biliary cavity was communicating with dystrophic intrahepatic ducts at the porta hepatis, and all of these patients underwent cystojejunostomy. Lastly, 1 child with biliary atresia limited to the common bile duct underwent cholecystojejunostomy.

Of the 271 children, 1 child who survived with her native liver was lost to follow-up at age 13 years, 175 died (mostly before liver transplantation was commonly practiced in France), 32 underwent liver transplantation before the age of 20 years, and the remaining 63, who survived with their native liver for at least 20 years, form the basis of this report. The indications for liver transplantation before the age of 10 years were persistent jaundice and/or endstage liver disease in 17 children and hepatopulmonary syndrome in 1 child. The indications for liver transplantation between the ages of 10 and 20 years were hepatopulmonary syndrome in 5 children, pulmonary hypertension in 2 children, and persistent or relapsing jaundice in 7 children.

Data were collected from patients' hospital records at their latest checkup or at the time of transplantation for patients who underwent transplantation after the age of 20 years. These data concerned clinical evaluation of growth and liver and spleen sizes, biochemical study of liver function, and a search for ultrasonographic and endoscopic signs of portal hypertension and signs of hepatopulmonary syndrome, pulmonary hypertension, and liver cancer. Cirrhosis was considered to be present either when proven by liver histology (studied in 33 patients aged 5 months to 33 years; median, 7 years), or as shown on abdominal ultrasonography by a nodular liver with signs of portal hypertension, and/or when a hard, enlarged liver was associated with splenomegaly. In 44 patients, ursodeoxycholic acid was given at a dose of 600 mg/m2/d. Assessment of patients' condition also included data regarding general health, professional status, and whether they had children.

The following survival rates were calculated: (1) survival with native liver, which starts at birth and ends at either death or liver transplantation; and (2) patient survival, which starts at birth and ends at death. Actual survival rates, as well as categorical data, were compared using the χ2 test (with Yate's correction if indicated) and the Fisher exact test. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. All significance tests were two-tailed. Differences were considered significant at a P value of less than .05. All analyses were performed with Statview software, version 5.0 (SAS Institute Inc., Cary, NC).

Results

Twenty-Year Survival After Kasai Operation

After the Kasai operation, 63 (23%) of the 271 children survived with their native liver for at least 20 years. They comprised 27 females and 36 males. Two patients died of liver failure at the ages of 24 and 30 years, respectively. Ten patients underwent liver transplantation at ages 20 to 28 years; the indications for this transplantation were endstage liver disease in 6 patients, persistent jaundice in 3 patients, and hepatopulmonary syndrome in 1 patient. Two patients died within 6 months of transplantation. Therefore, at the time of writing, 59 patients are still alive, including 51 with their native liver; the oldest patient is 35 years old (Fig. 1).

Figure 1.

Curve for survival with native liver among 271 infants who underwent the Kasai operation for biliary atresia between 1968 and 1983.

The relationship between the type of operation and 20-year survival with native liver is indicated in Table 1. Twenty-year survival was significantly better in children who underwent hepatic portocholecystostomy or cystojejunostomy (35% and 40%, respectively) than in children who underwent hepatic portoenterostomy (19%). Age at surgery did not differ significantly in these two groups. However, when only patients surviving with their native liver and displaying normal total serum bilirubin at the last follow-up were considered, there was no significant difference in outcome according to type of initial surgery.

Table 1. Survival With Native Liver Among 271 Children Undergoing Surgery for Biliary Atresia According to Type of Surgery
 Type of Surgery
Hepatic PortoenterostomyHepatic PortocholecystostomyOthers*TotalP Values
  • Abbreviation: NS, not significant.

  • *

    Cystojejunostomy, 19 patients; cholecystojejunostomy, 1 patient.

Number of children2084320271 
Alive with native liver at 20 years40 (19%)15 (35%)8 (40%)63 (23%).02
Median age at operation (d) of patients alive with native liver at 20 years (range)68 (27–136)73 (32–150)66 (48–163)69 (27–163)NS
Alive with native liver and normal serum bilirubin at last follow-up15 (7%)3 (7%)3 (15%)21 (7.7%)NS

The median age at the time of operation was 69 days (range, 27-163) and was 90 days or more in 12 patients (19%). The relationship between 20-year survival and age at operation is shown in Table 2. Twenty-year survival with native liver was significantly better in children who were operated on before the age of 90 days. However, there was no significant difference according to age at initial surgery in patients alive with a native liver and normal serum bilirubin at the last follow-up.

