Biliary atresia associated with multiple unrelated anomalies: what about it?

The prognosis of extrahepatic biliary atresia (EHBA) and multiple apparently not linked anomalies has never been disclosed. We reported a rare case affected by biliary, anorectal and esophageal atresia, and collected the uncommon associations of EHBA with multiple unrelated congenital defects to make known the prognosis. An elevated rate of hepatic failure despite surgery and an early poor outcome were found in the above-mentioned associations. A liver transplantation at the first months of life could be considered to improve outcome.     

Biliary Atresia Revisited

Extrahepatic biliary atresia (EHBA) is an inflammatory fibrosing process affecting the extrahepatic and intrahepatic biliary tree resulting in fibrous obliteration of the extrahepatic biliary tract, ductopenia of intrahepatic bile ducts, and biliary cirrhosis. EHBA is divided into a correctable and a noncorrectable type with focal patency of the otherwise atretic biliary tree in the former and no patency of the biliary tree in the noncorrectable type. EHBA is divided in a fetal, prenatal or embryonic, and a more common, perinatal, acquired form. The symptoms of the former start shortly after birth and there is frequently an association with a variety of congenital anomalies. Children with the perinatal form become jaundiced several weeks after birth; no associated congenital anomalies are present. Morphologically, an inflammatory and fibrosing process of the extrahepatic biliary tree leads to complete lumenal obliteration. The liver is characterized by a nonspecific giant cell transformation, and portal expansion by fibrous connective tissue with marked ductular proliferation. With time, ductopenia and biliary cirrhosis develop. The diffential diagnosis with other conditions with similar microscopic patterns such as as alpha-1 antitrypsin deficiency, total parental nutrition, obstruction by a choledochal cyst, arteriohepatic dysplasia, familial progressive intrahepatic cholestasis, and alteration of the bile acid metabolism is discussed. In the fetal group, abnormalities in different genes seem to play a role; ductal plate malformation is another possibility. Different etiologies have been postulated in the perinatal form of EHBA: genetic susceptilibility, vascular factors, toxins, and infections mainly by rotavirus and reovirus. The pathogenesis is complex. EHBA is a heterogenous disease, resulting from a combination of genetic factors, insults, and activition of different genetic and immunologic pathways. The treatment of EHBA is surgical, with anastomosis between the biliary tree and the intestine in the correctable type and a hepatic portoenterostomy (HPE) for the noncorrectable group. HPE is a temporizing treatment allowing the infant to develop and grow, followed in the majority of the patients by liver transplantation.     

Rejection is less common in children undergoing liver transplantation for hepatoblastoma

To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post‐transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.     

Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age

In order to determine the accuracy of serum gamma-glutamyl transferase (GGT) as a test for biliary atresia, we reviewed the charts of 29 infants with cholestatic jaundice less than one year of age. All patients underwent liver biopsy or laparotomy with cholangiogram to establish neonatal hepatitis (NH) or extrahepatic biliary atresia (EHBA). We also gathered information from 176 patients from published studies. Sensitivity, specificity, and likelihood ratios (LR) were calculated with 95% confidence interval (95% CI). GGT levels of the EHBA group were higher than those from the NH group. For diagnosis of EHBA at a cut-off level >250 U/L, sensitivity was 83.3% (95% CI, 55.2- 95.3%); specificity, 70.6% (95 CI, 46.9-86.7%); and negative LR, <2.0. When we added data from other studies considering age (<4 weeks, 4-8 weeks, and >8 weeks), GGT performance increased, especially for the first age group: with cut-off of 150 U/L, sensitivity was 91.7%; specificity, 88%; and positive LR, 7.8. Thus, for improving reliability of GGT levels for EHBA diagnosis, they need to be correlated to infant age.     

Need for liver transplantation in Indian children

BACKGROUND: Liver transplantation (LT) is the most successful and accepted mode of therapy for failing liver in children. Pediatric LT has neither been widely attempted nor its need objectively assessed in our country. OBJECTIVE: To assess requirement of LT in children at a tertiary care hospital. METHODS: Data of children admitted to pediatric GE services (January 1992 to June 1997) were retrospectively analyzed. Subgroups of children with acute liver disease (ALD), chronic liver disease (CLD), neonatal cholestasis syndrome (NCS) and other etiology were evaluated for need for LT according to established criteria. RESULTS: Of the total 301 inpatients with liver diseases assessed at our center, ALD constituted 26% (n=79), CLD 35% (n=106), NCS 27% (n=82) and miscellaneous 11% (n=34). Among ALD, 19% (n=15) had FHF and 67% (n=10) qualified for LT (INR>4.0). Of CLD, LT was warranted in 13% (2/15) cases of Wilson's disease (Wilson's score > 6) and 60% of cirrhotics (n=40/66) with decompensation. NCS comprised extrahepatic biliary atresia (EHBA) in 43, choledochal cyst in 2, paucity of intralobular bile duct (PILBD) in 2, neonatal hepatitis in 23, and was of indeterminate etiology in 12 cases. Of NCS groups, LT was the only therapeutic option in 45% (n=36) of cases (EHBA 34, choledochal cyst 2). Of 34 cases of EHBA requiring LT, 32 presented after 4 months of age and other 2 children had decompensation before four months of age. Both children with choledochal cysts had decompensated liver disease. One patient of Crigler Najjar syndrome type I had kernicterus and qualified for LT. CONCLUSION: Our data shows need for LT in 30% of children with liver diseases constituted by cirrhosis (45%), biliary atresia (38%) and FHF (11%).     

