The significance of serum hepatocyte growth factor levels in planning follow-up of postoperative jaundice-free patients with biliary atresia

Purpose

The aim of this study was to clarify the significance of serum hepatocyte growth factor (HGF), interleukin (IL)-6, and IL-1 receptor antagonist (ra) levels in the evaluation of disease status in jaundice-free survivors with biliary atresia after Kasai operation.

Patients and Methods

Serum concentrations of HGF, IL-6, and IL-ra were measured in 31 long-term jaundice-free patients with biliary atresia after Kasai operation and 29 controls. Patients were divided into 4 groups: group A (n = 8), normal liver function; group B (n = 9), mild liver dysfunction without portal hypertension; group C (n = 9), moderate liver dysfunction with controllable portal hypertension; and group D (n = 5), receiving liver transplantation.

Results

Serum IL-6 levels were significantly higher in patients than in controls. There was no difference in serum IL-6 levels among groups B, C, and D. Serum IL-1ra levels were elevated according to liver dysfunction. Serum HGF levels in group D were significantly higher than in controls and the other groups. Serum hyarulonic acid levels were positively correlated with serum levels of IL-1ra and HGF.

Conclusions

Elevation of serum IL-1ra and HGF levels correlated with the progression of liver fibrosis and dysfunction. In particular, serum HGF levels could be used as a predictor for requiring liver transplantation.     

Serum hepatocyte growth factor and clinical outcome in biliary atresia

Purpose

Biliary atresia (BA) remains one of the most intractable liver diseases leading to liver fibrosis. Serum hepatocyte growth factor (HGF) has been shown to increase in cirrhotic patients. The aim of this study was to investigate the possible role of HGF in BA.

Methods

Serum levels of HGF were determined using an enzyme-linked immunosorbent assay from 28 BA patients and 25 healthy children. The patients were categorized into 3 groups according to their clinical outcomes (good, fair, and poor): group A (good), jaundice-free patients (total bilirubin [TB] < 2.0 mg%); group B (fair), patients with mild to moderate jaundice (TB, 2 to 10 mg%); and group C (poor), patients with marked jaundice (TB > 10 mg%). Unpaired t test and analysis of variance (ANOVA) with post-hoc tests were used. Data were expressed as mean and SEM.

Results

Serum HGF levels in BA patients were higher than the controls (P = .02). Subgroup analysis found that there were 12 patients in group A, 8 patients in group B, and 8 patients in group C. The mean age of patients in groups A, B, and C were 5.34 ± 0.52, 7.45 ± 1.98, and 5.49 ± 1.57 years (P > .05). Serum HGF in controls and groups A, B, and C were 0.24 ± 0.03, 0.28 ± 0.04, 0.36 ± 0.09, and 0.56 ± 0.07 ng/mL, respectively. Serum HGF levels in BA patients with poor outcome were higher than patients with good outcome (P = .02). There was no difference in serum HGF of BA patients with fair outcome compared with other groups.

Conclusions

Serum HGF is elevated in BA. Furthermore, BA patients with poor outcome have significantly elevated HGF compared with patients with good outcome. Serum HGF levels may be predictive of prognosis with respect to the progression of liver dysfunction. However, the results of HGF in patients with fair outcome are inconclusive, probably because of the small sample size. Further studies are needed to elucidate the detailed mechanisms.     

Connective tissue growth factor expression is increased in biliary epithelial cells in biliary atresia

Background/Purpose

Connective tissue growth factor (CTGF) has been implicated in the pathogenesis of hepatic fibrosis and is elevated in the serum of children with biliary atresia (BA). The objective of this study was to evaluate hepatic CTGF messenger RNA (mRNA) expression and its relationship to hepatic histology in children with BA.

Methods

Connective tissue growth factor mRNA expression was evaluated by in situ hybridization in 26 liver biopsies from 11 patients with BA, 11 with other diseases, and 4 autopsy controls. Serial sections were immunostained with cell-specific markers to characterize the cells expressing CTGF. Biopsies were scored for CTGF expression (0-4) and inflammation and fibrosis (1-4).

