Hepatic portoenterostomy for biliary atresia. A comparative study of histology and prognosis after surgery.

Specimens of excised tissue from the porta hepatis in 26 infants with extrahepatic biliary atresia undergoing hepatic portoenterostomy were analysed histologically for the presence and size of biliary ductules. No correlation could be found between the establishment of effective biliary drainage and the number or size of biliary ductules. it is suggested that prognosis after surgery may be related to the intrahepatic lesion and age of the child at operation rather than to the histology of the extrahepatic bile duct remnants.     

Expression of osteopontin correlates with portal biliary proliferation and fibrosis in biliary atresia

The acquired or perinatal form of biliary atresia is a Th1 fibro-inflammatory disease affecting both the extrahepatic and intrahepatic bile ducts. Osteopontin (OPN) is a Th1 cytokine implicated in several fibro-inflammatory and autoimmune diseases. We examined the expression of OPN in acquired biliary atresia in comparison to normal liver and several pediatric cholestatic liver diseases. We also assessed OPN expression by cultured human bile duct epithelial cells. We found that liver OPN mRNA and protein expression were significantly increased in biliary atresia versus normal and other cholestatic diseases. OPN expression in biliary atresia was localized to epithelium of proliferating biliary structures (ductules and/or ducts) and bile plugs contained therein. No portal biliary OPN expression could be demonstrated in normal liver, syndromic biliary atresia, biliary obstruction not due to biliary atresia, and idiopathic neonatal hepatitis. OPN expression by human bile duct epithelial cells in culture was responsive to IL-2 and TNF-alpha. Our results demonstrate an up-regulation of OPN expression by interlobular biliary epithelium in biliary atresia, which correlates with biliary proliferation and portal fibrosis. These findings suggest a role for OPN in the pathogenesis of biliary atresia.     

Anatomy of the porta hepatis (PH) as rational basis for the hepatoporto-enterostomy (HPE).

PURPOSE: In a prospective study it was investigated whether and to what degree the morphology of the porta hepatis has a bearing on the early prognosis of children with EHBA. The results will point to consequences of surgery and to the formulation of a rational understanding of the successes and failures of HPE. METHODS: The macroscopy and the microscopy of the liver was studied on native specimen and corrosion preparations of deceased adults, children and embryos. The area potentially draining the bile was determined in excised PH specimen of children with EHBA. The histologically and planimetrically measured areas were correlated to clinical follow-up studies. In order to be able to study exclusively the influence of the PH morphology, the conditions of the intrahepatical structural changes (level of fibrosis, metric and morphic changes of biliary ductules in the Glisson's triads) had to be equal. Under these conditions 61 excised PH specimen were evaluated. The level of fibrosis was determined according to the definition of Schweizer/Müller 1984 (9). RESULTS: 1) Biliary ductules of the PH end in three definable zones according to a regular pattern. 2) Biliary ductules of the PH run in a narrow and immediate relation to the vascular structures. 3) Biliary ductules of the PH are often hidden between the vascular structures of the PH and are not always accessible to preparatory exposure for the anastomosis. 4) The quantity of the bile flow is a significant function of the total area of the biliary ductules secured in the excised PH specimen. 5) Incised biliary ductules at the excision edge may be obstructed again in the scarring of the anastomosis, leading to an early interruption of bile flow. 6) The opening-up of the biliary ductules in the central zone alone is not enough to guarantee a permanent bile flow. Only if intact biliary ductules of the two lateral hepatical lobes are secured, can a positive prognosis be made.     

Abnormalities associated with extrahepatic bile duct atresia]

In 19 cases of extrahepatic biliary atresia there were other malformations, 9 of which could be included in the polysplenia syndrome. The importance of these associated with malformations for the early diagnosis of extrahepatic biliary atresia and for eventual surgery for secondary portal hypertension is emphasized. The histological findings of the fibrous remnants of the biliary system are similar in those with and without associated malformations. Thus, these abnormalities do not contribute of the understanding of the pathophysiology of extrahepatic biliary atresia but they do suggest that the initial insult may occur early in pregnancy.     

