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Extrahepatic biliary atresia
Introduction
Extrahepatic biliary atresia or biliary atresia (BA) is an obstructive fibroinflammatory disease that presents in infancy. First described in a case series of 49 patients by John Thompson in 1892, this disease is characterized by a destructive inflammatory cholangiopathy that can affect both the intrahepatic and extrahepatic biliary tree. If left untreated, the disease is progressive and leads to death from complications of biliary cirrhosis by age 2 years in most cases (see Chapters 74 and 76 ). There are two therapies that are currently used and widely accepted for this condition: the Kasai hepatoportoenterostomy (HPE) and liver transplantation (see Chapters 105 and 110 ). Although there is still some controversy as to whether patients should proceed to transplant as the primary therapy, most centers, including ours, agree with performing the HPE first and as early as possible to allow for the possibility of biliary drainage and delay the need for transplant.
BA affects approximately 1 in every 10,000 live births with higher incidences in Asian/Polynesian and black South African ethnicities. For example, the populations of Taiwan, Japan, and Hawaii have been shown to have 1.5 to 2 times the rate of BA compared with European countries. The reasons for this are unclear, but a study of Asians born in the United States (US) shows a higher prevalence of BA than the general US population, suggesting a strong genetic component to the disease.
Several classification schemes have been proposed to describe the anatomic variants of BA, but the most widely used is the Japanese Association of Pediatric Surgeons classification, which groups BA into three main variants ( Fig. 40.1 ). Type I, or the distal BA present in approximately 5% of cases, affects only the common bile duct (CBD) distal to the cystic duct, with the cystic duct and hepatic ducts remaining patent. In type II BA (approximately 5% of cases), the hepatic duct is obliterated but the proximal intrahepatic ducts are patent and frequently terminate in an extrahepatic cystic structure. Type II is further subdivided into IIa, in which the gallbladder and CBD are patent, and IIb, in which the gallbladder, CBD, and hepatic ducts are scarred and atretic. The most common variant of BA is type III or complete BA, present in greater than 90% of cases, in which the intrahepatic as well as extrahepatic ducts are completely obliterated.
Although most patients have isolated BA, a minority (10%–20%) of patients with BA have a congenital or syndromic association with additional anatomic anomalies affecting the spleen, heart, hepatic anatomy and orientation, and intestinal rotation; this is known as BA splenic malformation syndrome (BASM). In contrast to isolated BA, patients with BASM are more likely to be found in European populations. This is further supported by Japanese BA registry data, which found associated anomalies in only 2% of their patients.
Etiology
Despite advances in medical and surgical care in the management of BA, its etiology remains a mystery. The association of multiple anatomic anomalies in addition to a significant poorly understood inflammatory component suggest a multifactorial origin to BA. This is further supported by the fact that animal models have failed to isolate a specific gene that leads to the BA phenotype. This section will outline our current progress and understanding of the etiology of the disease.
A genetic component
BASM describes a distinct association of anatomic anomalies found in a minority of BA patients, including cardiovascular defects, situs inversus or heterotaxy, intestinal malrotation, polysplenia, preduodenal portal vein, and interrupted inferior vena cava with azygous continuation. Mutations in the developmental genes CFC1 and inversin , which have been associated with heterotaxy/malrotation, have been speculated to be associated with BASM. , However, CFC1, despite a higher association, was not found in all patients with BASM and although inversin mutations cause situs inversus as well as hyperbilirubinemia in mice, inversin was not found to be associated with these findings in BASM patients. ,
Using a powerful tool that can determine the association of individual common genetic variants to a given disease, known as single nucleotide repeats (SNPs), genome-wide association studies (GWAS) have identified several genes associated with BA. For example, a Chinese study identified an SNP variant in the ADD3 gene, which led to lower expression levels of ADD3 and was associated with BA in the Han population of China. Another candidate identified through GWAS in China is glypican 1 or GPC1. This gene, when knocked out in a zebrafish animal model, leads to disorganized biliary tract/ductule formation. ADD3 SNPs have been examined in Caucasians, and although a different SNP of ADD3 was found to be correlative of BA in Caucasians, the data suggest that defects in ADD3 expression may have implications in the development of BA. Other SNPs that have been examined and are thought to be associated are ARF6 and EFEMP1. More definitive analyses of these SNP variants in other populations have not been done but are underway.
