An unusual case of biliary atresia

Intrahepatic biliary cysts are rarely seen in the patients with biliary atresia. We describe a ten-month-old child with biliary atresia in whom the abdominal imaging studies (ultrasonography, computed tomographic scan and magnetic resonance cholangiopancreatography) revealed multiple intrahepatic biliary cysts ('bile lakes'). The child also had intrapulmonary shunting of blood due to pulmonary arteriovenous fistulae, which were demonstrated on contrast-enhanced echocardiography. Both these findings, 'bile lakes' and pulmonary arteriovenous fistulae occur rarely in biliary atresia.     

胆道闭锁肝内外胆系组织病理形态学分析

目的 通过胆道闭锁（BA）肝门纤维块、肝脏组织的病理及其超微结构观察，对肝门成纤维细胞分化程度进行评分，并与肝纤维化分级进行相关分析。方法 选取BA患儿作为研究对象，术中取肝门纤维块及肝脏组织标本；研究同期选取疑似BA经术中胆道造影除外BA，诊断为胆汁淤积综合征和先天性胆管扩张症患儿作为对照组，留取肝脏组织标本。在光镜和电镜下观察标本的病理改变，以及肝细胞、毛细胆管和肝门成纤维细胞的超微结构。采用SPSS14．0软件，半定量比较BA与对照组肝脏纤维化的差异，检验肝门纤维块成纤维细胞活跃程度与肝纤维化分级的相关性。结果 2005年7月至2006年5月复旦大学附属儿科医院收治的21例BAKasai根治术病例，手术平均年龄（66±20）d；对照组为5例胆汁淤积综合征和10例先天性胆管扩张症患儿。BA组肝组织病理改变主要是肝内门脉区胆管炎症及纤维化形成，肝纤维化程度明显高于同年龄胆汁淤积综合征和先天性胆管扩张症患儿；肝门纤维块毛细胆管增生，部分管腔闭锁、狭窄，腔内炎细胞浸润及部分淤胆，大量间质成分增生；电镜下肝门成纤维细胞活跃、肝脏毛细胆管上皮微绒毛缺失、肝细胞及肝血窦内电子致密物质增多及部分毛细胆管扩张；肝门成纤维细胞分化程度与肝组织纤维化程度相关（P=0．04）。结论 BA肝组织病理改变主要是肝内门脉区胆管炎症及严重纤维化形成；超微结构改变提示肝门部成纤维细胞活跃，其分化程度与肝纤维化程度相关。     

Neutrophils in biliary atresia. A study on their morphologic distribution and expression of CAP37

Biliary atresia is a rare pediatric disorder that results in obstructive jaundice in early infancy. Liver biopsies are characterized histologically by cholestasis, portal inflammatory infiltrate, and marked bile ductular proliferation. We studied the distribution of neutrophils in biliary atresia in patients who have undergone the Kasai procedure. Thirteen different liver biopsies were accompanied by hilar section in eight cases. Control liver specimens were from two patients with choledochal cysts, three patients with neonatal hepatitis, and three patients with alpha-1 antitrypsin deficiency. We also studied the expression of CAP37, an antimicrobial protein present in neutrophils, using immunohistochemistry in biopsy and hilar sections. Neutrophils were present in the portal tracts in all cases and widely distributed in the parenchyma in nine cases. In six cases, infiltration of neutrophils was associated with discrete foci of liver cell necrosis. There was a significantly higher number of portal tract neutrophils in biliary atresia and choledochal cyst cases than in neonatal hepatitis and alpha-1 antitrypsin deficiency (p<0.05). All neutrophils stained diffusely and strongly with CAP37. Medium staining was also seen in the proliferating portal bile ductules in six cases. This study confirms the wide distribution of neutrophils in biliary atresia, occurring as a result of bile duct obstruction. Infiltrating neutrophils are better highlighted with CAP37 immunostain. Proliferating bile ductules may play a role in the inflammatory response in biliary atresia through expression of CAP37.     

Intrahepatic biliary cystic lesions

Intrahepatic biliary cysts encompass a large lesional spectrum including hereditary diseases as polycystic liver disease or Caroli's syndrome, malformative lesions as non hereditary Caroli's disease or simple biliary cyst and true neoplastic lesions as cystadenoma or cystadenocarcinoma. The diagnostic approach of these lesions relies firstly on imaging. Nevertheless, the pathologist not exceptionally receives surgical specimens from cystic fenestration or liver specimen resection with one or several cystic lesions. The clues for pathological diagnosis of these lesions have to be known by pathologists. As regards neoplastic cystic lesions, true non-communicating cystic tumors and cystic variants of intraductal biliary tumors have to be distinguished; in both cases, the classification is now identical to the one of pancreatic cystic tumors.     