Immunosuppression in infants with short bowel syndrome undergoing isolated liver transplantation

BACKGROUND: Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD). AIM: To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx). METHODS: A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function). RESULTS: Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06). CONCLUSION: Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.     

A scoring system to predict the need for liver transplantation for biliary atresia after Kasai portoenterostomy

A retrospective analysis was performed of the records of 133 patients with extrahepatic biliary atresia (EHBA) who had undergone a Kasai portoenterostomy. The patients were divided into a non-transplantation group who survived but did not receive liver transplantation after the procedure and a failure group of those who died or received liver transplantation. A score was calculated that assessed nine factors, including laboratory values and complications. The data were assessed at the time complications occurred. The scores were analysed by a trend analysis to see if serial scores predicted the evolution of liver disease. A receiver operating characteristic (ROC) curve was plotted to assess the optimal cut-point for the scoring system. There were 98 patients in the non-transplantation group and 35 in the failure group. The latter group had significantly higher post-operative bilirubin (9.3±7.2 mg/dl versus 3.5±3.1 mg/dl), ALT (136±89 U/l versus 92±88 U/l), prothrombin time, and incidence of cirrhosis, ascites, oesophageal varices, portal hypertension, cholangitis and sepsis than the non-transplantation group ( P <0.05). A score of 8 had a high sensitivity (96.9%) and specificity (89.5%) for predicting the need for liver transplant. Conclusion:based on easily available clinical information, our scoring system can predict which patients with biliary atresia who have already undergone a Kasai procedure should be considered for liver transplantation.Abbreviations EHBA extrahepatic biliary atresia - ROC receiver operating characteristic     

Extrahepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants.

In a prospective regional survey of neonatal hepatitis syndrome 32 infants had extrahepatic biliary atresia (EHBA) and 103 had hepatitis. No cause for the lesion was found in infants with extrahepatic biliary atresia, but in 32 with hepatitis a specific cause was identified, 24 having genetic deficiency of the serum protein alpha1-antitrypsin. No differences were observed in parental age, mother's health in pregnancy, month of birth, birth order, or sex of the infants. Familial idiopathic hepatitis occurred in 3 of 67 sibs of patients with idiopathic hepatitis, but the 33 sibs of EHBA patients had no liver disease. Of the infants with hepatitis, 36 were of low birthweight, less than 2.5 kg, and 23 were born prematurely. Infants with biliary atresia were all of normal birthweight and only one was born prematurely. Consideration of clinical and biochemical abnormalities in the first 2 months of life showed no differences between the two groups except that infants with EHBA were more commonly jaundiced from birth (80%) and had more frequently acholic stools (83%). The frequency of these features in patients with hepatitis being 68% and 52%. Standard tests of liver function were not discriminatory. Percutaneous liver biopsies were diagnostic in 75% of those with EHBA and in 92% of those with hepatitis. The I131 Rose Bengal faecal excretion was less than 10% in 26 of 28 infants with EHBA and in only 5 of 18 with hepatitis. These latter two investigations together allowed a correct preoperativer diagnosis of EHBA in all instances. Bile drainage was achieved surgically in only 3 cases. A major reason for these poor results may have been the late referral of cases for diagnosis and laparotomy, which should be performed as soon as the diagnosis is suspected and always by 70 days of age.     

Prognosis of extrahepatic bile-duct atresia after hepatoportoenterostomy

 Clinical and histologic findings from 206 patients operated upon for extrahepatic biliary atresia (EHBA) are analyzed in order to define the prognosis of patients with EHBA. The prospective study took into consideration both initial fibrosis of the liver and the morphology of the porta hepatis (PH) at surgery. Kaplan-Meier survival estimates and statistical calculations demonstrated a relationship between long-term survival and histologic findings in the liver and porta hepatis. The efficacy of HPE is significantly influenced by the morphology of the PH and to a lesser extent by the initial liver fibrosis. Surgery should thus achieve pattern 1 morphology of the PH, but this is problematic because of the close relationship of the vascular and biliary structures in its two lateral zones. Accepted: 8 November 1999     

