Screening for biliary atresia
Authors: Benjamin L. Shneider
Journal: Hepatology (2008)

Biliary atresia (BA) remains the leading single indication for pediatric liver transplantation and is a cause of significant morbidity and mortality in children.1 There are a number of distinct ways in which the outlook for children with biliary atresia might be brightened (Table 1). Prevention of this disease will require identification of the etiology of BA; however, with multiple proposed etiologies for BA in play, it will be a daunting task to devise strategies to prevent the fibroobliterative destruction of the biliary system that occurs in BA. Prevention will be particularly difficult if an aberrant immune reaction to a prevalent neonatal infection is found to be a common etiology.2, 3 Prevention of this prenatal infection would require a novel and challenging immunization strategy for newborn infants or their mothers. Such a strategy would likely miss the 10%-15% of BA cases that appear to be embryonic in origin. A second approach to enhancing outcomes would be to improve the efficacy of the hepatoportoenterostomy (HPE) or Kasai procedure. This might be accomplished by optimization of the timing of surgery, technically perfecting surgical approaches, and developing better perioperative medical regimens with the ultimate goal of enhancing postoperative bile drainage. A third avenue for improving outcomes would be to address long-term medical management including optimizing nutrition, promoting continued bile flow, minimizing episodes of ascending cholangitis, and slowing or arresting the development of fibrosis/biliary cirrhosis. BA, biliary atresia; HPE, hepatoportoenterostomy. The current work by Hsiao et al. and the Taiwan Infant Stool Color Card Study Group represents a major step forward in improving the outcome for infants with BA.4 The focus of this effort has been to optimize the timing of HPE. A number of clinical series have shown that outcome after HPE is related, at least in part, to the timing of the procedure with better results being observed in children who undergo the procedure earlier in life.5-9 It appears that outcomes may be better with surgery performed at less than 45-60 days and worse after 90 days of age. The exact age at HPE may not be the critical feature, but instead the duration of the disease process. The remarkable achievements of the current study derive from a comprehensive and effective educational program coupled to a network of centers that collaborate in the care of all children in Taiwan with BA. The ability to track outcomes in all of the newborn children in Taiwan has permitted an unprecedented ability to examine the efficacy of this approach. In a 2-year period, all neonates born in Taiwan, totaling more than 400,000 infants, were screened for BA using a relatively simple stool color card. Overall, 84% of infants with BA were identified in part by this screening method, with a remarkable nearly perfect record (34 of 35 cases) in the second year of the program. A more important outcome of this screening method was to improve the timing of HPE. The percentage of infants undergoing HPE before 60 days of age steadily increased with implementation of this program. In addition, there were no infants who were greater than 90 days of age at the time of HPE. This is an accomplishment that has not been possible in published large clinical series from the United Kingdom (5 of 148 cases; primary procedure liver transplant for late presentation), France (48 of 723 cases; primary procedure liver transplant for late presentation), Canada (42 of 349 cases; > 90 days at HPE), Japan (190 of 1181 cases; > 90 days at HPE), or the United States (12 of 100; > 90 days at HPE).8-12 The ultimate relevance of the screening program can be appreciated by examining the rate of clearance of jaundice after HPE, which improved from 37% to 60%. This improvement in outcome in Taiwan is accounted for in part by the absence of infants who underwent HPE at greater than 90 days of age. In the historical cohort, 15% of infants underwent surgery at more than 90 days, and the jaundice-free rate in this group was only 23%. Jaundice-free rates improved in infants less than 60 days of age, indicating that some of the observed effect relative to the historical control might be related to improvements in surgical or medical care. The group from Taiwan should be congratulated for completing an important step in improving outcomes in BA. The power of their approach, which involves education and clinical collaboration, could be applied to additional clinically relevant issues. In the current study, the mean age at identification of pale stools in infants with BA was 28 days, while the mean age at HPE was 55 days. A new area of focus in Taiwan might be an effort to reduce the time period from the identification of pale stools to the time of HPE. A goal of performing HPE prior to 45 days of age might yield even better rates of bile drainage. In addition, more expeditious work-up might increase the percentage of children who are less than 60 days of age at the time of HPE. Additional educational programs and establishment of relatively rapid diagnostic paradigms will be required to accomplish this important goal. The findings of the study by Hsiao et al. should encourage other health care systems to establish similar screening programs. The incidence of BA in Taiwan, estimated to be 1:4,000, is higher than that observed in many other countries where rates of 1:10-18,000 have been reported. Screening programs in the United States search for disorders with frequencies similar to that of BA (for example, phenylketonuria, with rates of 1:15,000, and medium chain acyl-CoA dehydrogenase, with rates of 1:20,000).13 The missing element for BA has been a convenient and efficient screening test, which may now be available.3, 4 What are the potential benefits and problems with instituting this approach? One immediate concern is cost, both for the establishment of the program and for evaluation of infants who are incorrectly identified by this method of screening. The costs of producing the informational cards would be minimal and certainly could be justified as part of routine anticipatory guidance. Protocols for handling reports of pale stools could be established within the framework of existing newborn screening programs. In the study by Hsiao et al., only 279 of 422,273 infants were found to have pale stools; this is an amazingly small proportion. The method for screening appears to be adequately sensitive, because very few cases of BA were missed, especially in the second year of the program. Two-thirds of the infants identified by the stool cards had "transient" pale stools that presumably could have been excluded as clinically irrelevant by a simple and inexpensive measurement of fractionated bilirubin. Thus, the costs of this program are not anticipated to be overwhelming. The benefits, on the other hand, could be tremendous. It is likely that the percentage of late referrals for HPE would drop significantly, yielding better short-term outcome in the form of clearance of jaundice. Total serum bilirubin level 3 months after HPE has been shown to be an excellent biomarker that predicts good outcome at least as defined by the absence of a need for liver transplantation in the first 2 years of life.12 Thus, this type of program is likely to yield a reduction in the need for early transplantation and would reduce the prevalence of complications of end-stage liver disease in the first few years of life. Late referral for HPE is also a theory advanced in malpractice cases. Programs like this would reduce the number of these claims and yield important savings. In summary, the Taiwan Infant Stool Color Card Study Group has very convincingly shown that initiation of an educational program coupled with a relatively simple screening system is feasible and has the ability to increase earlier recognition and diagnosis of biliary atresia. This health care advance translates into a measurable improvement in clinical outcome, in the form of improved biliary drainage after HPE. This type of screening program should be strongly considered by policy makers for health care systems in other countries. Continued advances like this one are sure to brighten the horizons for families with children with BA.