Table 2. Survival With Native Liver Among 271 Children Undergoing Surgery for Biliary Atresia According to Age at Time of Surgery
 Age at Initial Surgery
≤90 Days>90 DaysTotalP Value
  1. Abbreviation: NS, not significant.

Number of children18190271 
Alive with native liver at 20 years51 (28%)12 (13%)63 (23%).0064
Alive with native liver and normal serum bilirubin at last follow-up17 (9%)4 (4%)21 (7.7%)NS

Only 1 of the 14 children with associated polysplenia syndrome is alive with a native liver after 20 years. Of the other 13, 6 died of end-stage liver disease before liver transplantation became available, 4 died of bacterial infection, 1 died of unexplained sudden death, and 2 underwent liver transplantation. Twenty-year survival with native liver was similar in children who were operated on during the early period of study (1968-1977) and the late period (1977-1983) (25 of 125 [20%] vs. 38 of 146 [26%]; P value not significant).

Characteristics of the 63 Patients Alive With Their Native Liver at 20 Years or More (Tables 3 and 4)

Growth.

Adult height was equal to or above the mean in 49 patients. The tallest man measured 190 cm; the tallest woman, 176 cm. Two women had a height below −1.5 SD; 1 had had an intracranial hemorrhage and bacterial meningitis at the age of 5 years combined with growth hormone deficiency and primary amenorrhea, and 1 had mental retardation and ventricular dilatation. Except for these patients, all the girls had their first menstrual periods between the ages of 12 and 15 years. All male patients had achieved pubertal maturation.

Table 3. Hepatic Complications in 63 Patients Who Survived With Their Native Liver for 20 Years or More After Surgery for Biliary Atresia
ComplicationNumber of Patients
Pruritus13
Total serum bilirubin concentration >17 μmol/L42
Prothrombin time <70%19
Cirrhosis61
Portal hypertension44
Gastrointestinal bleeding20
Late bacterial cholangitis19
Gallstones6
Hepatopulmonary syndrome1
Table 4. History of 6 Long-term Survivors With a Native Liver After Surgery for Biliary Atresia who Presented With Gallstones
PatientType of SurgeryAge at Appearance of Symptoms (yr)Type of SymptomsSite of LithiasisTreatmentOutcome
1Cystojejunostomy17–20Relapsing bacterial cholangitisIntrahepaticPartial hepatectomyAlive and well
2Cholecystojejunostomy21Acute bacterial cholangitisBiliodigestive anastomosisSurgical removal of stoneAlive and well
3Hepatic portocholecystostomy9JaundiceGallbladderCholecystoduodenostomy 
  17JaundiceMultiple intrahepaticPatient refused transplantationDeath at age 23
4Hepatic portocholecystostomy17Fortuitous findingGallbladderNoneAlive and well
5Hepatic portocholecystostomy20Fortuitous findingGallbladderNoneAlive and well
6Hepatic portocholecystostomy24Jaundice Liver failureGallbladderAwaiting liver transplantation 

Liver Condition.

Hard hepatomegaly and splenomegaly were present in 21 and 29 patients, respectively. Thirteen complained of pruritus. Total serum bilirubin levels were within normal limits (below 17 μmol/L) in 21 patients (including 33% of survivors); 12 of these patients also displayed normal serum γ-glutamyltransferase and transaminase activities. Total serum bilirubin levels were elevated (range, 18-656 μmol/L) in the 42 remaining patients; 26 of these (62%) had a normal serum bilirubin level at least once but experienced a relapse of jaundice later. The others never had normal serum bilirubin levels. All patients with elevated total serum bilirubin levels at or after 20 years also had elevated serum transaminase levels (range, 2-7 × N) and γ-glutamyltransferase levels (range, 1.5-30 × N). Prothrombin time was below 70% in 19 patients, all with elevated total serum bilirubin levels; however, in 7 of these patients, serum bilirubin levels were only slightly above normal (<40 μmol/L). Serum albumin concentrations were below 3.5 g/dL in 11 patients, all with elevated total serum bilirubin levels; in 2 of these patients the serum bilirubin concentration was only slightly above normal (<40 μmol/L). Histological, clinical, and/or ultrasonographic signs of cirrhosis were present in all but 2 patients. One large liver nodule (>6 cm) was seen on ultrasound in 5 patients and proven by histology to be a regenerative nodule; serum alpha-fetoprotein levels were normal in all patients studied. Two patients are hepatitis C virus carriers.

