Pediatric Biliary Atresia

Biliary atresia represents the most common surgically treatable cause of cholestasis encountered during the newborn period. If not surgically corrected, secondary biliary cirrhosis invariably results. Patients with biliary atresia can be subdivided into 2 distinct groups: isolated biliary atresia (postnatal form) and associated situs inversus or polysplenia/asplenia with or without other congenital anomalies (fetal/embryonic form).

Postnatal biliary atresia

Patients with isolated biliary atresia (postnatal form) account for 65-90% of cases. The neonatal type is characterized by a progressive inflammatory lesion, which suggests a role for infectious and/or toxic agents causing bile duct obliteration.

Embryonic biliary atresia

Patients with associated situs inversus or polysplenia/asplenia with or without other congenital anomalies (fetal/embryonic form) comprise 10-35% of cases. The fetal/embryonic form of atresia is associated with other congenital anomalies.

See the image below.

Biliary atresia.

The pathology of the extrahepatic biliary system widely varies in these patients, and the following classification is based on the predominant site of atresia:

• Type I involves obliteration of the common duct; the proximal ducts are patent

• Type II is characterized by atresia of the hepatic duct, with cystic structures found in the porta hepatis

• Type III (>90% of patients) involves atresia of the right and left hepatic ducts to the level of the porta hepatis. These variants should not be confused with intrahepatic biliary hypoplasia, which comprises a group of distinct and surgically noncorrectable disorders.

Although histopathologic features of biliary atresia have been extensively studied in surgical specimens from excised extrahepatic biliary systems of infants undergoing portoenterostomy, the pathogenesis of this disorder remains poorly understood. Early studies postulated a congenital malformation of the biliary ductular system. Problems of hepatobiliary ontogenesis are suggested by the fetal/embryonic form of atresia that is associated with other congenital anomalies. However, the more common neonatal type is characterized by a progressive inflammatory lesion, which suggests a role for infectious and/or toxic agents causing bile duct obliteration.

In type III, the most prevalent histopathological variant, the fibrous remnant demonstrates complete obliteration of at least a portion of the extrahepatic biliary system. Ducts within the liver, extending to the porta hepatis, are initially patent during the first few weeks of life but may progressively be destroyed. The same agent or agents that damaged the extrahepatic ducts may be causative, and the effects of retained toxins in bile are contributing factors.

Identification of active and progressive inflammation and destruction of the biliary system suggests that extrahepatic biliary atresia likely represents an acquired lesion. However, no single etiologic factor has been identified. Infectious agents seem to be the most plausible candidates, particularly in the isolated (neonatal) form of atresia. Several studies have identified elevated antibody titers to reovirus type 3 in patients with biliary atresia when compared with controls. Other viruses, including rotavirus and cytomegalovirus (CMV), have also been implicated.

The disorder is rarely seen in infants who are stillborn or in premature infants, which supports a late gestational etiology. By contrast, infants with idiopathic neonatal hepatitis, which is the major differential diagnosis, are often preterm, small for gestational age, or both.

Infectious agents

No single agent has been identified as causative for biliary atresia, although the role of infecting organisms has been the most extensively studied.

Fischler et al reported cytomegalovirus (CMV) infection in almost 25% of affected infants in one study based on immunoglobulin M (IgM) serology.[2]  Interestingly, an even higher frequency of CMV infection has been found by Chang et al in cases of idiopathic neonatal hepatitis, lending support to the concept that both disorders are ends of the same pathological spectrum, originally described by Landing as infantile obstructive cholangiopathy.[3]

Investigations of reovirus type 3 have yielded conflicting results. Wilson et al noted in one study that the virus damages the bile ducts and hepatocytes in mice,[4]  whereas another study by Steele et al failed to demonstrate evidence of infection in infants with cholestasis.[5]

Other studies have examined the role of rotavirus groups A, B, and C and the common hepatitis viruses A, B, and C; however, no clear associations have been found. One study, using a murine model of biliary atresia induced by rhesus rotavirus, isolated trophism for the cholangiocyte to a specific genetic region.[6]

Genetic factors

The existence of the fetal/perinatal form of biliary atresia, frequently associated with other GI and cardiac anomalies, suggests the possibility of a disorder in ontogenesis. Studies have identified specific genetic mutations in mice with visceral heterotaxy and cardiac anomalies, defects similar to those found in conjunction with the fetal/perinatal form of biliary atresia.

