Number of cholangitis episodes as a prognostic marker to predict timing of liver transplantation in biliary atresia patients after Kasai portoenterostomy

Biliary atresia (BA) is a potentially fatal disease in young infants, with an incidence ranging from approximately 1:3200 to 1:19,800 live births worldwide [1‐3]. Its pathogenesis involves progressive obliteration of biliary ducts. With early diagnosis and timely performance of Kasai portoenterostomy (KP), BA patients can have a significantly improved prognosis, and liver transplantation (LT) can be postponed [4‐6]. Since stool card screening is universally implemented in Taiwan, the positive prediction rate for BA diagnosis can reach 97%, and the rate of patients undergoing KP before 60 days of age is increasing nationally [7, 8]. However, some studies have reported a considerable number of BA patients still requiring LT during childhood in spite of the timely performance of KP [9‐11]. In addition, several risk factors, such as the jaundice-free period and occurrence of cholangitis, as well as age at the time of KP, are predictive of liver failure in BA patients after KP. Among these variables, cholangitis is one of the most commonly seen complications in BA patients after KP, and affects more than 50% of patients despite the use of treatment strategies employing corticosteroid and prophylactic antibiotics after the operation [12‐14]. Moreover, studies have shown that early cholangitis may have an impact on late-presenting liver failure, [15] and cholangitis within 3 months after KP appeared to associate with LT [16]. The aim of the study was to evaluate whether the number of cholangitis episodes could be used as a prognostic marker for LT in BA patients after KP.

Since the outcome of KP has greatly improved worldwide, BA patients are living increasingly longer after KP with a native liver [20‐22]. However, according to a study of a Japanese population, about 40% of BA patients still required LT within 5 years after KP [9] A few reports have shown that jaundice-free period, cholangitis, and age at the time of KP are associated with LT and late-presenting liver failure referred as patients who survive with their native liver more than 20 years [14, 15, 23] In the present study, BA patients who underwent KP before 60 days of age had a favorable outcome, which is consistent with the findings of previous reports [4, 23‐25].

A large cohort study from a North American multicenter consortium reported that 162 (62.1%) of 219 BA patients experienced cholangitis at least once after KP [26]. In addition, cholangitis has been reported to affect BA patients most commonly within 1–2 years after KP [19, 27, 28] and is considered an important factor in accelerating the process of cirrhosis [14, 29]. A multivariate analysis of risk factors of LT in 77 BA patients after KP found that cholangitis occurred in 59% patients. [13] However, early cholangitis, which was defined as occurrence within 6 months after KP, was not an independent risk factor for LT. In the current study, 67.7% of BA patients experienced cholangitis after KP, and over two-thirds of first-time cholangitis events occurred within 2 years in BA patients with and without LT, even though prophylactic steroid and antibiotics are used as a standard therapy for BA patients after KP in Taiwan [19]. We found that the cumulative incidence of cholangitis was not related to LT in the first 2 years after KP.

On the other hand, repeated cholangitis is a consideration that may influence a patient’s liver condition and lead to LT [30]. Our study indicated that the number of cholangitis episodes was significantly higher in patients with LT than in those without LT at the second year after KP. This suggests that repeated cholangitis within 2 years after KP may be an important factor contributing to LT. We would speculate that a greater number of cholangitis episodes leads to more inflammation in the liver. In addition, the number of cholangitis episodes was only significantly higher in the LT group than in the non-LT group at the second year after KP. This difference may be the result of younger patients having smaller canaliculi and relatively slow bile flow, thus allowing bacterial translocation to occur easily in both groups [13, 31]. However, when the system matures, bacterial colonization and scarring caused by portoenterostomy reaches a new balance, such that if cholangitis still occurs, bile flow will be inadequate, and obliteration of the intra-hepatic bile duct will progress which leads to liver failure. This mechanism may partially explain why patients in the LT group had cholangitis more frequently than those in the non-LT group.

Our study had some limitations. Since the median age at LT was 1.1 years, the association between cholangitis and LT was only observed within the first 2 years after KP. Second, operative approach and liver biochemistry data relevant to prognosis, such as bilirubin, aspartate transaminase, alanine transaminase, and r-glutamyl transpeptidase levels after KP, were not analyzed because these data are not encoded in the NHIRD. Therefore, it was not possible to observe any relationship between jaundice-free time and cholangitis. In addition, a multivariate analysis adjusting for these factors was not carried out. Finally, the number of cases and the follow-up period may have been inadequate, although this was a nationwide, 14-year cohort study.

The earlier BA patients developed cholangitis after KP, the more likely they were to require LT. However, our findings indicated LT was not related to age at first cholangitis episode, and the cumulative incidence of cholangitis was not related to LT in the first 2 years after KP. By contrast, the number of cholangitis episodes within 2 years after KP appeared to be a prognostic marker to predict future LT. This information could improve patient care and lead to more targeted research about optimizing treatment protocols for BA patients after KP.