Author: Jan Goedeke, M.D.
Editor: Stefan Scholz, M.D.
Biliary atresia (BA) is characterized by a fibroproliferative obliteration of the biliary tree that progresses toward hepatic fibrosis, cirrhosis, and end-stage liver failure. It exclusively presents in the neonatal period (1). Although the overall incidence is low (about one in 10,000 to 20,000 live births (2) (3) (4) (5), BA is the most common cause of neonatal jaundice for which surgery is indicated and the most common indication for liver transplantation in children.
The etiology of BA is likely multifactorial. In classic textbooks, the cause of BA was described as an “arrest of development during the solid stage of bile duct formation”. Previously proposed theories of the cause of BA have focused on defects in hepatogenesis, prenatal vasculogenesis, immune dysregulation, infectious agents, and exposure to toxins. More recently, genetic mutations were identified as possible reasons for development of BA. The exclusive occurrence of BA in the neonatal liver and extrahepatic biliary tree suggests that ongoing development may be the key in pathogenesis, and thus genes affecting biliary development may confer susceptibility to BA. Studies have identified a few genomic loci with increased susceptibility to BA. (6) (7). In addition, mutations in the human Jagged1 gene, which are responsible for Alagille syndrome, have been found in a few cases of BA. (8). The Jagged1 gene encodes a ligand in the Notch signaling pathway, which is critical in the determination of cell fate during development and may also alter production of inflammatory cytokines. Most recently, a possible association with the gene GPC1, which encodes a glypican 1-a heparan sulfate proteoglycan, has been reported. (9). This gene is located on the long arm of chromosome 2 (2q37). It is involved in the regulation of the hedgehog gene and inflammation. In addition to the association of mutations in the gene and the abnormally low levels of this protein in human cases, knock out mutants in zebra fish develop similar lesions in the liver. Hedgehog inhibitors ameliorate the features in the mutated fish and the addition of hedgehog to normal fish, produce lesions. Epigenetic factors have also been postulated as important factors impacting biliary development and the pathogenesis of BA. Both microRNA and DNA methylation have been studied in animal models and humans. (10) (11). In addition, the finding of a higher incidence of maternal microchimerism in the livers of males with BA (12) has led to the suggestion that consequent expression of maternal antigens may lead to an autoimmune process that results in inflammation and obliteration of the biliary tree. Different animal studies also implicate possible perinatal exposure to viruses like the reovirus. (13) (14) Such viral exposure may lead to periportal inflammation mediated by interferon-γ and other cytokines.
Most infants with BA are born at full term, have a normal birth weight, and initially thrive and appear healthy. They present with jaundice at birth, or shortly thereafter up to six to eight weeks after birth. For this reason, a delay in diagnosis is not unusual. Besides jaundice, other symptoms include acholic, pale gray stools, dark urine (bilirubin excretion into urine), swollen abdominal region and large hardened liver (which may or may not be observable by the naked eye) secondary to obstructed bile flow. Prolonged jaundice that is resistant to photo therapy and/or exchange transfusions should prompt a search for secondary causes. Liver enzymes may be grossly deranged, but most indicative are elevated gamma glutamyl transferase (gGTP) and persistent direct hyperbilirubinemia. Hyperbilirubinemia is conjugated and therefore does not lead to kernicterus. With further passage of time, these infants manifest progressive failure to thrive and, if untreated, develop stigmata of liver failure and portal hypertension, particularly splenomegaly and esophageal varices.
The obliterative process of BA involves the common duct, cystic duct, one or both hepatic ducts, and the gallbladder, in various combinations. Histopathologic findings for patients with BA include inflammatory changes in the parenchyma of the liver, as well as fibrous deposition at the portal plates observed on trichrome staining of frozen tissue sections. In certain cases, bile duct proliferation may be seen, a relatively nonspecific marker of liver injury.
