Biliary atresia.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Evaluation of ventricular systolic function by speckle tracking technique in patients with biliary atresia before and after liver transplantation.

To evaluate the ventricular function of patients with biliary atresia (BA) before and after liver transplantation using two-dimensional speckle tracking. Observational, analytical study with healthy control group, volunteers. We recruited patients from 0 to 18 years old who were candidates for liver transplantation and patients after six months of liver transplantation performed for BA from January 1997 to August 2015 at Children's Institute of São Paulo University Medical School. The patients were submitted to a complete conventional echocardiographic study. After that, the images were captured for global longitudinal strain (GLS). A blood sample was collected for brain natriuretic peptide (BNP) level. Ejection fraction obtained by Simpson's method was significantly higher in the hepatic pre-transplantation group (p < 0.001), as well as left atrial size (p < 0.001) and left ventricle size (p = 0.039). The left ventricular mass index was significantly higher in pre-transplantation group (p < 0.001). The left atrium volume (p = 0.008) and the left ventricular mass index (p t = 0.035) were higher in the post-transplant group. It was observed that the lower the BNP, the lower/more negative the GLS in the post-transplant group (p = 0.038 and r = 0.427). Significant reduction in the overall longitudinal strain of the left ventricle was detected before (p = 0.01) and after liver transplantation (p = 0.019). A subclinical left ventricular systolic dysfunction was evidenced by two-dimensional speckle tracking technique before and after liver transplantation, even when compared to normal values of the last pediatric meta-analysis.

Pediatric living donor left lateral segment liver transplantation for biliary atresia: Doppler ultrasound findings in early postoperative period.

PURPOSE: To analyze hepatic hemodynamic parameters detected by Doppler ultrasound (DU) of uncomplicated children with biliary atresia who underwent left lateral segment living donor liver transplantation (LLS-LDLT), explore its normal change trend over time and determine the normal reference interval. METHODS: We retrospectively involved the data from 227 biliary atresia patients (100 Males,127 Females). Hemodynamic parameters include peak systolic velocity (PSV), end-diastolic velocity (EDV), resistivity index (RI), and pulsation index (PI) of the hepatic artery (HA), portal vein velocity (PVV), portal vein flow (PVF) and hepatic vein velocity (HVV) during intra-operative and on the 1st, 3rd, 5th and 7th day after operation were collected. Repeated measures analysis of the variance and Friedman test were used to analyze the changing trend of hemodynamic parameters over time in the first week after the operation. RESULTS: PSVHA and EDVHA showed a similar changing tendency at one week after surgery, with an overall decrease-rise trend; RIHA and PIHA also changed similarly with an overall rise-decrease trend. The HVV and PVV at surgery were lower than at all time points after surgery. As for PVF, the value of POD5 was the highest and then decreased. Additionally, this study provided the normal reference interval of hemodynamic parameters for LLS-LDLT patients, which were PSVHA: 18.4-98.3 cm/s, EDVHA: 0-43.3 cm/s, RIHA: 0.41-1.0, PIHA: 0.51-2.0, PVV: 19.0-83.7 cm/s, HVV: 19.4-68.0 cm/s, and PVF:99.5-500.0 ml/min/100 g at intraoperation. Within the first postoperative week: PSVHA: 21.0-97.7 cm/s, EDVHA: 0-32.7 cm/s, RIHA: 0.47-1.0, PIHA: 0.62-2.0, PVV: 23.0-92.0 cm/s, HVV: 19.7-86.0 cm/s, and PVF: 100.0-513.0 ml/min/100 g. CONCLUSION: The hepatic hemodynamic of post-transplanted children detected by DU had specific changing trends and normal ranges, which provides valuable reference values for ultrasonologists and pediatric transplant clinicians.

Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.

Biliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at ~ 2 months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via interruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic target for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded by SLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical programs of 2 IBAT inhibitors in development for the treatment of pediatric cholestatic liver diseases, maralixibat and odevixibat, are highlighted.

Biliary atresia in twins: a systematic review and meta-analysis.

