Addressing Social Adversity to Improve Outcomes for Children After Liver Transplant.

The social determinants of health, defined as the conditions in which we live, learn, work, and play, undoubtedly impact health outcomes. Social adversity in childhood perpetuates over the life course and has consequences extending into adulthood. This link between social adversity and adverse outcomes extends to children undergoing liver transplant, with children from socioeconomically deprived neighborhoods experiencing a greater burden of morbidity and mortality after transplant. Yet, we lack an in-depth understanding of how to address social adversity for these children. Herein, we lay out a strategy to develop and test interventions to address social adversity for children undergoing liver transplant. To do so, we believe that more granular data on how specific social risk factors (e.g., food insecurity) impact outcomes for children after liver transplant are needed. This will provide the liver transplant community with knowledge on the most pressing problems. Then, using the National Academies of Sciences, Engineering, and Medicine's framework for integrating social needs into medical care, the health system can start to develop and test health system interventions. We believe that attending to our patients' social adversity will realize improved outcomes for children undergoing liver transplant.

Laparoscopic Kasai portoenterostomy for cystic biliary atresia: midterm follow-up results of 35 patients.

PURPOSE: To investigate the clinical characteristics of cystic biliary atresia (CBA) and evaluate the midterm follow-up outcomes after laparoscopic treatment. METHODS: We analyzed and compared data retrospectively on CBA patients (group A) and nonsyndromic type III biliary atresia (BA) patients (group B), who underwent laparoscopic Kasai portoenterostomy (LKPE) during the same period. RESULTS: There were no significant differences in operative time, conversion rate, or the incidence of any postoperative complications between groups A and B (P > 0.05). The mean age at surgery (P < 0.01), rates of clearance of jaundice (CJ), cholangitis (P < 0.05), and 5-year survival with a native liver (SNL) were significantly lower in group A than in group B. Among the 35 patients with CBA, the CJ and 5-year SNL rates were significantly better in those with type I (n = 27) than in those with type IIId (n = 8) (P < 0.05). CONCLUSIONS: LKPE is a feasible and safe procedure for CBA. The 5-year SNL after LKPE was better in patients with CBA than in those with nonsyndromic type III BA. The 5-year SNL after LKPE for type I CBA was better than that for type IIId CBA.

Impacts of Early Kasai Portoenterostomy on Short-Term and Long-Term Outcomes of Biliary Atresia.

There are discrepancies regarding the clinical impact of age at Kasai portoenterostomy (KP) on surgical outcomes. Hence, we re-assessed the clinical significance of age at KP. We analyzed 224 patients with type III (atresia of bile duct at the porta hepatis) biliary atresia at Tohoku University Hospital. We classified patients into two groups: KP at ≤60 days of age (group TE) and >60 days of age (group TL). Group TE was subdivided into three groups (TE1, TE2, and TE3) according to age at time of surgery. Subsequently, 2,643 patients in the Japanese Biliary Atresia Registry were classified similarly. Background and surgical outcomes were compared. Of the 2,643 cases, 323 patients who underwent revision KP were analyzed separately. The jaundice clearance rates (JCRs) were 81.4%, 100%, 64.7%, 83.0%, and 65.2% of patients in the TE, TE1, TE2, TE3, and TL groups, respectively. The 15-year native liver survival rates of patients in the TE, TE1, TE2, TE3, and TL groups were 62.2%, 88.9%, 33.9%, 64.4%, and 42.9%, respectively. The 30-year native liver survival rates of patients in the TE, TE1, TE2, TE3, and TL groups were 38.6%, 74.1%, 25.4%, 35.8%, and 31.7%, respectively. The JCRs were 66.2%, 69.4%, 64.1%, 66.7%, and 59.7% for patients in groups JE, JE1, JE2, JE3, and JL, respectively. The 15-year native liver survival rates were 48.1%, 56.7%, 43.9%, 48.9%, and 37.2% for patients in groups JE, JE1, JE2, JE3, and JL, respectively. The JCRs following revision KP were higher in the JE1 group than in the other groups. Conclusion: Early KP was associated with favorable outcomes except in patients aged 31-45 days.