Other developmental genes that have been investigated and implicated in clinical investigations or preclinical models in the development of BA are listed in Table 40.1 . Although the exact mechanism in which they may contribute to the development of BA in patients is unknown, it has been inferred from their function and/or association with BA tissue samples. These are genes that are important for bile duct/system development, bile acid transport, vasculogenesis, left-right axis/development, and organogenesis. Although still unclear, efforts to elucidate the role of these genes in the biology of BA continues with the goal of targeted therapy for BA patients.
TABLE 40.1
Genes Associated With the Development of Biliary Atresia and Their Cellular Function
| GENE | FUNCTION |
|---|---|
| ADD3 (Aducin) | Regulation of cell-cell contact |
| GPC1 (Glypican-1) | Signaling/developmental pathways |
| ARF6 (adenosine diphosphate-ribosylation-6) | Bile duct development (?) |
| EFEMP1 (extracellular matrix protein 1) | Bile duct development (?) |
| JAG1 (Jagged 1) | Cell-cell signaling, associated with Allagile’s syndrome |
| CFTR (Cystic fibrosis transmembrane conductance receptor) | Ion transport |
| ZIC3 (Zic family member 3) | Zinc finger protein |
| INVS (Inversin) | Left-right axis development |
| VEGF (Vascular endothelial growth factor) | Growth factor |
| FXR (Farnesoid X receptor) | Bile acid receptor |
| CFC1 (Cryptic) | Growth factor, associated with heterotaxy |
| SOX17 |
Infection and inflammation in biliary atresia
Because no clear single genetic factor has been found in all BA patients, some investigators have suggested that infection may play a critical role in the etiology of BA, particularly given the well-known seasonal variation in the incidence of BA. It has been proposed that a virally induced bile duct injury could lead to a progressive fibroinflammatory and obliterative process that ultimately leads to the destruction of the biliary tree. Several viruses have been implicated in BA, such as cytomegalovirus (CMV), reovirus, and rotavirus.
With a worldwide seroprevalence that ranges from 70% to 100% depending on the country, infection with CMV in most patients is typically benign, with most infections described as asymptomatic. The association of CMV with the development of BA varies widely depending on the study referenced. CMV infection has also been suggested to delay the resolution of jaundice in BA patients. However, results are inconclusive because these studies suffer from low numbers and associative nonmechanistic findings that make interpretation of the data difficult.
Reovirus has also been implicated in BA development. This association is based on murine studies and the identification of reoviral particles in neonates with BA. Unlike CMV or other viruses, however, reoviral infections produce no identifiable symptomology in patients and no study has demonstrated a definite link between the two processes. Another virus that has been associated with the development of BA is rotavirus. Animal models using specific rotaviral strains appear to cause similar cholangiopathy to what is seen in humans and studies examining for the presence of rotavirus suggest an increase in viral titers or rotavirus antibody compared with controls. As with all of the viral studies previously described, however, the numbers of patients included within these studies is small and it is still unclear as to whether or not any of these viral infections lead to or exacerbate BA.
Because inflammatory infiltrates are typically found throughout the liver of explants of patients with BA at the time of transplant, many have speculated that inappropriate innate/adaptive immune responses or even an autoimmune component may be driving the progressive fibro-obliterative process in BA. , In this setting, the innate immune response is responsible for the production of many inflammatory cytokines and chemokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. This can be through the stimulation of pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs), which are present not only on innate immune effector cells but also on cholangiocytes. These PRRs are designed to respond to pathogens but can also be stimulated by damage-associated molecular patterns (DAMPs), which are intracellular “self” proteins that are released during cell death. Therefore it is possible that cholangiocyte cell death, through either infection or other processes, could set off an unchecked cyclical inflammatory response that could lead to the pathology we associate with BA. Pang et al. examined the serum of 124 BA patients pre-Kasai and found that 56.5% of these patients were positive for one or multiple autoantibodies compared with less than 5% in healthy controls. In addition, a study of T-cell receptors (TCR) in BA patients demonstrated that the TCR repertoire was more limited and oligoclonal in nature, suggesting that these patients might be mounting an immunologic response to an autoantigen. Also, cholangiocytes from BA patients have also been found to express not only major histocompatibility complex (MHC) Class I but also MHC Class II, which is likely caused by the inflammatory milieu. This is important because this aberrant expression of MHC Class II on cholangiocytes could also be propagating an adaptive immune response in situ as well as systemically.
