Thank you. I'd like to thank the ASLD for inviting me to speak. Here's my disclosure. So our case today is a two-month-old female infant with jaundice, mild hepatosplenomegaly, elevated liver tests including elevated direct bilirubin of 3.2 milligrams per deciliter. And after a liver biopsy she has an intraoperative cholangiogram confirming biliruatresia followed by the CASI hepatoportoenterostomy. The questions raised with this case include what are the risk factors and best performing diagnostic tests for biliruatresia? Are there clinical and molecular markers that predict outcome? What are the adjuvant therapies that improve the CASI surgical outcome? And for all the adults in the room, adult hepatologists, how likely will this patient survive into young adulthood with their native liver and how should we best monitor for morbidities? So biliruatresia is a progressive inflammatory sclerosing lesion of the biliruatree that presents with extrahepatic obstruction by age three months. At the time of diagnosis the intrahepatic biliruatree entails a periductal inflammation as well as fibrosis. The extrahepatic biliruatree is partially or completely occluded as shown here. At diagnosis the extrahepatic remnant is removed and a CASI hepatoportoenterostomy is performed in an attempt to reestablish bioflow. In general the sooner you intervene with the CASI procedure the better the outcome. Classifications of biliruatresia include isolated biliruatresia without any other anomalies and that's the vast majority in 84% of cases. In 10% of cases there is syndromic biliruatresia or biliruatresia splenic malformation with spleen anomalies such as the polysplenia shown here and laterality defects. Syndromic BA is rare in China and the reason for this is unclear. 6% of cases include biliruatresia with other anomalies not associated to laterality defects and then there's a rare cystic extrahepatic biliruatresia form. The etiology of biliruatresia is not known and the current theory is that in the genetically predisposed individual there is a prenatal bileduct injury that may be triggered either by a virus infection or toxin induced and that's followed shortly after birth by autoinflammatory and autoimmune responses that further damage the biliruatresia leading to fibrosis. There may also be a component of a unique developmental susceptibility to biliruatresia pathogenesis and this entails differences between the neonatal and adult biliruatresia, for example, differences in the glycocalyx or the collagen content in the submucosa. So what are the risk factors in best performing diagnostic tests for biliruatresia? One of the largest risk factors is based on geographic occurrence. The incidence of biliruatresia is highest in an indigenous New Zealand Maori population with an incidence of 1 out of 920 live births. Next highest incidence include a Polynesian population in France and the Taiwanese at 1 out of 5,600 live births. Biliruatresia is most or least common in Europe at 1 out of 18,000 live births and the reason for these differences in geographical occurrence are not well understood and likely reflect both genetic and environmental susceptibilities. Other risk factors for biliruatresia include female gender, Asian or Pacific Islanders, genetic mutations associated with laterality defects for the splenic malformation, rare form and then preterm or low birth weight infants are at increased risk. However, the vast majority of biliruatresia patients are full term. Risk factors not associated with biliruatresia include family occurrence and twin status as well as other prenatal demographic information as shown here. Now the diagnostic workup of the jaundiced infant includes fractionating the bilirubin and if the direct is greater than 1 or greater than 20% of total, an ultrasound and L1A trypsin studies are performed. If these are negative, then you proceed with a liver biopsy and if it shows evidence of extrahepatic obstruction, you contact your surgeons and proceed with intraoperative cholangiogram and CASI procedure for biliruatresia. I'm going to be showing you some diagnostic biomarkers that may negate the need for liver biopsy in the near future. The first potential biomarker is the direct bilirubin level. This is a study that had access to direct bilirubin levels in the newborn nursery and they looked at their biliruatresia cohort and looked back at those direct bilirubin levels in the newborn nursery and found that the patients with biliruatresia actually had a mild, but significant increase in direct bilirubin level in the first 24 hours of life. And in that cohort in the first few days of life, they showed that the bilirubin actually increased, suggesting that the newborn direct bilirubin level may be a sensitive screen for biliruatresia. Now through proteomics arrays, the group in Cincinnati discovered that matrix metalloprotease 7 is also a sensitive diagnostic biomarker in biliruatresia. Patients with biliruatresia had significantly