Etiopathogenesis of Biliary Atresia

• ABSTRACT
• CLINICAL ASPECTS OF BILIARY ATRESIA
• VIRUSES AND BILIARY ATRESIA
• IMMUNE INJURY IN BILIARY ATRESIA
• EVIDENCE OF AUTOIMMUNITY IN BILIARY ATRESIA
• CONCLUSIONS
• ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Biliary atresia, a progressive sclerosis of the extrahepatic biliary tree that occurs only within the first 3 months of life, is one of the most common causes of neonatal cholestasis and accounts for over half of children who undergo liver transplantation. In biliary atresia, a number of prenatal or perinatal insults to the biliary tree appear to culminate in complete obliteration of the lumen of the extrahepatic biliary tree and continued injury and sclerosis of intrahepatic bile ducts, even after portoenterostomy is successful. A minority of cases of biliary atresia may be caused by defects in morphogenesis of the bile ducts. Potential etiologies for the more common perinatal form of biliary atresia include viral infections, immune-mediated bile duct injury, and autoimmune disease involving the bile ducts. Two viruses, reovirus and rotavirus, have received increasing attention as possible inciters of an immune-mediated injury to the biliary tree. Fas ligand upregulation and apoptosis of bile duct epithelia have been demonstrated in human specimens, as well as T-lymphocyte and macrophage activation in portal tracts. An experimental model using rotavirus infection in newborn mice has been useful in characterizing the mechanisms underlying bile duct injury. It is proposed that virally induced neoantigens displayed on biliary epithelium may play a role in initiating the immune processes involved in destruction of the extrahepatic bile duct and ongoing intrahepatic ductal injury in the perinatal form of biliary atresia. The short window of time after birth during which this disease presents suggests that immaturity of the neonatal immune system and genetic susceptibility also may be key factors. Delineation of the mechanisms underlying bile duct injury will be essential to the development of new potential therapies for this important pediatric disorder.

CLINICAL ASPECTS OF BILIARY ATRESIA

Biliary atresia is the most frequent hepatobiliary disorder, causing obstructive jaundice in the first 3 months of life, occurring in approximately 1 in 8,000 to 1 in 15,000 live births, and is the indication for 50-60% of liver transplants performed in children.[1] Biliary atresia is most likely a clinical phenotype resulting after the occurrence of a number of different prenatal or perinatal insults to the biliary tree, culminating in complete obliteration of the lumen of the extrahepatic biliary tree within the first 3 months of life. Therefore, biliary atresia can be looked upon as both a defect in embryonic/ fetal morphogenesis of the extrahepatic bile duct and as a progressive inflammatory and fibrosing disorder of the biliary tree in infants that may involve any portion of the extrahepatic bile ducts as well as intrahepatic ducts. The clinical presentation of biliary atresia is similar, despite the underlying etiology: jaundice, pale stools, and hepatomegaly in the first 3 months of life and liver blood tests indicating cholestatic liver injury. If biliary atresia is diagnosed before 60 days of age, a portoenterostomy surgical procedure designed to reestablish a patent conduit for bile flow from the liver to the small bowel should restore bile flow in 70-80% of patients.[2] However, only 20-30% of patients will survive long term without liver transplantation (10 years) in Western countries following this procedure,[2] [3] [4] because of progressive biliary cirrhosis and its complications.

Two major forms of biliary atresia are now recognized, based on the presumed timing of the obliteration of the lumen of the extrahepatic bile duct: the fetal or embryonic or prenatal form and the acquired or perinatal form. The fetal form, which occurs in up to 20% of cases of biliary atresia, is associated with other congenital anomalies (e.g., the polysplenia syndrome), presents earlier in infancy with acholic stools, and may be caused by a defect in morphogenesis of the biliary tree. Associated congenital anomalies include malrotation of abdominal viscera, interrupted inferior vena cava, midline liver, preduodenal portal vein, polysplenia, situs inversus, and congenital heart anomalies. It is proposed that this constellation of anomalies is caused by abnormal expression of genes that determine laterality of thoracic and abdominal organ development, homologous to the altered development of the biliary tree that has been described in the inv mouse in which situs inversus occurs.[5] [6] The more common (70-80% of cases) perinatal form is believed to occur at or following birth with progressive postnatal destruction of a biliary tree that developed normally during embryogenesis. Although the pathogenesis of this form of biliary atresia is not understood, several factors have been proposed to be involved, including infectious, vascular, toxic, and immune factors. In this review, we will examine the data supporting the proposed viral and immunologic pathogenesis of biliary atresia and outline deficiencies in our knowledge of the events causing this disease.