Results

High levels of CTGF expression were observed in 9 of 11 BA with localization to biliary epithelial cells and vascular endothelial cells. Connective tissue growth factor mRNA expression was correlated with fibrosis in BA and all livers. In the 11 patients with other liver diseases, 7 had CTGF expression limited to hepatic stellate cells and vascular endothelial cells. None of the 4 livers in children without liver disease had significant levels of CTGF.

Conclusions

In BA livers, novel biliary epithelia CTGF mRNA expression is high and correlates with severity of fibrosis. These data support a role for biliary epithelial cell signaling in fibrogenesis.     

胆道闭锁肝纤维化无创性诊断的研究进展

胆道闭锁是儿童进行肝移植的最常见的胆源性肝脏疾病,进行性肝纤维化是本病的显著特点,即使进行了肝门空肠R-Y吻合术,大多数患儿术后仍不可避免的出现肝纤维化的进行性加重,直至发展成为肝硬化、肝衰竭,并出现一系列并发症.因此肝纤维化评估是胆道闭锁患儿术后随访的重要内容,准确了解肝纤维化程度,对胆道闭锁患儿的病情评估有着重要的意义.肝组织活检是判断肝纤维化分级的金标准,但是其本身存在许多问题.运用多项无创性指标对患儿肝纤维化程度进行评估成为目前胆道闭锁预后研究的热点,本文对主要应用于胆道闭锁患儿肝纤维化的若干无创性诊断进行系统性分析,并分别从影像学和血清学两个方面进行综述.     

Reoperation in patients with biliary atresia

Twenty-seven reoperations were done on 23 patients among 100 infants with biliary atresia who have been treated at Tohoku University Hospital between 1971 and 1981. Nineteen patients had a single reoperation and 4 patients had 2 reoperations. We present the results and the role of reoperation in biliary atresia patients in our institution. Excellent bile drainage after reoperation was obtained in 13 of 15 patients with good bile flow after the initial operation. On the contrary, good bile drainage was not obtained by reoperation in 8 of 12 cases without active bile flow after the initial operation. Cessation of bile flow after successful initial operation is an absolute indication for reoperation. Aggressive reoperations under proper indications improve the surgical results in biliary atresia patients.     

Problems during and after pregnancy in female patients with biliary atresia

Background/Purpose

Advances in the management for biliary atresia (BA) have improved the prognosis and has greatly increased the number of long-term survivors. Even the long-term survivors, however, still face some problems. This retrospective review was performed to assess pregnancy-associated issues in long-term survivors after surgery for BA.

Materials and Methods

Of 55 patients with BA surviving for 16 years or more without liver transplantation, 9 patients have experienced pregnancy and delivery. Clinical courses, the outcome of pregnancy and delivery, and current statuses were retrospectively evaluated from their clinical records.

Results

The study revealed 14 pregnancies and 11 deliveries. Before pregnancy, no patient showed visible jaundice, but 6 patients had some complications such as episodes of cholangitis and portal hypertension. Two of the patients had both conditions and 2 others developed visible jaundice after pregnancy. One intrauterine fetal death occurred.

Conclusions

Our retrospective review suggests that the previously mentioned conditions can be risk factor for cholangitis and gastrointestinal bleeding during or after pregnancy but are not considered to be contraindications for pregnancy and delivery. Complications can occur with pregnancy even during the normal course. Thus, careful observation is recommended.     

The Kasai portoenterostomy for biliary atresia: A review of a 27-year experience with 81 patients

Purpose

The aim of this study was to utilize clinical outcome methodology through multivariable analysis of perioperative factors to predict a successful Kasai-portoenterostomy (PE).

Methods

Records of 81 patients treated for biliary atresia (BA) were reviewed. Outcome was defined as successful if the patient was alive and had no liver transplant (LT). To predict future successful or failed PE, patients were categorized at 6 months post-PE into 2 groups: Success: direct bilirubin (DB) less than 2.0 mg/dL; Failure: DB greater than 2 mg/dL, or the patient was listed/had undergone LT, or had died. Groups were analyzed for positive or negative predictive values (PPV, NPV) at 2 and 5 years after PE. Cox regression was used to determine risk factors for PE.