Mortality Determinants in Children with Biliary Atresia Awaiting Liver Transplantation.

OBJECTIVE: To determine risk factors for waitlist mortality in children with biliary atresia listed for liver transplantation. STUDY DESIGN: There were 2704 children with biliary atresia (<12 years of age) listed for a first liver transplant (2002-2018) in the United Network for Organ Sharing database. Fine-Gray regression models for competing risks analysis (main risk = waitlist mortality/delisting owing to too sick; competing risk = liver transplantation) were implemented to identify risk factors for waitlist mortality. RESULTS: The median waitlist time was 83 days (IQR, 34-191). The cumulative incidence of waitlist mortality was 5.2%. In multivariable analysis (n = 2253), increasing bilirubin level (P < .001), portal vein thrombosis (P = .03), and ventilator dependence (P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing (P = .009) was associated with a lower risk of waitlist mortality. When ascites at listing was included in multivariable analysis (n = 1376), it was associated with a higher risk for the composite outcome (P = .03). Encephalopathy at listing was not associated with waitlist mortality (n = 1376; P = .15). CONCLUSIONS: These parameters can be used to more objectively prioritize children with biliary atresia awaiting liver transplantation and identify children with biliary atresia-related end-stage liver disease at high-risk of mortality.

Impact of sarcopenia in infants with liver transplantation for biliary atresia.

While sarcopenia is an important predictor of LT outcomes in adults, few studies have examined the association of sarcopenia with LT outcomes in pediatric patients. We investigated the clinical influence of sarcopenia on the post-transplant outcomes in infants with BA. To define sarcopenia in infants, the cross-sectional area of the tPMA in 93 healthy control infants was measured by computed tomography. Sarcopenia was defined as a tPMA lower than two standard deviations below the mean of healthy control infants. Eighty-nine infants with BA with a median age at LT of 7.6 months old were enrolled. The clinical characteristics and outcomes of LT were verified in the sarcopenia group (n = 21) and non-sarcopenia group (n = 68). The sarcopenia group had a significantly longer operation time and greater blood loss during LT than the non-sarcopenia group (P = .03 and 0.02). The incidence of portal vein stenosis and post-operative bloodstream infection was also significantly higher in the sarcopenia group than in the non-sarcopenia group (23.8% vs 4.4%, P = .02 and 28.6% vs 10.3%, P = .04, respectively). The total length of hospital stay did not differ significantly. The 1-year patient and graft survival rates tended to be lower in the sarcopenia group than in the non-sarcopenia group (90.5% vs 98.5%, P = .07 and 85.7% vs 97.1%, P = .05, respectively). Sarcopenia in infants with BA may be associated with the patient survival and serve as an effective marker for post-operative outcomes of LT.

Should We Offer Surgery for Biliary Atresia in Low-Resource Settings? Surgical Outcomes in Rwanda.

BACKGROUND: In many resource-limited settings, patients with biliary atresia present too late for surgical correction to be offered, and the diagnosis is fatal. As pediatric surgical and anesthesia capabilities have improved, patients in Rwanda have been offered surgical exploration. This study explores initial outcomes. METHODS: Patients presenting with direct hyperbilirubinemia and clinical suspicion of biliary atresia were identified at the main university teaching hospital in Kigali, Rwanda, from January 2016 to June 2019. Patient demographics, referral history, geographic location, preoperative imaging, preoperative laboratory studies, operative details, postoperative laboratory studies, in-hospital complications, length of stay, and survival were abstracted from retrospective chart review. Descriptive analysis was performed, and univariate analysis evaluated survival and complications. RESULTS: Seventeen patients were identified with biliary atresia, and thirteen were offered surgery. The median age of admission was 77 d (interquartile range [IQR] 63-92 d), with the median time wait for the operation being 19 d (IQR 9-27 d). The median age at operation was 93 d (IQR 76-123 d). In-hospital postoperative mortality was 15.4% (n = 2) and postoperative complications occurred in 46.2% (n = 6). Eleven patients survived to hospital discharge (84.6%), with a median length of stay of 8 d (IQR 6-13 d). CONCLUSIONS: While future studies are needed to evaluate the long-term outcomes, this series shows that surgical treatment of biliary atresia can be safely performed in Rwanda. Early referral of direct hyperbilirubinemia is essential, particularly as limited resources and personnel may impact the time from diagnosis to operation.