Persistent external biliary fistula after surgery for hepatic hydatid cyst]

Post-operative persistent biliary fistulae due to hydatid cysts are difficult to manage. We report 3 cases of external biliary fistulae complicating surgery for hepatic hydatid cyst (2 cases) and intraperitoneal hydatid cyst (1 case). Endoscopic sphincterotomy was successful with closure of the fistulae in all patients. This procedure should be the first-line treatment for post-operative external biliary fistulae related to liver hydatid disease. Usually difficult and haemorrhagic surgery can thus be avoided.     

Abnormalities of intrahepatic bile ducts in extrahepatic biliary atresia

The infantile cholangiopathies are a group of conditions associated with neonatal jaundice, which include extrahepatic biliary atresia, paucity of intra-hepatic bile ducts and disorders associated with persistence of fetal biliary structures, the so-called ductal plate malformations. Although previously regarded as distinct entities, it has recently been suggested that they may represent parts of a disease spectrum in which the principal process is one of bile duct destruction, the morphological manifestations in individual cases being influenced by the stage of intra-uterine development at which such injury occurs and by the site within the biliary system at which there is maximum damage. To further examine this concept, we have studied liver biopsy specimens from 37 neonates with extrahepatic biliary atresia, with particular reference to abnormalities of the intrahepatic bile ducts. Paucity of intrahepatic ducts, defined as a bile duct: portal tract ratio of less than 0.9, was identified in six cases (16.2%). In eight cases (21.6%) we found concentric tubular ductal structures similar to those observed in ductal plate malformations. In one case, both abnormalities could be demonstrated. Our findings support the concept that there is overlap between the various types of infantile cholangiopathy.     

Congenital extrahepatic biliary atresia

Ten cases of congenital extrahepatic biliary atresia were studied ultrastructurally. Samples of liver were obtained from each and in six of the cases, fibrous tracts, which we hoped would contain extrahepatic bile ducts, were also secured. The observed extrahepatic biliary structures were real, but hypoplastic, bile ducts. In places, necrosed epithelial cells, without obvious inflammatory processes, could be observed. The ductular cell cytoplasmic changes and the inflammatory reaction are different according to whether extrahepatic or intrahepatic sites are considered. These differences, as well as the cytoplasmic modifications of liver parenchymal cells, seem to be the result of impaired bile flow. On the contrary, extrahepatic bile duct hypoplasia and necrosis seem to be directly related to the unknown origin of this disease. Whether the nuclear changes of hepatocytes are the expression of direct injury of the liver is another important question. If there is direct injury, it is possible that the disease might evolve as an independent liver disease despite a correctly performed and uncomplicated surgical intervention.     

The pattern of differentially expressed genes in biliary atresia

Biliary atresia is a progressive obliterative cholangiopathy, but the etiology of this disorder remains uncertain. Identifying genes specifically expressed in biliary atresia and analyzing the pattern of expression may lead to a better understanding of the pathogenesis. Liver tissues were taken from a recipient with biliary atresia and a normal donor during liver transplantation. Total RNA was extracted from each sample and reversely transcribed to cDNA. Then radiolabeled cDNA probe pools were made by random primed DNA labeling method and used for screening of differentially expressed genes by hybridizing with expressed sequence tags (EST) dot blot panel. Northern blot hybridization was done to confirm that these genes are also differentially expressed in other liver tissues. Among 1730 EST clones, 26 cDNA clones were significantly overexpressed in biliary cirrhosis, while 2 clones were significantly decreased in biliary atresia. By Northern blot hybridization, the results of tissue inhibitor of metalloproteinase (TIMP)-1 and IGFBP-2 were well correlated with differential EST screening (DES). This study identified the pattern of differentially expressed genes in the biliary cirrhosis due to biliary atresia using DES technique.     

Congenital biliary dilatation in autosomal dominant adult polycystic disease of the liver and kidneys

Specimens of autopsied livers and biliary tracts of three patients with autosomal dominant adult polycystic disease of the liver and kidneys were examined morphologically with adjunct postmortem cholangiography. The cholangiograms revealed nonobstructive diffuse dilatation of intrahepatic bile ducts in all cases. Macroscopic examination confirmed the nonobstructive ductal dilatation and also showed a number of cysts in all cases. Microscopically, the dilated bile duct walls were composed of fibrous walls and were free of other pathologic changes, suggesting that the biliary dilatation was congenital in origin. Small microscopic bile ducts, however, were not dilated and were free of ductal plate malformation. In addition, Meyenburg's complexes and liver cysts not communicating with the biliary tract lumen were seen. It was suggested that adult polycystic disease, Meyenburg's complexes, and congenital intrahepatic biliary dilatation could coexist in some patients.     

