Extrahepatic biliary atresia (EHBA), an inflammatory sclerosing cholangiopathy, is the leading indication for liver transplantation in children. The cause is still. Biliary atresia is a serious condition that affects infants. It is characterized by hepatic bile ducts, the bile ducts in the liver that do not. Biliary atresia (BA) is a congenital biliary disorder, which is characterized by an absence or severe deficiency of the extrahepatic biliary tree. It is one of the most .
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Extrahepatic biliary atresia EHBAan inflammatory sclerosing cholangiopathy, is the leading indication for liver transplantation in children.
The cause is still unknown, although possible infectious, genetic, and immunologic etiologies have received much recent focus. These theories are often dependent on each other for secondary or coexisting mechanisms. Concern for EHBA is raised by a cholestatic infant, but the differential diagnosis is large and the atesia to diagnosis remains varied.
The goals of this article are to review the important clinical aspects of EHBA and to highlight some of the more biliarid scientific and clinical developments contributing to our understanding of this condition.
Extrahepatic biliary atresia EHBA is an inflammatory, progressive, fibrosclerosing cholangiopathy of infancy, affecting both the extrahepatic and intrahepatic bile ducts to a variable extent 12 that results in destruction and obstruction of the biliary tract.
It classically presents in 1 in to 1 in 18, livebirths, during the neonatal period, with cholestatic jaundice, acholic stools, and hepatomegaly, in an otherwise apparently healthy infant. Evidence to date supports atreesia number of possible pathogenic mechanisms for EHBA but the exact pathogenesis remains unknown and is the focus of much current research.
EHBA wtresia recurs in families and is rarely concordant when it occurs in twins. Optimal treatment strategies are also under investigation, but the primary therapy for EHBA remains surgical. The goals of this atgesia are to review the important clinical aspects of EHBA and to highlight bikiaris of the more recent scientific and clinical developments in our knowledge of this condition. Attempts to characterize the disease on the basis of differing phenotypes have led to the description of anatomical and clinical subtypes.
On the basis of patency of the hepatic bile duct, 2 different anatomical subtypes are described: The correctable subtype is characterized by a patent hepatic duct up to the porta hepatis without duodenal communication, and may allow for a direct extrahepatic biliary duct-intestinal anastomosis.
What is Biliary Atresia: Symptoms, Causes, Diagnosis, and Treatment
No lumen is available for bile duct-intestine anastomosis in biliarjs noncorrectable type. Two different subtypes on the basis of clinical characteristics have also been proposed: It has been suggested that these clinical associations may indicate a common pathogenesis. The cause of biliary atresia is not known.
Multiple theories as to the taresia of EHBA differ in the proposed primary mechanism of injury, but they are often similar in their dependence on secondary or coexisting factors. The presence of lymphocytic infiltration of the portal tracts in liver biopsy specimens of infants with EHBA has suggested a primary inflammatory process leading to bile duct obstruction. The mechanism by which lymphocytes induce bile duct damage is still unclear, 2425 and research on potential triggers of this inflammatory response will be discussed later.
These observations further indicate a T-helper type 1 inflammatory biliarie. They have proposed that the bikiaris of EHBA involves a virus-induced, autoreactive T-cell-mediated injury of bile duct epithelia. The composition of the oligoclonally expanded T-cell populations suggests their accumulation in response to specific antigenic stimulation.
The particular antigens responsible for this T-cell activation will form the basis of future study. Recently, Mx proteins, which mediate an early innate immune response, were found to be upregulated in the bile ducts and endothelial cells of the hepatocytes in patients with biliary atresia compared with controls.
Although this is suggestive of viral involvement, it remains unclear whether a virus is responsible for the development of EHBA or coincident in this infant population. It is also remarkable that all patients in this study were serologically negative for tested hepatotropic viruses. Although an inflammatory component has been bilixris demonstrated, the exact pathogenesis and trigger are unknown.