Cardiac-associated biliary atresia (CABA): a prognostic subgroup.

OBJECTIVES: To describe the range of concurrent cardiac malformations in biliary atresia (BA) while providing a functional framework of risk. METHODS: Demographic and variables were collected from a prospectively maintained single-centre database. Infants were grouped according to a cardiac functional framework (A=acyanotic, B=cyanotic and C=insignificant shunt). Primary outcome was set as clearance of jaundice (bilirubin ≤20 µmol/L) following Kasai portoenterostomy (KPE). Native liver survival and overall actuarial survival were compared with a date-matched control infant with BA (n=77). P value <0.05 was regarded as significant. RESULTS: 524 infants with histologically confirmed BA were treated between January 1999 and December 2018, 37 (7%) had a concurrent cardiac anomaly (A: n=23 (62%), B: n=10 (27%), C: n=4 (11%)). Infants with biliary atresia splenic malformation (BASM) or cat-eye syndrome (CES) contributed over half of the cases (21/37; 57%).Overall, 20 (54%) infants cleared jaundice (vs 50/77 (65%) controls; p=0.2), but with higher mortality compared with the non-cardiac controls (15/37 (40%) vs 3/77 (4%); HR 15.5 (95% CI 5.5 to 43.4); p<0.00001). Infants requiring cardiac intervention in the first year of life (n=15) were more likely to clear jaundice (6/7 vs 2/8; p=0.04) and had a trend towards higher survival (6/7 vs 3/8; p=0.1) when KPE followed cardiac surgery. Yet, the type of cardiac pathology did not impact clearance of jaundice or mortality. CONCLUSION: We propose the term cardiac-associated biliary atresia (CABA) as a high-risk group. We believe that restorative cardiac surgery should precede KPE wherever possible to improve outcome.

Prognostic Factors for Survival of Patients with Biliary Atresia Following Kasai Surgery.

Biliary atresia (BA) is a progressive obstruction and fibro-obliteration of the extrahepatic and intrahepatic biliary tract that causes cholestatic jaundice in infants, resulting in biliary cirrhosis and even death in the first year of life if the Kasai procedure is not performed at an earlier age. There are many prognostic factors that could affect the survival of patients with BA after Kasai surgery, however results still show some conflicting findings. A retrospective study was conducted using medical records of patients with BA who underwent Kasai surgery at Dr. Sardjito Hospital, Yogyakarta, Indonesia from June 2012 to April 2018. Twenty-nine BA patients were involved in our study, with 16 males and 13 females. Log-rank analysis showed a significant association between survival rate of BA patients with albumin level 1 month and 3 months after Kasai surgery, with p-values of 0.043 and 0.016, respectively. Interestingly, multivariate analysis revealed that cholangitis tended to have an association with BA patients' survival (p=0.09). In conclusion, the BA patients' survival might be affected by the presence of cholangitis after Kasai surgery. Further multicenter studies with a larger sample size are important to verify our results.

Predicting native liver injury and survival in biliary atresia.

Several patient and treatment related factors significantly modify outcomes of biliary atresia. The extremely variable prognosis mandates intensive postoperative monitoring following portoenterostomy. Accurate prediction of outcome and progression of liver injury would enable individualized treatment and follow-up protocols, patient counseling and meaningful stratification of patients into clinical trials. While results on most biomarkers of cholestasis, hepatocyte function, fibrosis and inflammation studied so far are inconsistent or have not been validated in independent patient cohorts, postoperative serum bilirubin level 3 months after portoenterostomy remains the most accurate clinically feasible predictor of native liver survival. Although liver stiffness and a novel marker of cholangiocyte integrity, serum matrix metalloproteinase-7, correlate with liver fibrosis and may discriminate biliary atresia from other causes of neonatal cholestasis, further information on their ability to predict portoenterostomy outcomes is needed. Recent gene expression profiling has shown promise in overcoming the sampling error associated with histological quantification of liver fibrosis, and provides an important possibility to stratify patients for clinical trials according to the prognosis of native liver survival already preoperatively. As activity and extent of ductular reaction is linked with progression of liver fibrosis in cholangiopathies, further research is also warranted to evaluate predictive value of ductular reaction, matrix metalloproteinase-7 and the underlying gene expression signatures in relation to circulating bile acids in biliary atresia. Discovery of accurate predictive tools will ultimately increase our understanding of the unpredictable response to surgery and pathophysiology of progressive liver injury in biliary atresia.