VIRUSES AND BILIARY ATRESIA

In 1974, Benjamin Landing, a pediatric pathologist, proposed that biliary atresia, as well as choledochal cyst and neonatal hepatitis, represented varied manifestations of a single basic disease process, and coined the term infantile obstructive cholangiopathies to describe these entities.[7] Histologically, all three disorders share common findings of syncytial giant cell transformation of hepatocytes, extramedullary hematopoiesis, lobular disarray, and cellular and canalicular cholestasis with variable degrees of portal and lobular inflammation. Histological examination of the bile duct removed from patients with biliary atresia (and no other congenital anomalies) supports a process of injury to the bile duct that was normally formed, showing a mixed inflammatory infiltrate around the bile duct epithelia with apoptosis of individual epithelial cells and surrounding deposition of collagen and extracellular matrix, most likely culminating in obliteration of the lumen of the extrahepatic bile duct. Landing proposed that a viral infection was responsible for the infantile obstructive cholangiopathies. Although Landing initially suggested that the hepatitis B virus was a likely candidate virus, subsequent studies have shown that this virus is not associated with biliary atresia in North America[8] despite a suggestive report evaluating liver immunohistochemistry for hepatitis B virus (HBV) antigens from Japan.[9] Electron microscopic evaluation of tissue from biliary atresia patients showed the presence of intranuclear inclusions suggestive of a non-A, non-B hepatotrophic virus of an unidentified type in 16 of 20 cases.[10] Based on these studies, the possible role of a number of hepatotrophic viruses have been examined over the past 15 years.

Attention has focused on five viruses in recent years, each of which will be discussed in detail.

For many years, cytomegalovirus (CMV), has been proposed as a possible etiologic agent because a modest proportion of biliary atresia infants appear to be infected with this virus.[11] However, normal infants are also commonly infected postnatally with CMV without development of any overt liver disease. In addition, congenital symptomatic infection with CMV may cause hepatitis as well as central nervous system, cardiac, hematologic, and systemic involvement, but is rarely, if ever, associated with biliary atresia in this clinical scenario. A recent study from Sweden[12] showed a higher prevalence of CMV antibodies in mothers of biliary atresia infants, and CMV DNA was present in livers from 9 of 18 biliary atresia infants. However, a Canadian group could not demonstrate CMV DNA in bile duct remnants removed from 12 children with biliary atresia at the time of the portoenterostomy procedure.[13] CMV cannot be conclusively excluded as an etiology of biliary atresia in selected patients, but it does not appear to be involved in the large majority of cases.

Interest in reovirus in the etiology of biliary atresia stems from an animal model in weanling mice in which infection causes pathologic features in the intrahepatic and extrahepatic bile ducts and in the liver similar to those observed in infants with biliary atresia or choledochal cyst.[14] Murine reovirus infection is associated with necrosis of bile duct epithelium and hepatocytes, portal tract inflammation, and viral inclusions in bile duct epithelial cells. Pathologic changes in the bile duct and liver persisted long after infectious virus or viral antigens could no longer be detected.[15] Wilson et al.[16] have demonstrated that specific changes in the amino acid sequence in the viral cell attachment protein, sigma, which is the product of the S1 gene, in the T3 Abney strain of reovirus type 3, are important in determining the tropism of this virus for murine bile duct epithelia. Reovirus antigens and viral particles resembling reovirus have been found in the bile duct of an infant rhesus monkey, which spontaneously developed a disease that appeared to be biliary atresia.[17] Moreover, reovirus antigens were detected in bile duct remnants resected from infants with biliary atresia,[18] and reovirus-like virions were observed in this tissue by electron microscopy.[19] However, another group of investigators could not detect reovirus viral antigen using similar techniques in biliary tissue removed at diagnosis from eight biliary atresia patients.[20] Serological studies of reovirus antibodies in neonates with hepatobiliary diseases have likewise been inconclusive. Three studies reported an increased prevalence or higher titers of anti-reovirus immunoglobulin G (IgG) or IgM antibodies[18] [21] [22] in biliary atresia patients versus non-biliary atresia controls, yet two other studies found no differences.[20] [23] It should be pointed out that these studies may have been confounded by the high incidence of passively transferred maternal antireovirus IgG. An additional study from Australia[24] reported a relatively high prevalence (25-50%) of serum IgM antibodies to reovirus type 3 in infants with biliary atresia, neonatal hepatitis, parenteral nutrition-associated liver disease, and a variety of other causes of neonatal cholestasis compared with control infants (<10%). In this study reovirus antibodies were not specifically associated with biliary atresia, but rather with any form of neonatal cholestasis.