Pertussis in nonimmunized postsurgical biliary atresia

A case of pertussis in a patient who had undergone hepatic portocholecystostomy for biliary atresia is described. It has been recommended that infants with postsurgical biliary atresia forgo immunizations because of the high incidence of “ascending cholangitis.” The patient in this study, however, had two characteristics that decreased her susceptibility to ascending cholangitis. This report suggests that patients with postsurgical biliary atresia who undergo hepatic portocholecystostomy rather than hepatic portoenterostomy or do not achieve bile drainage should be immunized according to schedule.     

Insulin-like growth factor-1 (IGF-1) in children with postoperative biliary atresia: a cross-sectional study

Biliary atresia is the leading cause of chronic infantile cholestasis which eventually leads to cirrhosis. Re-establishment of biliary drainage by Kasai portoenterostomy and liver transplantation for end-stage liver disease has favorably altered the clinical outcome. However, growth failure, one of the major complications of chronic liver disease, remains a major problem. The aim of the study is to evaluate growth, nutritional status and serum growth factor IGF-1 in children with biliary atresia after Kasai operation and at comparing these data between the groups with successful and unsuccessful operation. Fifty-four children with postoperative biliary atresia were evaluated for their clinical outcome, height, blood biochemistry related nutritional status and serum IGF-1. Height and serum IGF-1 were expressed as standard deviation score (SDS) to minimize the influence of age. With 44.4% of the enrolled patients the operation had been unsuccessful and jaundice persisted. The mean age of children with jaundice in comparison with the jaundice free groups was not significantly different (42.0 and 49.9 months, p = 0.458). In jaundice-free patients, hematocrit, serum albumin, calcium and phosphorus were normal and significantly higher. In the successful Kasai group, the height SDS and serum IGF-1 SDS were within the normal range and significantly higher (height SDS 0.2 +/-1.0 vs. -0.9 +/- 1.2, p < 0.01 and IGF-1 SDS 0.5 +/- 2.2 vs. -1.3 +/- 1.0, p < 0.01). The mean IGF-1 SDS in the failed Kasai group was less than -1. Children with good outcome of postoperative biliary atresia showed better growth, better nutritional status and higher serum IGF-1 levels when compared to those with unsuccessful operation.     

Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia

Biliary atresia is the most common cholangiopathy of childhood. During infancy, an idiopathic activation of the neonatal immune system targets the biliary epithelium, obstructs bile ducts, and disrupts the anatomic continuity between the liver and the intestine. Here, we use a model of virus-induced biliary atresia in newborn mice to trace the initiating pathogenic disease mechanisms to resident plasmacytoid (pDCs) and conventional (cDCs) dendritic cells. We found pDCs to be the most abundant DC population in the livers of newborn mice, and we observed pDCs in the livers of infants at the time of diagnosis. In the livers of newborn mice, cDCs spontaneously overexpressed the costimulatory molecule CD80 soon after birth, and pDCs produced the cytokine interleukin-15 (IL-15) in response to a virus insult. Both subtypes of primed DCs were required for the proliferation of T lymphocytes and the activation of natural killer cells. Disruption of this cellular network by depletion of pDCs or blockade of IL-15 signaling in mice in vivo prevented epithelial injury, maintained anatomic continuity of the bile duct, and promoted long-term survival. These findings identify cellular triggers of biliary injury and have implications for future therapies to block the progression of biliary atresia and liver disease.     

Histopathological distinction and evaluation of biliary and peribiliary cysts in pig liver

The majority of hepatic cysts identified in animals are considered to derive from the intrahepatic bile ducts (biliary cysts). An alternative origin is the peribiliary glands located in the hilum of the liver and large portal tracts (peribiliary cysts). The distinction between biliary and peribiliary cysts, and whether these have different clinical significance, has rarely been considered previously. This study reports the pathological features of five cystic porcine livers. Four of these five livers had both biliary and peribiliary cysts and the fifth had only biliary cysts. Biliary cysts were not associated with distortion of adjacent hepatic parenchyma, whereas peribiliary cysts appeared to cause local compression and circulatory disturbance. It would therefore appear that peribiliary cysts have greater potential clinical significance than those of biliary origin.     

胆道闭锁的影像学诊断研究进展

胆道闭锁(BA)是一种由肝内外胆管系统堵塞引发的小儿消化外科疾病,如不及时治疗将导致胆汁性肝硬化,最终发展为肝衰竭导致患儿死亡;而BA的早期诊断是实现其早期治疗的关键.目前,肝组织活检被认为是诊断BA的金标准,但该法存在侵入性、重复取样及主观性强等缺点.与之相比,超声成像(US)、核磁共振成像(MRI)和肝胆闪烁显像(HBS)等影像技术因其具有无创性、可重复性及操作灵活等特点而在BA的临床诊断中起着重要的作用,已发展成为BA诊断的研究热点.主要聚焦BA影像学诊断的临床应用和最新研究进展.     