Living Donor Liver Transplantation in Children: Perioperative Risk Factors and a Nomogram for Prediction of Survival.

BACKGROUND: Living donor liver transplantation (LDLT) in children has achieved promising outcomes during the past few decades. However, it still poses various challenges. This study aimed to analyze perioperative risk factors for postoperative death in pediatric LDLT. METHODS: We retrospectively analyzed medical records of pediatric patients who underwent LDLT surgery from January 1, 2014, to December 31, 2016, in our hospital. Predictors of mortality following LDLT were analyzed in 430 children. Cox regression and Kaplan-Meier curve analysis were used for covariates selection. A nomogram was developed to estimate overall survival probability. The performance of the nomogram was assessed using calibration curve, decision curve analysis, and time-dependent receiver operating characteristic curve. RESULTS: Among the 430 patients in this cohort (median [interquartile range] age, 7 [6.10] mo; 189 [43.9%] female; 391 [90.9%] biliary atresia), the overall survival was 91.4% (95% confidence interval, 89.2-94.4), and most of the death events (36/37) happened within 6 months after the surgery. Multivariate analysis indicated that the Pediatric End-stage Liver Disease score, neutrophil lymphocyte ratio, graft-to-recipient weight ratio, and intraoperative norepinephrine infusion were independent prognostic factors. A novel nomogram was developed based on these prognostic factors. The C index for the final model was 0.764 (95% confidence interval, 0.701-0.819). Decision curve analysis and time-dependent receiver operating characteristic curve suggested that this novel nomogram performed well at predicting mortality of pediatric LDLT. CONCLUSIONS: We identified several perioperative risk factors for mortality of pediatric LDLT. And the newly developed nomogram can be a convenient individualized tool in estimating the prognosis of pediatric LDLT.

Biliary atresia screening in Shenzhen: implementation and achievements.

OBJECTIVE: To elaborate on the implementation and achievements of a biliary atresia (BA) screening programme in Shenzhen. METHODS: In 2015, we partnered with the government in Shenzhen and attached the stool colour card (SCC) to the health handbook for mothers and children. These handbooks have been distributed through official channels to every pregnant woman in Shenzhen since 1 January 2015. A total of 118 patients diagnosed with BA at Shenzhen Children's Hospital were enrolled and divided into two cohorts based on their date of diagnosis: cohort A before and cohort B after introduction of screening. The cohorts were compared to evaluate differences in age at diagnosis, jaundice-free rate, 2-year native liver survival rate and so on. RESULTS: After the implementation of the screening programme, the age at diagnosis decreased from 81±12 to 56±15 days old (p<0.05), the incidence of postoperative complications decreased from 58.8% to 52.6% (p<0.05), the jaundice-free rate increased from 47.1% to 54.4% (p<0.05), and the 2-year native liver survival rate increased from 44.4% to 52.6% (p<0.05). The percentage of patients who underwent surgery increased from 68.0% to 83.8% (p<0.05). CONCLUSION: In Shenzhen, our screening programme led to earlier diagnoses and better prognoses. The latter resulted in an increased willingness to undergo the Kasai procedure. Through a hospital and government collaboration, this programme exerted a considerable influence, and guardians observed benefits with only a small cost of implementation. Our results may eventually help promote the widespread use of the SCC across the whole country.

Ki67 expression at Kasai portoenterostomy as a prognostic factor in patients with biliary atresia.