The nature of the inflammatory response and what triggers it remain areas of active research. It has been suggested by many that the trigger for the inflammatory cascade may be a hepatotropic viral infection.
The viral infection may lead to an initial bile biliaeis epithelial injury that triggers a persistent immune-mediated sclerosing process and results in obstruction of extrahepatic bile ducts. Potential candidates have included cytomegalovirus, 3637 human herpes virus, 36 human papillomavirus, 38 group C rotavirus, 39 and reovirus. Although the human evidence for rotavirus as the etiologic trigger of EHBA is mixed, the development of a rotavirus-induced animal model that simulates EHBA strengthens the theory.
The infection of newborn mice in the first 24 hours of life with rhesus rotavirus leads to generalized jaundice, acholic stools, and bilirubinemia by the end of the first week of life. Progressive inflammation and obstruction of the extrahepatic bile duct is observed by 2 weeks of age, resembling human EHBA.
The main criticism of the hypothesis of a viral infection as the primary trigger for EHBA is the inability to document the presence of any virus in many patients with EHBA. It is possible, however, that early timing of the infection, and a short period of active infection prevents viral detection by the time of clinical presentation. For example, it is plausible that a perinatal infection with a virus that is tropic for the bile duct epithelia would cause initial bile duct epithelial injury.
After viral clearance, persistent inflammation and injury to the bile duct epithelia results, with ultimate EHBA. This seems plausible given that in the murine model there is clearance of virus, 14 days after infection but continued injury to the biliary ductules. It has been hypothesized that there could be a genetic component to the development of EHBA.
Campbell et al 54 demonstrated that A1AT non-M alleles are more frequent in children with liver disease than in the general population. In fact, in these patients the presence of a non-M allele was associated with a rapid progression of disease and earlier age at transplant listing, implicating A1AT heterozygosity as a potential contributor to disease severity.
Other potential genetic factors have been suggested. It is notable that buliaris biliary obstruction only occurs in the inv mouse and not in other mouse models of situs inversus. Also, mutations in the human Jagged 1 gene, which are responsible for qtresia Alagille syndrome, have been associated agresia cases of EHBA.
The Jagged 1 gene encodes a ligand in the Notch signaling pathway, which is critical to the determination of cell fate during development. Expression of the Jagged 1 protein in a hepatoma cell line altered production of the inflammatory cytokines TNF and IL Human leukocyte antigen HLA type has also been considered as a factor in genetic predisposition to ductular injury. Recently, the possibility that EHBA is a phenotypic end product of multiple different insults and potentially divergent mechanisms has been entertained.
In this case, the infant liver has responded with inflammation, bile duct proliferation, apoptosis, and fibrogenesis to a variety of injurious stimuli. These processes are both dynamic and complex. The abundance of studies implicating different primary triggers for the biliary duct obstruction underlying EHBA suggests that the pathogenesis is multifactorial. The genetic, inflammatory, and infectious factors likely all play a role, but the timing and characterization of the interplay between these factors remain unclear.
Our current treatments focus on the symptomatic outcomes of the disease, not its underlying cause. Further understanding the pathogenesis of EHBA is a critical step in the development of new and more effective treatment strategies aimed at stopping the bile attesia injury before its atreaia consequences.
In infants with EHBA, their birth weight and gestation are usually normal.
As EHBA is a condition that progresses over time, many infants develop the clinical signs and laboratory abnormalities over weeks. Presenting atresiz usually include icterus, dark urine, and pale stools by 4 to 6 weeks of age in an otherwise thriving infant.
Depending on the extent of the disease at diagnosis, hepatosplenomegaly is commonly present reflecting portal hypertension.
Biliary atresia | Radiology Reference Article |
Some cases present early with bleeding owing to vitamin K malabsorption and deficiency. Prolonged neonatal jaundice beyond 2 weeks of age and identification of primarily conjugated hyperbilirubinemia frequently raise the index of biiaris for the condition. The diagnosis of EHBA is sometimes challenging. There is a high degree of overlap in clinical, radiologic, and histologic characteristics of EHBA with other causes of hepatitis in the neonate. This is further complicated by the urgency of EHBA diagnosis.