PURPOSE: Biliary atresia (BA) in twins is extremely rare reported in the literature, but twin studies are useful methods of examining the associated factors of a complex disease. The objective of this study was to analyze the characteristics and patterns of biliary atresia in twins from reviewing available articles. METHODS: PubMed and EMBASE databases were reviewed for related articles using the keywords ''biliary atresia'', ''twins'', ''monozygotic (MZ)'', and ''dizygotic (DZ)'', including relevant papers in the reference lists. RESULTS: This analysis was extracted from 12 articles, with a total of 35 twin pairs included. BA was found in 36 out of 70 twin subjects (51.4%), of which had an even gender split. 97.1% twins were discordant, among 55.9% of which were monozygotic twin sets, indicating that BA may be related to genetic phenotype or penetrance. Isolated BA was the largest group with 27 (75%) affected twins. Only one pair of dizygotic twins (2.9%) demonstrate concordance for BA, and have one affected family member. CONCLUSION: BA was found in nearly half of twin subjects with an even gender split. Isolated BA was the largest group, in which the number of monozygotic twins was similar with dizygotic twins, so the onset of the disease may not associate with the zygosity of twins. Most of twin sets had discordant disease presentation, especially monozygotic twins therein, emphasizing the role of epigenetic factor in the pathogenesis of BA. Future studies should take genetic testing among any twin sets in BA, especially the disease-associated mutations, thus be useful to investigate the etiology of disease.

The impact of serum total bilirubin, alanine transaminase and gamma-glutamyl transferase on survival of biliary atresia patients following Kasai procedure.

BACKGROUND: Many prognostic factors have been reported for the outcomes of biliary atresia (BA) patients after Kasai procedure, however, it still shows a conflicting result. Our study was to determine the impact of total bilirubin postoperative day-7 and pre-operative ratio (TB7/TB0), gammaglutamyl transferase post-operative day-7 and pre-operative ratio (GGT7/GGT0), and alanine transaminase post-operative day-7 and pre-operative ratio (ALT7/ALT0) on the survival of BA patients following Kasai surgery. METHODS: We reviewed the medical records of BA patients who underwent Kasai procedure at the Dr. Sardjito Hospital, Indonesia from August 2012 to December 2018. The cut-off values of TB7/TB0, GGT7/GGT0, and ALT7/ALT0 for prediction of patients' survival were determined by receiver operating characteristics (ROC) curves. Log-rank tests were utilised to test the association between cut-off values and overall survival. RESULTS: In all 46 BA patients (23 males and 23 females) after Kasai procedure were included, consisting of one type 1, 17 type 2A, seven type 2B, and 21 type 3. The cut-off values of TB7/TB0, ALT7/ALT0 and GGT7/GGT0 for overall survival was 0.455 (sensitivity 87.5%, specificity 22.7%, area under curve (AUC) 0.59; 95% Confidence Interval (95%CI): 0.42, 0.75), 0.481 (sensitivity 87.5%, specificity 18.2%, AUC 0.49; 95%CI: 0.31, 0.65), and and 0.31 (sensitivity 79.2%, specificity 9.1%, AUC 0.34; 95%CI: 0.18, 0.50), respectively. However, these cut-off values were not significantly associated with overall survival, with p-values of 0.18, 0.49, and 0.56, respectively. CONCLUSION: The TB7/TB0, ALT7/ALT0, and GGT7/GGT0 might not predict the overall survival of BA patients after Kasai procedure. Further multicentre studies with a larger sample size is needed to clarify our findings.

Natural history, risk factors, and outcome of hepatopulmonary syndrome in pediatric liver diseases.

