Optimizing outcomes and bridging biliary atresia into adulthood
Authors: Ronald J. Sokol, Cara L. Mack
Journal: Hepatology (2005)

Biliary atresia (BA) is a progressive, inflammatory cholangiopathy that uniquely presents only during the first few months of life. It is characterized by initial inflammation, fibrosis, and obliteration of the extrahepatic bile ducts, with subsequent sclerosis of intrahepatic bile ducts culminating in biliary cirrhosis sometime during childhood in the majority of patients.1 Although the etiology of BA is not clearly understood, in most cases a perinatal insult (e.g., a viral infection) appears to trigger an immune (or autoimmune) response causing inflammation and sclerosis of a normally formed biliary tree (the perinatal form of BA). In approximately 20% of patients, defective development of the extrahepatic bile ducts is suggested by its clinical association with other major congenital anomalies of the gastrointestinal and cardiovascular systems (the embryonic form of BA). Without surgical intervention or liver transplantation, children with BA die from complications of end-stage liver disease in the first 2 years of life. If a child is diagnosed before reaching 3 to 4 months of age, surgical construction of a roux-en-Y portoenterostomy achieves bile flow in a variable percentage of patients and delays the need for liver transplantation, which is eventually required in 70% to 80% of patients in Western countries. Thus, BA accounts for almost 50% of all liver transplants performed in children. Approximately 28% to 35% of BA patients at experienced centers in the United Kingdom,2 France,3 Italy,4 and the United States5 survive at least 10 years with their native liver, compared with 53% in the Japanese BA Registry.6 At Tohoku University in Japan, Ohi7 reports that 75% of long-term survivors with their native liver (92 patients >10 yr of age with almost half >20 yr of age) lead a normal or nearly normal life, although the remaining patients have complications such as easy fatigability, esophageal varices, hypersplenism, hepatopulmonary syndrome, and recurrent cholangitis. Based on the experience in Japan, it appeared that perhaps three quarters of long-term survivors with BA could survive well into adulthood without the need for liver transplantation. BA, biliary atresia. In this issue of HEPATOLOGY, Lykavieris et al.8 report findings that raise questions about whether such favorable long-term, transplant-free survival is likely to occur in BA in Western countries. The group from the Hôpital Bicetre describe 63 BA patients in France who survived 20 years with their native liver following portoenterostomy, which was equivalent to 23% of patients who underwent BA surgery as infants. Although one third of long-term survivors had normal serum bilirubin concentration, all but two patients had signs of cirrhosis or portal hypertension, and 16 underwent liver transplant or died after 20 years of age. Thus survival without liver transplantation approached 10% at 30 years of age. Long-term complications included ascites, esophageal and gastric variceal hemorrhage, hepatopulmonary syndrome and pulmonary hypertension, recurrent and severe cholangitis, cholelithiasis, and the risk of alcoholic hepatitis.8 If these data are applicable to other Western countries, the long-term prognosis for survival with native liver in BA is not as favorable as that reported from Japan. The explanation for this difference in outcome may relate to differences in unknown genetic factors that favor long-term survival in Asian BA patients or to the known determinants for success of the initial portoenterostomy treatment for BA: age at portoenterostomy, the experience of the Center in which the surgery is performed, and differences in postoperative medical care. Close scrutiny of these factors may lead to potential interventions that can be instituted early in life to optimize the outcome of BA patients, leading to longer survival into adulthood without transplantation. In this editorial, we will examine the evidence that supports these interventions. The age at referral for corrective BA surgery is one of the most important factors determining outcome. Delays in diagnosis of BA remain a considerable problem in many countries. Neonatal jaundice through the first 2 weeks of life is frequently ascribed to "breast milk jaundice" or physiological jaundice. It is the presence of acholic stools, dark urine staining diapers, failure to thrive, enlarged liver or spleen, or persisting jaundice that should prompt evaluation for hepatobiliary disorders. In the United States, normal infants are generally seen by health care providers for routine care at ages 2 and 8 weeks. If evaluation of persisting jaundice is not performed after the 2-week visit but is delayed until after the 8-week visit, the infant is approaching the age limits for optimal results of portoenterostomy. It is generally regarded that effective bile drainage with resolution of jaundice can be achieved in up to 70% of BA patients if the portoenterostomy is performed before 60 to 70 days of life, while surgery performed between 70 and 90 days of life yields 40% to 50% of patients with good bile drainage, between 90 and 120 days up to 25% of patients, and after 120 days only 10% to 20% of patients.1 Long-term survival is similarly associated with age at the time of portoenterostomy.9, 10 Consequently, it is essential that infants who remain jaundiced after age 2 to 3 weeks be expediently evaluated for the presence of conjugated hyperbilirubinemia, and if present, for BA. To identify BA at an earlier age, some countries are evaluating the use of a stool color card as a screen for acholic stools, which would be brought in by the parents at the routine health visit in the first month of life.11 The experience of the center performing the portoenterostomy bears a strong influence on the likelihood that BA patients will drain bile following surgery, and, moreover, will survive with their native livers. Three studies have carefully evaluated this "center effect" on outcome. McClement et al.12 analyzed the surgical outcome for BA in 95 patients in the United Kingdom from 1980 to 1982. The 16 different centers performing portoenterostomies were grouped by the number of cases performed each year. In centers with 1 case per year, 11% of patients were jaundice-free following surgery; in centers with 2 to 5 cases per year, 29% became jaundice-free; and in centers with more than 5 cases per year, 43% were jaundice-free. The age at which surgery was performed was similar in all centers and did