One classification system of BA is the Ohi classification system used by the Japanese Biliary Atresia Registry and it has been adopted to describe the anatomic variants. (15)
Three types of biliary anatomy are described:
Type I: atresia of the common bile duct (10% of patients)
Type II: atresia of the hepatic ducts (2% of patients)
Type III: atresia at the porta hepatis (88% of patients).
Approximately 15 to 30 percent of patients with biliary atresia have coincidental malformations. Therefore infants with BA can also be grouped into three categories:
- BA without any other anomalies or malformations – This pattern is sometimes referred to as perinatal BA and occurs in 70 to 85 percent of infants with BA. (16) (17) Typically, these children are born without jaundice, but within the first two months of life, jaundice develops and stools become progressively acholic.
- BA in association with laterality malformations – This pattern is also known as Biliary Atresia Splenic Malformation (BASM) or “embryonal” BA, and occurs 10 to 15 percent of infants with BA. (16) (17) (18) (19). The laterality malformations include situs inversus, asplenia or polysplenia, malrotation, interrupted inferior vena cava, and cardiac anomalies. Data suggests that children with BASM have poorer outcomes compared to those with perinatal BA. (18) (19).
- BA in association with other congenital malformations – This occurs in the remaining 5 to 10 percent of BA cases. Associated congenital malformations include intestinal atresia, imperforate anus, kidney anomalies, and/or heart malformations. (17) (20) (21).
Common anomalies associated with BA. Commonly associated anatomic findings in patients who have situs inversus and BA include (A) polysplenia, (B) interrupted inferior vena cava with azygous discontinuation, (C) aberrant arterial supply with left hepatic artery from either left gastric artery or from superior mesenteric artery, (D) preduodenal portal vein, and (E) gut malrotation. (22)
Regardless of the type of BA, the cholangiogram and, possibly, the histology are characteristic.
BA seems slightly more prevalent in girls. It is common for only one child in a pair of twins or only one child within the same family to have BA. Asians and African-Americans are affected more frequently than Caucasians. There does not appear to be any link to medications or immunizations given immediately before or during pregnancy.
In general, the diagnosis of BA is made using a combination of studies, because no single test is sufficiently sensitive or specific. Fractionation of the serum bilirubin is performed to determine if the associated hyperbilirubinemia is conjugated or unconjugated. The conjugated bilirubin is elevated (conjugated bilirubin ≥2 mg/dL). Also mild or moderate elevations in serum aminotransferases with a disproportionately increased gGTP are measured. If coagulopathy is present at diagnosis, it is most likely due to vitamin K deficiency. Further work-up commonly includes the analysis of TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) infection titers as well as tests for viral hepatitis. Typically, ultrasonography is performed to assess for the presence of other causes of biliary tract obstruction, including choledochal cyst. The absence of a gallbladder is highly suggestive of the diagnosis of BA. However, the presence of a gallbladder does not exclude the diagnosis of BA, because in approximately 10 to 20 percent of BA patients, the distal biliary tract is patent and a gallbladder may be visualized, even though the proximal ducts are atretic. Sometimes, a “triangular cord” sign is noticed. This is a triangular echogenic density seen just above the porta hepatis on the ultrasound scan and its presence is highly suggestive of BA. (23). One should note that the intrahepatic bile ducts are never dilated in patients with BA.
A nuclear medicine scan using technetium TC 99m mebrofenin, performed after pretreatment of the patient with phenobarbital, has proven to be helpful in exclusion or diagnosis of BA (cholescintigraphy, previously called “HIDA-Scan”; the name HIDA comes from an early tracer [hydroxy iminodiacetic acid] used for the scan). If radionuclide appears in the intestine, the biliary tree is patent and the diagnosis of BA is excluded. However, if excretion is noted on a scan that is performed when the infant is very young (i.e., less than six weeks old), and cholestasis persists, the scan should be repeated one to two weeks later because the disease may progress during the neonatal period. If radionuclide is concentrated by the liver but is not excreted, despite treatment with phenobarbital, and results of the metabolic screen, particularly alpha1-antitrypsin level, are normal, the presumptive diagnosis is BA.
