Introduction

Biliary atresia is a uniquely perinatal disease that 30 years ago would have been universally fatal. With the development of the palliative Kasai portoenterostomy (Morio Kasai, 1922–2008), along with advances in pediatric liver transplantation (first performed by Thomas Starzl, 1926–2017), survival into adulthood and long-term quality of life are excellent. Biliary atresia is the main indication for liver transplantation in pediatrics.

Biliary atresia is a rapidly progressive, obliterative, fibrosing cholangiopathy affecting the intrahepatic and rebreak: extra-hepatic bile ducts. It occurs throughout the world and affects all ethnicities; however, there are differences in the incidence of biliary atresia according to geographic location, with the incidence in Europe being about 1 in 17,000 to 20,000.

Although biliary atresia is usually an isolated developmental defect, there are other development anomalies in up to 15% of cases that require thorough evaluation before transplant ( Table 34.1 ). This is known as biliary atresia splenic malformation syndrome (BASM).

The exact cause of biliary atresia remains unknown, but it is thought that a number of pathological processes may result in the same clinical phenotype of biliary atresia. A postulated pathogenesis includes viral infection, genetic polymorphisms, ciliopathy, autoimmune and alloimmune mediation, and toxins. There is no recurrence of the disease following transplantation.

Kasai Portoenterostomy

The Kasai portoenterostomy is a palliative operation aiming to reestablish bile flow. It is usually carried out using a transverse laparotomy incision following immediately after diagnostic operative cholangiography. The entire extrahepatic biliary tree is excised by transecting the bile duct remnant of the porta hepatis at the level of the liver capsule and exposing the remaining ductules. A jejunal Roux loop is anastomosed to the exposed cut surface to enable bile to enter the bowel.

A successful Kasai procedure is defined by the clearance of jaundice within 6 months, which in expert centers occurs in up to 60% of cases. If the Kasai procedure is not successful at establishing bile flow, liver transplantation will be required. Factors influencing successful bile flow include the following:

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  Age at Kasai—the success rates are lower when the Kasai procedure is performed at more than 6 weeks after birth.

  
  
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  Signs of chronic liver disease at the time of the Kasai procedure include ascites and intraabdominal varices.

  
  
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  Prematurity may perhaps be attributed to diagnostic difficulties or a more severe phenotype.

  
  
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  Concomitant cytomegalovirus (CMV) infection confers a worse prognosis.

  
  
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  Prophylactic antibiotics are used to reduce the risk of cholangitis within the first 3 months after birth.

However, the Kasai procedure is a palliative operation, because even with the clearance of jaundice, the intrahepatic bile ducts remain diseased, and chronic liver disease develops. Lifelong hepatology specialist follow-up will be required to manage the chronic liver disease and identify complications that will require liver transplantation; most patients with biliary atresia will require liver transplantation at some time. In patients who clear their jaundice and have their native liver at 2 years of age, up to 50% will survive to adulthood with their native livers but may need transplantation as adults. There is, however, a 6% risk of pre-transplantation mortality because of complications of chronic liver disease.

Liver Transplantation

Liver transplantation for biliary atresia is an excellent therapeutic option, with up to a 95% 5-year survival. It is curative for the liver disease. Survival rates and quality of life following transplantation are good.

However, children may clinically deteriorate while on the waiting list, despite adequate and complete medical management. The Eurotransplant registry suggests that those who require listing at a very early age (< 6 months) with advanced liver disease, as demonstrated by a high pediatric end-stage liver disease (PELD) score in 25% of cases, died while awaiting transplantation. This information aids in the prioritizing of patients. However, the PELD score does not accurately differentiate the severity of the liver disease in biliary atresia compared with other liver diseases.

It is important to provide support for families while awaiting transplantation, because patients may have a significant period of time on the liver transplantation waiting list.

Indications

Primary Transplantation

This is necessary if at presentation the child already has signs of advanced liver disease (e.g., hepatosplenomegaly, ascites, intraabdominal varices), because in this setting a Kasai procedure is unlikely to be successful and could potentially cause decompensation of liver function. This is more likely if the child presents late (> 10 weeks). However, if the child presents late but does not have advanced liver disease, the Kasai procedure may still be successful and mitigate the need for early transplantation.