Notch配体、受体在小儿胆道畸形肝组织中的表达及意义

目的 探讨Notch信号通路在小儿胆道畸形发病机制中的作用.方法 收集23例胆道畸形患儿临床资料(胆道闭锁12例,胆总管扩张11例),术中取肝脏组织样本;9例正常肝脏组织样本作为正常对照.免疫组化方法和实时荧光定量PCR方法检测肝脏组织中的Notch配体、受体的表达分布和相对表达量.结果 Jag1在胆道闭锁增生胆管表达明显增强,Jag2在各组门管区表达为阴性;荧光定量PCR显示:胆道闭锁组及胆总管扩张组Jag1 mRNA的表达明显高于对照组(P＜0.01);Jag2 mRNA的表达在三组问差异无统计学意义(P＞0.05).Notch1、Notch 2在对照组及胆总管扩张组主要表达于肝细胞和成熟胆管细胞,胆道闭锁组胆管细胞无阳性表达.Notch 3在胆道闭锁汇管区新生血管、基质中有较为明显的表达.荧光定量PCR显示:Notch1、Notch 2mRNA的表达在三组间差异无统计学意义(P＞0.05),胆道闭锁组Notch 3 mRNA的表达高于对照组(0.013±0.003比0.009±0.003,P＜0.01).Notch 4表达为阴性.结论 胆道闭锁肝脏组织Notch配体、受体表达异常,增生胆管细胞Jag1的过表达及Notch受体表达缺陷可能参与了胆道闭锁的病理过程.     

不同年龄胆总管囊肿的临床与肝纤维化特点探讨

目的 探讨不同年龄胆总管囊肿的临床与肝脏纤维化特点与相互关系。方法 分析12例婴儿及36例幼儿、儿童胆总管囊肿的临床资料;肝组织HE染色观察纤维化程度和炎性细胞浸润情况,免疫组化染色观察细胞角化蛋白(AE1/AE3)、人类组织相容性抗原DR(HLA—DR)表达,并与18例胆道闭锁作对照。结果 婴儿胆总管囊肿黄疸出现率12/12,显著高于幼儿儿童组8/36(P<0.01);肝纤维化程度、小叶周边AE1/AE3阳性细胞和HLA—DR在肝脏表达显著高于非婴儿组(P<0.01),低于胆道闭锁组(P<0.01)。肝纤维化程度与黄疸及肝小叶周边AE1/AE3表达分级呈正相关(P<0.05)。结论 婴儿胆总管囊肿以黄疸为主要临床表现,其肝纤维化重于幼儿及儿童组,胆道梗阻和胆小管增生可能是其发生肝纤维化的原因。     

Differentiation between extrahepatic and intrahepatic cholestasis by discriminant analysis

Discriminant analysis was used to differentiate between extrahepatic biliary atresia and intrahepatic cholestasis. Among the ten laboratory variables tested, three (gamma-glutamyl transpeptidase, alkaline phosphatase and total serum bilirubin) were useful in the differential diagnosis. gamma-Glutamyl transpeptidase contributed most to the discrimination (85%). From a population study of 28 babies with extrahepatic biliary atresia and 24 infants with intrahepatic cholestasis, the procedure achieved a diagnostic accuracy and specificity of 92.9% and an efficiency of 92.3%. The jackknife procedure has also confirmed that the mathematical model was robust for discriminant analysis and therefore it may be valid for screening infants with cholestasis for early surgical intervention. Discriminant analysis is a useful adjunct for differentiation between intrahepatic cholestasis and extrahepatic biliary atresia.     

Clinical and pathological characteristics of cystic lesions of extrahepatic bile duct in neonates

Aim: To investigate the differences in clinical and pathological manifestations between biliary atresia with extrahepatic biliary cyst and choledochal cyst in neonates. Methods: Symptoms and clinical signs in 5 neonates with biliary atresia with extrahepatic biliary cyst (4 of type I and 1 of type III) and 17 neonates with choledochal cyst were recorded. The levels of serum alkaline phosphatase, bilirubin, direct bilirubin, transaminase, gamma-glutamyl transpeptidase were analysed. Width and length of gallbladder and choledochal cyst were measured on B-mode ultrasound before surgery. Intrahepatic or extrahepatic biliary ducts were visualized with intraoperative cholangiography. The pathologic features in specimens of the liver were studied with light- and electron transmission microscopy. Results: All malformations occurred more commonly in girls, and obstructive jaundice was the main manifestation in both groups. Laboratory tests showed similar results for all patients in this study. With regard to pathological features, no significant difference was seen in either light microscopy or transmission electron microscopy, but it was shown with ultrasound that the length and width of the cysts and the gallbladder in neonates with biliary atresia were all shorter than the measurements in patients with choledochal cyst. The intrahepatic bile ducts could not be visualized on intraoperative cholangiography in type III biliary atresia. Deformation of the biliary ducts within the liver and stricture of the portal bile duct were the predominant features in type I biliary atresia, while the bile duct within the liver was normal or dilated in neonates with choledochal cyst.

Conclusions: Cystic lesions of the extrahepatic bile duct might be a common manifestation of biliary atresia and choledochal cyst. Intraoperative cholangiography is a precise and effective technique in the differential diagnosis of those lesions and helps decide on the most rational method of treatment.     