Subsequent percutaneous liver biopsy findings might potentially distinguish between BA and other sources of jaundice. Biopsy findings that indicate another etiology other than BA include bile duct paucity (Alagille syndrome), PAS positive diastase resistant granules (consistent with alpha-1 antitrypsin deficiency), loss of MDR3 staining (suggestive of progressive familiar intrahepatic cholestasis, PFIC3), or giant cell hepatitis without proliferation of ducts (neonatal hepatitis). The earliest histological changes associated with BA may be relatively nonspecific, and biopsies done too early may result in false negative results. (24). At times it is necessary to repeat a liver biopsy at an older age (e.g., two to three weeks later). When the results of these tests point to or cannot exclude the diagnosis of BA, surgical exploration is warranted. At surgery, a cholangiogram (gold standard in the diagnosis of BA) may be performed using the gallbladder as a point of access. This may be accomplished minimally invasively using a laparoscope, especially if the gallbladder is of normal size. The cholangiogram proofs patency of the biliary tree and reveals whether extrahepatic bile duct atresia is present. It is very important to demonstrate the anatomy of the intrahepatic bile system. Reflux of contrast into the liver bile system can be facilitated by placing the patient in a head-down position and to obstruct the distal porta hepatis mechanically. The cholangiogram may demonstrate hypoplasia of the extrahepatic biliary system. This condition is associated with hepatic parenchymal disorders that cause severe intrahepatic cholestasis, including alpha1-antitrypsin deficiency and biliary hypoplasia (Alagille syndrome). The term inspissated bile syndrome is applied to patients with normal biliary tracts who have persistent obstructive jaundice. Increased viscosity of bile and obstruction of the canaliculi are implicated as causes. The condition has been seen in infants receiving parenteral nutrition, but is also encountered in patients with disorders associated with hemolysis and in patients with cystic fibrosis. In some instances, no etiologic factors can be defined. Cholangiography is both diagnostic and therapeutic for inspissated bile syndrome.
An alternative, yet valid approach used at some centers is to perform a percutaneous gallbladder cholangiogram or an ERCP. (25) (26) (27). These procedures are less invasive than an intraoperative cholangiogram, but performance of these procedures in infants requires special expertise and equipment. Moreover, if BA is confirmed, the infant will still need to undergo an operation for treatment.
First-line therapy consists of creation of a hepatoportoenterostomy (HPE) through open surgery, as originally described by Morio Kasai in Japan. The surgical treatment is usually undertaken after the diagnostic cholangiogram during the same procedure. The purpose of this procedure is to promote bile flow into the intestine. The procedure is based on Kasai’s observation that the fibrous tissue at the porta hepatis obstructs microscopically patent biliary ductules that communicate with the intrahepatic bile system. Transecting this fibrous tissue at the portal plate, which is invariably encountered cephalad to the bifurcating portal vein, opens these channels and establishes bile flow into a surgically constructed intestinal conduit, usually a Roux-en-Y limb of jejunum. A liver biopsy is performed at the time of surgery to determine the degree of hepatic fibrosis that is present.
Schematic illustration of extended Kasai HPE at the level of porta hepatis – from bifurcation of the right vascular pedicle to the junction of the umbilical vein and left portal vein in the Rex fossa. Arteries have been removed for clarity. (28)
Schematic illustration after extended Kasai HPE. The gallbladder and the entire extrahepatic biliary tree are excised together with the fibrous tissue situated inside the bifurcation of the portal vein at the level of the porta hepatis. A 45 cm Roux en Y loop is prepared and passed through the mesocolon to the liver hilum. An anastomosis is fashioned between the cut edge of the transected tissue in the porta hepatis and the antimesenteric side of the Roux loop. (29)
The advent of minimally invasive surgery and laparoscopic techniques probably reached its apogee with a successful laparoscopic Kasai HPE by a Brazilian team in 2002. (30). Several small-series case reports followed, together with a prospective trial from Hannover, Germany. (31) (32) (33). Most pioneers came to recognize that, while possible, the laparoscopic technique was sufficiently different to lead to poorer outcomes. (33) (34) Isolated centers in China, Japan and South America still offer this technique, but most centers have reverted. In the future, with more precise laparoscopic or robotic techniques the laparoscopic Kasai operation might achieve the same results as the open procedure.