多药耐药蛋白3在婴儿肝外胆道闭锁和巨细胞病毒性肝炎肝组织的表达及其意义

摘要：目的　研究肝外胆道闭锁及巨细胞病毒性肝炎患儿肝组织中的多药耐药蛋白3（MDR3）的表达,探讨MDR3与胆汁淤积的关系。方法　收集2000年1月至2009年10月广西医科大学第一附属医院儿童病例,分为肝外胆道闭锁（EHBA）组20例,CMV肝炎组12例,正常对照组10例,采用免疫组化法检测肝组织中MDR3的表达情况,通过图像分析技术进行定量分析。结果　MDR3在正常对照组、EHBA和CMV肝炎组患儿肝组织均有不同程度表达,以肝细胞膜表达最为明显,MDR3在肝组织的阳性表达随γ-GT的增高而增强,呈正相关（r = 0.438,P = 0.003）,CMV肝炎组、EHBA组和正常对照组MDR3表达吸光度值分别为0.13±0.02、0.18±0.06和0.10±0.03,MDR3在EHBA肝组织中的表达强度明显高于CMV肝炎组和对照组（P < 0.05）。结论　MDR3蛋白水平与胆汁淤积程度密切相关,EHBA肝组织MDR3的上调可能为机体的适应性反应,以利于增强磷脂的转运,减轻对胆管上皮的损伤。     

肝组织病理学检查在肝外胆道闭锁与婴儿肝炎综合征鉴别诊断中的意义

目的 探讨肝组织病理学检查在肝外胆道闭锁和婴儿肝炎综合征鉴别诊断中的价值.方法 将1997年8月-2006年10月经手术或尸检后确诊的32例肝外胆道闭锁和16例婴儿肝炎综合征进行回顾性病理学检查.结果 肝外胆道闭锁以胆管增生和汇管区纤维化伴炎性细胞浸润为主要病变,而婴儿肝炎综合征以肝细胞变性坏死、肝巨细胞样变和髓外造血为主要病变,但少数病例部分病变具有重叠性.结论 肝外胆道闭锁和婴儿肝炎综合征具有某些相似的早期病理改变,但前者主要为胆管的病变,后者则以肝细胞病变为主,故肝组织病理学检查对于两者的鉴别诊断有重要意义.     

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.     

Intrapulmonary shunting in the biliary atresia/polysplenia syndrome: reversal after liver transplantation

One hundred and seventy three children, including 93 with biliary atresia, received liver grafts at Addenbrooke's Hospital between 1983 and 1993. Of these, only seven developed cyanosis due to intrapulmonary shunting as a complication of their liver disease, and all seven of these had the biliary atresia/polysplenia syndrome. Intrapulmonary shunting was confirmed by a radioisotope scan in four children. Only one child with the syndrome did not have cyanosis when undergoing transplantation. Seven of the eight children are alive 6-54 months after transplantation, with normal pulmonary and hepatic function. Cyanosis recurred in one child who developed chronic rejection with liver failure. In conclusion: (a) there is a strong association between the biliary atresia/polysplenia syndrome and cyanosis due to intrapulmonary shunting; (b) intrapulmonary shunting is fully reversible after successful liver transplantation; and (c) cyanosis, once present, is progressive, and these children should be considered for liver transplantation as soon as it occurs.     

Intrapulmonary shunting in the biliary atresia/polysplenia syndrome: reversal after liver transplantation.

One hundred and seventy three children, including 93 with biliary atresia, received liver grafts at Addenbrooke's Hospital between 1983 and 1993. Of these, only seven developed cyanosis due to intrapulmonary shunting as a complication of their liver disease, and all seven of these had the biliary atresia/polysplenia syndrome. Intrapulmonary shunting was confirmed by a radioisotope scan in four children. Only one child with the syndrome did not have cyanosis when undergoing transplantation. Seven of the eight children are alive 6-54 months after transplantation, with normal pulmonary and hepatic function. Cyanosis recurred in one child who developed chronic rejection with liver failure. In conclusion: (a) there is a strong association between the biliary atresia/polysplenia syndrome and cyanosis due to intrapulmonary shunting; (b) intrapulmonary shunting is fully reversible after successful liver transplantation; and (c) cyanosis, once present, is progressive, and these children should be considered for liver transplantation as soon as it occurs.     

Gamma-glutamyl transpeptidase activity and its serial measurement in differentiation between extrahepatic biliary atresia and neonatal hepatitis

The liver functions of 17 babies with extrahepatic biliary atresia (EHBA) and 19 babies with neonatal hepatitis (NNH) were analyzed. The serum gamma-glutamyl transpeptidase (GGTP) level and its rate of rise were significantly higher in the EHBA group. Both cross-sectional and longitudinal studies showed a positive correlation between the GGTP activity and the duration of the disease. The diagnostic accuracy is 79% for EHBA and 95% for NNH. It is suggested that GGTP and its rate of rise are the most important biochemical parameters in the differential diagnosis of these two diseases.     