Using more specific techniques for detection of reovirus infection, two groups of investigators have more recently examined hepatobiliary tissues from infants with biliary atresia for reovirus nucleic acids. Steele et al.[25] failed to detect reovirus RNA in archived preserved hepatic tissues of 14 biliary atresia patients, 20 idiopathic neonatal hepatitis patients, or 16 controls, and in preserved common bile duct from 8 biliary atresia patients using a nested reverse transcriptase polymerase chain reaction (RT-PCR) assay specific for reovirus RNA. However, Tyler et al.[26] subsequently reported finding nested RT-PCR evidence of reovirus infection in fresh frozen liver or bile duct obtained at 1-3 months of age from 11 of 20 patients with the perinatal form of biliary atresia, in none of 3 with the fetal form of biliary atresia, and in only 8-15% of material from autopsy controls or infants with other liver diseases under 1 year of age. In addition, 7 of 9 patients with choledochal cysts had evidence of reovirus RNA, whereas 12-21% of appropriately aged controls were positive for reovirus RNA. This study provided strong evidence for an association of reovirus infection in approximately half the cases of biliary atresia and 80% of choledochal cyst patients. The discrepancies between these two studies may lie in the methods of preparation of the tissue (frozen vs. archived fixed tissue), different methods of RNA isolation, and the use of PCR primers for different reovirus genes. Although there has been controversy as to the role that reovirus might play in biliary atresia, the bulk of evidence points toward a possible role in perhaps half of patients with the acquired perinatal form of the disease.

Recent interest has also focused on the relationship of infection with group C rotavirus (another virus of the Reoviridae family) and biliary atresia. In 1993 Riepenhoff-Talty et al.[27] showed that group A rotavirus, administered orally or intraperitoneally, produced extrahepatic biliary obstruction in newborn mice, with intrahepatic histology that was strikingly similar to human biliary atresia. In 1997, Petersen et al.[28] [29] further demonstrated that this model mimics human biliary atresia. Intraperitoneal injection of rhesus rotavirus group A into newborn BALB/c mice resulted in cholestasis in 80% of animals. One week after infection, the cholestatic mice showed edema of the entire extrahepatic bile duct and severe diffuse inflammation of small and large intrahepatic and extrahepatic bile ducts, including a mixed infiltrate of neutrophils and mononuclear cells and epithelial destruction. At 2 weeks of life, as biliary inflammation receded, the extrahepatic bile duct evolved from edematous swelling to concentric stricture with fibrosis and reduction of the lumen size. This led to short atresia of the distal common hepatic duct or long atresia with complete or interrupted occlusion. By the 3rd week of life the intrahepatic cholangitis regressed and proliferation of bile ductules was evident. These findings are similar to those observed at the time of diagnosis of human biliary atresia. Petersen et al.[30] subsequently reported that the administration of interferon-α (IFN-α) prior to rotavirus infection prevented biliary disease. The same dose of IFN-α administered 5 days postinfection had no protective effect, despite inhibition of viral replication. Qiao et al.[31] recently compared the pathogenesis of rotavirus induced bile duct obstruction in normal BALB/c mice and SCID mice, finding an increased incidence of ductal obstruction in the normal BALB/c mice, indicating that the immune system plays a role in the ductal destruction and subsequent fibrosis.

These laboratory investigations led Riepenhoff-Talty et al.[32] to investigate the role of rotavirus in infants with biliary atresia. This group found RT-PCR evidence of group C rotavirus in hepatobiliary tissues of 10 of 18 biliary atresia patients and none of 12 liver samples from liver disease control patients; however, many of the control patients were from Europe while the biliary atresia patients were from the United States. Four patients of Tyler et al.[26] were also tested for rotavirus in this study: one had evidence of reovirus but not of rotavirus, one had evidence of rotavirus and no reovirus, and two were negative for both viruses. In contrast, Bobo et al.[33] failed to find RNA evidence for rotavirus groups A, B, or C in tissues from 10 biliary atresia patients using a nonisotopic, RT-PCR enzyme immunoassay; however, 4 patients were over 12 months of age at the time that tissues were obtained at liver transplantation, when RT-PCR evidence of prior infection could potentially be absent. Because of the similarities between the infant mouse models of reovirus and rotavirus infection and at least one study showing about a 50% frequency of each of these viruses in infants with biliary atresia, further study of the roles of these and related viruses in the etiology of biliary atresia are warranted. In addition, these mouse models may prove instrumental in defining the immunopathogenesis of biliary atresia and for testing new therapeutic strategies.