BACKGROUND: Biliary atresia is a rare paediatric biliary obliteration disease with unknown aetiology, and is the most common indication for paediatric liver transplantation (LT). However, no consensus for predicting Kasai portoenterostomy (KP) outcomes using liver histological findings exists. Ki67 is a popular biomarker for measuring and monitoring cellular proliferation. METHODS: Ki67 (clone, MIB-1) liver parenchyma expression was measured by immunohistochemical staining of samples from living donors and patients with biliary atresia to assess its value in predicting outcomes after KP. RESULTS: Of 35 children with biliary atresia, 13 were native liver survivors (NLS), 17 were non-NLS, and five had primary LT. The median proportion of Ki67 immunostained areas in donors and patients with biliary atresia at KP was 0·06 and 0·99 per cent respectively. Univariable analysis identified a high proportion of Ki67 areas, high Ki67 cell numbers and high Ki67-positive/leucocyte common antigen-positive cell numbers at KP as significant predictors of poor native liver survival after KP (hazard ratio 9·29, 3·37 and 12·17 respectively). The proportion of Ki67 areas in the non-NLS group was significantly higher than that in the NLS group (1·29 versus 0·72 per cent respectively; P = 0·001), and then decreased at LT (0·32 per cent versus 1·29 per cent at KP; P < 0·001). CONCLUSION: This study has demonstrated the clinical data and time course of Ki67 expression in patients with biliary atresia. High Ki67 expression at KP may be an important predictor of native liver survival following the procedure.

ANTECEDENTES: La atresia biliar (biliary atresia, BA) es una enfermedad pediátrica rara que consiste en una obstrucción biliar de etiología desconocida, y es la indicación pediátrica más frecuente de trasplante hepático (liver transplantation, LT). Sin embargo, no existe consenso para predecir los resultados de la portoenterostomía de Kasai (Kasai portoenterostomy, KP) en base a los hallazgos histológicos hepáticos. El Ki67 es un biomarcador conocido para medir y controlar la proliferación celular. MÉTODOS: Se midieron los niveles de expresión del parénquima hepático de Ki67 (clon, MIB-1) por tinción inmunohistoquímica de las muestras de cinco donantes vivos y 35 pacientes con BA, para evaluar su valor predictivo de los resultados de la KP. RESULTADOS: Los pacientes con BA incluían 13 sobrevivientes con hígado nativo (native liver survivors, NLS), 17 no NLS y 5 pacientes que se sometieron inicialmente a LT. La proporción media de las áreas de expresión de Ki67 en donantes y pacientes con BA en KP fue de 0,06% y 0,99%, respectivamente. El análisis univariado identificó una alta proporción de áreas de Ki67, un alto número de células Ki67, un alto número de células Ki67 positivas (+)/leucocitos (LCA/CD45) + en KP como predictores significativos de una peor supervivencia del hígado nativo después de KP (cociente de riesgos instantáneos, hazard ratio, HR 9,29, 3,37 y 12,17, respectivamente). La proporción de las áreas Ki67 fueron significativamente superiores en los pacientes sin NLS que en los pacientes con NLS (P = 0,001). Entre los pacientes sin hígado nativo, los niveles de Ki67 disminuyeron posteriormente de acuerdo con la presencia de una lesión hepática irreparable, tales como son los hígados con BA en LT (en KP versus en LT = 1,29% versus 0.32%; P < 0,001). CONCLUSIÓN: Demostramos los datos clínicos y la evolución temporal de la expresión de Ki67 en los pacientes con BA. El alto nivel de expresión de Ki67 en KP puede ser un predictor importante para la supervivencia del hígado nativo después de KP.

Routine Postoperative Antithrombotic Therapy in Pediatric Liver Transplantation: Impact on Bleeding and Thrombotic Complications.

