Familial extrahepatic biliary atresia

Only a small number of cases with familial extrahepatic biliary atresia, suggesting a recessive autosomal inheritance, have been reported. However, the cases reported in twins are consistent with an acquired disease. Here the case of two brothers with familial atresia of the extrahepatic biliary system is studied. Diagnosis was confirmed by laparotomy and histologic study of biliary fibrous remnants. In the present cases parental consanguinity might suggest a recessive autosomal inheritance. However, clustering of cases in a family might also suggest a common exposure to responsible factors not so far identified.     

Type I biliary atresia without extrahepatic biliary cyst

Currently, magnetic resonance cholangiography (MRC) is used for the differentiation of biliary atresia (BA) from other causes of infantile cholestasis. The authors present a case of type I BA without an extrahepatic biliary cyst in a 2-month-old girl. MRC clearly visualized the patency of the gallbladder, cystic duct, and hepatic ducts with disappearance of the common bile duct. Intraoperative cholangiography demonstrated a cloudy appearance of the intrahepatic bile ducts, confirming the diagnosis of type I BA. We believe that this is the first reported case of type I BA without an extrahepatic biliary cyst diagnosed by MRC.     

Prognosis of extrahepatic biliary atresia.

We carried out a retrospective investigation of the 89 patients with extrahepatic biliary atresia born in The Netherlands during a 10 year period. Of these 89 patients 10 had a diagnostic laparotomy only. Eight patients had an anastomosis between the proximal bile duct and the intestine, and the remaining 71 had hepatic portoenterostomies. Bile drainage was re-established in 46 (65%). After successful hepatic portoenterostomy the development of cholangitis was the most important determinant of long term survival; five year survival was 54% in the 19 patients who had cholangitis and 91% in the 27 who did not. In the whole group of 71 patients the five year survival was 47%. Seventeen patients were at least 5 years of age at the time of writing, three of whom had had liver transplantation. Three patients have cirrhosis and hyperbilirubinaemia, and the other 11 have normal bilirubin concentrations and normal or slightly raised transaminase activities. To improve these results early surgical intervention in all children with extrahepatic biliary atresia is necessary, as are better methods of prophylaxis and treatment of cholangitis.     

Vitamin D metabolism in pre-operative extrahepatic biliary atresia

In order to clarify the pathogenesis of rickets in preoperative patients with extrahepatic biliary atresia, we evaluated baseline serum 25-OHD and 1,25(OH)2D levels and correlated serum 25-OHD levels with increase in age and season of birth in 16 preoperative patients. Further, parenteral vitamin D2 tolerance tests were performed in 5 cases. Serum 25-OHD and 1,25(OH)2D levels were significantly lower than those in 15 normal controls. There was a negative correlation between the serum 25-OHD levels and increase in age. The patients born during the winter had lower serum 25-OHD concentrations than those born in summer. The mean value of increased 25-OHD levels after the parenteral vitamin D2 tolerance tests did not differ from that of 6 controls. Since there was no impairment of vitamin D 25-hydroxylation, the reduction in serum 25-OHD may therefore be mainly due to disturbed intestinal vitamin D absorption. It was also concluded that season of birth and increase in age are pathogenic factors in the etiology of rickets in preoperative patients with extrahepatic biliary atresia.     

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.     

The prelaparotomy diagnosis of extrahepatic biliary atresia.

The diagnostic accuracy of laboratory investigations in the prelaparotomy differentiation between extrahepatic biliary atresia (EHBA) and intrahepatic disease (IHD) was assessed in 86 consecutive infants presenting with conjugated hyperbilirubinaemia. Forty five infants had EHBA and 41 IHD. The mean serum bilirubin concentration, gamma-glutamyltranspeptidase (GGT) activity, and the GGT/aspartate transaminase (AST) ratio were appreciably higher in infants with EHBA than in those with IHD. In infants with IHD, however, serum bilirubin concentrations were in the EHBA range in 19 (47%), as were GGT values in 29 (71%), and GGT/AST ratios in 33 (80%). In individual patients neither increasing nor decreasing GGT values were of diagnostic importance. Failure of biliary excretion of 99Tcm-p-Butyl-ida occurred in 29 of 30 (97%) patients with EHBA but also in 22 of 23 (67%) with IHD. In all 5 patients with IHD associated with alpha 1 antitrypsin deficiency these 4 investigations gave results in the EHBA range. Liver biopsy specimen interpretation, correct in 38 of 42 infants with EHBA, gave an overall accuracy of diagnosis of 86%: the results of 3 further biopsies were equivocal. In 33 of 40 infants with IHD bile duct obstruction was excluded; the remaining 7, including 4 with alpha 1 antitrypsin deficiency, showed equivocal changes. Faecal excretion of 131I rose bengal faecal excretion was less than 10% in 36 of 37 patients with EHBA and in 9 of 26 with IHD, giving an overall accuracy of diagnosis of 84%. In patients in whom genetic disorders, such as alpha 1 antitrypsin deficiency had been excluded, interpretation of liver biopsy specimens together with 131I rose bengal faecal excretion remain the most accurate means of identifying those who need surgery for EHBA and of avoiding unnecessary laparotomy in infants with IHD.     