Results

PE was successful in 38% and failed in 62%. PPV of future success was 96% at 2 years post-PE and 95% at 5 years post-PE, NPV of failure was 76% and 74%, respectively. Bridging liver fibrosis at the time of PE and postoperative cholangitic episodes were interdependent risk factors for a failed PE (P < .05). Other covariates showed no significant relationship for PE outcome.

Conclusion

Classifying of patients 6 months postoperatively allowed us to determine a successful PE outcome. Bridging liver fibrosis at the time of the Kasai, and the increased number of postoperative cholangitic episodes were predictive of a poor PE outcome.     

Optimum prednisolone usage in patients with biliary atresia postportoenterostomy

Purpose

Prednisolone is used routinely after portoenterostomy (PE) in patients with biliary atresia (BA). The authors reviewed their patients with BA post-PE to assess prednisolone protocols.

Method

Severity of fibrosis at PE (moderate or severe), age at PE (30-70 days), size of bile ductules in the fibrotic biliary remnant at the porta hepatis (>100 μm), and type of BA (uncorrectable type) were used as criteria for selecting 63 subjects from our patients with BA post-PE. Subjects were divided into 5 groups according to prednisolone dosage: group 1, no prednisolone; groups 2 to 4, single courses of intravenous prednisolone commencing on day 7 post-PE administered in decreasing dose for 3 days each as follows: group 2, 6, 4, and 2 mg; group 3, 10, 5, and 2.5 mg; group 4, 20, 15, 10, 5, and 2.5 mg; group 5, same as group 4, but stool color was used to monitor bile excretion and a course was restarted from 20 mg whenever stools began to turn pale. If necessary, single courses were repeated until serum total bilirubin was less than 2.0 mg/dL. Protocol efficacy was assessed by comparing the number of patients who became jaundice free, the period taken to become jaundice free, and the incidence of side effects related to prednisolone.

Results

The number of patients who became jaundice free in the no prednisolone group (group 1, 7/12 or 58.3%) was not significantly different from the number in the single-course groups (group 2, 8/12 or 66.6%; group 3, 10/13 or 76.9%; and group 4, 11/15 or 73.3%). The number in the stool-monitored group (group 5, 10/11 or 90.9%) was significantly greater (P < .05). The mean period taken to become jaundice free in group 1 (82.6 ± 29.1 days) was not significantly different from the single-course groups (group 2, 74.5 ± 29.3 days; group 3, 49.6 ± 19.8 days; and group 4, 48.3 ± 26.0 days). The mean period taken in the stool-monitored group (group 5, 33.3 ± 6.4 days) was significantly shorter (P < .05). The number of subjects who developed cholangitis after becoming jaundice free was not significantly different (group 1, 2/7; group 2, 2/8; group 3, 2/10; group 4, 2/11; group 5, 2/10). There were no prednisolone-related complications identified in any subject.

Conclusions

These results provide strong evidence that large-dose prednisolone therapy with stool color monitoring of bile flow has a positive impact on the time taken for patients with BA post-PE to become jaundice free and the number of patients who remain jaundice free.     

转肝细胞生长因子基因肝细胞模型的建立

目的：利用脂质体介导法在体外建立转肝细胞生长因子（HGF）基因的人肝细胞模型。方法：建立HGF真核细胞表达载体，利用脂质体介导法在体外将HGF基因转染入人肝细胞，利用荧光显微镜观察、免疫组织化学、原位杂交方法检测HGF真核细胞表达载体的转录和表达情况。结果：以阳离子脂质体LipofectAMINE为载体将HGF基因转染人肝细胞后，经400mg/L的G418筛选后可形成抗性克隆；Neo基因原位杂交结果显示转染基因的细胞有阳性表达；荧光显微镜下观察到有绿色荧光；免疫组织化学证实转染HGF基因的肝细胞有HGF蛋白的表达。结论：HGF基因可被成功转染入人肝细胞并能有效表达，这可能为肝病的基因治疗提供一种新途径。     

Corticosteroid therapy in biliary atresia

Sixteen patients with biliary atresia had 44 steroid courses for treatment of cholangitis or diminution of bile flow following Kasai hepatic portoenterostomy operations. A "blast" type (high dose/short duration) steroid administration was employed to potentiate the choleretic and anti-inflammatory effect. There was a significant augmentation of bile flow and a reduction in maximum temperature, serum bilirubin, and alkaline phosphatase.     