Unsuccessful Kasai Procedure

If bile flow is not established following the Kasai portoenterostomy, liver disease progresses rapidly, and these children usually need a liver transplantation within the first 2 years of life ( Fig. 34.1 ). Bilirubin levels continuing to be elevated at 1 and 3 months following the Kasai procedure, as well as abnormal hepatic vascular flow, and have been shown to be predictive of the need for early transplantation; this should aid clinicians in identifying patients who would benefit from listing early after the Kasai procedure.

A child with biliary atresia with a failed Kasai procedure. Shown is jaundice, a distended abdomen attributed to ascites, with protrusion of the umbilicus, and prominent abdominal veins. The abdomen is distended by ascites; the child’s arms and legs show cachexia because of her severe liver disease, despite receiving supplemental nasogastric tube feeding.

Success after surgery can best be judged by the restoration of bile flow and clearance of jaundice. At 3 months post Kasai, there is a clear difference in 2-year transplant-free survival between children with total serum bilirubin less than 2 mg/dL and those with total bilirubin more than 6 mg/dL (84% vs. 16%; P < .001). If the jaundice persists, the transplant-free survival at 3 years is only 20%. Therefore, it is prudent to evaluate for transplantation early to avoid the development of complications.

Recurrent Life-Threatening Cholangitis

A small number of children develop severe cholangitis, which is life threatening and requires intensive care support. In these cases, liver function and bilirubin levels may be normal; however, prevention of further episodes of life-threatening sepsis is by liver transplantation.

Failure to Thrive

Poor nutritional weight is a negative predictor of outcome following transplantation, and all attempts should be made to avoid it. In those whose weight is faltering despite intensive nutritional support, transplantation should be carried out as early as possible. With an unsuccessful Kasai procedure, failure to thrive is inevitable. There is malabsorption of lipids and protein-energy malnutrition, resulting in failure to thrive and developmental delay. Nasogastric tube feeding is often necessary.

Supplementation with fat-soluble vitamins ( Table 34.2 ) will be needed. Metabolic bone disease and fractures are common. Failure to thrive despite nutritional support is an indication for liver transplantation.

Table 34.2

Fat-soluble vitamin supplementation

Supplement	Dosage
Vitamin A	5000 units/day
Ergocalciferol (vitamin D)	1200 IU/day
Alfacalcidol (aid calcium absorption)	50 ng/kg/day
Vitamin E—α-tocopherol acetate or polyethylene glycol (Vedrop)	50 mg/day 25 IU/kg/day
Vitamin K	2.5 mg/day
Ursodeoxycholic acid	10 mg/kg twice daily

 

Portal Hypertension

Although a successful Kasai procedure will lead to the resolution of jaundice, fibrosis of the liver often continues, resulting in the development of portal hypertension. This can be predicted from the degree of fibrosis found at the time of the Kasai procedure. It is usually identified by increasing spleen size, resulting in hypersplenism. Patients with increasing spleen size should be investigated for upper gastrointestinal varices and managed with band ligation as necessary. In a small cohort of patients, the portal hypertension is not amenable to medical therapy and therefore is an indication for liver transplantation. It has been postulated that in these children a shunt could be considered, and a recent publication by Guérin et al. reported that a surgical shunt in this setting could delay the need for liver transplantation by many years.

Transjugular intrahepatic portosystemic shunt placement may also be possible as a rescue therapy as a bridge to transplantation in some pediatric patients, but the development of hepatic encephalopathy is high. Complications of the shunt, such as encephalopathy or hepatopulmonary syndrome (HPS), are also indications for transplantation.

Up to 25% of patients with biliary atresia develop variceal bleeding. A variceal bleed may compound the poor function of the liver, resulting in further decompensation and the need for transplantation.

Pruritus

This is a rare indication for transplantation in biliary atresia, because the pruritus is often not as severe as in other cholestatic conditions. However, in rare cases in which daily activity is impaired, liver transplantation should be considered.

Hepatopulmonary Syndrome

HPS is defined as a defect in arterial oxygenation caused by the presence of intrapulmonary vascular dilations in the context of liver disease. The hypoxia onset is often insidious and causes few symptoms in the early stages. Pulse oximetry, microaggregation studies, and ventilation perfusion scans are diagnostic. Liver transplantation is the only effective treatment. HPS may progress quickly and is associated with increasing mortality. Right-to-left shunting in this setting is a risk for the development of a brain abscess.