Medical care following HPE consists of the following interventions (35) (36):
- Choleretics and possible use of anti-inflammatory medications
- Nutritional rehabilitation
- Fat-soluble vitamin supplementation
- Prevention of cholangitis
- Management of portal hypertension and its sequelae
Choleretics – Administration of choleretics such as ursodeoxycholic acid (UDCA) is standard practice in BA, although its clinical utility has not been definitively established. Given by mouth this hydrophilic bile acid shifts the balance of bile acids towards hydrophilic forms. This is thought to stabilize membranes and reduce generation of free radicals, thus protecting mitochondria from damage.
The recommended dose of UDCA in BA ranges from 15 to 30 mg/kg/day within the first 24 months of life and should not exceed 30 mg/kg/day. To avoid potential toxicity, UDCA therapy should be discontinued if the total bilirubin level rises above 15 mg/dL.
Observational studies suggest a number of possible benefits of UDCA treatment in BA, ranging from enhanced weight gain to reduced episodes of cholangitis and improved bile flow, but definitive evidence from randomized trials is lacking. (37) (38).
Glucocorticoids – Whether adjuvant treatment with glucocorticoids after HPE improves outcomes has not been established. This question has been addressed with several retrospective studies and with open-label prospective trials, using a variety of treatment protocols, with inconsistent results. (38) (39) As an example, a randomized placebo-controlled trial found that adjuvant treatment with glucocorticoids improved bilirubin levels at one month postoperatively, but not at the six or 12 month time points. (40) The study protocol used a relatively low dose and duration of glucocorticoid treatment, and was somewhat underpowered. The START trial by the Childhood Liver Disease Research and Education Network (ChiLDREN) is a North American randomized, double-blind, placebo-controlled trial of corticosteroid therapy following portoenterostomy. The trial is now closed and final results will be published in 2014 (Study ID: NCT00294684).
Nutrition – Nutritional problems in BA are common and difficult to overcome. Poor nutrition is a significant clinical problem and is one of the most common indications for liver transplantation.
Caloric needs – Several factors contribute to malnutrition in patients with BA, including malabsorption due to cholestasis, chronic liver inflammation, and lack of gallbladder. Because of malabsorption and metabolic alterations, the total caloric needs in infants with BA are approximately 150 percent of the recommended energy intake for healthy infants and children. To compensate for losses and catabolism, the expected protein needs are 3 to 4 g/kg/day in infants and 2 to 3 g/kg/day in children. (41) (42) (43).
In order to meet these nutritional requirements, several strategies are utilized. These strategies are similar to those used for infants with other causes of growth failure, except that they should be implemented proactively because of the high rates of growth failure in patients with BA.
- For infants, formulas are concentrated or expressed breast milk is fortified to provide additional energy. After Kasai HPE, the feed is typically designed to provide 24 kcal per ounce. If growth is inadequate, the feed may be increased to 27 kcal per ounce; additional energy content can be added in solid foods when the infant is old enough.
- High-energy supplements, such as glucose polymers (which provide 8 cal/teaspoon) or medium chain triglyceride oil (which provides 7.7 cal/mL), are used to fortify formula or solid foods. (42) MCT oil / MCT based formula is useful because it is calorically rich, and it is readily absorbed by patients with cholestasis because it does not require micellar solubilization.
- Despite these measures, many infants and children with BA require supplemental feeding by nasogastric tube because they are unable to take enough energy by mouth to meet their increased nutritional needs. Gastrostomy tubes are not recommended because many patients develop portal hypertension, leading to gastric varices and the propensity to develop varices around the gastrostomy tube site. Candidates for nasogastric feeds are identified by poor weight gain and/or poor linear growth. Proactive management is recommended because the malnutrition may worsen the overall prognosis, with or without liver transplantation.
