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Background Biliary atresia (BA) is a severe hepatobiliary disease in infants that ultimately results in hepatic failure; however, its pathological mechanism is poorly elucidated. Current surgical options, including Kasai hepatoportoenterostomy and orthotopic liver organ transplantations, are palliative; thus, innovation in BA therapy is urgent. Methods To examine whether BA-specific post-natal stem cells are feasible for autologous cell source for BA treatment, we isolated from human exfoliated deciduous teeth, namely BA-SHED, using a standard colony-forming unit fibroblast (CFU-F) method and compared characteristics as mesenchymal stem cells (MSCs) to healthy donor-derived control SHED, Cont-SHED. BA-SHED and Cont-SHED were intrasplenically transplanted into chronic carbon tetrachloride (CCl4)-induced liver fibrosis model mice, followed by the analysis of bile drainage function and donor integration in vivo. Immunohistochemical assay was examined for the regeneration of intrahepatic bile ducts in the recipient’s liver using anti-human specific keratin 19 (KRT19) antibody. Results BA-SHED formed CFU-F, expressed MSC surface markers, and exhibited in vitro mesenchymal multipotency similar to Cont-SHED. BA-SHED showed less in vitro hepatogenic potency than Cont-SHED. Cont-SHED represented in vivo bile drainage function and KRT19-positive biliary regeneration in chronic carbon tetrachloride-induced liver fibrosis model mice. BA-SHED failed to show in vivo biliary potency and bile drainage function compared to Cont-SHED. Conclusion These findings indicate that BA-SHED are not feasible source for BA treatment, because BA-SHED may epigenetically modify the underlying prenatal and perinatal BA environments. In conclusion, these findings suggest that BA-SHED-based studies may provide a platform for understanding the underlying molecular mechanisms of BA development and innovative novel modalities in BA research and treatment.

Background and Aims: Biliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High-mobility group box 1 (HMGB1) is an important member of the danger-associated molecular patterns capable of mediating inflammation during infection-associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis. Approach and Results: In cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen-activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post-HPE and a lower survival of their native liver at 2 years. Conclusions: These results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1.

Hepatoportoenterostomy remains the cornerstone of treatment for biliary atresia. Current employed techniques include laparoscopy and open surgery. This study aims to determine if either method provides an advantage. Following PRISMA guidelines, a systematic review was conducted. Nineteen studies were included. Mean operative time 34.98 (95% CI 20.10, 49.85; p ≤ 0.00001) was longer in laparoscopic while bleeding volumes - 16.63 (95% CI - 23.39, - 9.86; p ≤ 0.00001) as well as the time to normal diet - 2.42 (95% CI - 4.51, - 0.32; p = 0.02) were lower in the laparoscopic group. No differences were observed in mean length of stay - 0.83. Similar complication, transfusions, postoperative cholangitis 0.97, and transplant free survival rates 1.00 (0.63, 1.60; p = 0.99) were seen between groups. Laparoscopic portoenterostomy provides advantages on operative time and bleeding as well as to normal diet when compared to open procedures. Both procedures showed no differences in length of stay, complications, cholangitis, and importantly, native liver survival. Level of evidence: III.

Biliary atresia (BA) is a challenging liver disease in infancy. Early diagnosis of BA is important for timely hepatoportoenterostomy. We evaluated the age‐specific diagnostic performance of transient elastography (TE) with a liver stiffness measurement (LSM) greater than 7.7 kPa in BA among infants with cholestasis. A total of 61 infants with cholestasis (5‐121 days of age) were enrolled in this prospective follow‐up study; 15 infants were BA. Four age groups were defined (≤30, 31‐60, 61‐90, and 91‐180 days). Picrosirius red staining was performed to quantify the percentage of collagen fibers in liver specimens. The utility of an LSM greater than 7.7 kPa for diagnosis of BA among infants with cholestasis was compared among age groups. In all four groups, TE showed high diagnostic power for BA using the criterion of an LSM greater than 7.7 kPa. Positive predictive values were 100%, 100%, and 100% in the groups aged 30 days or younger, 31 to 60 days, and 61 to 90 days, respectively. Respective negative predictive values were 90.9%, 94.7%, and 100%, and respective diagnostic accuracies were 92.9%, 95.2%, and 100%. The positive predictive value, negative predictive value, and diagnostic accuracy were 100%, 100%, and 100%, respectively, for LSM greater than 8.8 kPa in the group aged 91 to 180 days. The LSM was positively correlated with the percentage of collagen fibers stained by picrosirius red (P = 0.03). Conclusion: In this prospective follow‐up study, TE had good diagnostic accuracy for differentiation of BA from non‐BA cholestasis in infants with cholestasis who were 90 days of age or younger. The LSM was significantly positive correlated with the liver fibrosis status stained by picrosirius red in infants with cholestasis.