Malignancy

Hepatoblastoma and hepatocellular carcinoma have been identified in children who have biliary atresia with their native liver. Alpha-fetoprotein level determination may be useful in patients who are identified to have nodules in the liver on imaging. Both are indications for transplantation, with excellent outcomes. Often, the tumors are identified following explantation and histological examination of the cirrhotic liver. There has been a case report of an adult whose native liver developed cholangiocarcinoma that was only detected in the explanted liver.

Portopulmonary Syndrome

Portopulmonary hypertension is more commonly seen in adults with chronic liver disease; it is defined as pulmonary arterial hypertension complicated by portal hypertension, with or without advanced hepatic disease. It can be difficult to identify in children. Therefore, this needs a high index of suspicion but is important to diagnose to facilitate medical therapy optimization of pulmonary hypertension and improve outcomes following transplantation. Without treatment, significant portopulmonary hypertension is associated with heart failure following transplantation, with a high mortality rate. The brain natriuretic peptide level increases in portopulmonary hypertension and hence could be a potential marker of early disease. Such a marker would aid in listing patients for transplantation before significant pulmonary disease becomes a contraindication.

Hepatorenal Syndrome

Hepatorenal syndrome is defined as the development of renal failure in patients with severe liver disease (acute or chronic) in the absence of any other identifiable cause of renal pathology. It is owing to severe renal vasoconstriction and results in poor urine output, with low urinary and serum sodium levels. It is rare in children but may lead to the need for dialysis. Medical therapy with vasopressors such as terlipressin may improve hepatorenal syndrome, but liver transplantation is curative. Following isolated liver transplantation, renal function improves to normal within 1 month and is sustained long term.

Cardiomyopathy

Cirrhotic cardiomyopathy is a known complication of chronic liver disease but is poorly identified in children. When severe, it is associated with increased length of stay in intensive care, increased need for inotropic support, and multiorgan dysfunction. If identified, consideration should be given to listing early for transplantation. In most patients, however, the cardiac changes are mild and reversible after liver transplantation.

Considerations While Awaiting Liver Transplantation

A holistic approach to care while awaiting transplantation could be provided by the multidisciplinary team at a center that can manage all the complications of end-stage liver disease, including transplantation. The team may include a pediatric hepatologist, transplantation surgeon, nurse, dietician, social worker, psychologist, and pharmacist.

Technical Considerations for Transplantation in Biliary Atresia

The portal vein is often underdeveloped, so consideration is required about the need for an interpositional graft. A computed tomography scan may be required before transplantation to assess this further. The hypoplastic nature of the portal vein also means that in children with biliary atresia post-transplantation, there is an increased risk of portal vein thrombosis resulting in portal hypertension. A technique in which the rex vein (within the left porta venous system) is attached via a conduit from the superior mesenteric vein can achieve excellent results. Situs inversus can lead to difficult anatomical construction of the vasculature and placement of the graft.

Transplants are often done in young infants, in whom a left lateral lobe can still be too large for the abdominal cavity. Infants may therefore have “respiratory embarrassment” requiring prolonged ventilation and a staged abdominal closure, and an abdominal patch may be necessary.

Most patients will have had previous surgery in the form of a Kasai procedure and hence will have adhesions, which may be complicated by intra-abdominal varices attributed to portal hypertension. The Kasai Roux-en-Y loop, however, can be reused at the time of the transplantation.

In the early post-transplantation period, despite grafts being adequately selected for size, the child can develop hyperperfusion of the liver via the portal vein, leading to symptoms of a small for size graft. Many of the recipients have large spleens; a better indicator about the graft being small for size may be the graft volume to spleen volume, with a ratio of over 0.88. Up to 80% of patients may develop small-for-size features of ascites, thrombocytopenia, and jaundice. It is therefore also important to consider the spleen size when selecting a graft. Spontaneous shunts can also have the same effect and may need closing.

Long-Term Biliary Atresia Care

With improvements in medical and surgical care, infants with biliary atresia are now surviving into adulthood with their native livers. Cirrhosis is inevitable in those surviving into adulthood with their native livers, with up to 70% also having significant portal hypertension and 14% having ascites. Adult hepatologists and transplant surgeons need to be knowledgeable of pediatric diseases and the complications that might arise in adulthood so that appropriate treatment is available, and the need for liver transplantation at any age is addressed.