Fat-soluble vitamin supplements – Deficiencies of fat-soluble vitamins are common in patients with BA. Vitamin deficiencies occur despite recommended supplementation and are particularly common among patients with residual cholestasis after Kasai HPE (serum bilirubin ≥2 mg/dL). (44) Therefore, vitamin levels should be monitored frequently (i.e., several times in the first year), starting at the first month after HPE, in order to adjust supplements (for instance AquADEKs®) appropriately for deficiencies or toxicities. Infants with BA and prolonged jaundice may especially be deficient in vitamin K. Patients should receive additional supplementation with oral vitamin K, and should be monitored for coagulopathy. Some infants may even require parenteral vitamin K supplementation due to poor absorption of oral medications in the setting of severe cholestasis.
Complications – Children with successful bile drainage following HPE must be followed closely for complications including ascending cholangitis and portal hypertension.
Ascending cholangitis is a common complication in patients with BA who have undergone a Kasai HPE because of the abnormal anatomy and bacterial stasis in the region of the roux limb (incidence 40-90%). The majority of patients are experiencing at least one episode prior to two years of age. (45) (46) Because cholangitis can be life threatening and may impact long and short term outcomes (46) (47), most clinicians prescribe prophylactic antibiotics within the first six to 12 months of life. Small nonrandomized trials suggest that the benefits of antibiotic prophylaxis outweigh the risks of antibiotic resistance. (48) (49) Either trimethoprim/sulfamethoxazole (4 mg/kg/day trimethoprim and 20 mg/kg/day sulfamethoxazole, divided twice daily) or neomycin (25 mg/kg/day divided four times daily) appear to be equally effective in decreasing the incidence of cholangitis. (48) Recurrent cholangitis may predict the need for liver transplantation as it can lead to progressive cirrhosis. (46) However, one episode of cholangitis does not predict early transplantation. (16).
The chronic hepatobiliary inflammation characteristic of BA leads to progressive biliary cirrhosis, which causes portal hypertension with possible variceal bleeding and ascites. In a study of 163 children with BA in North America who had not undergone liver transplantation (average age 9.2 years), half of the patients had definite portal hypertension. (50) Among those children with portal hypertension, 53 percent had a history of variceal bleeding, 17 percent had ascites, and 34 percent had reduced hepatic synthetic function (PT >15 seconds or albumin <3 g/dL). Recurrent variceal bleeding and refractory ascites are indications for liver transplantation. (51) (52) Variceal bleeding is commonly managed with sclerotherapy or band ligation and surveillance endoscopy. The management varies between different centers. While it is unclear whether one approach is more beneficial than the other, the risk of portal hypertension and variceal bleeding is present throughout the lives of children with BA. (53).
If ascites develops and is severe enough to compromise respiratory function, it is usually treated with paracentesis followed by chronic administration of diuretics, β-blockers, salt and/or water dietary restriction, or a combination of these interventions.
The diameter of bile ducts at the portal plate is predictive of the likelihood of long-term success of biliary drainage through the HPE. If the HPE is successful, the remaining small patent bile ducts will drain into the roux limb and jaundice will start to resolve in the weeks following surgery. If unsuccessful, bile drainage is not achieved, and the child remains jaundiced. If there is persistent jaundice three months after the Kasai, the patient should be referred for liver transplant evaluation. (36) Even if bile flow initially is established and cholestasis improves, many patients will have slowly progressive liver disease with or without complications from portal hypertension or cholangitis despite undergoing the Kasai procedure, and the majority of patients with BA will ultimately require liver transplantation. At least 50 percent of patients who undergo HPE will require liver transplantation by two years of age as a result of primary failure of the HPE and/or growth failure. (16) (54).
Revision of a non-functioning HPE generally is not recommended, because it is unlikely to be effective if the original HPE did not achieve bile drainage, and because the revisional procedure is likely to cause adhesions that increase the technical difficulty of a subsequent transplant procedure. (55).