BACKGROUND: Limited pediatric literature is available regarding hepatopulmonary syndrome (HPS) especially in subjects with biliary atresia (BA) despite its proven prognostic significance. Thus, we aimed to study the natural history, risk factors, and outcome of HPS in BA and other chronic liver disease (CLD) subjects. METHODS: All children (BA and other non-BA CLDs) older than 6 months of age were included in the study. HPS was diagnosed on the basis of standard international criteria. Also, fractional exhaled nitric oxide (FeNO) was measured at baseline. RESULTS: During the study period from January 2017 to December 2018, there were 42 children in BA and 62 in the CLD group. The overall prevalence of HPS was 42.3%: 57.1% in the BA group and 32.2% in the CLD group. Median age at HPS diagnosis was 14.4 months and 90 months in the BA and non-BA CLD groups, respectively. By the end of study period, the prevalence of HPS in the BA group further increased to 73.8% at 0.7% per month. Lower serum albumin (p < 0.05) in BA and higher splenic Z scores (p 0.013) in other CLDs were found to be significant risk factors for HPS. FeNO measurement did not reach diagnostic significance. CONCLUSION: Prevalence of HPS is higher and also develops at an earlier age in the BA group compared to other CLDs. Also, risk of HPS development increases with increasing disease duration in BA. Lower serum albumin in BA and higher splenic Z scores in other CLDs may predict risk for HPS development.

Biliary Excretion Noted on Hepatobiliary Iminodiacetic Acid Scan Does Not Exclude Diagnosis of Biliary Atresia.

A hepatobiliary iminodiacetic acid (HIDA) scan is frequently used in an attempt to exclude biliary atresia in infants who are cholestatic. We present 6 cases of confirmed biliary atresia in infants who had biliary patency reported on HIDA scan. We demonstrate that misinterpreted HIDA scans led to delayed diagnosis and surgical intervention for biliary atresia.

Hepatic subcapsular or capsular flow in biliary atresia: is it useful imaging feature after the Kasai operation?

OBJECTIVES: To evaluate the implications of hepatic subcapsular and capsular flows using ultrasonography (US) in children after Kasai operation. METHODS: Children who underwent liver US including color Doppler US and microvascular imaging (MVI) from May 2017 to October 2017 were retrospectively included. Children who underwent the Kasai operation for biliary atresia were included in the Kasai group and children with normal liver were included in the control group. Using US results, the number of intrahepatic biliary cysts and the maximum diameter of the spleen were evaluated in the Kasai group. Liver stiffness values were included when patients in the Kasai group had transient elastography (TE) or shear wave elastography (SWE) results. Hepatic subcapsular and capsular flows on color Doppler US and MVI were compared between the two groups using the following scores: 0, no flow reaching the hepatic capsule; 1, any flow reaching the hepatic capsule; and 2, contiguous hepatic capsular flow. The logistic regression test was used to identify associations between age, intrahepatic biliary cysts, spleen size, SWV, TE results, and flow scores measured on Doppler US and MVI in the Kasai group using the odds ratio (OR) and 95% confidence interval (CI). RESULT: A total of 65 children (mean 7.6 ± 5.3 years), 44 in the Kasai group and 21 in the control group, were included. In the control group, one child had score 1 on MVI and others had score 0 on both Doppler US and MVI. Among the Kasai group, 28 children (63.6%) had score 1, while others had score 0 using Doppler US. Using MVI, 24 children (54.5%) had score 2, 18 children had score 1, and one child had score 0. In the Kasai group, increased liver stiffness on TE was the only factor significantly associated with the presence of subcapsular flow on color Doppler US (OR 1.225, 95% CI 1.020-1.470) and increased spleen size was the only factor significantly associated with increased flow scores on MVI (OR 1.397, 95% CI 1.002-2.724). CONCLUSION: Detection of hepatic subcapsular, capsular flows on US would be meaningful for children after receiving the Kasai operation. KEY POINTS: • Hepatic subcapsular or capsular flows can be useful not only for the diagnosis but also for the postoperative follow-up in patients with biliary atresia. • Increased liver stiffness and splenomegaly after the Kasai operation were associated with presence of subcapsular or capsular flow on ultrasonography. • Evaluation of hepatic subcapsular and capsular flows could be needed to assess disease progression after receiving the Kasai operation.