BACKGROUND: Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) are serious causes of morbidity and mortality after pediatric liver transplantation. To reduce thrombotic complications, routine antithrombotic therapy consisting of 1 week heparin followed by 3 months acetylsalicylic acid, was implemented in our pediatric liver transplant program in 2003. This study aimed to evaluate incidences of bleeding and thrombotic complications since the implementation of routine antithrombotic therapy and to identify risk factors for these complications. METHODS: This retrospective cohort study includes 200 consecutive pediatric primary liver transplantations performed between 2003 and 2016. Uni- and multivariate logistic regression analysis, Kaplan-Meier method, and Cox regression analysis were used to evaluate recipient outcome. RESULTS: HAT occurred in 15 (7.5%), PVT in 4 (2.0%), and venous outflow tract thrombosis in 2 (1.0%) recipients. Intraoperative vascular interventions (odds ratio [OR] 14.45 [95% confidence interval [CI] 3.75-55.67]), low recipient age (OR 0.81 [0.69-0.95]), and donor age (OR 0.96 [0.93-0.99]) were associated with posttransplant thrombosis. Clinically relevant bleeding occurred in 37%. Risk factors were high recipient age (OR 1.08 [1.02-1.15]), high Child-Pugh scores (OR 1.14 [1.02-1.28]), and intraoperative blood loss in mL/kg (OR 1.003 [1.001-1.006]). Both posttransplant thrombotic (hazard ratio [HR] 3.38 [1.36-8.45]; p = 0.009) and bleeding complications (HR 2.50 [1.19-5.24]; p = 0.015) significantly increased mortality. CONCLUSION: In 200 consecutive pediatric liver transplant recipients receiving routine postoperative antithrombotic therapy, we report low incidences of posttransplant vascular complications. Posttransplant antithrombotic therapy seems to be a valuable strategy in pediatric liver transplantation. Identified risk factors for bleeding and thrombotic complications might facilitate a more personalized approach in antithrombotic therapy.

Severity of Ascites Is Associated with Increased Mortality in Patients with Cirrhosis Secondary to Biliary Atresia.

BACKGROUND: Very few prior studies have investigated the presence of ascites as a prognostic factor in children with cirrhosis. To the best of our knowledge, there are no prior studies evaluating the relationship between severity of ascites and patient survival in children with biliary atresia and cirrhosis. AIMS: To evaluate the association between severity of ascites and survival of children with cirrhosis and biliary atresia. METHODS: All children with cirrhosis secondary to biliary atresia evaluated at our institution from 2000 to 2014 were included in this study. Patients were classified into four groups: NA = no ascites; A1 = grade 1 ascites; A2 = grade 2 ascites; and A3 = grade 3 ascites. The primary endpoint of the study was mortality within the first year after patient inclusion. Ninety-day mortality was also evaluated. Prognostic factors related to both endpoints also were studied. RESULTS: One-year patient survival for NA was 97.1%, versus 80.8% for A1, versus 52% for A2, versus 13.6 for A3 (p < 0.001). The presence of ascites increased mortality by 17 times. In the multivariate analysis, clinically detectable ascites (HR 3.14, 95% CI 1.14-8.60, p = 0.026), lower sodium (HR 1.15, 95% CI 1.04-1.27, p = 0.006), higher bilirubin (HR 1.06, 95% CI 1.00-1.12, p = 0.023), and higher PELD score (HR 1.05, 95% CI 1.02-1.08, p = 0.001) were all associated with decreased survival. Lower serum sodium (HR 1.20, 95% CI 1.09-1.32, p < 0.001) and higher PELD score (HR 1.03, 95% CI 1.001-1.063, p = 0.043) were associated with increased 90-day mortality. CONCLUSIONS: Clinically detectable ascites is associated with decreased 1-year survival of children with biliary atresia. These patients should be treated with caution and prioritized for liver transplantation.

Hepatic glypican-3 and alpha-smooth muscle actin overexpressions reflect severity of liver fibrosis and predict outcome after successful portoenterostomy in biliary atresia.