However, in patients in whom the initial HPE was successful, revisional HPE may be appropriate if the patient abruptly develops jaundice, or experiences recurrent episodes of cholangitis but has no other evidence of chronic liver disease. In one report of 24 patients who underwent revisional HPE for these indications, 75 percent achieved bile drainage and 46 percent survived with their native liver (mean follow-up 92 months). (56).
Among all variables, serum bilirubin post HPE appears to be the most predictive biomarker of outcome. Data suggest that the serum total bilirubin level measured three months after HPE is predictive of native liver survival. Among patients with bilirubin <2 mg/dL three months post HPE, two year survival without transplantation was 84 percent. Among patients with bilirubin ≥6mg/dL three months post HPE, survival without transplantation was only 16 percent. (16)
Studies also suggest that the likelihood of surgical success is inversely related to the age at the time of portoenterostomy. Infants treated before 60 days of age are more likely to achieve successful and long-term biliary drainage than older infants. (57) (58) (59)
Although the outlook is less favorable for patients after the twelfth week, it seems reasonable to proceed with surgery even beyond this point, because the alternative is certain liver failure. It is noteworthy that a significant number of patients have had favorable outcomes after undergoing HPE despite advanced age at the time of diagnosis.
Surgical success is also dependent on the expertise of the center and surgeon. Although controversial, it appears that a center that performs at least five HPE’s per year has a better success rate, as measured by 5 or 10 year long-term survival with the native liver. (60) (61) (62).
Another surgical factor is anatomic pattern of BA identified at time of HPE. Children born without atresia at the porta hepatis have the lowest risk of death or transplantation by two years of age. (63).
Thus, the vast majority of individuals with BA will eventually require liver transplantation. Nonetheless, the HPE obviates the need for liver transplantation in a substantial minority and significantly delays the liver transplantation for many others. Pre-emptive transplant is avoided because of the advantages of transplanting older, larger patients and because of the potential for improved transplantation therapies in the future.
For long-term prognosis also the risk of developing cancer in the native liver remains an important concern. Careful monitoring and treatment of late complications is essential. Pregnancy in female survivors of BA is also not without risk, and the pregnancy must be monitored to ensure the health and safety of the mother and child. But given the improvements in medical therapy after HPE, including prophylaxis against cholangitis and improvements in nutrition and bile flow, it is reasonable to expect that long-term survival from current cases will exceed that of older series. Experimental areas of therapy such as anti-fibrotic or anti-inflammatory agents may improve outcomes in the future.
Childhood Liver Disease Research and Education Network (ChiLDREN)
In 2002, the National Institutes of Health–supported multicenter Biliary Atresia Research Consortium (BARC) was founded. The consortium was later absorbed in the Childhood Liver Disease Research and Education Network (ChiLDREN). The long-term goal is to establish a database of clinical information and serum and tissue samples from children with BA to facilitate research and to perform clinical, epidemiological and therapeutic trials in this rare liver disease. The network has previously reported that rapid normalization of serum bilirubin levels and weight gain are predictive of survival with the native liver. Kaplan-Meier analysis of survival without liver transplantation revealed markedly improved survival in children with total bilirubin level < 2 mg/dL at 3 months after HPE (84% vs. 16%; P<.0001). (16) These very important data were obtained retrospectively and their further evaluation is now aim of a new prospective study. Research by the network did also show that growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome. (64).
A histologic assessment system for cholestasis in infancy was designed and validated. The BARC histologic assessment system identified features of liver biopsies from cholestatic infants with a high level of sensitivity for BA and with good inter-observer agreement. Based on these results, it might be used in diagnosis and determination of prognosis in the future. (65).
In a prospective randomized controlled trial, the network is currently analyzing the efficacy of corticosteroids in promoting sustained bile flow after HPE (START study, unpublished data). With the same hypothesis that reduced perioperative inflammation could enhance the bile flow after HPE a nationwide study recommending perioperative intravenous immunoglobulin (IVIG) substitution just has started (PRIME study).
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