Microvascular proliferation of the portal vein branches in the liver of biliary atresia patients at Kasai operation is associated with a better long-term clinical outcome.

AIM OF THE STUDY: We previously showed an increased number of smaller portal vein (PV) branches in the portal areas of liver biopsy specimens of biliary atresia (BA) patients. We evaluated the correlation between this histopathological feature and the prognosis. PATIENTS AND METHODS: Twenty-five consecutive patients with BA encountered between 2000 and 2012 were classified into three prognostic groups based on their postoperative outcomes: Excellent (n = 11) for native-liver survivors with a normal liver function, Good (n = 6) for native-liver survivors with liver dysfunction, and Poor (n = 8) for survivors after liver transplant or on a waiting list. Data from morphometrical analyses, including the fibrotic portal area, numbers of PVs, diameter and total area of PV branches, were statistically compared among the three groups. MAIN RESULTS: The number of PV branches per unit area of the whole-liver specimen in the poor prognostic group was significantly lower than that in the excellent group (3.1 ± 0.6 vs. 5.2 ± 2.0/mm2, p = 0.03). There were no significant differences in the other parameters. CONCLUSIONS: This is the first report on the relationships between morphometrically analyzed PV branches and the postoperative course in BA patients. The portal venous system is involved as the primary lesion in BA.

Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets.

INTRODUCTION: The common predominant clinical features of cholangiopathies such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and biliary atresia (BA) are biliary damage/senescence and liver fibrosis. Curative therapies are lacking, and liver transplantation is the only option. An understanding of the mechanisms and pathogenesis is needed to develop novel therapies. Previous studies have developed various disease-based research models and have identified candidate therapeutic targets. Areas covered: This review summarizes recent studies performed in preclinical models of cholangiopathies and the current understanding of the pathophysiology representing potential targets for novel therapies. A literature search was conducted in PubMed using the combination of the searched term 'cholangiopathies' with one or two keywords including 'model', 'cholangiocyte', 'animal', or 'fibrosis'. Papers published within five years were obtained. Expert opinion: Access to appropriate research models is a key challenge in cholangiopathy research; establishing more appropriate models for PBC is an important goal. Several preclinical studies have demonstrated promising results and have led to novel therapeutic approaches, especially for PSC. Further studies on the pathophysiology of PBC and BA are necessary to identify candidate targets. Innovative therapeutic approaches such as stem cell transplantation have been introduced, and those therapies could be applied to PSC, PBC, and BA.

Recent advances in understanding biliary atresia.

Biliary atresia (BA) is a neonatal liver disease characterized by progressive obstruction and fibrosis of the extrahepatic biliary tree as well as fibrosis and inflammation of the liver parenchyma. Recent studies found that infants who will go on to develop BA have elevated direct bilirubin levels in the first few days of life, suggesting that the disease starts in utero. The etiology and pathogenesis of BA, however, remain unknown. Here, we discuss recent studies examining potential pathogenetic mechanisms of BA, including genetic susceptibility, involvement of the immune system, and environmental insults such as viruses and toxins, although it is possible that there is not a single etiological agent but rather a large group of injurious insults that result in a final common pathway of extrahepatic bile duct obstruction and liver fibrosis. The management and diagnosis of BA have not advanced significantly in the past decade, but given recent advances in understanding the timing and potential pathogenesis of BA, we are hopeful that the next decade will bring early diagnostics and novel therapeutics.

Prognostic markers at adolescence in patients requiring liver transplantation for biliary atresia in adulthood.

