Treating biliary atresia: the challenge continues

Since Dr. Morio Kasai described the Kasai portoenterostomy (KPE) in 1955, few medical or surgical advances have improved transplant-free survival in neonates with biliary atresia (BA). Early diagnosis and successful surgical drainage via the KPE continue to be the mainstays of treatment. The development of new therapies for BA have been hindered by a lack of understanding of events that incite this obliterative cholangiopathy.

Murine studies using an infectious model of neonatal bile duct injury support the role of the adaptive and innate arms of the immune system in the pathogenesis of BA (1). However, translation of these findings in mice to human BA have been limited. For example, administration of corticosteroids after KPE, a long-utilized treatment thought to reduce inflammation and progressive fibrosis, did not improve post-KPE bile drainage or change overall survival of children with their native liver in a previous trial (2).

In this issue of JPGN, Mack et al. report their findings from a phase I/IIa trial of intravenous immunoglobulin (IVIg) following KPE in children with BA (3). Based on the pleiotropic nature of IVIg to modulate adaptive and innate immune responses, the authors hypothesized that IVIg might reduce post-KPE biliary and hepatic damage by neutralizing auto-antibodies or promoting regulatory T cells. Although Mack et al. demonstrate that IVIg therapy is safe and feasible to administer in neonates with BA, the trial did not show efficacy of IVIg as a potential therapy to improve post-KPE outcomes. Furthermore, patients treated with IVIg after KPE had a trend towards poorer survival with their native liver, suggesting there may be mild adverse effects related to IVIg treatment compared to placebo controls. These results appropriately reduced the authors’ enthusiasm for studying IVIg further as a potential therapy for BA.

Despite its negative results, this trial is an important contribution to—and model for future work on—treatments for BA. Carefully designed and monitored, prospective trials like this one are essential in the translation of bench findings to the bedside. This trial continues the Childhood Liver Disease Research Network’s commitment to building a solid evidence basis for clinical care in these children. Furthermore, this trial demonstrates the importance of testing potential therapeutics for these children in research trials, despite the challenges of performing studies in neonates with a rare disease.

The lack of treatment response by IVIg may be due to several factors. First, whether the inflammatory and immunological events that occur during the pathogenesis of BA in humans are pro-reparative vs. pathogenic remains unknown. Neutralization or suppression of inflammation in BA may have detrimental consequences if a part of the inflammatory response is pro-reparative in nature. Second, despite a reduction in bile duct inflammation after high-dose IVIg administration in mice, animals still had an elevation in serum direct bilirubin compared to healthy controls; thus, bile duct obstruction and cholestasis still occurred despite IVIg therapy. More importantly, animals treated with IVIg had no improvement in their overall survival (4). These data indicate that the reduction of inflammation after IVIg therapy did not eliminate serological evidence of bile duct obstruction and its systemic effects. Finally, there is compelling evidence that BA originates in utero (5). Therefore, administration of a postnatal therapy at the time of KPE may be too late to reverse the pathogenic events that lead to the progression of the disease.

Further studies focused on understanding perinatal immune mechanisms of liver inflammation and injury may shed light on BA pathogenesis. The fetal and neonatal liver is a highly complex and dynamic immunologic environment. In addition to the abrupt exposure to a plethora of new foreign antigens, newborns encounter new microbes from which they must protect themselves (6). The fetal and neonatal liver also has unique demands as it relinquishes its role as the primary hematopoietic organ during this developmental window. Understanding the immunologic mechanisms involved with maintaining tissue homeostasis and responding to injury in the fetal and neonatal liver may elucidate the biological events that lead to BA, thereby providing specific targets for therapy.