Increased expression of intercellular adhesion molecules in biliary atresia.

The expression of the inflammatory adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1, was studied in six infants with biliary atresia using an immunoperoxidase technique on frozen sections. Controls consisted of five patients with various conditions including total parenteral nutrition-induced cholestasis, choledochal cyst, viral hepatitis, metastatic carcinoma, and thrombotic thrombocytopenic purpura. None of the patients were in liver failure. Bile ducts from the control subjects did not express any of the inflammatory adhesion molecules on ductal epithelium. In marked contrast, all of the biliary atresia specimens demonstrated strong intercellular adhesion molecule-1 expression and occasional vascular cell adhesion molecule-1 staining on epithelial cell membranes of both intra- and extrahepatic ductal structures. Hepatocytes and sinusoidal lining cells including Kupffer cells showed a pattern of intense intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in all specimens with active inflammation that could not differentiate the biliary atresia cases from the control group. Lymphocyte function-associated antigen-1 intensely stained the inflammatory cell infiltrate in the biliary atresia and inflamed control specimens. The strong expression of intercellular adhesion molecule-1 on biliary ductal epithelium in patients with biliary atresia suggests a potential role for this adhesion molecule in the pathogenesis of this devastating neonatal hepatic disorder.     

Restrictive cardiomyopathy in a patient with extrahepatic biliary atresia.

The most commonly associated anomalies in patients with extrahepatic biliary atresia are cardiovascular, digestive and splenic defects. Of the cardiovascular anomalies, there are very few reports of biliary atresia with cardiomyopathy. We report the first case of a child with extrahepatic biliary atresia and restrictive cardiomyopathy. The patient was a 13-month-old boy diagnosed with extrahepatic biliary atresia at the age of 2 months, when he underwent laparotomy for definite diagnosis.Hepatic portoenterostomy was performed after confirmative cholangiogram. Recently, he developed severe cough and dyspnea, and his respiratory symptoms worsened. Chest radiograph showed cardiomegaly. Two- dimensional echocardiography showed marked biatrial enlargement. On M- mode echocardiogram, a slight increase in left ventricular dimension was seen in early diastole with a relatively good left ventricular function. Mitral inflow Doppler tracing showed an increased E-velocity (1.1 m/sec) with decreased deceleration time (75 m/sec), and increased E/A ratio (0.33). He was diagnosed as having restrictive cardiomyopathy with characteristic echocardiographic features.     

Biliary atresia and its complications

Infants with idiopathic perinatal fibroinflammatory obliteration of the lumen of the extrahepatic biliary tree ("biliary atresia") invariably died of biliary cirrhosis before surgical techniques were devised to permit drainage of bile into the duodenum. Survival rates in operated patients now approach 75 percent at 10 years. While definitive diagnosis of biliary atresia without the use of cholangiography at laparotomy is difficult, because other disorders have similar clinical features, early diagnosis is important. The earlier surgery is undertaken, the more successful it is. With delay, irreversible changes occur in the liver that produce portal hypertension. This and liver failure eventually make liver transplantation necessary even in some operated patients. Hepatic disease associated with biliary atresia is in part due to delay in diagnosis, but complications of surgical therapy, such as ascending cholangitis, also play a role. With prolonged survival and as numbers of liver transplant recipients rise, new therapy-related complications, such as those associated with immunosuppression, will become more important in surgically treated biliary atresia.     

胆道闭锁肝脏病理组织学诊断标准的探讨及其临床意义

采用定量方法，对手术证实的２０例胆道闭锁和３例新生儿肝炎患儿肝脏病理组织学进行观察研究。发现胆道闭锁肝脏的主要特征性病变为胆管明显增生。并提出平均３个汇管区胆管增生数目在１５个以上，大部分小叶间、小叶内胆栓数目在２～３个以上，结合参考多核巨肝细胞、间质增生成分、炎性细胞浸润程度及胆汁性肝硬化等变化即可确诊为胆道闭锁。另外，通过对２０例胆道闭锁不同年龄组肝脏病理组织学比较观察，发现２月内年龄组病人与２月后患儿，肝脏形态学变化没有明显差异。从而认为胆道闭锁预后与手术时令关系不大，而与肝脏病变程度有关。从病理学角度提示在手术的选择上，年龄应提前至３０天以前；术前月龄超过２个月患儿，应经皮肝穿活检，观察肝脏病理形态学变化，那些病变为严重不可逆肝硬化者应放弃手术。