BACKGROUND & AIMS: In patients with biliary atresia (BA), the rate of native liver survival (NLS) to adulthood has been reported as 14-44% worldwide. Complications related to portal hypertension (PHT) and cholangitis are common in adulthood. For those requiring liver transplantation (LT), the timing can be challenging. The aim of this study was to identify variables that could predict whether young people with BA would require LT when they are >16 years of age. METHODS: This study was a single-centre retrospective analysis of 397 patients who underwent Kasai portoenterostomy (KP) between 1980-96 in the UK. After KP, 111/397 (28%) demonstrated NLS until 16 years of age. At final follow-up, 67 showed NLS when >16 years old (Group 1) and 22 required LT when >16 years old (Group 2). Laboratory, clinical and radiological parameters were collected for both groups at a median age of 16.06 years (13.6-17.4 years). RESULTS: The need for LT when >16 years old was associated with higher total bilirubin (hazard ratio 1.03, p = 0.019) and lower creatinine (hazard ratio 0.95, p = 0.040), at 16 years, on multivariate analysis. Receiver-operating characteristic curve analysis demonstrated that a total bilirubin level of ≥21 µmol/L at 16 years old (AUROC = 0.848) predicted the need for LT when >16 years old, with 85% sensitivity and 74% specificity. Cholangitis episode(s) during adolescence were associated with a 5-fold increased risk of needing LT when >16 years old. The presence of PHT or gastro-oesophageal varices in patients <16 years old was associated with a 7-fold and 8.6-fold increase in the risk of needing LT, respectively. CONCLUSIONS: BA in adulthood requires specialised management. Adult liver disease scoring models are not appropriate for this cohort. Bilirubin ≥21 µmol/L, PHT or gastro-oesophageal varices at 16 years, and cholangitis in adolescence, can predict the need for future LT in young people with BA. Low creatinine at 16 years also has potential prognostic value. LAY SUMMARY: Patients with biliary atresia commonly require liver transplantation before reaching adulthood. Those who reach adulthood with their own liver are still at risk of needing a transplant. This study aimed to identify tests that could help clinicians predict which patients with biliary atresia who reach the age of 16 without a transplant will require one in later life. The study found that the presence of bilirubin ≥21 µmol/L, lower creatinine levels, and a history of portal hypertension or gastro-oesophageal varices at 16 years, as well as cholangitis in adolescence, could predict the future likelihood of needing a liver transplant for young people with biliary atresia.

Suppressing microRNA-29c promotes biliary atresia-related fibrosis by targeting DNMT3A and DNMT3B.

This study was designed to investigate the potential role of microRNA-29c (miR-29c) in biliary atresia-related fibrosis. The expression of miR-29c was determined in 15 pairs of peripheral blood samples from infants with biliary atresia (BA) and infants with non-BA neonatal cholestasis using quantitative real-time PCR. EMT was established by induction with TGF-ß1 in HIBEpiC cells. MiR-29c was inhibited by lipofectamine transfection. The expressions of proteins related to epithelial-mesenchymal transition (EMT), i.e., E-cadherin, N-cadherin and vimentin, were determined using quantitative real-time PCR and western blotting. Direct interaction between miR-29c and DNMT3A and DNMT3B was identified using a luciferase reporter assay. The expressions of DNMT3A and DNMT3B were suppressed by treatment with SGI-1027. Patients with BA showed significantly lower miR-29c levels in peripheral blood samples than the control subjects. In vitro, TGF-ß1-induced EMT significantly decreased the expression of miR-29c. Downregulation of miR-29c had a promotional effect on BA-related fibrosis in HIBEpiC cells, as confirmed by the decrease in E-cadherin and increase in N-cadherin and vimentin levels. MiR-29c was found to target the 3'UTR of DNMT3A and DNMT3B and inhibit their expression. Suppression of DNMT3A and DNMT3B reversed the effects of miR-29c downregulation on BA-related fibrosis in HIBEpiC cells. These data suggest that BA-related fibrosis is closely associated with the occurrence of EMT in HIBEpiC cells. MiR-29c might be a candidate for alleviating BA-related fibrosis by targeting DNMT3A and DNMT3B.

Ultrasound Evaluation of Biliary Atresia Based on Gallbladder Classification: Is 4 Hours of Fasting Necessary?