Various genetic abnormalities, including deletion of the mouse c-jun gene (a proto-oncogene transcription factor) and mutations of homeobox transcription factor genes, are associated with hepatic and splenic defects. In a recent murine model, insufficient SOX17 expression in the gallbladder and bile duct epithelia resulted in biliary atresia. However, confirmation of a similar abnormality in human gene expression, and its potential etiopathogenetic role in this disorder, must await further studies.[7]

Other causes

Disorders of bile acid synthesis are part of the differential diagnosis of biliary atresia. In fact, bile acids almost certainly contribute to ongoing hepatocellular and bile ductular damage in infants with the disorder. Although associated defects in bile acid metabolism may hasten progression of liver disease, no primary role for bile acids in the development of biliary atresia has been identified.

Several investigators have studied the potential effects of other etiological agents, including teratogens and immunological factors. Again, no clear correlations with biliary atresia have been demonstrated.

United States data

Individual studies suggest an overall incidence in the United States of 1 per 10,000-15,000 live births.

International data

The incidence of biliary atresia is highest in Asian populations, and it may be more common in Chinese infants compared with Japanese infants.

Race-, sex-, and age-related demographics

Incidence of biliary atresia is highest in Asian populations. The disorder also occurs in black infants, with an incidence approximately 2 times higher than that observed among white infants.

Extrahepatic biliary atresia is more common in females than in males.

Biliary atresia is a disorder unique to the neonatal period. Two presentations are described in this chapter (see Background). The fetal/perinatal form is evident within the first 2 weeks of life; the postnatal type presents in infants aged 2-8 weeks.

Data regarding outcome from centers worldwide widely vary. The initial success rate of Kasai portoenterostomy (for achieving bile flow) is 60-80%. Clearly, the most critical determinant of outcome remains age at the time of operation. Although individual centers have reported favorable surgical results in some infants older than 3 months, patients are significantly less likely to require early liver transplantation if the portoenterostomy is performed when they are younger than 10 weeks. In the postoperative period, the rate of decline in serum bilirubin levels directly correlates with a positive prognosis.

One study evaluated 244 infants who were enrolled in the prospective Childhood Liver Disease Research and Education Network and underwent Kasai portoenterostomy (KPE). The results noted that at 1 and 2 years post-KPE, the transplant-free survival rate was 53.7% and 46.7%, respectively. Risk of transplant/death was significantly lower in patients who achieved bile drainage within 3 months post-KPE, while it increased in patients with porta hepatis atresia, nonpatent common bile duct, biliary atresia splenic malformation syndrome, nodular liver appearance compared with firm, and age at KPE. No association with outcome was noted with gestational age, sex, race, ethnicity, or extent of porta hepatis dissection.[8]

Bile flow, even if achieved at surgery, may be inadequate in as many as one third of patients after the initial postoperative period. These children require early (< 2 y) liver transplantation. Practice guidelines for the evaluation of a patient for liver transplantation have been established by the American Association for the Study of Liver Diseases.[9]  Factors that predict improved long-term outcome after Kasai portoenterostomy include the following:

• Younger than 8 weeks at operation

• Preoperative histology and ductal remnant size

• Presence of bile in hepatic lobular zone 1

• Absence of portal hypertension, cirrhosis, and associated anomalies

• Experience of the surgical team

• Postoperative clearing of jaundice

The following 3 categories of patients with extrahepatic biliary atresia should be considered for reexploration following a Kasai or modified Kasai portoenterostomy:

• Infants who become jaundiced after an initial anicteric phase postoperatively

• Infants with favorable hepatic and biliary duct remnant histology at initial operation, who do not successfully drain bile

• Infants who may have had an inadequate initial surgery

Extrahepatic biliary atresia is the most common primary diagnosis in children requiring orthotopic liver transplantation (OLT), comprising more than 50% of patients with liver transplants in most series.[10]  Overall, a review demonstrated that 66% of infants undergoing the Kasai procedure ultimately required OLT, including more than 50% of patients who initially achieved bile drainage.

