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Transplantation for Biliary Atresia in Children
Biliary atresia (BA) is the result of an idiopathic, progressive, fibroinflammatory process that affects intra hepatic and extrahepatic bile ducts. It typically presents in the first few weeks of life and without early recognition and surgical treatment progresses rapidly to biliary cirrhosis, leading to either liver transplantation or death by 2 years of age. This chapter provides clinicians and surgeons with a detailed overview of the history, incidence, etiology, clinical forms and findings, histology, and medical and surgical management of BA and also provides a specific focus on BA from a transplant perspective.
History
The first major review of BA was written by Thompson in 1891. In his review of 50 reported cases from the literature, Thompson described the signs, symptoms, gross pathological characteristics, and natural history of this inflammatory lesion. Among the reported patients, 16% were thought to be theoretically amenable to surgical correction. Holmes in 1916 added to this review and reinforced the concept of “correctable” and “noncorrectable” conditions. It was not until 1928, however, that the first successful reconstruction of the correctable type of BA was reported by Ladd. In 1953 Gross documented that BA was the most common cause of obstructive jaundice in infants, with most of Gross’s patients having “noncorrectable” biliary ductal occlusion. Unfortunately, over the next 20 years little progress was made in surgical management of the noncorrectable forms of BA.
In 1968 Kasai reported a 10-year experience in achieving operative relief of BA through hepatic portoenterostomy in infants previously thought to be noncorrectable. This report ultimately led to the acceptance of hepatic portoenterostomy as the treatment of choice in patients with BA. With increased experience it became apparent that early diagnosis and timely operations were essential to successful restoration of bile flow, yet long-term success was still rare. Starzl and colleagues introduced liver transplantation as a treatment option for BA in 1963. Indeed, the first attempted liver transplantation (LT) in humans was performed on March 1, 1963, by Starzl in a 3-year-old child with BA. However, it was not until the introduction of cyclosporine in the early 1980s that LT became a viable therapeutic option for children with BA. Today the strategy for surgical therapy in most patients involves an initial Kasai procedure with subsequent LT when biliary drainage cannot be successfully reestablished or when progressive complications of end-stage liver disease develop. BA is the leading indication for pediatric LT, accounting for up to 75% of transplants in children under 2 years of age. BA has been responsible for innovations and technical advancements in the field of liver transplantation over the past 50 years.
Incidence
BA is among the most common causes of chronic cholestasis in children. The disease occurs worldwide and affects an estimated 1 in 5000 to 18,000 live births (1 in 5000 in Taiwan, 1 in 12,000 in the United States, 1 in 18,000 in Europe) with a slight female preponderance. In the United States 250 to 400 new cases of BA are reported per year. Some reports have cited the highest risk for BA in nonwhite children and those born during the winter through early springtime. BA is the leading cause for pediatric LT, accounting for over 40% of children undergoing their first transplant.
Genetics of Biliary Atresia
Genetic association of BA remains unclear. Although BA does not generally occur in siblings, there are case reports of twins with BA, and some studies have suggested a genetic predisposition. Recent genome-wide association studies from China have revealed a strong association of BA with two genes found on chromosome 10q24 that are expressed in biliary epithelia and potentially are involved in immune dysregulation and fibrosis. These include X-prolyl aminopeptidase P1( XPNPEP1 ), which is involved in the metabolism of inflammatory mediators, and adducin 3 ( ADD3 ), which could be responsible for excessive deposition of actin and myosin and contribute to biliary fibrosis. The single nucleotide polymorphisms (SNPs) identified in this study require further investigation to validate whether these genetic defects are applicable to all ethnicities. Nonetheless, genetic predisposition alone does not seem to be enough to explain the cause of BA.
Etiology
At one time it was widely postulated that BA resulted from failed recanalization of embryonic bile ducts. This theory has for the most part been abandoned, and it is generally felt that there are two major forms of BA: the embryonic/fetal form and the acquired/perinatal form.
Ongoing areas of research into the cause of BA include defects in morphogenesis, viral and environmental factors, and immune-mediated injury.
Defect in Morphogenesis
The fetal form of BA accounts for less than 20% of all children with BA and is associated with other extrahepatic congenital anomalies described in the following paragraph. Several investigators have described interruption in the normal remodeling of the biliary tree during embryogenesis. These patients have ductal plate malformations on histological examination.
Clinically infants with the fetal form of BA have no jaundice-free interval after birth and a high frequency of associated malformations (10% to 20%), the most common of which is the polysplenia syndrome. In this syndrome the combination of BA and splenic abnormalities (polysplenia or asplenia) is often accompanied by other malformations, including intestinal malrotation, abdominal situs inversus, annular pancreas, gastrointestinal tract atresia, renal anomalies, cardiac defects, and vascular abnormalities (such as a preduodenal or absent portal vein, an interrupted retrohepatic vena cava, and anomalous hepatic arterial circulation). Patients with the fetal form also have been reported by some as having worse surgical outcomes. In contrast to the fetal form, the perinatal form of BA does not have associated congenital anomalies.
Viral Infections
A favored theory in the development of the acquired or perinatal form of BA has implicated viral infections as activating an exaggerated inflammatory response that targets bile duct epithelia and results in progressive bile duct injury and secondary biliary cirrhosis.
Several viruses have been implicated, and the three most extensively studied are reovirus type 3, rotavirus type C, and cytomegalovirus. It is postulated that these viral infections may initiate cholangiocyte apoptosis and release of antigens that trigger a host immune response. There are animal models in which these viruses can induce BA, but no consistent data support these viruses as a cause of BA in humans. The search for a viral cause or environmental toxin began after it was proposed that there was seasonal variation or time-space clustering of cases of BA. At least two studies of the epidemiology of BA do not support the theory that there is time-space clustering of cases.
Immune-Mediated Injury
It has been proposed that patients with BA may have an abnormality in their immune system or inflammatory response. Indeed there is some evidence of immune activation in BA patients in comparison to controls. Patients with BA have been reported to have an increase in the number of CD68 + macrophages and a corresponding increase in serum interleukin-18. Other potential proposed mechanisms include an exaggerated T H 1 immune response, overactive humoral immunity, and a possible role for regulatory T cells. Whether the immune system is reacting to a stimulus in a genetically predisposed host is yet to be determined.
Classification
BA is classified with a comprehensive system based on the macroscopic and cholangiographic appearance of the biliary ducts. Type 1 BA consists of atresia of the common bile duct with or without cystic dilatation of the distal patent duct. Type 2 is defined as atresia of the common hepatic duct, and type 3 has atresia of the right and left hepatic ducts up to the porta hepatis. Type 3 is the most common type and occurs 70% to 90% of the time. The three major types can be further subdivided according to the pattern of the distal bile ducts and the pattern of the hepatic hilar radicles. This further classification, however, appears to have little bearing on operative outcomes.
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