OBJECTIVES: The aim of this study was to evaluate the influence of fasting time on the ultrasound identification and exclusion of biliary atresia in jaundiced infants through the use of the gallbladder classification scheme and to test the value of the gallbladder classification scheme in the diagnosis of biliary atresia in inexperienced individuals. METHODS: A total of 188 jaundiced infants were enrolled in this study. All patients received detailed abdominal sonograms. Diagnoses were confirmed via liver biopsy, surgical findings, or follow-up. Infants were grouped into either the fasting group (fasting time ≥ 4 h) or the nonfasting group (fasting time < 4 h). According to the gallbladder classification scheme, the gallbladders were classified into 4 types. The accuracy of diagnosing biliary atresia based on the gallbladder classification scheme was compared between the 2 groups. The gallbladders of 177 infants that were detectable by ultrasonography were used to compare the diagnostic performances between a junior radiologist and an experienced radiologist. RESULTS: The accuracies in the diagnosis of biliary atresia with the gallbladder classification scheme were 86.3% (82 of 95 patients) for the fasting group and 93.5% (87 of 93 patients) for the nonfasting group (P = .100). The diagnostic accuracies of biliary atresia were 88.7% (157 of 177 patients) for the junior radiologist and 90.4% (160 of 177 patients) for the experienced radiologist (P = .250). The κ value for the agreement between the 2 radiologists was 0.859. CONCLUSIONS: The performance of gallbladder diagnoses was not influenced by the fasting time with the use of the gallbladder classification scheme. Additionally, the gallbladder classification scheme may help junior radiologists to more effectively identify biliary atresia and nonbiliary atresia.

Growth of children with biliary atresia living with native livers: impact of corticoid therapy after portoenterostomy.

We addressed growth of biliary atresia (BA) patients living with native livers between ages 0-6 and effects of post-surgical corticosteroid treatment on growth. Growth charts of 28 BA patients born in Finland between 1987 and 2017 were retrospectively evaluated. Dosage and length of corticosteroid treatment and hydrocortisone substitution were reviewed. At birth, BA patients were shorter (median height - 0.6 (interquartile range (IQR) - 1.3 to - 0.1) SDS, n = 28, P < 0.001) than general population. Height remained stable during early childhood (median height - 0.6 (IQR - 1.4 to 0.1) SDS for girls and - 0.4 (IQR - 1.6 to 0.2) SDS for boys at 6 years of age). Patients were of normal height adjusted weight at 6 years with a median age and sex-adjusted body mass index (ISO-BMI) of 20.9 (IQR 19.3 to 25.0) for girls and 22.1 (IQR 20.7 to 25.6) for boys. Higher (≥ 50 mg/kg) cumulative post-portoenterostomy prednisolone dosage resulted in 0.18 SDS lower height per treatment week (ß - 0.18, SE 0.04, P < 0.001) compared to lower dosage (< 50 mg/kg).Conclusion: BA patients grow normally during early childhood. As high postoperative corticosteroid dosage has a short-term negative effect on height, very high dosages should be avoided. What Is Known: • Growth of biliary atresia patients has mostly been shown to be within normal limits • Corticosteroids may decrease growth rate What Is New: • Biliary atresia patients surviving with their native livers are shorter than general population and their mid-parental target height at birth • A high (> 50 mg/kg) cumulative prednisolone dosage has a negative transitory impact on height gain after portoenterostomy.

Five-year native liver survival analysis in biliary atresia from a single large Chinese center: The death/liver transplantation hazard change and the importance of rapid early clearance of jaundice.