In most series reported to date, the primary indications for OLT are the symptoms of end-stage liver disease and/or hepatic failure, including progressive cholestasis, recurrent cholangitis, poorly controlled portal hypertension, intractable ascites, decreased hepatic synthetic function (eg, hypoalbuminemia, coagulopathy unresponsive to vitamin K), and growth failure.

As long-term outcomes following OLT in children continue to improve (along with increased living donor availability) using split-liver grafts, application of this surgical modality for early treatment of biliary atresia will likely increase, certainly in patients with inadequate bile flow following portoenterostomy.

A study by LeeVan et al that included 626 children with biliary atresia reported that even though those that underwent primary liver transplant had a higher mortality rate after 3 months, those who underwent primary liver transplant had a reduced risk of long-term mortality than those managed with biliary-enteric drainage treatment after 6 months.[11] ​

Morbidity/mortality

Prior to the development of liver transplantation as a therapeutic option for children with end-stage liver disease, the long-term survival rate for infants with biliary atresia following portoenterostomy was 47-60% at 5 years and 25-35% at 10 years. In one third of all patients, bile flow is inadequate following surgery, and these children succumb to complications of biliary cirrhosis in the first few years of life unless liver transplantation is performed. Following portoenterostomy, complications include cholangitis (50%) and portal hypertension (>60%).

Hepatocellular carcinoma may be a risk for patients with cirrhosis and no clinical evidence of portal hypertension. Progressive fibrosis and biliary cirrhosis develop in children who do not drain bile. Thus, as discussed below (see Prognosis), liver transplantation may be the only option for long-term survival in most patients.[12]

A study by Leung et al evaluated 1,215 children (994 with biliary atresia, 221 with chronic liver disease) in the United Network for Organ Sharing registry data from 2003 to 2013 to investigate wait-list mortality associated risk factors, and outcomes of young children <  2 years of age. The study reported 12.4% wait-list mortality among this group and 8% posttransplant mortality. The wait-list mortality for children under 2 with chronic liver disease was 23.9% compared to 9.8% for bilateral atresia. The study also reported that the risk of death was 60% greater among patients with biliary atresia who did not have abdominal surgery (Kasai hepatoenterostomy) than among those with prior abdominal surgery.[13]

Complications

Complications following portoenterostomy in patients with biliary atresia include both acute and chronic problems. In the early postoperative phase, an unsuccessful anastomosis with failure to achieve adequate bile drainage is the most common complication. In this case, adequacy of bile flow may be predicted by the preoperative liver histology and the caliber of bile ductular remnants in the porta hepatis. In one third of all patients, bile flow is inadequate following surgery, and these children succumb to complications of biliary cirrhosis in the first few years of life unless orthotopic liver transplantation is performed.

Later in the course, complications related to progressive liver disease and portal hypertension occur in more than 60% of infants who achieved initial surgical success. Cholangitis develops in 50% of patients following portoenterostomy.

Hepatocellular carcinoma may be a risk for those patients with cirrhosis and no clinical evidence of portal hypertension. Progressive fibrosis and biliary cirrhosis develop in children who do not drain bile, and liver transplantation is the only option for long-term survival.

Detailed management of these complications is described in Histologic Findings, Medical Care, Consultations, Diet, and Medications.

Regardless of etiology, the clinical presentation of neonatal cholestasis is remarkably similar in most infants. Typical symptoms include variable degrees of jaundice, dark urine, and light stools.[14]

In the case of biliary atresia, most infants are full-term, although a higher incidence of low birthweight may be observed.

In most cases, acholic stools are not noted at birth but develop over the first few weeks of life. Appetite, growth, and weight gain may be normal.

Physical findings do not identify all cases of biliary atresia. No findings are pathognomonic for the disorder. Infants with biliary atresia are typically full term and may manifest normal growth and weight gain during the first few weeks of life.

Hepatomegaly may be present early, and the liver is often firm or hard to palpation. Splenomegaly is common, and an enlarging spleen suggests progressive cirrhosis with portal hypertension.

Direct hyperbilirubinemia is always an abnormal finding and it is typically present from birth in the fetal/embryonic form. Consider biliary atresia in all neonates with direct hyperbilirubinemia.