Analysis of delay in diagnosis of extrahepatic biliary atresia]

Prognosis of extrahepatic biliary atresia depends on an early surgical treatment. This survey studied the delay to surgery of infants treated for biliary atresia and analysed the causes of late diagnosis and referral. MATERIAL AND METHODS: Medical files of 21 infants treated for biliary atresia between 1988 and 1998 were retrospectively analysed. RESULTS: Median age at biliary operation was 57 days and did not change during time. In only 3/21 cases, surgery was performed before 45 days of age. The first clinical or biological sign of cholestasis was noted at a median age of 12 days. In eight cases, the first medical visit for cholestasis (median age of 21 days) was not followed by a blood test. In 11 cases, infants presenting with biological cholestasis were referred to hospital more than seven days later. False diagnosis was noted in seven cases and delayed significantly the operation. CONCLUSION: The delay to surgical treatment is too long and does not decrease whereas a majority of infants visit their physician early. Medical information is mandatory for all physicians taking care of infants.     

Nutritional support for the infant with extrahepatic biliary atresia

Some infants with biliary atresia obtain dramatic improvement for prolonged periods after the performance of hepatic portoenterostomy. Such infants may have life styles not substantially different from those of normal children. In others, the benefit from this operation, if any, is short lived. These infants are very vulnerable to the debilitating effects of severe, prolonged malabsorption and ultimately require orthotopic liver transplantation to sustain life. The physician caring for infants awaiting liver transplantation can do much, not only to prolong survival but to maintain satisfactory growth and development. The key consideration is to provide adequate nitrogen and nonnitrogen calories, liberally utilizing modern methods of enteral alimentation when necessary. In addition, attention must be directed toward several vitamin and mineral deficiencies, particularly those of the fat-soluble vitamins, that inevitably accompany severe malabsorption in children. Management of extrahepatic biliary atresia in infants is difficult and requires meticulous attention to details. Nevertheless, the long-term cure of this disorder provided by liver transplantation makes their care a rewarding experience.     

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     

Analysis of the pathomorphology of the intra- and extrahepatic biliary system in biliary atresia

OBJECTIVE: Aim of the study was to investigate the pathomorphological changes in the liver and triangular cord of the porta hepatis in biliary atresia and assess the relationship between the degree of differentiation of fibroblasts in the triangular cord of the porta hepatis and the liver fibrosis scores. METHODS: From September 2005 to May 2006, 21 patients with biliary atresia (66+/-20 days old) underwent a Kasai procedure. The liver biopsy and the remnant of the porta hepatis were conserved. Five cases with cholestasis syndrome and 10 cases with choledochal cyst were used as a control group. Liver biopsies were performed in the control group. The micro- and ultrastructure of the liver and the remnant of the porta hepatis were assessed in the biliary atresia and the control group. Ultrastructural features were examined by transmission electron microscopy. The semiquantitative differences in liver fibrosis grading between the biliary atresia and the control group was evaluated with a 3-grade staging system. The degree of differentiation of fibroblasts (FB) in the triangular cord of the porta hepatis was assessed as follows: 1) juvenile type: above 50 % FBs were juvenile, 2) senior type: above 50% FBs were senior, 3) median type: between the former 2 types. The differentiation scores of FB in the porta hepatis were assessed in relation to the liver fibrosis score. RESULTS: 1) The pathological changes with BA are characterized by inflammation and fibrosis in the hepatic portal area. The fibrosis scores in the biliary atresia group (I: 2 cases, II: 12 cases, III: 7 cases) were significantly higher than in the control group (I: 8 cases, II: 5 cases, III: 2 cases; p=0.01. 2) In the biliary atresia group, the extrahepatic biliary system of all cases showed a triangular cord in the porta hepatis. The triangular cord of porta hepatis was characterized by hyperplasia of canaliculi, atresia or stenosis of the bile ducts, inflammation infiltration, cholestasis, and interstitial fibrosis. 3) The ultrastructural features of BA showed active fibroblasts, a loss of microvilli, dense deposits in the hepatocytes and liver sinusoid, and dilatation of canaliculi. 4) The differentiation scores of FB in the porta hepatis were positively related to the liver fibrosis score (p=0.04). CONCLUSION: The main pathological changes of biliary atresia are inflammation and fibrosis in the hepatic portal area. The ultrastructural features of biliary atresia suggested that the differentiation scores of FB in the triangular cord of the porta hepatis were positively related to the liver fibrosis score.     