Portal Hypertension.

Clinical (splenomegaly), ultrasonographic, or endoscopic signs of portal hypertension were present or had been detected previously in 44 of the 63 20-year survivors with their native liver. Gastrointestinal bleeding had occurred in 20 patients at ages 2 to 27 years (median, 8 years). Three patients bled after age 20 years. Thirteen children underwent a successful surgical portosystemic shunt; none of them had further bleeding at follow-ups ranging from 4 to 22 years (mean, 15 years), but 1 patient presented with a transient episode of encephalopathy at age 22 years, 19 years after surgery. Four other patients underwent sclerosis or ligation of varices, and 2 received propranolol. Eleven of the remaining 17 patients in whom upper gastrointestinal endoscopy (performed at ages 16 to 24 years) disclosed esophageal varices are also being given propranolol. Another patient bled from a peptic ulcer related to Helicobacter pylori infection. One patient presented with hepatopulmonary syndrome at the age of 24 years.

Biliary Lesions.

Nineteen patients, all of whom underwent hepatic portoenterostomy, cystojejunostomy, or cholecystojejunostomy, presented at ages 17 to 30 years with at least one episode of acute bacterial cholangitis, which responded to antibiotics. Six patients presented with gallstones during the follow-up period (Table 4): in all but one of these patients, the gallbladder had been used for surgery; in 2 patients the stones were asymptomatic, but the other 4 patients presented with jaundice and/or bacterial cholangitis.

Quality of Life.

Complete information regarding quality of life was available for 52 patients. Thirty-eight can be considered to lead a normal life, because 21 are regularly employed and 17 are university students. Twenty are married or have a stable partnership. Seven female patients have given birth to 9 children, 2 of them small for their birth date. Three male patients have each fathered 2 healthy children. Six patients are suffering from depression, and 3 of them are heavy drinkers.

Outcome at Last Follow-Up.

Of the 271 children operated on for biliary atresia between 1968 and 1983, 51 are currently alive with their native liver. However, 4 of these survivors are awaiting liver transplantation because of permanent jaundice and bilirubinemia above 150 μmol/L; survival without the immediate need for liver transplantation can therefore be estimated at 17% of the cohort. All but 2 of the 51 survivors have cirrhosis; 21 (7%) have normal serum bilirubin levels; 8 (3%) have normal transaminase and γ-glutamyltransferase activities and no signs of portal hypertension; and 5 (2%) have normal transaminase and γ-glutamyltransferase activities, no signs of portal hypertension, and no late cholangitis.

Discussion

If untreated, children with biliary atresia rarely survive beyond the age of 3 years.6 Regular use of the Kasai operation since the late 1960s and of liver transplantation since the mid-1980s has significantly improved the prognosis; consequently, the successive use of these two types of surgery by experienced teams currently yields an overall short- and medium-term survival of approximately 90%.7 Liver transplantation is chiefly needed when the Kasai operation fails to restore a significant bile flow and jaundice persists; such children undergo liver transplantation in the first years of life. However, reports on the medium-range outcome of the Kasai operation after a significant improvement in bile flow8, 9 indicate that liver transplantation nevertheless has to be performed later in some of these children for relapse of jaundice or the complications of portal hypertension. The results reported here in a group of 63 patients who were operated on for biliary atresia and reached adulthood indeed indicate that, except for a small minority of patients, the Kasai operation cannot be considered as a cure for the disease and that careful lifelong follow-up is necessary to detect the complications of biliary cirrhosis that require liver transplantation, even well into adulthood. This is chiefly because biliary atresia is not restricted to the extrahepatic bile duct; thus even children in whom the Kasai operation has been successful display abnormalities of the intrahepatic biliary tree, including stenoses, dilatation, and sometimes pseudocystic areas. The resulting image on cholangiograms is similar to that of sclerosing cholangitis.10 This has two main consequences: (1) ongoing cholestasis, which further aggravates (although at a variable pace) the cirrhosis already present in virtually all children at an early age11; and (2) bile duct damage due to bacterial cholangitis in children whose bile ducts are directly in contact with the gut cavity, and cholelithiasis, the risk of which may be greater in children whose gallbladder was patent and used for anastomosis.