not account for the observed differences in outcome. In a large study from France, Chardot et al.9 analyzed survival data on 440 BA patients from 1986 to 1996 with a mean follow-up of 65 months. Univariate analysis revealed significant improvement in survival (with native liver, after liver transplant, and overall) in the center which performed more than 20 portoenterostomies per year (36.4 ± 3.9% 10-year survival with native liver) compared with centers that performed 3 to 5 portoenterostomies per year (20.9 ± 6.2%) and 2 or fewer per year (18.0 ± 3.5%). Multivariate analysis also demonstrated that the size (i.e., the experience) of the center was a significant predictor of survival. Finally, McKiernan et al.13 reviewed the outcome of infants with BA in the United Kingdom and Ireland from 1993 to 1995. Cases were identified prospectively by the British Pediatric Surveillance Unit, which distributes monthly reporting cards to all pediatricians. Ninety-one cases of BA were managed in 15 individual surgical centers with a mean follow-up time of 42 months. The two centers that performed more than 5 portoenterostomies per year had better restoration of bile flow and significantly better 5-year survival with native liver than the 13 centers that performed fewer than 5 per year (61.3 vs. 13.7% survival). Multivariate Cox regression analysis showed that the number of cases per year was the only significant independent factor predictive of survival without liver transplantation and overall survival. As a result of this study, the UK Department of Health issued a directive that surgery for BA be restricted to only three centers in England and Wales, resulting in improved survival during the subsequent 1999-2002 period.14 No similar studies have been performed in the United States to date; however, it is likely that there is a "center effect," reflecting the experience of the surgeons and other caregivers at individual centers. The third factor that may potentially influence outcome relates to different approaches to BA postoperative care among countries and centers. For example, in Japan infants are routinely treated with corticosteroids for up to 2 months following portoenterostomy (to reduce inflammation and stimulate bile flow), intravenous antibiotics for several weeks to months (to prevent ascending cholangitis), intravenous and then oral hydrophilic bile acids (to stimulate bile flow), and herbal therapy to improve liver health (e.g., kanzou or licorice root).1, 7, 10 The anti-inflammatory properties of corticosteroids are known to reduce production of inflammatory cytokines (e.g., tumor necrosis factor α, interleukin 1, interleukin 8), prostaglandins, and nitric oxide, all of which have been implicated in the pathogenesis of BA.15 Corticosteroids also inhibit inflammatory cell migration to sites of inflammation and promote the death of lymphocytes through apoptosis. The results of four open-label studies (without control groups) suggest that postoperative corticosteroids improve the likelihood of bile drainage and survival in BA.16-19 However, these studies are severely limited by the lack of randomization to corticosteroids versus placebo in a blinded fashion, the lack of systematic follow-up to assess the safety of corticosteroid therapy, and the confounding effect of different surgeons and postoperative care regimens in addition to the use of corticosteroids. Clearly, a prospective randomized controlled trial of sufficient size will be required to truly assess the potential value and determine the safety of corticosteroids in the management of BA. The use of perioperative intravenous antibiotics is commonplace at the time of Kasai portoenterostomy; however, the duration of intravenous antibiotics varies widely. Most institutions administer intravenous antibiotics for 2 to 3 days. As stated, many centers in Japan routinely administer intravenous antibiotics for the first 2 to 3 months after surgery. Oral antibiotics are frequently administered as prophylaxis against cholangitis for varying periods, initiated either immediately after surgery or following the first bout of cholangitis. Two oral antibiotics that have been used are trimethoprim-sulfamethoxazole and neomycin. Although there are no prospective trials of oral antibiotics, Bu et al.20 compared the efficacy of trimethoprim-sulfamethoxazole and neomycin used as prophylactic agents against recurrence of cholangitis until 3 years of age in 19 children who had one episode of cholangitis, and compared the results with those of 18 historical control patients who did not receive antibiotic prophylaxis. Patients who received prophylaxis had lower recurrence rates of cholangitis (relative risk of 0.52 and 0.42 for trimethoprim-sulfamethoxazole and neomycin, respectively). This study was limited by the retrospective nature of the control group. Prospective evaluation of timing and dosing of antibiotic prophylaxis is clearly needed. Ursodeoxycholic acid has been administered to BA patients for variable lengths of time following portoenterostomy, because of its cytoprotective, choleretic, and immunomodulatory effects.21 Although there are no published randomized controlled trials of ursodeoxycholic acid in BA, it has been shown to be of benefit in adults with primary biliary cirrhosis22 and in cystic fibrosis.23 However, BA patients with unsuccessful portoenterostomies may have virtually no bile flow from the liver, raising concern that ursodeoxycholic acid could be retained in the liver in these patients and be potentially toxic. Thus further research on the efficacy and safety of ursodeoxycholic acid in BA is needed. In summary, optimizing the outcome of patients with BA will require innovative approaches to establishing earlier diagnosis, the possible development of surgical centers of excellence, and improvement of current postoperative therapy. Clearly, large, randomized, controlled trials will be needed to determine the efficacy and safety of such therapies. Despite these efforts, the disappointing truth is that only a fraction of affected infants will survive into adulthood with our current treatments. Thus, there is an urgent need to better understand the etiology, genetics, and pathogenesis of BA so that novel therapeutic and preventative strategies can be developed in the future. The new BA Clinical Research Consortium supported by the National Institutes of Health24 and similar consortia in Europe and Asia will provide the platform and organizational structure to address many of the issues, with the goal of extending quality survival of children with BA into adulthood.