higher levels of MMP7 compared to other liver disease and normal controls. If you combine the MMP7 level with GGT, there was a 95% positive predictive value for the diagnosis of biliruatresia. Now what are MMPs? They're actually a group or family of endopeptidases involved in a variety of liver diseases as shown here. They're involved in extracellular matrix remodeling, liver regeneration, as well as both pro- and anti-inflammatory... or I'm sorry, anti-fibrogenic pathways. And finally, recently a group in Taiwan looked at the newborn stool color card screening as a diagnostic biomarker for biliruatresia. In the screening, the mother is given this stool color card at the time of discharge from the nursery and if the baby develops colors one through three, the pale acolic stool colors, the mother is advised to contact the physician and be seen immediately to work up for biliruatresia. And what they found is that those who underwent the stool color card screening, there was a significant increase in the percent that underwent the CASI operation in the first 30 days of life at 61% compared to only 35% in historical controls. And as I mentioned earlier in the diagnosis, this was associated with a significant improvement in overall survival in the stool color card screening year compared to historical. Next, are there clinical and molecular markers that predict outcome? As I mentioned earlier, the sooner you diagnose and intervene with the CASI, the better the outcomes. Shown here are the frequency of survival with the native liver and if you had your CASI procedure at 31 days, as shown in red, you had the best survival and if you did not get your CASI until 90 days, you had the worst survival. Overall, the five-year survival with the native liver was 41% at five years and only 22% at 30 years. The serum total bilirubin level at three months after the CASI also predicts two-year outcome in biliruatresia. At that three-month time point post-CASI, if your bilirubin is less than two, it's highly likely that you will survive with the native liver in the first few years of life. However, if your bilirubin is greater than six, it's dismal results and you will not survive with your native liver and those children should proceed more quickly to transplant. Now as I mentioned earlier in the pathogenesis, there is a proposed viral trigger in the prenatal time point and this is Dr. Davenport's work where he looked at the CMV status, one of the potential triggers, and found that if the patient was CMV positive at the time of diagnosis as shown in red, they had significantly poorer survival with the native liver as well as overall survival compared to patients who were CMV negative. Now what about MMP7 as not only a diagnostic biomarker but also a prognostic biomarker? This is a pilot study out of Taiwan where they looked at the MMP7 level at the time of diagnosis and found that the probability of needing a liver transplant was significantly higher if your MMP7 level was greater than 10 compared to less than 10.3. And finally, autotaxin, which we've heard earlier today in other cholangiopathies, also predicts outcome in bilirubin atresia. Autotaxin hydrolyzes LPC to LPA and then LPA has downstream effects on hepatic stellate cells including proliferation, survival, and increased fibrosis. This is a study looking at bilirubin atresia patients with their native liver. Average age was nine years and they found that those patients who were jaundiced or had portal hypertension had significantly higher autotaxin levels than those without those symptoms or normal controls. Importantly, autotaxin levels positively correlated with liver stiffness and negatively correlated with albumin suggesting that autotaxin is a sensitive marker for disease severity. Now what are the adjuvant therapies that improve outcome after the CASI procedure? This section is going to be very brief because there are no adjuvant therapies that improve outcome. In 2014, the Childhood Liver Disease Research Network performed a double-blinded, placebo-controlled, randomized trial on the use of corticosteroids in bilirubin atresia and this was 140 patients, and what they found was that there was no difference in the percent of patients with good bile flow at six months between steroids and placebo as well as no difference in survival with the native liver in the first two years. What they did find was a significant increase in serious adverse events in the steroid group. So shown here is the proportion of subjects without a serious adverse event and only 32% of the steroid group did not have a serious adverse event. Recently a pilot study on the immunosuppressive agent IVIG was trialed in bilirubin atresia. Again, no difference in outcome as far as survival with the native liver in the first year between historical placebo controls and IVIG and this lack of immunosuppressive response that we're finding in bilirubin atresia is very similar to the early studies in both PBC