BACKGROUND: Glypican-3 plays a vital role in regulating embryonic morphogenesis of the liver. This study aimed to investigate associations of hepatic expressions of glypican-3 and alpha-smooth muscle actin with clinical parameters in biliary atresia. METHODS: Liver specimens were obtained from 20 biliary atresia infants and 7 non-biliary atresia controls. Relative mRNA expressions of glypican-3, alpha-smooth muscle actin, and signaling molecules of Wnt/ß-catenin were measured using real-time polymerase chain reaction. Protein expressions of glypican-3 and alpha-smooth muscle actin were examined using immunohistochemistry. Masson's trichrome staining was conducted to evaluate the stage of liver fibrosis. RESULTS: Up-regulation of glypican-3 mRNA expression was observed in biliary atresia livers, and its expression was positively associated with alpha-smooth muscle actin, ß-catenin, c-Myc, and cyclin D-1. Immunostaining scores of glypican-3 and alpha-smooth muscle actin were significantly increased in biliary atresia livers. Biliary atresia patients with poor outcomes had significantly greater glypican-3 expression than those with good outcomes, consistent with hepatic alpha-smooth muscle actin expression analysis. Hepatic glypican-3 expression was associated with age, albumin, aspartate transaminase, and alkaline phosphatase in biliary atresia patients, while hepatic alpha-smooth muscle actin expression was correlated with alkaline phosphatase in the patients. Moreover, glypican-3 and alpha-smooth muscle actin expressions were positively associated with fibrosis stage in biliary atresia livers. There was a positive relationship between glypican-3 and alpha-smooth muscle actin expression in biliary atresia livers. Combined high expressions of glypican-3 and alpha-smooth muscle actin were associated with poor survival. CONCLUSION: Hepatic overexpressions of glypican-3 and alpha-smooth muscle actin were associated with hepatic dysfunction and the degree of liver fibrosis in biliary atresia.

Clearance of jaundice after the modified Kasai`s operation predicts survival outcomes in patients with biliary atresia.

Tamgal J, Damrongmanee A, Khorana J, Tepmalai K, Ukarapol N. Clearance of jaundice after the modified Kasai`s operation predicts survival outcomes in patients with biliary atresia. Turk J Pediatr 2019; 61: 7-12. The aim of this study was to assess the probability of survival with native liver (SNL) and the rate of esophageal variceal bleeding (EVB) as well as their potential risk factors, in patients diagnosed with Biliary Atresia (BA), who underwent the hepaticoportoenterostomy (HPE) by retrospectively reviewing medical records between 2007 and 2016. The subjects were classified as poor outcomes if they died or a liver transplant (LT) was performed. A total of 73 cases were enrolled. The average age at HPE was 106.2 +/- 58.5 days. Poor outcome was observed in 27.4%, 54.8% survived with native liver and 17.8% were lost to follow-up. The principal cause of death was sepsis, followed by massive upper GI hemorrhage. The overall 10-year SNL was 66.8%. Only total bilirubin (TB) > 3 mg/dL at 3, 6 months after HPE and presence of associated anomalies negatively affected SNL (p=0.0155, 0.0042 and 0.001, respectively). Most of the patients experienced EVB within 3 years of age, in which TB > 9 mg/dL at 12 months after HPE was significantly associated with probability of the EVB outcome. Any interventions to improve jaundice clearance after HPE should be strongly pursued in order to improve outcomes in BA patients, particularly in centers where liver transplantation (LT) is not available. Surveillance esophagogastroduodenoscopy around the age of 1.5 years in patients having TB > 9 mg/dL may be beneficial to identify large varices having potential fatal bleeding.

Management of Biliary Atresia in France 1986 to 2015: Long-term Results.

OBJECTIVES: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available. METHODS: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed. RESULTS: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin ≤20 µmol/L) was documented in 516 patients (39%). Age at KOp (median 59 days, range 6-199) was stable over time. Survival with native liver after KOp was 41%, 35%, 26%, and 22% at 5, 10, 20, and 30 years, stable in the 4 cohorts. 25-year survival with native liver was 38%, 27%, 22%, and 19% in patients operated in the first, second, third month of life or later, respectively (P = 0.0001). Center caseloads had a significant impact on results in the 1986 to 1996 cohort only. 16%, 7%, 7%, and 8% of patients died without LT in the 4 cohorts (P = 0.0001). A total of 753 patients (55%) underwent LT. Patient survival after LT was 79% at 28 years. Five-year patient survival after LT was 76%, 91%, 88%, and 92% in cohorts 1 to 4, respectively (P < 0.0001). Actual BA patient survival (from diagnosis) was 81%. Five-year BA patient survival was 72%, 88%, 87%, and 87% in cohorts 1986 to 1996, 1997 to 2002, 2003 to 2009, and 2010 to 2015, respectively (P < 0.0001). CONCLUSIONS: In France, 87% of patients with BA survive nowadays and 22% reach the age of 30 years without transplantation. Improvement of BA prognosis is mainly due to reduced mortality before LT and better outcomes after LT.

Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.

BACKGROUND & AIMS: Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage. METHODS: Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n = 121) and validation sets (n = 50), and analyzed by RNA sequencing. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without liver transplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the antioxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry. RESULTS: We identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P < .001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children who survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P < .001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of antioxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times. CONCLUSIONS: In studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants who did not survive for 2 years, whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants who survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.

Revisiting long-term prognostic factors of biliary atresia: A 20-year experience with 81 patients from a single center.

BACKGROUND/AIMS: The present study aimed at investigating the long-term outcomes and prognostic factors of patients with biliary atresia (BA) diagnosed and followed at a single center. MATERIALS AND METHODS: Patients with BA treated during 1994-2014 at a large-volume pediatric tertiary referral center were reviewed retrospectively with regard to demographic, clinical, laboratory, and diagnostic characteristics for identifying the prognostic factors and long-term clinical outcomes. RESULTS: Overall, 81 patients (49 males, 32 females) were included. Mean age at diagnosis was 73.1±4.7 (median: 64) days. Of the patients included, 78 patients (96%) underwent a portoenterostomy procedure. Mean age at operation was 76.8±4.7 (median: 72) days. The surgical success rate was 64.8%. A younger age (either at diagnosis or surgery) was the only determinant of surgical success. The 2-, 5-, and 10-year overall survival (OS) rates, including all patients with or without liver transplantation, were 75%, 73%, and 71% respectively, whereas the 2-, 5-, and 10-year survival rates with native liver (SNL) were 69%, 61%, and 57%, respectively. Mean follow-up duration was 9.4±7.5 years. Successful surgery, presence of fibrosis and/or cirrhosis on the liver pathology, and prothrombin time [international normalized ratio (INR)] at presentation were independent prognostic factors for both OS and SNL. CONCLUSION: A younger age at diagnosis is strongly associated with surgical success in BA. Surgical success, the prothrombin time (INR) at presentation, and liver pathology are independent prognostic factors affecting the long-term outcomes in patients with BA. Therefore, timely diagnosis and early referral to experienced surgical centers are crucial for optimal management and favorable long-term results in BA.

Technical Considerations in Liver Transplantation for Biliary Atresia With Situs Inversus.

In liver transplantation (LT) for biliary atresia (BA) with situs inversus (SI), the surgical procedure is technically challenging due to multiple anatomical variations. We evaluated the surgical procedures and the outcomes in our patients and in the previously reported patients undergoing LT for BA with SI. Between November 2005 and October 2018, 235 children underwent LT with an overall 10-year graft survival of 94.7%. Of these, 6 (2.6%) patients received LT for BA with SI. Living donor liver transplantation (LDLT) was applied in all patients. Vascular anomalies at our center included the absence of the inferior vena cava (IVC; n = 5), a preduodenal portal vein (PV; n = 4), and an aberrant hepatic artery (HA; n = 1). Hepatic vein (HV) outflow obstruction occurred in 1 patient with an absent IVC and necessitated repositioning of the graft immediately after LDLT. PV stenosis occurred in 1 patient with a preduodenal PV at 5 months after LDLT. The overall survival of our patients was 80.0% at 3 years. In the literature, 49 patients with LT for BA with SI were reviewed. The survival rate was 91.8%, and the vascular complications included HV outflow obstruction (2.0%), PV complications (10.2%), and HA thrombosis (4.1%). All PV complications occurred in LDLT patients with a preduodenal PV (5/23; 21.7%). In conclusion, the detailed assessment of the surgical procedures and the systematic literature review demonstrated excellent outcomes after LT for BA with SI. Liver recipients with a preduodenal PV are exposed to a higher risk for vascular complications after a very challenging LT procedure with overall good outcomes.