In the more common postnatal form, physiologic jaundice frequently merges into conjugated hyperbilirubinemia. The clinician must be aware that physiologic unconjugated hyperbilirubinemia rarely persists beyond 2 weeks. Infants with prolonged physiologic jaundice must be evaluated for other causes.

Harpavat et al reported that screening newborns with direct or conjugated bilirubin measurements detected all known cases of biliary atresia in their study population of 124,385 infants. In addition, after screening was instituted, the mean age at which infants underwent Kasai portoenterostomy was significantly younger (36 days vs 56 days before routine screening).[15]

In patients with the fetal/neonatal form (polysplenia/asplenia syndrome), a midline liver may be palpated in the epigastrium. The presence of cardiac murmurs suggests associated cardiac anomalies.

A high index of suspicion is key to making a diagnosis because surgical treatment by age 2 months has clearly been shown to improve the likelihood of establishing bile flow and to prevent the development of irreversible biliary cirrhosis.

The following laboratory studies may be included in the workup:

• Serum bilirubin (total and direct): Conjugated hyperbilirubinemia, defined as any level exceeding either 1 mg/dL (total bilirubin < 5 mg/dL) or 20% of total bilirubin (total bilirubin >5 mg/dL), is always abnormal. Interestingly, infants with biliary atresia typically show only moderate elevations in total bilirubin, which is commonly 6-12 mg/dL, with the direct (conjugated) fraction comprising 50-60% of total serum bilirubin.[16]

  • A study by Shneider et al found that infants whose total bilirubin does not fall below 2.0 mg/dL within 3 months of hepatoportoenterostomy were at high risk for early disease progression, suggesting they should be considered for liver transplantation in a timely fashion. The study also added that interventions increasing the likelihood of achieving total bilirubin < 2.0 mg/dL within 3 months of hepatoportoenterostomy may enhance early outcomes. ^[17]

• Alkaline phosphatase (AP), 5' nucleotidase, gamma-glutamyl transpeptidase (GGTP), serum aminotransferases, serum bile acids

  • These candidate tests have been proposed as a means to increase both sensitivity and specificity of routine laboratory evaluation. Unfortunately, no single biochemical determination accurately discriminates between biliary atresia and the other causes of neonatal cholestasis.

  • In addition to direct hyperbilirubinemia (a universal finding in neonatal cholestasis), enzyme abnormalities include elevated AP levels. In some cases, skeletal sources of AP can be differentiated from hepatic sources by measuring the liver-specific AP fraction, 5' nucleotidase.

  • GGTP is an integral membrane protein of the bile canaliculus and is elevated in cholestatic conditions. GGTP levels closely correlate with AP findings and are increased in all biliary obstructive conditions. However, GGTP levels may be within the reference range in some forms of cholestasis of hepatocellular origin.

  • Aminotransferase levels are not particularly helpful in establishing a diagnosis, although a markedly elevated alanine aminotransferase level (>800 IU/L) indicates significant hepatocellular injury and is more consistent with the neonatal hepatitis syndromes.

• Serum alpha1-antitrypsin with Pi typing: Alpha1-antitrypsin deficiency is the most common inherited liver disease that presents with neonatal cholestasis. The abnormal PiZZ phenotype, as determined by electrophoresis, is associated with neonatal cholestasis in approximately 10% of subjects.

• Sweat chloride (Cl): Biliary tract involvement is a well-recognized complication of cystic fibrosis (CF), and an association between meconium ileus in the newborn and cholestasis has been described. A diagnosis of CF should be strongly considered in any infant with direct hyperbilirubinemia, particularly if other associated signs or symptoms (ie, respiratory, GI) are present. Sweat Cl iontophoresis remains the criterion standard for diagnosing CF.

Ultrasonography

In neonatal cholestasis syndromes, ultrasonography can exclude specific anomalies of the extrahepatic biliary system, particularly choledochal cysts. Today, a diagnosis of choledochal cyst should be made in utero using fetal ultrasonography.

In biliary atresia, ultrasonography may demonstrate absence of the gallbladder and no dilatation of the biliary tree.[18] Unfortunately, the sensitivity and specificity of these findings, even in the most experienced centers, probably do not exceed 80%. For this reason, ultrasonography has been found unreliable in the evaluation of biliary atresia.