The outcome of the older (> or =100 days) infant with biliary atresia

Background

There is a detrimental effect of increasing age on the results of the Kasai portoenterostomy for biliary atresia (BA), and some centers routinely advocate primary liver transplantation for the older infant, irrespective of other criteria. This perception that such infants are indeed irretrievable was tested by retrospective analysis.

Methods

All infants who had undergone surgery for BA during the period 1980 through 2000 aged ≥100 days were reviewed. Actuarial survival was calculated using 2 end-points (death and transplantation). A retrospective review of their ultrasonography (n = 12) and preoperative liver histology (n = 22) was also undertaken to ascertain possible predictive criteria.

Results

A total of 422 infants had BA diagnosed during this period, of which 35 (8.2%) were ≥100 days at surgery (median [interquartile range], 133 [range, 108 to 180] days). Surgery included portoenterostomy (n = 26), hepaticojejunostomy (n = 7), and a resection and end-to-end anastomosis (n = 1). A laparotomy only was performed in 1. Five- and 10-year actuarial survival rate with native liver was 45% and 40%, respectively. Currently, 12 (35%) patients are alive with their native liver (8 are anicteric), 9 (28%) have undergone transplantation, and 13 have died. Although there were some survival advantages for types 1 or 2 BA and “noncirrhosis” at time of surgery, neither reached statistical significance. Individual histologic features (eg, degrees of fibrosis, giant cell transformation, bile duct destruction) in the retrospective review of available material were not discriminatory. The finding of a “heterogeneous” parenchyma on ultrasonography was predictive of poor outcome but lacked sensitivity.

Conclusions

The potential for reasonable medium-term survival is present in about one third of infants 100 days or older coming to primary corrective surgery. In the absence of accurate discrimination, the authors continue to favor this option rather than subject all to transplant simply on the basis of age.     

急性肝衰竭大鼠载肝细胞生长因子纳米粒子肝细胞移植后有丝分裂指数和Ki-67表达变化及意义

目的 探讨急性肝衰竭(ALF)大鼠载肝细胞生长因子(HGF)的聚乳酸-氧-羧甲基壳聚糖(PLA-O-CMC)纳米粒子肝细胞移植后有丝分裂指数和Ki-67抗原的表达变化及意义.方法 D-氨基半乳糖腹腔内注射制作大鼠ALF模型,48 h后分别将Ⅰ型胶原(Ⅰ组)、PLA-O-CMC纳米粒子(Ⅱ、Ⅳ组)、载HGF的PLA-O-CMC纳米粒子(Ⅲ组)培养的大鼠肝细胞(均为5×107个,5 ml)移植到ALF大鼠腹腔内.以每日静脉注射HGF 10μg/kg×7 d(Ⅳ组)、5 Ml RPMI 1640腹腔内注射(Ⅴ组)作为对照.观察其14 d存活率、血清及肝组织HGF浓度、肝组织病理及有丝分裂指数(MI)、Ki-67变化.结果移植后14 d Ⅰ～Ⅴ组ALF大鼠的存活率分别为50.00％、68.75％、81.25％、75.00％、18.75％.各纳米移植组高于V组.Ⅲ组3 d时肝组织HGF浓度最高,平均为5882.91 μG／L.Ⅲ组肝组织结构恢复更快,5 d时平均MI 10.20％0、7 d时平均MI 10.20‰、7 d时Ki-67平均标记指数16.8‰,均高于Ⅴ组.结论 应用载HGF的PLA-O-CMC纳米粒子培养的大鼠肝细胞腹腔内移植治疗ALF大鼠能促进肝再生相关抗原表达.