Bile duct atresia following extended right hepatectomy because of a tumor

A 19 month old male infant with a mesenchymal hamartoma of the liver underwent an extended right hepatectomy. Serum bilirubin gradually rose until 3 months after the surgery, and obstructive jaundice and acholic stools were manifested at 6 months. Percutaneous transhepatic cholangiodrainage was performed. Cholangiography showed dilation of the intrahepatic bile duct of the residual lateral segment and complete obstruction of the extrahepatic bile duct. A second operation for reconstruction of the biliary tract was performed 10 months after the first surgery. No aspect of an extrahepatic biliary tract was found. Histological inspection of a surgical specimen of remnant tissue revealed only cicatricial connective tissue without any biliary structures. The clinical course has been uneventful for 18 months since the second surgery. The cause of bile duct atresia in this case is strongly suggested to be an ischemic change due to devascularization of the extrahepatic biliary tract following hepatic resection because of a tumor. To prevent this kind of complication, hepaticoenterostomy should be performed close to the cut surface of the liver.     

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

Neonatal hepatitis and extrahepatic biliary atresia associated with cytomegalovirus infection in twins.

Prenatally acquired cytomegalovirus infection in twins was temporally associated with a discordant development of neonatal hepatitis and extrahepatic biliary atresia. This case presents evidence suggesting an association between perinatal cytomegalovirus infection and selected extrahepatic biliary atresia and neonatal hepatitis. Congenital cytomegalovirus infections and cytomegalovirus hepatitis are also discussed.     

Biliary infusion therapy in the inspissated bile syndrome of cystic fibrosis

A 3.5-month-old white boy was born with meconium ileus, peritonitis, and jejunal atresia from cystic fibrosis. He subsequently developed unrelenting and severe extrahepatic biliary obstruction as demonstrated by liver biopsy showing periportal inflammation, cholestasis, and fibrosis. Surgical exploration confirmed the diagnosis of extrahepatic biliary obstruction by severely inspissated bile. A cholecystostomy tube was left in place. The cholestasis remained unresponsive to conservative medical therapy. The obstruction was relieved by hydrostatic infusion of 2% N-acetylcysteine into the biliary tree over a 6-day period. The child also received concurrently four i.v. injections of synthetic cholecystokinin. This therapeutic modality was thought to be both safe and effective.     

HYALINE CARTILAGE AT PORTA HEPATIS IN EXTRAHEPATIC BILIARY ATRESIA

Hyaline cartilage was found on microscopy of sections of the extrahepatic biliary tree in two infants with extrahepatic biliary atresia (EHBA). Respiratory epithelium was not present, and the cartilage did not seem to block the bile duct lumen. Hyperbilirubinemia was manifest in one infant on the second postnatal day, but clinical courses were otherwise unremarkable. In neither infant was the ductal plate malformation found on light microscopy of liver biopsy specimens, and in neither infant was visceral topography abnormal. Hyaline cartilage at the porta hepatis appears to be a novel finding in EHBA. Its significance remains to be defined.     

Porcelain gallbladder with extrahepatic bile duct obstruction in a child

An extrahepatic bile duct obstruction was diagnosed in a 13-year-old boy presenting with pruritus, abdominal pain and jaundice. Several weeks after sphincterotomy and biliary stenting via endoscopic retrograde cholangiopancreaticography which relieved the obstruction, the patient was operated on. Severe fibrosis encased the extrahepatic biliary tract, so only cholecystectomy was performed because planned hepaticojejunoanastomosis could jeopardize the vascular supply to the liver. Histopathology showed calcification of the gallbladder wall and chronic fibroproliferative changes in the surrounding tissue. The stricture of extrahepatic biliary duct resolved after 3 years of repeated replacement of stents. The stenting was thereafter terminated. In the following 3 years no dilation of intrahepatic bile ducts and no laboratory signs of cholestasis recurred and the now 19-year-old boy is doing well. Neither a case of porcelain gallbladder with extrahepatic bile duct obstruction in a child nor a successful treatment of the obstruction by long-term stenting has been described in the literature yet.     

Bleeding as the first symptom of extrahepatic biliary atresia

Four cases of extrahepatic biliary atresia are reported. Each of these infants presented with haemorrhagic phenomena rather than with prolonged jaundice. The increased bleeding tendency was due to a vitamin K deficiency, probably caused by cholestasis-induced malabsorption. Therefore extrahepatic biliary atresia should be considered in each infant with a bleeding diathesis.Abbreviations Hb haemoglobin - SGOT aspartate transaminase - SGPT alanine aminotransferase - ^99mTc-IDA ^99mTechnetium-labelled iminodiacetic acid     

Intrahepatic biliary tract abnormalities in children with corrected extrahepatic biliary atresia

Three children with surgically corrected extrahepatic biliary atresia developed recurrent cholangitis associated with bile lakes that failed to drain via the hepatoportoenterostomy. Surgical or percutaneous drainage of these cysts was followed by both resolution of the infection and spontaneous internal drainage. We postulate that the ongoing inflammatory process resulted in intrahepatic biliary obstruction, which caused cholangitis and bile cysts. Successful treatment required not only antibiotics but drainage of the bile lakes. Development of bile cysts is a new cause of recurrent cholangitis seen in extrahepatic biliary atresia.     