Biliary atresia (BA) is the leading indication to perform a pediatric liver transplantation (LT). Timely hepatoportoenterostomy (HPE) attempts to interrupt the natural history and allow for enteric bile flow; however, most patients who are treated with HPE require LT by the age of 10 years. We determined the cost-effectiveness of foregoing HPE to perform primary LT (pLT) in children with BA compared with standard-of-care HPE management. A Markov model was developed to simulate BA treatment over 10 years. Costs were measured in 2018 US dollars and effectiveness in life-years (LYs). The primary outcome was incremental cost-effectiveness ratio (ICER) between treatments. Model parameters were derived from the literature. In the base model, we assumed similar LT outcomes after HPE and pLT. Sensitivity analyses on all model parameters were performed, including a scenario in which pLT led to 100% patient and graft survival after LT. Children undergoing HPE accumulated $316,692 in costs and 8.17 LYs per patient. Children undergoing pLT accumulated $458,059 in costs and 8.24 LYs per patient, costing $1,869,164 per LY gained compared with HPE. With parameter variation over plausible ranges, only post-HPE and post-LT costs reduced the ICER below a typical threshold of $100,000 per LY gained. On probabilistic sensitivity analysis, 93% of iterations favored HPE at that threshold. With 100% patient and graft survival after pLT, pLT cost $283,478 per LY gained. HPE is more economically favorable than pLT for BA. pLT is unfavorable even with no graft or patient loss. The ability to predict those patients who may experience high costs after HPE or low costs after LT may help identify those patients for whom pLT could be considered.

Objectives: Biliary atresia (BA) causes neonatal cholestasis that requires hepatoportoenterostomy or liver transplantation (LT) for long-term survival. Nutritional optimization is necessary as sarcopenia and sarcopenic obesity have been associated with adverse clinical outcome. Currently, mid upper arm circumference (MUAC) is considered the most accurate indicator. The aim of the study was to determine computed tomography (CT)-based body metrics in infants with BA and to evaluate its correlation with MUAC.Methods: We retrospectively analyzed all BA infants below 2 years of age who underwent CT as part of LT screening at our hospital between 2006 and 2019. Measured variables were indexed with length and included: MUAC, total psoas muscle surface area (tPMSA), cross-sectional skeletal muscle area (CSMA), and total abdominal fat area. Intraclass correlation coefficients and Pearson coefficients were calculated. CSMA-to-abdominal fat area ratio was divided in quartiles, the lowest quartile group was considered sarcopenic obese.Results: Eighty infants with a median age of 4.6 months at LT screening were included. Intraclass correlation coefficients were: tPMSA = 0.94, CSMA = 0.92, and total abdominal fat area = 0.99. Correlation between MUAC z-score and indices of tPMSA, CSMA, and total abdominal fat area were r = 0.02, r = 0.06, and r = 0.43, respectively. The cut-off for sarcopenic obesity was CSMA-to-abdominal fat area ratio below 0.93.Conclusions: In BA infants, it is possible to determine CT-based body metrics during LT screening with very strong interobserver agreement. Poor correlation between CT-based body metrics and MUAC suggests that CT-based body metrics provide additional information on body composition in BA infants, such as relative muscle mass.