Abstract：

Objective To evaluate the change and significance of Ki-67 antigen expression follow ing hepatocyte transplantation using hepatocyte growth factor (HGF) loaded polylactic acid-O-carboxymethylchitosan (PLA-O-CMC) nanoparticles in rats with acute liver failure (ALF). Methods ALF models of rats were established by D-galactosamine intraperitoneal injection. Rat hepatocytes type Ⅰ collagen suspension (group Ⅰ ),rat hepatocytes co-cultured with PLA-O-CMC nanoparticles ( groups Ⅱ ,Ⅳ ) and rat hepatocytes co-cultured with HGF loaded PLA-O-CMC nanoparticles ( group Ⅱ ) (5 × 107 cells each group,5 ml) were transplanted into the abdominal cavity of SD rats at 48 h after D-Gal injection. Intravenous injection of HGF ( 10 μg/kg for 7 days) ( group Ⅳ ) and RPMI 1640 injection (group Ⅴ ) were used as the negative groups. The 14th-day survival rate of rats,pathological change and mitotic index of liver,Ki-67 antigen labeling index of ALF rat livers were observed. Results The 14th-day survival rate in groups Ⅰ -Ⅴ was 50.00％,68. 75％,81.25％,75.00％,18.75％,and that in nano-transplanted groups was higher than in group Ⅴ. At the 3rd day,the concentration of HGF in liver tissue of group Ⅲ,average 5882. 91 μg/L was the highest. The hepatic lobules structure in group Ⅲ recovered faster. The average mitotic index in group Ⅱ at the 5th day was 10. 20‰ and the average Ki-67 labeling index at the 7th day was 16. 8‰,which were all higher than in group Ⅴ. Conclusion Intraperitoneal transplantation of HGF loaded PLA-O-CMC nanoparticle-attached hepatocytes for treatment of ALF can promote the liver regenerationassociated antigen expression.     

活体肝移植治疗儿童胆道闭锁44例

目的 观察活体肝移植治疗儿童胆道闭锁的效果,总结其临床经验.方法 2006年10月至2010年12月间共有44例胆道闭锁患儿接受了活体肝移植,其中男性26例,女性18例,年龄(12.1±9.0)个月,中位数为9个月(6～60个月);44名供者全部为患者直系亲属,年龄(32.7±8.0)岁,中位数为31岁(20～54岁).供、受者ABO血型相容,供肝均为供者肝脏的左外叶.对供、受者术前评估过程、手术方法、术后管理以及预后等临床资料进行总结.结果 术后对全部供者进行系统随访,随访时间(17.5±13.3)个月,无供者发生严重并发症和死亡,所有供者均恢复健康.44例受者中,死亡9例,死因分别为门静脉栓塞3例、肝动脉栓塞1例、胆道并发症2例、切口感染1例、腹腔出血1例及肺部感染1例,其余35例健康存活.术后1年和2年累积存活率分别为81.2%和76.1%,无一例受者接受再次肝移植.术后主要并发症有门静脉血栓、肝动脉血栓、胆汁漏及逆行性胆管炎、肺部感染、切口感染及急性排斥反应等.结论 活体肝移植是治疗儿童胆道闭锁的有效方法,预后良好.完善缜密的术前评估,熟练精细的手术操作以及精心的术后管理是改善受者预后的关键因素.