Amino acid abnormalities in infants with extrahepatic biliary atresia and cirrhosis

We measured fasting plasma amino acids in 26 children aged 6 months to 5 years with extrahepatic biliary atresia and cirrhosis and compared them with fasting values in 95 normal control children aged 4 months to 12 years. We found that the cirrhotic children had elevations of total free plasma amino acids implying reduced hepatic metabolism of amino acids and that the molar ratio of the branched chain amino acids (isoleucine, leucine, and valine) to the aromatic amino acids (phenylalanine and tyrosine) was significantly depressed. Methionine was also markedly elevated, and taurine concentrations were significantly decreased. Manipulation of the amino acid distribution in dietary protein to normalize plasma amino acids prior to orthotopic hepatic transplantation may be helpful in improving amino acid utilization.     

Bone density and 25-hydroxyvitamin D level in extrahepatic biliary atresia

Biliary atresia (BA) represents a common cholestatic affliction of the gastrointestinal tract affecting infants and children. The objective of the present study was to evaluate 42 patients (20 with and 22 without jaundice) diagnosed with extrahepatic BA for bone mineral content and serum 25-hydroxyvitamin D (HVD) levels. Physical examination and anthropometric nutritional assessment were performed. The investigation included liver function tests and serum calcium (Ca), phosphate (P), magnesium (Mg), and 25-HVD levels. Dual-energy X-ray absorptiometry was used to measure the bone mineral density (BMD) of the lumbar spine (L₁–L₄). Our results showed that 16 jaundiced␣patients (80%) and only 3 nonjaundiced patients (13.6%) showed osteoporosis (P< 0.05). All patients had normal serum Ca and P levels. Only 1 nonjaundiced patient had a low serum Mg level. Serum 25-HVD levels (mean ± SD) were 20.71 ± 8.24, 16.12 ± 4.3, and 9.18 ± 5.84 ng/ml, respectively, in subjects with normal bone density (n=7), osteopenia (n=3), and osteoporosis (n=11). Bone disease represents a well-known complication among long-term survivors of BA. To date, the pathogenesis has remained unexplained. Since, as demonstrated in the present study, jaundiced patients develop osteoporosis more frequently than nonjaundiced patients, hyperbilirubinemia may have an influence. Bone-mineral deficiency can be detected earlier by means of BMD measurement (non-invasive method) than by measuring serum Ca, P, and Mg levels in these patients. Accepted: 27 November 2000     

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SPSS 14.0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BA Kasai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。     

Prediction of survival in extrahepatic biliary atresia by hepatic duplex sonography

BACKGROUND: The clinical course of biliary atresia patients is extremely variable. To optimize conservative treatment and correctly schedule liver transplantation, noninvasive investigations that are predictive of individual survival and that can be performed regularly are needed. In this study, the prognostic value of Doppler sonography was investigated in these patients. METHODS: Thirty biliary atresia patients (age range, 1 month to 15.2 years; mean, 4.0 years) and 38 control subjects underwent standardized Doppler sonography of liver and spleen. Biochemical tests of liver function and of fibrogenesis were performed in parallel. Individual clinical outcome was registered 1 and 2 years later. RESULTS: In control subjects, maximum portal flow velocity (Vmax) was more than 16 cm/sec, and the hepatic vein flow pattern was triphasic. Among children with biliary atresia, those with diminished portal Vmax, a flattened hepatic vein flow curve, or a hepatic artery resistance index of 0.8 or more had significantly lower indices of hepatic protein synthesis (albumin, cholinesterase), higher bilirubin levels, and higher concentrations of markers of connective tissue turnover (procollagen peptides, laminin P1) than did those with normal Doppler sonography measurements. The rate of survival without transplantation during the following 2 years was significantly lower in children with abnormal Doppler findings. From portal and hepatic vein flow measurements, patient survival 2 years later could be predicted with an accuracy of 93%. CONCLUSIONS: In children with extrahepatic biliary atresia, Doppler sonography of the hepatic blood flow is a noninvasive indicator of disease severity. Moreover, it allows a highly accurate prediction of patient survival for the following 2 years.     

Prostaglandin and fatty acid metabolism in patients with extrahepatic biliary atresia

The relationship between essential fatty acid (EFA) deficiency and disturbance of prostaglandin (PG) biosynthesis was studied in children after radical operation for extrahepatic biliary atresia (EBA). In addition, to investigate the method for treatment of postoperative EFA deficiency and disturbance of PG biosynthesis, the serum fatty acid and plasma PG levels were determined before and after supplementation of an EFA-rich powder (38 g of linoleic acid per 100 g of powder) through Suruga II enterostomy. Before administration of the EFA-rich powder, linoleic acid, arachidonic acid, PGE1, and PGF2 alpha levels were significantly lower in both good bile excretion and poor bile excretion groups than in the control group. After administration, linoleic acid and PGE1 levels significantly increased in the good bile excretion group as compared with the preadministration values. These results suggest that the supplementation of EFA-rich powder is an effective treatment for linoleic acid deficiency and disturbance of PGE1 biosynthesis in postoperative EBA patients.