Even when biliary atresia is successfully treated via the Kasai operation, it is an ongoing disease that, as already indicated, requires careful management throughout life. This becomes clear when one compares the results of the present study of 63 children who had surgery for biliary atresia between 1968 and 1983 and survived for 20 years with their native liver to the results for 40 children who survived with their native liver for more than 10 years after surgery performed between 1968 and 1977.8 The rates of survival with native liver for the 20- and 10-year groups (23% vs. 32%), as well as the proportions with normal serum bilirubin levels (33% vs. 52%) and normal liver function tests (21% vs. 27%), were all less satisfactory in the 20-year population, but the proportion of children with portal hypertension (69% vs. 70%) was high in both groups. Early detection of the cardiopulmonary complications of portal hypertension is especially important: here, 6 of the 85 patients who were operated on between 1968 and 1983 and survived for over 10 years with their native liver developed hepatopulmonary syndrome between the ages of 10 and 24 years, while 2 developed pulmonary hypertension at ages 10 and 11 years, respectively.12 The risk of liver cancer also must be carefully explored.13, 14

There are few reports of the rate of survival with native liver for 20 years or more in children who have undergone surgery for biliary atresia. In one report by the Sendai group,15 survival with native liver was 40% (45 of 112 children who underwent surgery between 1969 and 1980). In another report by the Tokyo group,16 survival with native liver was 14% (16 of 115 children who underwent surgery between 1968 and 1985); here the proportion of survivors was intermediate (23%). There is little information in the previous reports to explain the differences in survival, although the longer experience of the Sendai group may have helped to improve their results. The results of this group also show that fewer than 10% of patients survive with their native liver after age 30 years (7 of 78 children who underwent surgery between 1951 and 1968).

Furthermore, little information has been published on the medical status of survivors into adulthood with a native liver after the Kasai operation. Two Sendai group reports respectively describe the condition of 21 and 30 patients aged 20 years or more. Although the proportion of patients with elevated serum bilirubin levels was smaller than in the present study, these two reports included examples of relapse of jaundice in adulthood and stressed the risks of portal hypertension and gallstones; moreover, the rate of cholangitis may have been higher than in the present series.17, 18 Similar observations were reported by another Japanese group for 6 (15%) of 39 patients who survived for 20 years after the Kasai operation.19

In a multicenter study,20 the anatomical pattern of the extrahepatic biliary remnant was shown to be linked to the medium-term results of the Kasai operation. Actuarial 10-year survival with native liver decreased from 83% in type I atresia (limited to the common bile duct) to 56% in type II atresia (atresia with a cyst in the liver hilum communicating with dystrophic intrahepatic ducts), 36% in type III atresia (biliary atresia with a patent gallbladder, cystic duct, and common bile duct), and 21% in type IV atresia (complete extrahepatic biliary atresia). The present single-center study shows that the prognostic value of the anatomical pattern persists in adulthood because 20-year survival with native liver was 40% in patients who underwent cholecystojejunostomy and cystojejunostomy (types I and II), 35% in those who underwent hepatic portocholecystostomy (type III), and 19% in those who underwent hepatic portoenterostomy (type IV). These results suggest that the severity of intrahepatic biliary lesions correlates with the severity of the extrahepatic lesions, and that the worst prognosis is associated with complete extrahepatic biliary atresia.

Many reports show that the positive medium-term results of the Kasai operation decrease when the age at surgery increases.9, 21–23 The present study shows the same trend in long-term results. Similarly, the unfavorable prognostic value of the polysplenia syndrome,20, 24 which was not found in some studies,21, 25 seems confirmed by our long-term results; in the present series, only 1 patient with this syndrome survived with a native liver for more than 20 years.

In conclusion, although the Kasai operation undoubtedly improves survival and should therefore be maintained as a first-line treatment for infants with biliary atresia, the results reported here indicate that assiduous, lifelong care must be given to all long-term survivors to identify those who will require liver transplantation well into adulthood for relapse of jaundice or the complications of cirrhosis.

Acknowledgements

We are grateful to our colleagues who provided follow-up information on some patients—especially Drs. E. Fort, Willy Alo, Marianne Besnard, Laurent Schouler, Stefano Martellossi, and Pietro Vajro—and to Mathilde Dreyfus for English-language editing.

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