Abstract：

Objective To observe the outcomes of living donor liver transplantation (LDLT) for children with biliary atresia (BA) and to summarize the clinical experiences. Methods Forty-four BA patients (26 boys and 18 girls) underwent LDLT between October 2006 and December 2010. Mean (SD) and median (range) age at operation was (12.1 ± 9.0) months and 9 (6-60) months,respectively. The 44 donors were lineal relatives to the consorted recipients. Their mean (SD) and median (range) age at operation was (32. 7 ± 8. 0) months and 31 (20～54) years, respectively. All donor graft types were the left lateral segments with compatible ABO blood groups. Clinical data,including pre-operative evaluations, surgical technique, postoperative management and outcomes in all donors and recipients were retrospectively analyzed. Results All donors were followed up for (17. 5 ± 13. 3) months. No donor mortality was encountered, with a minimal morbidity and no long-term sequelae. Nine out of 44 recipients died. Three patients died of portal vein thrombosis (PVT), one of hepatic artery thrombosis (HAT), two of biliary complications, one of surgical site infections, one of abdominal bleeding and one of pulmonary infection. The overall 1-year and 2-year cumulative survival rate in recipients was 81. 2% and 76. 1 %, respectively. No re-transplantation was done. Postoperative complications included PVT, HAT, biliary leakage and refluxing cholangitis, pulmonary infections,surgical site infections and acute rejection. Conclusion LDLT has been the effective treatment for pediatric recipients with BA and provides favorable prognosis. To improve prognosis of recipients, the key points are pre-operative evaluations, surgical technique, and postoperative management     

Analysis of patients with biliary atresia coming to liver transplantation

Seventy-two patients with end-stage liver disease underwent liver transplantation between March 1981 and March 1984; 35 (49%) with biliary atresia, the remainder with other disorders. This provided us with a unique opportunity to analyze factors leading to liver failure in patients who had undergone biliary drainage procedures for "uncorrectable" biliary atresia. Four patients in the biliary atresia group were excluded (no corrective procedure done, 3; "correctable" biliary atresia, 1), leaving 31 patients for study. Transplantation survival was 84% for the study group and 73% in children with other primary liver disorders. Most patients were less than 3 months old at the time of initial surgery, had minimal liver disease, and had accepted corrective operations by experienced surgeons. Despite these "favorable" factors, bile drainage was rarely achieved. All patients with continued bile drainage at the time of transplantation had repeated episodes of cholangitis, and cholangitis was associated with cessation of bile drainage in half of those with transient function. Findings at hepatectomy suggested that in four cases where bile drainage was never achieved, reexploration may have been successful. Complications included those associated with hepatic failure and portal hypertension. Of note were a high incidence of bone disease and a 43% incidence of stomal hemorrhage in patients with stomas. The short-term survival after transplantation was comparable in the biliary atresia group and the children with other disorders. This suggests that while the presence of a previous biliary drainage procedure may increase the technical difficulty of transplantation, it does not decrease survival.     

Successful revision of portoenterostomy in an infant with biliary atresia

We present a case report of a boy with biliary atresia who, after hepatoportoenterostomy performed on day 21 of life, had immediate resolution of cholestasis and remained anicteric until 3.5 months of age. He then abruptly developed acholic stools. Nuclear medicine imaging study showed no excretion. Broad-spectrum antibiotics and corticosteroids were administered but did not lead to clinical improvement; a surgical revision of the original anastomosis was undertaken at 4 months of age. At 14 months of age, the child is anicteric and growing well. In this case, successful revision of hepatoportoenterostomy averted the need for liver transplantation.     

Revision of porto-enterostomy in congenital biliary atresia

For the patients with insufficient bile flow following porto-enterostomy for congenital biliary atresia, removal or resection of granulation or scar tissue at the porta hepatis has been performed. Of 11 reoperations, constant bile excretion was obtained in four. Sufficient resection of scar tissue at the porta hepatis was most important for revision of porto-enterostomy. For resection of scar tissue, a special scissors devised by us was used.     

Risk factors affecting late-presenting liver failure in adult patients with biliary atresia

Purpose

Following the Kasai operation, a number of patients have developed liver failure, even after long-term postoperative courses. We assessed the clinical parameters to clarify the early risk factors affecting late-presenting liver failure in biliary atresia.

Materials and Methods

From 1955 to 1991, 277 patients underwent a Kasai operation. Among those patients, 92 survived with their native liver for more than 20 years, and 72 continue to survive with their native liver in good condition (Group 1). In 20 patients, persistent jaundice recurred after the age of 20 years (Group 2). The postoperative courses of these patients were assessed retrospectively, and the clinical parameters, including age at the time of the Kasai operation (AGE, days), the period required for jaundice to disappear (PJD, days), and the association with early cholangitis (CG), were compared between the 2 groups.