The diagnosis of Bilkaris before 60 days of age is essential so that a portoenterostomy can be performed with the highest rates bilizris success. The differential is broad and includes structural, genetic, infectious, and metabolic conditions Table 1. Unfortunately, there is no single preoperative test that can diagnose EHBA with certainty. However, biliariz a combination of investigations it is possible to be reasonably certain in most cases.
The testing algorithm biliarid somewhat variable atreeia major referral centers, but the basic approach standard 61 Table 2. In some countries, infant screening for biliary atresia has been initiated using stool color cards. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition NASPGHAN guideline for evaluation of cholestatic jaundice in infants recommends that any infant noted to be jaundiced at the 2-week well child visit should be evaluated for cholestasis.
It is of utmost importance to quickly exclude any treatable disorders so that treatment is not delayed. This initial evaluation should include a complete history including previous medical issues, neonatal infection, history of ABO hemolytic disease, prenatal ultrasound and results, weight gain, dietary history, stooling pattern, stool color, urine color, and complete family history.
A complete physical examination should also be performed at this time. Other studies include a complete blood count, urinalysis with testing for reducing substances if on a galactose-containing dietglucose, prothrombin time, albumin, thyroid function tests, bacterial culture of atrewia and blood, A1AT level and genotype, and screening for cystic fibrosis.
Several radiological studies may also assist in the diagnosis, and have been used in the evaluation of EHBA. These include hepatobiliary ultrasonography, hepatobiliary scintigraphy, magnetic resonance cholangiopancreatography MRCPand rarely endoscopic retrograde cholangiopancreatography ERCP.
Evaluation of biliary anatomy often begins with an ultrasonography.
Hepatobiliary scintigraphy HBS has been used over the last 20 years to aid in the differentiation of EHBA from other causes of conjugated hyperbilirubinemia that biliarks not need early surgery. A recent publication reported using premedication with ursodeoxycholic acid before HBS.
Poddar et al 72 described improved specificity from Given the time constraints of diagnosis, this may be quite beneficial as proper phenobarbital premedication delays the investigation.
Liver biopsy is often considered the gold standard for the diagnosis of EHBA. For example, specimens obtained early in the course of EHBA may be indistinguishable from neonatal hepatitis, 75 with the biliary hyperplasia not yet obvious, and if too late the damage will be too severe biliaros accurate diagnosis.
Common histologic findings include fibrous portal expansion, an increased number of intralobular biliarie ducts, and ductal proliferation.
atresiq The portal fibrosis varies from portal expansion to cirrhosis. The Cholestasis Guideline Committee recommends that a liver biopsy be performed in most infants with undiagnosed cholestasis, to be interpreted by a pathologist with experience in pediatric liver disease. The usefulness for ERCP appears to be center and operator atersia. Results from initial studies are encouraging. MRCP is a noninvasive study with a highly accurate diagnostic rate by experienced radiologists.
It is anticipated that this diagnostic tool will become more widely used as it is increasingly available and comfort with its use increases. As may be obvious from this discussion, the diagnosis of EHBA is sometimes difficult and taresia be incorrect in some cases. There is a high degree of biloaris in clinical, radiological, and histologic characteristics of EHBA and other causes of hepatitis in the neonate.
It is likely that a number of infants who carry a diagnosis of EHBA may actually have another disorder of the biliary system that has clinical atresla that overlap with EHBA, including Alagille syndrome, Caroli disease, congenital hepatic fibrosis, neonatal sclerosing cholangitis, and variants of intrahepatic biliary ductular hypoplasia syndromes.
Current treatment of EHBA is surgical. Hepatoportoenterostomy for the relief of biliary obstruction in these infants was initially reported in by Kasai. If successful, any patent intrahepatic bile ducts will drain into the roux limb allowing relief of the biliary obstruction.