Answered and unanswered controversies in the surgical management of extra hepatic biliary atresia

Almost a half-century since Kasai described the portoentersotomy for extrahepatic biliary atresia (EHBA), some questions about the management of this condition have been resolved and many are unanswered. The most useful diagnostic steps to aid in the diagnosis are debated. Sonography can be helpful but its sensitivity and selectivity are arguable with strong advocates for its effectiveness. Likewise, the magnetic resonance imaging has forceful advocates but also has not been universalized. The liver biopsy, done commonly before an operation for cholestasis, is often not discriminating. The radionuclide scan hepatobiliary iminodiacetic acid (HIDA) scan after phenobarbital stimulation is helpful if negative, but false positive results are common. It is agreed to proceed expeditiously to the operation in the cholestatic infant after a prompt investigation. The proposal to avoid this step and provide liver transplantation as initial management for EHBA has been suppressed by several clinical findings. The Kasai procedure has not worsened the outcome of eventual liver transplantation. The Kasai, even if it eventually fails, will often buy time and allow the child to grow before transplantation is needed. Multiple reoperations prior to the transplant are discouraged. Revisions to improve bile flow have not gained wide popularity. Use of a stoma to divert the bile has been largely abandoned. The need for frozen section examination of the liver at the site chosen for the portoenterostomy is no longer demanded. The preferred type of intestinal conduit is argued. Unanswered questions about the post-operative management include the role of steroids and of prophylactic antibiotics. The Biliary Atresia Research Consortium, a multi-institutional National Institutes of Health (NIH)-supported project, will address many of the unanswered issues.     

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目的研究肝外胆道闭锁及巨细胞病毒性肝炎患儿肝组织中的多药耐药蛋白3(MDR3)的表达,探讨MDR3与胆汁淤积的关系。方法收集2000年1月至2009年10月广西医科大学第一附属医院儿童病例,分为肝外胆道闭锁(EHBA)组20例,CMV肝炎组12例,正常对照组10例,采用免疫组化法检测肝组织中MDR3的表达情况,通过图像分析技术进行定量分析。结果 MDR3在正常对照组、EHBA和CMV肝炎组患儿肝组织均有不同程度表达,以肝细胞膜表达最为明显,MDR3在肝组织的阳性表达随γ-GT的增高而增强,呈正相关(r=0.438,P=0.003),CMV肝炎组、EHBA组和正常对照组MDR3表达吸光度值分别为0.13±0.02、0.18±0.06和0.10±0.03,MDR3在EHBA肝组织中的表达强度明显高于CMV肝炎组和对照组(P<0.05)。结论 MDR3蛋白水平与胆汁淤积程度密切相关,EHBA肝组织MDR3的上调可能为机体的适应性反应,以利于增强磷脂的转运,减轻对胆管上皮的损伤。     

Biliary Atresia and Cytomegalovirus Infection: A DNA Study

The cause of extrahepatic biliary atresia (EHBA) is undetermined in most instances, but an infectious agent is widely suspected. Cytomegalovirus (CMV) infection has been associated with intrahepatic bile duct destruction and paucity, raising the question of its role in EHBA. We identified 12 children in the past 5 years with biliary atresia and examined the bile duct biopsy. These showed acute/chronic inflammation and epithelial degeneration. CMV inclusions were not identified. We used in situ hybridization and the polymerase chain reaction (PCR) for CMV-DNA on formalin-fixed, paraffin-embedded tissue. All samples showed the presence of amplifiable DNA using β-globin primers. No biopsy tissue showed CMV DNA using specific probes and primers. The absence of demonstrable CMV DNA by in situ hybridization and PCR in EHBA biopsies implies that it is unlikely that this virus has any major role in the pathogenesis of this condition. Received October 29, 1997; accepted March 27, 1998.     

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.     

放射性核素肝胆显像联合动态十二指肠液检查对婴儿持续性黄疸鉴别诊断的意义

目的 探讨99mTc-EHIDA肝胆显像联合动态十二指肠液引流检查对婴儿期持续性黄疸鉴别诊断的意义.方法 应用SPECT仪对84例15～90 d持续性阻塞性黄疸息儿进行肝胆核素显像和动态十二指肠引流液检查.结果 核素肝胆显像对先天性胆道闭锁(EHBA)诊断灵敏度为100.0%(29/29),特异度为74.5%(41/55);核素肝胆显像联合动态十二指肠引流对EHBA诊断灵敏度为100.0%(29/29),特异度为100.0%(55/55).结论 ,99mTc-EHIDA肝胆显像是一种无创、安全、有效的检查方法,与动态十二指肠引流法结合对婴儿持续性黄疸鉴别诊断具有较高的临床价值.