Results

Of the 20 patients in Group 2, 8 survived after a liver transplantation (LTx). Eight patients had recurrent jaundice, including 4 on the waiting list for anLTx. Additionally, 2 patients died after anLTx at the ages of 22 and 39. Another patient died of liver failure at the age of 28. One patient died of massive esophageal variceal bleeding at the age of 29. Significant differences were confirmed with respect to AGE (Group 1 < Group 2, p < .001), PJD (Group 1 < Group 2, p < .001), and CG (Group 1: Group 2 = 47 %: 75 %, p = .028).

Conclusions

A considerable number of adult patients developed liver failure, even after the age of 20 years. AGE, PJD, and CG were found to be risk factors affecting late-presenting liver failure. Therefore, close patient follow-up is essential, especially for long-term survivors with a late operative age and early postoperative complications.     

The extent of biliary proliferation in liver biopsies from patients with biliary atresia at portoenterostomy is associated with the postoperative prognosis

Background/Purpose

In biliary atresia (BA), a derangement in the biliary system remains, despite portoenterostomy performance. Many factors can influence the disease progression rate. This study aimed to analyze the association between biliary proliferation extent in biopsies from BA patients and postoperative prognosis.

Methods

Biliary proliferation was evaluated by a morphometric analysis of the cytokeratin 7 positivity percentage (PCK7) in wedge liver biopsies from 47 BA patients. The extent of fibrosis was evaluated by a fibrosis score (FS). The outcome 1-year native liver survival was correlated, using a multivariable regression analysis, with PCK7, FS, and age at portoenterostomy.

Results

The PCK7 ranged between 0.80% and 14.79% (M ± SD = 7.36% ± 4.15%). Patients who died or underwent transplantation had higher PCK7 than survivors with their native livers (P < .001). The area under the receiver operating characteristic curve for PCK7 in relation to the outcome was 0.845 (P < .001). The cutoff point of PCK7 for the maximal effect on postoperative prognosis was 10.18% (sensitivity = 0.71, specificity = 0.88). The PCK7 was the only studied variable associated with 1-year native liver survival, independently of age and FS (P = .002).

Conclusion

The extent of biliary proliferation at portoenterostomy, evaluated by PCK7, was associated with 1-year native liver survival of BA patients.     

Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia

Background

Biliary atresia (BA) is a unique neonatal disease resulting from inflammatory and fibrosing obstruction of the extrahepatic biliary tree. Previous studies have demonstrated the critical role of innate immunity and the Th1 response to activated inflammatory cells and overexpressed cytokines in the pathogenesis of BA. Myeloid differentiation factor 88 (MyD88) is a critical adaptor molecule that has been shown to play a crucial role in immunity. We investigated the role of MyD88 in the inflammatory response and development of cholangiopathy in murine BA.

Methods

MyD88 knockout (MyD88^−/−) and wild-type (WT) BALB/c pups were injected with Rhesus rotavirus or saline on day 1 of life. The mice were monitored for clinical symptoms of BA, including jaundice, acholic stools, bilirubinuria, and death. The liver and extrahepatic bile ducts were harvested for histologic evaluation and the quantification of viral content, determination of cytokine expression, and detection of inflammatory cells.

Results

Rhesus rotavirus infection produced symptoms in 100% of both MyD88^−/− and WT pups, with survival of 18% of WT and 0% of MyD88^−/− mice. Histologic analysis demonstrated bile duct obstruction in both MyD88^−/− and WT mice. Viral titers obtained 7 d after infection and expression of interferon-γ and tumor necrosis factor-α at day 3, 5, 8, and 12 after infection revealed no significant differences between the WT and MyD88^−/− mice. Flow cytometry demonstrated similar levels of activated CD8+ T cells and natural killer cells.

Conclusions

The pathogenesis of murine BA is independent of the MyD88 signaling inflammatory pathway, suggesting alternative mechanisms are crucial in the induction of the model.