and PSC. So what is the future for therapies with bilirubin atresia? We know that there's excessive bile acid accumulation in this disease which can be both hepatotoxic as well as directly activate inflammation. So future targets will likely include FXR agonists that promote bile acid transport as well as ileal bile acid transporter inhibitors to inhibit the bile acid reuptake. And finally, how likely is it that this patient will survive into young adulthood with the native liver and how should we best monitor for morbidities? So shown here is Junko Sugai who is now 63 years old. She is the oldest survivor with bilirubin atresia with her native liver and she is shown with Dr. Neal from Sendai. The worldwide frequency of bilirubin atresia patients surviving with their native liver past the age of 20 is shown here. On average, 28% of patients will make it into adulthood with their own liver. However, the vast majority of them have complications related to cirrhosis with approximately 75% of patients having cirrhosis and 50% having portal hypertension, bacterial cholangitis as well as 30% having pruritus. Now with regard to the cholangitis, this study analyzed imaging of 22 patients, adult patients, median age was 25 years, with their native liver and looked for evidence of biliary abnormalities and what they found either through ultrasound, CT or MRCP is that almost 60% of these patients had radiographic evidence of a secondary sclerosing cholangitis and this included biliary stricture with duct dilation, intrahepatic ductal stones and a thickened intrahepatic bile duct wall. So it's recommended that in your adult patients with signs of cholangitis to obtain imaging studies and determine if you've got a biliary stricture or stone that you could intervene upon. Now a recent study came out that attempted to prognosticate the 16-year-old medical status and the subsequent development of a poor outcome in adulthood. So they had a cohort of 16-year-olds and they analyzed their clinical status and then asked the question, based on what they looked like at 16, could we predict what happened 15 years later? And what they found is that if the 16-year-old had a history of cholangitis in adolescence or had evidence of portal hypertension at the age of 16, both of those parameters were associated with significantly poor survival with the native liver 15 years later into adulthood. Overall, the survival with the native liver 10 years after that 16-year time point, so age 26, survival with the native liver was only 60%. And so they recommend that in our teens that we're taking care of, if they have cholangitis or portal hypertension, it's likely that they're going to have a very poor outcome in early adulthood and that we should consider intervening with liver transplant earlier on. Pregnancy in biliary atresia has also been analyzed. This is a study out of Sendai of 55 females, nine of whom had 14 pregnancies and 11 deliveries. All of those 11 children are doing well. However, there are significant maternal complications related to the 14 pregnancies including recurrent cholangitis and complications related to portal hypertension. And it's recommended that adults with biliary atresia and their native liver who are going to be pregnant should really be followed in the high-risk obstetrics unit. Other information on the status of biliary atresia patients surviving with their native liver, up to 88% will attend or complete college and have employment. Health-related quality of life parameters have found that biliary atresia patients who survive with their native liver have lower scores in vitality and general health compared to their transplanted cohorts. And females scored significantly lower than males on multiple parameters related to general health perception. So it's advised to keep a close eye out for these patients, specifically with issues related to their quality of life in adulthood. So in summary, biliary atresia is a puzzling disease with a likely multifactorial etiology. And as we understand the pathogenesis of this disease, it will lead to novel targeted therapies. Direct bilirubin in the first week of life, stool color cards, and MMP7 will clearly increase earlier diagnoses and improve outcomes. However, currently neither the direct bilirubin level nor the stool color card screen have been implemented in our newborn nursery and so public health initiatives are necessary to incorporate these as part of the newborn screen in the United States. There are multiple prognostic indicators associated with outcome in biliary atresia, including those listed here, and collectively they may provide a powerful tool to predict outcome. Survival with the native liver into adulthood in biliary atresia is fraught with complications related to cirrhosis and further research on best practices for management in this unique population is warranted. Thank you.

jaundice

biliary atresia

bilirubin issues

Kasai procedure

genetic predispositions