Recently a group from Argentina found evidence of human papillomavirus (HPV) DNA in archived liver tissue from 16 of 18 biliary atresia patients compared with 0 of 30 control, age-matched autopsy specimens from patients without liver disease.[35] In addition, this group reported finding HPV DNA in cervical swabs of mothers of four biliary atresia patients, the types of HPV being concordant among infants and mothers. These investigators reported similar findings in mothers and infants with idiopathic neonatal hepatitis (INH).[30] More recently, Domiati-Saad et al.[36] failed to demonstrate by nested PCR any evidence of infection with HPV types 6, 16, 18, and 33 in 19 patients with biliary atresia or INH and 8 control infants from the United States. Furthermore, there is no animal model demonstrating HPV infection in infant liver, but the high frequency of apparent infection in INH and biliary atresia in Argentina requires further investigation. Interestingly, Domiati-Saad et al.[36] also detected human herpes type 6 viral DNA in hepatobiliary tissues from two biliary atresia, two INH, and two control infants. The possible role of this virus will need to be studied in the future.

Mason et al.[37] recently described the presence of immunoreactivity to retroviral proteins in serum from patients with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), and biliary atresia. They attributed this to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterized viral proteins that share antigenic determinants with these retroviruses. Further work in this potentially important area in both adult and pediatric biliary disorders is warranted.

IMMUNE INJURY IN BILIARY ATRESIA

It has been proposed that biliary atresia may be the result of a ``multiple hit'' phenomenon[38] in which a viral or toxic insult to the biliary epithelium leads to newly expressed antigens on the surface of bile duct epithelia, which, in the proper genetically determined immunologic milieu (e.g., specific major or minor histocompatibility complex haplotypes), are recognized by circulating T-lymphocytes that elicit a cellular immune response causing bile duct epithelial injury, inflammation, and fibrosis of the extrahepatic bile duct (Fig. [1]). In support of this notion, Silveira et al.[39] were the first to report an association of HLA-B12 (49% biliary atresia vs. 23% of controls) and of haplotypes A9-B5 and A28-B35 with biliary atresia. However, Jurado et al.[40] could not replicate these findings. Another group suggested a relationship to HLA Cw4/7.[41] In Japan, an association with A33, B44, and DR6 was described.[42] Thus, there has been no consistent or clear segregation of HLA types common to biliary atresia patients from different areas of the world, possibly due to ethnic differences.

A number of investigators have characterized the nature of the inflammatory infiltrate and associated cytokines in biliary atresia tissues. Histologic evidence supports the potential role of lymphocytes in mediating bile duct epithelial injury in biliary atresia. In 1977, Gosseye et al.[43] demonstrated lymphocytes in the connective tissue of the porta hepatis and common hepatic duct remnants of biliary atresia, and Bill et al.[44] described ``cholangitis'' of intrahepatic ducts with intramural mononuclear inflammatory cells associated with epithelial pyknosis and necrosis. In 1995, Ohya et al.[45] further showed that degeneration of intrahepatic bile ducts was associated with lymphocytic infiltration into biliary epithelial cells in liver biopsies obtained from 31 biliary atresia patients at the time of diagnosis. Although these studies did not analyze the type of lymphocytes present, they clearly established the possible role of T cell-mediated bile duct injury in this disease.

In order for T cells to effectively mediate inflammation, they must encounter antigen from a competent antigen presenting cell (APC), which must provide two signals for full T-cell activation: surface expression of self-MHC (major histocompatibility complex) molecules bearing peptide antigen, which interacts with the T-cell receptor, and costimulatory molecules (B7-1, B7-2) that interact with CD28. Competent APCs also express intracellular adhesion molecules (ICAMs), which are involved in adhesion of APCs with T cells. Cytotoxic T cells (CD8⁺) recognize antigen in the context of self-MHC class I, whereas helper T cells (CD4⁺) recognize antigen in the context of self-MHC class II.[46]