Physicians need to understand the complications that can arise in adulthood as a consequence of the pediatric disease, such as managing portal hypertension in pregnancy. Successful pregnancy following transplantation for biliary atresia is possible. Pregnancy is higher risk than in the general population, with increased need for cesarean section, preterm delivery, and up to a 15% risk of graft rejection.

Deterioration of native liver function in adulthood will lead to the need for liver transplantation. In countries where living related transplantation is commonly practiced for young children, and a deceased donor may be required for adults, the waiting list mortality is extremely high. In centers where deceased donors are commonly used for transplantation, it is unlikely that adults are disadvantaged when on the transplantation waiting list as compared with pediatric listing.

Quality of life with a native liver in adulthood may be poorer than in those who have received a liver transplant because of the ongoing medical interventions that are necessary, such as the endoscopic management of portal hypertension.

Many children develop green discoloration and hypoplasia of the teeth. This is owing to the bilirubin-induced cell death of the odontogenic stem cells. This can be reversible following transplantation, although a minority of children do develop discoloration of their permanent teeth.

Children with chronic illness are at risk of developmental delay and reduced neurodevelopmental outcome. Children with an unsuccessful Kasai procedure are at high risk of neurodevelopmental delay. In a study of those who had a successful Kasai procedure, neurodevelopmental delay also occurred when measured at 2 years of age, but not by the same amount. It is important that services be in place to provide adequate neurocognitive support for these patients.

All patients who have biliary atresia, whether transplanted or not, will require ongoing medical care. Children with biliary atresia can face the same complications as those transplanted for other reasons, such as the risk of infection with Epstein-Barr virus or CMV because many are young and are naïve recipients.

Controversial Topics

The Kasai portoenterostomy was developed when liver transplantation was not a feasible option for infants because of a lack of organs and ineffective immunosuppression. In the current era, in which liver transplantation is a realistic option for infants, Wang et al. showed that primary liver transplantation is a feasible option, with good outcomes, while avoiding the neurocognitive effects of long-term liver disease and the risk of life-threatening portal hypertension and infection. Li et al., however, demonstrated there was no detriment to subsequent transplantation surgery in those who had a previous Kasai. Indeed, even in those who present at older than 3 months of age, a Kasai procedure in select cases can provide good long-term outcomes.

Early refashioning of the portoenterostomy in infants who fail to clear their jaundice is controversial. Saito et al. presented a series of patients who underwent a redo Kasai procedure. In these patients, the primary operation had failed to produce bile flow, and 49% of those who had a redo portoenterostomy had their native liver at 10 years; without this, they all would have had to undergo previous transplantation. However, Urahashi et al. showed that a relaparotomy was detrimental to the subsequent liver transplantation; because most patients will require liver transplantation, it may be prudent to avoid further surgery.

In patients who have cleared their jaundice and have sudden-onset cholestasis, surgical removal of the fibrous tissue to restore bile flow is considered in some centers. This may allow long-term native liver survival but again leads to a laparotomy, which may be detrimental in subsequent transplantation surgery.

Specifically, in children with biliary atresia, time waiting for liver transplantation appeared to be a predictive factor for poorer outcomes in regard to verbal intelligence, working memory, mathematical abilities, and reading. This supports transplantation in patients early, when symptoms of end-stage liver disease begin to develop.

Anecdotally, some centers try a short course of oral steroids in children in whom the jaundice cleared initially but who then develop sudden-onset cholestasis, without other features of infective cholangitis. The hypothesis here is that any inflammatory component will be decreased and further fibrosis reduced. This has been shown to be the case in rat studies of biliary obstruction.

Future Considerations

A previously universally fatal disease now has excellent treatment options, but much is still unknown about biliary atresia. Future considerations should include:

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  Can biliary atresia be identified in utero so that timely postnatal surgery can be planned?

  
  
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  With poor bile flow, there is ongoing upregulation of inflammatory markers and transcription factors such as GATA6, leading to changes in the liver parenchyma, which may account for this and may be targets for intervention in the future.

  
  
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  Should consideration be given to earlier transplantation to avoid the neurocognitive concerns of living with chronic liver disease?