Long-term prognosis of patients with extrahepatic biliary atresia successfully treated with surgery. Our experience

The long-term prognosis of extrahepatic biliary atresia after surgical restoration of bile flow is still controversial. An ongoing process of cirrhosis and the development of portal hypertension continue to create frequent and frustrating management problems. Clinical features, hepatic function, echotomography aspect, calcium-phosphorus metabolism and serum levels of 25-OH-D-3 were evaluated in 12 anicteric patients with extrahepatic biliary atresia successfully treated in a period from 1974 through 1987. Seven of these children had a total of 21 episodes of cholangitis. In five patients liver biopsy, obtained at the time of the external diversion closure, showed a biliary cirrhosis. Growth, development and hepatic function were normal in all children studied; one patient had esophageal varices. The serum levels of 25-OH-D3 in patients without oral supplementation of vitamin D are lower than normal. This deficit can be corrected by oral administration of vitamin D. Our study revealed that the children with successful portoenterostomy appeared to thrive normally and that they tolerated the relatively mild liver damage. We believe that Kasai operation should be done in all patients with extrahepatic biliary atresia and that the liver transplantation is to be reserved only in those with unsuccessful Kasai. In our experience external diversion was not useful to prevent cholangitis and moreover it complicates the hepatectomy in case of transplantation.     

Spontaneous perforation of the extrahepatic biliary tract in infancy and childhood

Spontaneous perforation of the extrahepatic biliary tract in infancy and early childhood is a poorly understood and infrequently reported disorder of unknown etiology. The reported experience with 77 operative cases is reviwed. The onset is generally insidious, but may be acute in 25% of cases. The major symptoms are abdominal distention and jaundice. The younger the patient at the time of onset, the more likely is jaundice to be found. Drainage-type operations were most commonly used in the early reported cases while more recently anastomosis/bypass procedures have predominated due to the relatively frequent occurrence of distal biliary tract obstruction. This disorder appears to be a part of the biliary atresia — neonatal hepatitis — choledochal cyst complex which occurs in the neonatal period and early infancy and appears to be acquired rather than congenital. Because of the theoretical potential for late malignancy, lifelong follow-up with periodic evaluation of the intra- and extrahepatic biliary tracts is recommended. The advisability of liver transplantation (and accompanying immunosuppression) as the primary surgical treatment for biliary atresia may be questioned.     

Contemporary surgery of biliary atresia

The etiology of biliary atresia is not due to a congenital malformation but rather to a continuing process beginning in utero that affects not only the extrahepatic biliary ducts but also the intrahepatic parenchyma. Over the last decade, the outlook for patients who were previously felt to be uncorrectable has been significantly improved by Kasai's operation. Successful biliary reconstruction depends on early diagnosis and treatment (before three months of age). The essentials of hepatic portoenterostomy consist of excision of the entire extrahepatic duct structure with anastomosis of an intestinal conduit to the area of the transected duct at the liver hilus. After operation, many patients experience complications, including cholangitis, portal hypotension, and vitamin deficiencies. Despite these difficulties, growth and development continue on a relatively normal course, and long-term survival has been accomplished in many children. For those in whom biliary drainage is not achieved or with significant parenchymal damage, liver transplantation should be considered as part of ongoing care.     

Yellow is pale: The complications and challenges of late diagnosis of extrahepatic biliary atresia

Extrahepatic biliary atresia classically presents in the neonatal period with jaundice and pale stools. The lack of bile pigment in stool can be unrecognised, delaying diagnosis and surgical treatment. Vitamin K is given at birth to reduce the risk of haemorrhagic disease of the newborn, but this may be inadequate to prevent the development of coagulopathy secondary to fat soluble vitamin malabsorption. We present the case of a 3 month old infant who presented with an intracerebral haemorrhage and coagulopathy thought to be secondary to fat malabsorption resulting from delayed diagnosis of extrahepatic biliary atresia. This was despite the perinatal administration of intramuscular vitamin K. His parents did not recognise the stool pallor as being abnormal. This case illustrates the importance of educating parents on the significance of pale stools, and also the risk of coagulopathy in extrahepatic biliary atresia despite perinatal intramuscular vitamin K.