Bile duct epithelial cells have been proposed to function as APCs in biliary atresia. Normal bile duct epithelium expresses MHC class I antigens but not those of class II, the latter of which are usually present on professional APCs (i.e., B cells, macrophages, dendritic cells) and vascular endothelium.[47] Bile duct epithelium from patients with biliary atresia have been shown to aberrantly express MHC class II. Broome et al.[41] investigated the expression of HLA-DR (MHC class II) and ICAM-1 and the number of CD4⁺ and CD8⁺ T cells in the porta hepatis of 11 patients with biliary atresia. All biliary atresia specimens (but none of the normal controls) expressed both ICAM-1 and HLA-DR on bile duct epithelial cells, and the inflammatory cells present in the portal tracts were mainly CD4⁺ T cells (41). Nakada et al.[48] and Kobayashi et al.[42] confirmed that HLA-DR was expressed by the bile duct epithelium in liver specimens from biliary atresia patients. Davenport et al.[49] further showed that CD4⁺ lymphocytes and CD 56⁺ cells (natural killer [NK] cells) predominated in liver and extrahepatic bile duct in biliary atresia, and that LFA-1, the ligand on lymphocytes for ICAM-1, was highly expressed in the hepatocytes and portal tracts. Moreover, they showed the cellular infiltrate in the liver to be both activated (CD25⁺) and proliferating (CD71⁺). ICAM-1 was expressed in sinusoidal endothelium of all biliary atresia liver specimens. Furthermore, E-selectin was observed in 92% of biliary remnant tissue but only 32% of liver specimens from biliary atresia patients.[49] Taken together, these data indicate that bile duct damage in biliary atresia likely involves lymphocyte adhesion and T-cell activation and cytotoxicity.

The underlying stimulus for the immune-mediated bile duct injury in biliary atresia may involve an insult (e.g., viral infection) to the bile duct epithelium that leads to upregulation of ICAM and MHC class II expression (Fig. [1]). Viral antigens or new, previously ``unexposed'' self antigens may be presented in the context of MHC class II with subsequent recruitment of CD4⁺ lymphocytes and further ductal damage through cytokine driven mechanisms. However, as mentioned earlier, a competent APC also must express costimulatory molecules for full T-cell activation, which has not been demonstrated to date.

Another potential APC in biliary atresia is the Kupffer cell (resident liver macrophage). A recent study from Japan showed significantly increased numbers and size of Kupffer cells in liver and increased serum IL-18 levels at the time of diagnosis.[50] IL-18 is a macrophage-derived cytokine that promotes Th1 cell differentiation in the inflammatory setting and can augment Fas ligand (FasL)-mediated cytotoxicity of NK cells. Likewise, Tracy et al.[51] and Davenport et al.[49] showed marked proliferation of CD68⁺ cells (Kupffer cells) in portal tracts of a biliary atresia patient. Furthermore, Davenport et al.[49] showed that an increase in CD68⁺ macrophage infiltration in portal tracts and biliary remnant tissue was predictive of a poorer clinical outcome after the portoenterostomy procedure. Inasmuch as activated macrophages release cytokines (e.g., transforming growth factor-β) that can stimulate hepatic stellate cells to synthesize and secrete collagen, this correlation between macrophage activation and outcome in biliary atresia may relate to cytokine-mediated development of portal fibrosis and cirrhosis.

Macrophages may play another important role in the pathogenesis of bile duct injury in biliary atresia. Macrophages secrete other small molecules that may directly injury bile ducts and hepatocytes (e.g., tumor necrosis factor-α [TNF-α], reactive oxygen species, nitric oxide) through induction of both apoptotic and necrotic intracellular pathways. In this regard, Funaki et al.[52] have demonstrated a strikingly higher percentage of intrahepatic bile duct epithelial cells undergoing apoptosis in biliary atresia compared with normal liver or that from patients with congenital dilatation of the bile ducts. Liu et al.[53] showed that apoptotic intrahepatic bile duct epithelial cells were present in approximately half of biliary atresia patients at time of diagnosis, and only in livers in which FasL mRNA was demonstrated on bile duct epithelia. FasL is not normally expressed on bile duct epithelial cells. Fas, the receptor for FasL, was present in bile duct epithelia of all biliary atresia patients. Fas was weakly positive on hepatocytes of patients and controls, but was absent in bile duct epithelia of normal livers. Surprisingly, the results of bile drainage after the portoenterostomy were significantly better for the patients with negative signals for FasL on bile duct epithelia or infiltrating monocytes (58.8% of patients were jaundice free 1 year after surgery) compared to those with positive signals (10.6% were jaundice free).[53] These data suggest that bile ductule epithelial upregulation of FasL may result in apoptotic fratricide in which bile duct epithelial cells injure other similar cells. Alternatively, the FasL upregulation may represent an attempt by bile duct epithelium to resist attack by infiltrating lymphocytes by posing a ``counterattack'' against Fas-expressing lymphocytes.[53] Further study of the interaction between macrophages, T-lymphocytes, bile duct epithelial cells, hepatocytes, and hepatic stellate cells should shed light on the clinical role of these postulated mechanisms of hepatobiliary immune injury in biliary atresia.