Hepatobiliary scintiscanning

Hepatobiliary imaging, using technetium-labeled diisopropyl iminodiacetic acid (DISIDA) nuclear scintiscan, is useful in evaluating infants with suspected biliary atresia. Unequivocal evidence of intestinal excretion of radiolabel confirms patency of the extrahepatic biliary system.

Two cautionary notes are required. First, reliability of the scintiscan is diminished at very high conjugated bilirubin levels (>20 mg/dL). Second, the test has been associated with a 10% rate of false-positive or false-negative diagnostic errors.

Duodenal intubation and duodenal string test

These studies are performed in some centers to evaluate duodenal bile excretion; however, in the author's experience, these studies are cumbersome, time-consuming, and unreliable.

Endoscopic retrograde cholangiopancreatography (ERCP)

This diagnostic procedure has previously been unavailable for use during infancy because of technical considerations. However, endoscope manufacturers are now producing side-viewing instruments that may be successfully used in neonates.

Although not yet widely used, reports have demonstrated the use of ERCP in diagnosing biliary atresia; one recent study reported a diagnosis of biliary atresia in 5 infants undergoing ERCP for neonatal cholestasis. With continued refinement and wider use of this diagnostic modality, ERCP may become part of the management algorithm in assessing neonatal direct hyperbilirubinemia, for which other studies have failed to confirm a diagnosis.[19]

Percutaneous liver biopsy

Percutaneous liver biopsy is widely regarded as the most valuable study for evaluating neonatal cholestasis. Morbidity is low in patients without coagulopathy. When examined by an experienced pathologist, an adequate biopsy specimen can differentiate between obstructive and hepatocellular causes of cholestasis, with 90% sensitivity and specificity for biliary atresia. See the image below.

Bile ductular proliferation in liver biopsy specimen (hematoxylin and eosin stain) from patient with biliary atresia. Also note hepatocellular bile staining as a consequence of cholestasis.

Several cholestatic conditions, including biliary atresia, may demonstrate an evolving histopathological pattern. Accordingly, biopsies are not usually diagnostic in those younger than 2 weeks, and serial samples, usually at 2-week intervals, may be required to reach a definitive diagnosis.

Intraoperative cholangiography

This procedure definitively demonstrates anatomy and patency of the extrahepatic biliary tract. Perform intraoperative cholangiography when liver biopsy findings suggest an obstructive etiology. The study is also indicated when biopsy results are equivocal or scintiscan fails to demonstrate clear evidence of duodenal bile excretion.

Despite the fact that several variants of extrahepatic biliary atresia have been described, suggesting a role for both ontogenic and acquired causes, no discernible qualitative differences in histopathological characteristics are evident. Surgical specimens demonstrate a spectrum of abnormalities, including active inflammation with bile duct degeneration, a chronic inflammatory reaction with proliferation of both ductular and glandular elements, and fibrosis. The progressive nature of the disorder is confirmed by its evolving histological picture.

Ultimately, evidence of biliary tract obstructive disease confirmed by liver biopsy findings determines which infants require exploratory laparotomy and intraoperative cholangiography. Portal bile ductular proliferation, bile plugging, portal-portal fibrosis, and an acute inflammatory reaction are characteristic findings in infants with neonatal cholestasis of an obstructive etiology.

Periodic acid-Schiff (PAS) staining of biopsy tissue can also be used to confirm a diagnosis of alpha1-antitrypsin deficiency by finding intracellular PAS-positive granules resistant to digestion by diastase.

No primary medical treatment is relevant in the management of extrahepatic biliary atresia. The pediatrician's objective is to confirm the diagnosis.

Once biliary atresia is suspected, surgical intervention is the only mechanism available for a definitive diagnosis (intraoperative cholangiogram) and therapy (Kasai portoenterostomy).

Following a thorough evaluation for causes of neonatal cholestasis, intraoperative cholangiography establishes the diagnosis of extrahepatic biliary atresia. During the operation, the fibrotic biliary tract remnant is identified, and the patency of the biliary system is assessed.

In cases in which biliary patency is associated with ductal hypoplasia, further surgical intervention is not indicated, and bile may be collected to evaluate for disorders of bile acid metabolism.