Although the antigen that may be responsible for or contributing to this inflammatory response is unknown, another possibility is that BA may result from the activation of maternal resident T cells against a variety of paternal antigens resulting from maternofetal microchimerism. This suggestion comes from data in which infants with BA have been shown to have high numbers of maternally derived CD8 + T cells within their livers. In support of this, longitudinal studies of living related liver transplant recipients with maternal grafts have demonstrated increased graft survival, decreased rejection, and more successful undergoing of intentional withdrawal of immunosuppression.
Clinical features diagnosis and workup
The clinical presentation of infants with BA can be variable but usually includes jaundice lasting longer than the first 2 weeks of life, acholic stools, choluria, and hepatomegaly. If left untreated, all patients will progress to cirrhosis with the development of ascites, splenomegaly, and the stigmata of portal hypertension. Coagulopathy may also develop early in the course of disease, not from liver failure, but rather from poor fat-soluble bile acid absorption, malnutrition, and Vitamin K deficiency. This coagulopathy can be severe and lead to mortality from intracranial or gastrointestinal (GI) hemorrhage.
Evaluation of an infant with suspected BA begins with standard laboratory testing including a liver function test (including γ-glutamyl transpeptidase [GGT]), standard chemistries, prothrombin time (PT)/ international normalized ratio (INR), and complete blood counts (CBCs). Infants with BA typically have direct hyperbilirubinemia greater than 2 mg/dL and elevated alkaline phosphatase and GGT. Transaminases are typically mildly elevated, whereas chemistries and CBC are usually within normal limits. PT/INR elevation that cannot be corrected with Vitamin K administration is a late finding of decompensated cirrhosis. Numerous other conditions can cause conjugated hyperbilirubinemia in newborns, including neonatal infection with the TORCH pathogens (toxoplasma, other viruses, rubella, cytomegalovirus, and hepatitis), as well as metabolic disorders, cystic fibrosis, and alpha 1-antitrypsin deficiency, and should be considered during the evaluation as well.
An abdominal ultrasound is typically performed to evaluate the liver parenchyma and vascular flow and the presence of a gallbladder or intra/extrahepatic bile ducts. In infants with BA, the gallbladder is typically shrunken or absent and intrahepatic ducts are typically not visualized. The presence of the “triangular cord sign” on ultrasound is highly suggestive of BA and when combined with some novel ultrasound modalities to identify liver fibrosis has been suggested to increase the diagnostic sensitivity of ultrasound to greater than 90%. However, although these new data are promising, these are small preliminary studies and more rigorous evaluations are required (see Chapter 13 ).
Additional studies have also been suggested to be important in the evaluation of an infant with hyperbilirubinemia. The hepatobiliary iminodiacetic acid (HIDA) scan is typically performed during the patient evaluation (see Chapter 18 ). Although the HIDA scan is highly sensitive for detecting excretion of bile from the liver, it is not very specific to the diagnosis of BA. However, a HIDA scan demonstrating excretion rules out BA. Magnetic resonance cholangiopancreatography (MRCP) has also been suggested as a possible tool in the diagnosis of BA because of the increased fidelity and visualization of the intra- and extrahepatic biliary tree. Studies from the late 1990s and early 2000s suggested a reported sensitivity and specificity of greater than 90%. ,
Regardless of the imaging study, the vast majority of infants in whom the suspicion for BA is high will progress to the gold standard for diagnosis of intraoperative cholangiography with biopsy. Although some centers perform a liver biopsy before operative cholangiography, we generally do not because the pathologic findings in the liver of BA patients early in the disease are not pathognomonic and therefore cannot entirely rule out BA.
Surgical management
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