EVIDENCE OF AUTOIMMUNITY IN BILIARY ATRESIA

Although several experts have proposed that biliary atresia is an ``autoimmune'' disorder (female predominance, triggered by viral infection, aberrant HLA expression), there is sparse evidence of autoimmunity to support this contention. In a preliminary report, Vasiliauskas et al.[54] reported on serum IgG and IgM antineutrophil cytoplasmic antibodies (ANCAs) in 11 infants with biliary atresia, and a number of other groups of children and adult controls. Ninety one percent of biliary atresia patients expressed both of these antibodies; 60-100% of adults with varied liver diseases also expressed these antibodies, and 4 of 5 children with other liver diseases for the IgM only. The IgM-ANCA enzyme-linked immunosorbent assay was higher in the biliary atresia patients compared with other children and adults with hepatitis C virus, HBV, PSC, autoimmune hepatitis, or adult controls. The authors suggested that the strong IgM response indicates that perinatal initiation of inflammation is perpetuated by the child's immune dysregulation. These provocative data set the stage for a more thorough investigation of autoantibodies in infants with biliary atresia. In this regard, a preliminary report by Burch et al.[55] showed that low-titer anti-Rho antibodies were more common in mothers of infants with biliary atresia or INH than in controls. This finding suggested that the transplacentally passed antibodies that cause neonatal lupus could potentially be a sensitizing factor in INH and biliary atresia. Further evaluation of this provocative hypothesis is needed.

The existence of possible susceptibility genes for autoimmunity in biliary atresia has not been examined. However, recent reports of Bernal et al.[56] and Mitchell et al.[57] have shown that TNF-α gene polymorphisms are associated with susceptibility to primary sclerosing cholangitis (58% vs. 29% of controls in Bernal's study). This interesting observation raises the possibility that polymorphisms in genes that regulate immune function, the inflammatory response, cellular regeneration, and cell survival signals may predispose to biliary injury in various clinical settings. It is also possible that genes that regulate hepatocyte or bile duct metabolism and secretion of bile acids (e.g., bile salt export pump) and phospholipids (e.g., MDR3) may play a role in protection of bile duct epithelium from injurious agents that might cause biliary atresia. Thus, as new technology (e.g., genome screening, microarray assays, etc.) is developed for screening of polymorphisms and expression of pertinent genes, a formal evaluation of biliary atresia patients and proper disease and nondisease controls needs to be conducted.

CONCLUSIONS

The multiple hit etiology of the perinatal form of biliary atresia appears to be feasible. However, there is currently inadequate data to support a conclusion that an autoimmune mechanism is responsible for the initial extrahepatic bile duct sclerosis and the ongoing bile duct injury that occurs within the liver. Nevertheless, accumulating evidence suggests that immune-mediated bile duct injury plays an important role in biliary atresia. Further investigation in animal models and using human tissues and sera will be required to determine if intervention with immunosuppressive or antiviral agents should be tested in biliary atresia. In this regard, a provocative report suggests that the routine use of corticosteroids may improve the outcome in biliary atresia.[58] Because of immunological and MHC differences among ethnic groups and the rarity of biliary atresia and other neonatal liver diseases, multicentered collaborations and data bases will be necessary to accumulate adequate numbers of patients and controls to allow for meaningful statistical analysis to delineate the cellular and molecular mechanisms involved in the etiopathogenesis of biliary atresia and for the future development of improved therapies.

ACKNOWLEDGMENTS

This work was supported in part by grants from the National Institutes of Health (RO1 DK38446 and MO1RR00069) and the Abbey Bennett Liver Research Fund.

ABBREVIATIONS

ANCA antineutrophil cytoplasmic antibodies

APC antigen presenting cell

CMV cytomegalovirus

HBV hepatitis B virus

HPV human papillomavirus

IFN interferon

INH idiopathic neonatal hepatitis

MHC major histocompatibility complex

PSC primary sclerosing cholangitis

RT-PCR reverse transcriptase polymerase chain

reaction

TNF tumor necrosis factor

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