In the unusual circumstance of distal patency of the common duct with acceptable proximal luminal caliber, a modified portoenterostomy may be considered in place of the traditional Kasai procedure. However, the clinician must be aware that progression of disease pathophysiology may occur. The author has observed patients undergo modified portoenterostomies (gallbladder Kasai), only to subsequently experience continued inflammation and obliteration of the extrahepatic biliary tree and to ultimately require classic portoenterostomies.

In most cases of atresia, dissection into the porta hepatis and creation of a Roux-en-Y anastomosis with a 35-cm to 40-cm retrocolic jejunal segment is the procedure of choice.

Studies have shown that extension of the portal dissection beyond the portal vein bifurcation and the umbilical point in the left hilum may improve the likelihood of achieving adequate biliary drainage.

The evaluation of neonatal cholestasis may initially be carried out by the primary care provider, depending on the reliability of the laboratory in performing the necessary serum determinations indicated above. Obviously, further nonsurgical testing (eg, hepatobiliary imaging, liver biopsy) and surgical exploration should only be carried out in centers with considerable experience in managing this disorder.

The physician must not delay in the diagnosis of extrahepatic biliary atresia. Refer infants for appropriate subspecialty care as soon as a diagnosis of obstructive jaundice is suspected.

During the evaluation phase of biliary atresia, the infant's diet is typically not changed.

Postoperative breastfeeding is encouraged when possible because breast milk contains both lipases and bile salts to aid in lipid hydrolysis and micelle formation. Theoretically, breast milk may also protect against cholangitis, a common complication following portoenterostomy, by suppressing the growth of gram-negative and anaerobic flora. However, no data is available to support this claim.

Infants who are fed formula and who achieve adequate bile drainage should not require a special diet. Early in the postoperative course and when the status of biliary continuity may be in question, one of the medium-chain triglyceride-containing formulas (eg, Alimentum, Pregestimil) may enhance lipid digestion.

Long-term monitoring

A study examined the medical status of children with biliary atresia with their native livers after hepatoportoenterostomy (HPE) surgery. The study concluded that over 98% of this North American cohort of subjects with biliary atresia living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease. Cholangitis and fractures in long-term survivors also underscore the importance of ongoing medical surveillance.[20]

Follow-up care

A meta-analysis reported that moderate high-dose steroid therapy improves jaundice clearance, especially for infants who undergo hepatoportoenterostomy by 70 days of age. At the present time, however, and pending more randomized controlled trials with longer follow-up, routine post-Kasai corticosteroid therapy is not recommended.[21, 22]

In patients with chronic cholestatic conditions and bile duct patency, ursodeoxycholic acid (ie, ursodiol, UDCA) has also been shown to enhance bile flow.[23] For infants following portoenterostomy, UDCA may improve outcomes, and the drug was previously thought to be associated with minimal toxicity. However, one recent study evaluating UDCA in adults with primary sclerosing cholangitis found that long-term, high-dose treatment was associated with a higher rate of severe adverse events, including progression to cirrhosis. While the published experience with UDCA in biliary atresia has not shown similar deleterious outcomes, patients receiving long-term therapy with this agent should be carefully monitored.[24]

In order to prevent cholangitis postoperatively, prophylaxis with trimethoprim-sulfamethoxazole has been used on a long-term basis. Unfortunately, conclusive data supporting the use of this agent, or the other drugs described above, in the management of biliary atresia are not available.

In years past, high-dose methylprednisolone was used in the immediate postoperative period. Results from the START (Steroids in Biliary Atresia Randomized Trial) study was not superior to surgery alone. The trial concluded that the proportion of infants with biliary atresia who underwent hepatoportoenterostomy, high-dose corticosteroids following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Also, corticosteroid therapy was associated with earlier onset of serious adverse events in children with biliary atresia.[21]

Class Summary

These agents enhance bile salt-dependent biliary flow.

Ursodiol (Actigall, Urso)

Shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system. Following portoenterostomy in infants with biliary atresia, the drug may be useful in enhancing biliary drainage.

Class Summary

Long-term antibiotic prophylaxis may reduce the incidence of cholangitis following portoenterostomy.

Trimethoprim-Sulfamethoxazole (Bactrim, Septra)

Cholangitis is a common complication, both acutely and long term, following the Kasai procedure. When used prophylactically, may reduce the incidence of cholangitis, though conclusive supportive information is not available.