PURPOSE: This study aimed to analyze the change of death/liver transplantation hazard and biochemical indexes over time after Kasai procedure (KP) based on a retrospective biliary atresia (BA) cohort, and to evaluate the predictive value of early jaundice clearance rate to 5-year native liver survival (NLS). METHODS: A retrospective cohort with follow-up results of 139 BA patients from January 2009 to December 2012 was established, and the pre- and postoperative data were collected. NLS rates were estimated with Kaplan-Meier curves, and any differences between groups were tested by log-rank test. Hazard curve of death/liver transplantation was fitted with Weibull distribution, and hazards at certain time points were calculated. Trend charts of biochemical indexes were drawn to show any changes over time. Rate of jaundice clearance was indicated as the proportion of decreased total bilirubin level at a certain postoperative time point to preoperative total bilirubin level. In multivariate analysis for prediction of 5-year NLS, COX proportional hazard regression model was used and results were expressed as hazard ratios with 95% confidence intervals (CIs). The predictive value of early jaundice clearance rates for 5-year NLS was analyzed by receiver operating characteristic (ROC) curve, and a cut-off value of 4-week jaundice clearance rate was determined. RESULTS: The estimated 5-year NLS rate of the 139 patients was 58.0%. The patients had a high hazard of death/liver transplantation early after KP, which gradually decreased and stabilized at a lower level 1 year later. Most death/liver transplantation events occurred within 1 year after KP. The total bilirubin (TBIL), direct bilirubin (DBIL) and total bile acid (TBA) levels of successful Kasai group decreased continuously after KP, and the biggest decline was seen in the first month. The aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT) levels increased during the first month after KP and decreased continuously thereafter. All the biochemical indexes of successful Kasai group tended to stabilize within/close to normal range 1 year after KP. On the contrary, all the biochemical indexes of failed Kasai group fluctuated at obvious abnormal levels after KP. The estimated 5-year NLS rates of successful Kasai group and failed Kasai group were 90.1% and 10.7% (p = 0.000). The most significant clinical protective factor of 5-year NLS was 4-week jaundice clearance rate, revealed by COX proportional hazard regression model, and the HR was 0.089 (95%CI 0.018-0.432, p = 0.003). In predicting 5-year native liver survival, the largest area under ROC (AUROC) curve belonged to 4-week jaundice clearance rate, which was 0.731 (p = 0.000). A cut-off value of 0.457 was determined, with sensitivity 0.827, specificity 0.552, positive predictive value 0.720, and negative predictive value 0.696. NLS rates of patients divided by cut-off value showed significant statistical difference demonstrated by Kaplan-Meier curve and log-rank test (p = 0.000). CONCLUSIONS: The 5-year death/liver transplantation hazard of biliary atresia patients reduces greatly and stabilizes 1 year after KP. A successful KP enables patients to achieve long-term stable normal biochemical indexes. A rapid clearance of jaundice is of great positive significance to 5-year NLS, and the 4-week jaundice clearance rate is of some predictive value. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II, retrospective study.

Biliary atresia: 20-40-year follow-up with native liver in an Italian centre.

INTRODUCTION: Biliary atresia (BA) represents the leading indication for liver transplantation in childhood. Only few studies reported the outcome of patients who survived more than 20 years on their native liver, and up to date there are no Italian data available. We reported our 40-year single centre experience with long-term follow-up of BA patients. MATERIALS AND METHODS: All consecutive patients who underwent Kasai portoenterostomy (KPE) for BA managed at our Institution between 1975 and 1996 were retrospectively reviewed. Native liver (NLS) and overall survival (OS) were analyzed with Kaplan-Meyer curves and LogRank test. A p value of <.05 was regarded as significant. Quality of life of patients currently surviving with their native liver was assessed through a quality of life questionnaire. RESULTS: During the 22-year period of the study 174 patients underwent surgery (median age 60 days). Clearance of jaundice at 6 months from surgery was achieved in 90 patients (51.7%). NLS was 41% at 5 years, 32% at 10 years, 17.8% at 20 years and 14.9% at 40 years. Cholangitis was recorded in 32%, hepatocellular carcinoma in 0.5%. Twenty-six patients (14.9%) survived with their liver more than 20 years; 84.6% had normal serum bilirubin level and 23% had esophageal varices. Quality of life was comparable with the healthy Italian population in all but one patient. CONCLUSIONS: Our Italian experience confirms KPE represents the cornerstone of treatment for children with BA. Multidisciplinary and meticulous lifelong post-operative follow-up should be guaranteed for these patients because of the possibility of late-onset cholangitis, portal hypertension, hepatic deterioration and liver malignant tumors. TYPE OF THE STUDY: retrospective case series. LEVEL OF EVIDENCE: IV.