BA remains an enigmatic disease, almost 100 years after it was first described and more than a half century since the Kasai portoenterostomy was first reported.12, 20
Since the initial description by Kasai, the operation has undergone a number of modifications aimed at improving chances of establishing and maintaining bile flow.21, 22
However, even when bile flow is re-established and jaundice resolves, progression to biliary cirrhosis and end-stage liver disease develops in a substantial portion of patients.23, 24
As a result, outcomes for infants with BA following portoenterostomy still remain unpredictable, unsatisfying, and relatively disappointing. This study represents the first report from our North American-based, multi-institutional collaboration to prospectively collect clinical data on infants with BA cared for at 16 academic medical centers and children’s hospitals with specialized expertise in hepatobiliary diseases.
Published data regarding the impact of age at time of surgery on outcome are somewhat conflicting. Younger age at diagnosis and surgery was originally cited by Kasai as an important prognostic factor; however, this was not corroborated in the larger subsequent report from the Japanese registry.25, 26
Since then, other authors also reported age at time of surgery as an important determinant of outcome. Notably, a recent analysis of a large cohort of Taiwanese children showed that increasing the fraction of children who underwent surgery before 60 days of age with earlier diagnosis through screening, improved the rate of resolution of jaundice as well as 3 and 5 years survival rates with their native livers.27
Paradoxically, Davenport reported a 5-year 45% transplant-free survival in a limited number of children who had surgery at more than 100 days of age.28
In our study, we observed resolution of jaundice in 46% of infants postoperatively, similar to results reported by the French (40%), Swiss (39.5%), and British (56%) although lower than that reported by the Japanese (60%).8, 29–31
Average age at time of the portoenterostomy procedure was 58 days, also consistent with those reported by the British (58 days), French (60 days), American (61 days) and Japanese (60–70 days).19
Disappointingly, there has been no appreciable improvement in terms of earlier referral and diagnosis of patients with BA in the U.S. between 1997 and 2006 in a survey of both academic and non-academic centers, as reported by Raval et al.32
In our study, there was no improvement in age at portoenterostomy compared to previous reports. In fact, nearly 10% of infants were deemed to be too old or as having such advanced liver disease, that they did not undergo portoenterostomy but were listed for primary liver transplant.
We found that infants younger than age 75 days undergoing Kasai portoenterostomy were no more likely than infants older than 75 days to achieve a total bilirubin less than 2.0 mg/dL within the first 3 months. However, being less than 75 days old at time of surgery was associated with improved transplant-free survival compared to the older infants. Previous studies indicate a difference in the outcome of portoenterostomy between extremes of age with patients younger than 30 days attaining greater transplant-free survival than those older than 120 days.33, 34
In our study, the impact of age on outcomes may have been blunted by the limited number of infants who underwent Kasai portoenterostomy at an early age. Additionally, there were a significant number of older children who did not undergo Kasai portoenterostomy because it was felt that this intervention would be unlikely to impact the need for transplantation. The decision to list these infants for transplant is affected by other indicators of chronic liver disease such as failure to thrive, portal hypertension, and cholangitis, and not solely based on persistence of jaundice. It may be that age is only a gross reflection of the cumulative damage to the liver and that many other factors may alter the tempo of progression to cirrhosis and irreversible damage. Others have suggested that age at surgery may not be independent of other variables such as inflammation, fibrosis, size of ductules in the excised specimen, hepatic stellate cell activation, poor nutritional status, and phenotype of the BA.30, 35–39
Extra-hepatic malformations have historically been associated with BA, particularly splenic anomalies known as BASM, which has been associated with a poorer prognosis.40
We categorized our associated anomalies either as those associated with BASM or those not associated with BASM. In both instances, the presence of BASM or non-BASM associated anomalies did not influence the clearing of jaundice after portoenterostomy but was associated with decreased transplant-free survival over two years.
The incidence of the various types, subtypes, and subgroups in our series did not differ dramatically from those reported by Ohi.41, 42
Consistent with the published literature, patients in the Ohi type III group had significantly worse outcome than those in the other two groups, and patients with subtype “a” had a higher probability of clearing jaundice after surgery and surviving two years without a transplant than patients in the other subgroups. Unfortunately, there were not enough patients to test the hypothesis that patients with subgroup ”a” had better results and survival with a “gallbladder” Kasai than with a conventional portoenterostomy.
This study was not designed to address the issue of predicting outcome based on histological criteria. The gross appearance of the liver at the time of surgery was predictive of survival, but the histologic grade of liver fibrosis did not have an association with either the clearance of the jaundice or the 2-year transplant free survival.
In our series, there were five laparoscopically-performed Kasai portoenterostomies. We opted to include the laparoscopic cases in our outcomes analyses since there were so few cases. Although not statistically significant, these patients tended to do poorer than those who underwent open Kasai procedures. This is consistent with the recently published observations of Ure et al
, where infants undergoing laparoscopically-performed Kasai procedures did so poorly compared to conventional open, historical controls that the authors halted the study.43
It is unclear why patients undergoing laparoscopically-performed Kasai procedures do poorly. We speculate that the complexity of the procedure combined with the very limited experience any one surgeon is likely to amass likely contribute to poorer outcomes for patients who undergo laparoscopically-performed procedures. Regardless, currently, the conventional, open Kasai portoenterostomy remains the standard approach for re-establishing biliary drainage in BA patients.
Success of the Kasai procedure in achieving biliary drainage is modest at best. Beyond this however, successful drainage is not a perfect predictor of survival with one’s native liver. As such, efforts to improve transplant-free survival should extend beyond “fine-tuning” the surgical procedure alone. Our analysis partially supports the concept that diagnosis and treatment of BA is associated with better drainage and transplant-free survival. Accordingly, efforts to identify and treat infants with BA at an earlier age may be worthwhile. Given the high rates of liver transplantation in BA patients, efforts to improve drainage or halt the progression of liver fibrosis towards cirrhosis and end-stage liver disease remain critical. We have recently completed enrollment of patients in our prospective, randomized, double-blinded, placebo-controlled trial investigating the efficacy of corticosteroids to improve biliary drainage following portoenterostomy and results of the trial will become available in two years. Continued efforts to better understand the pathogenesis of BA and to identify intervention points within the disease progression remain ongoing.
In conclusion, this study represents the first contemporary North American collaborative effort to prospectively collect demographic and operative data in a group of children with biliary atresia. Our findings largely validate those of past retrospective and registry analyses. The distribution of anatomic variants is essentially unchanged compared to past published reports. Age does appear to impact survival with one’s native liver. Early clearance of jaundice is similarly predictive of transplant-free survival. Our observations establish North American benchmarks for future studies and provide a framework to guide clinicians and families regarding prognosis and the potential need for transplantation.