Biliary atresia (BA) is a progressive form of liver disease in the neonatal period usually requiring hepatoportoenterostomy (HPE). Cholangitis is a common sequelae of HPE but data about which patients are at risk for this complication are limited.The objective of the study was to determine risk factors associated with cholangitis in a large retrospective cohort after HPE.The Pediatric Health Information System (PHIS) was queried for BA (ICD-9 975.61) and HPE (ICD-9-CM 51.37) admissions from 2004 to 2013. We performed univariate analysis and linear regression with dependent variables of ≥ 2 or ≥ 5 episodes of cholangitis, and independent variables of age at time of HPE, race, ethnicity, gender, insurance, ursodeoxycholic acid (UDCA) use, steroid use, presence of esophageal varices (EV), and portal hypertension (PH).We identified 1112 subjects with a median age at HPE of 63 days and median number of cholangitis episodes of 2 within 2 years. On multiple regression analysis, black race (odds ratio (OR) 1.51, P = 0.044) and presence of PH (OR 2.24, P 0.001) were associated with increased risk of ≥ 2 episodes of cholangitis, whereas HPE at90 days was associated with less risk (OR 0.46, P = 0.001). Among those with ≥5 episodes, Asian race (OR 2.66, P = 0.038), public insurance (OR 1.72, P = 0.043), EV (OR 1.81, P = 0.017), and PH (OR 2.88, P 0.001) were associated with higher risk.Complications, such as cholangitis remain a common problem for patients, after HPE, with median of 2 episodes within 2 years. Higher rates of cholangitis are associated with portal hypertension whereas lower rate is associated with age at HPE of90 days. Asians, patients with public insurance, and those with portal hypertension are more likely to have recurrent cholangitis.

Atresia of the biliary tract, or biliary atresia (BA), is a destructive, inflammatory disease in which progressive biliary tree fibrosis in an infant leads to obstruction of the bile ducts and, as a result, to cirrhosis of the liver. If untreated, progressive cirrhosis leads to death by 2 years. Biliary atresia can be divided into 3 types, each of which depends on the level closest to biliary obstruction. Type I (obstruction of the common bile duct), type II (patency of the bile ducts to the level of the common hepatic duct), type III (obstruction at the level of the gates of the liver). It is very important to distinguish between types of BA and conduct differential diagnosis with other cholestatic diseases. There are nonsyndromic, syndromic, and BA, combined with other malformations. In diagnostics, in addition to clinical manifestations and specific changes in blood biochemical parameters characterizing cholestasis, an ultrasound examination of the abdominal cavity organs, gepatobiliscintigraphy, magnetic resonance cholecystopancreatocholangiography, according to indications, a puncture biopsy of the liver and histological examination are performed. The main method of treatment is hepatoportoenterostomy according to Kasai, which must be performed no later than 3 months, and with liver cirrhosis and hepatic insufficiency, liver transplantation. Additional methods of treatment include the use of ursodeoxycholic acid, fat-soluble vitamins.

(1) Background: Acute cholangitis during the first year after Kasai hepatoportoenterostomy (HPE) has a negative impact on patient and native liver survival. There are no consistent guidelines for the definition, treatment, and prophylaxis of cholangitis after HPE. The aim of this study was to develop definition, treatment, and prophylaxis guidelines to allow for expeditious management and for standardization in reporting. (2) Methods: the Delphi method, an extensive literature review, iterative rounds of surveys, and expert panel discussions were used to establish definition, treatment, and prophylaxis guidelines for cholangitis in the first year after HPE. (3) Results: Eight elements (pooled into two groups: clinical and laboratory/imaging) were identified to define cholangitis after HPE. The final proposed definitions for suspected and confirmed cholangitis are a combination of one element, respectively, two elements from each group; furthermore, the finding of a positive blood culture was added to the definition of confirmed cholangitis. The durations for prophylaxis and treatment of suspected and confirmed cholangitis were uniformly agreed upon by the experts. (4) Conclusions: for the first time, an international consensus was found for guidelines for definition, treatment, and prophylaxis for cholangitis during the first year after Kasai HPE. Applicability will need further prospective multicentered studies.

Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition–associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line–associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.

To determine a very early predictive biomarker after hepatoportoenterostomy (HPE) for the prediction of native liver survival in biliary atresia (BA) patients. A retrospective chart review was conducted of BA patients in our hospital between August 2000 and April 2019. The serum total bilirubin (T-bil), direct bilirubin, and gamma-glutamyl transferase level 1 week after HPE were analyzed. The clinical outcome predictors were investigated. A total of 90 BA patients were recruited. Receiver operating characteristic curve analysis showed that a post-HPE 1-week T-bil level ≤4.85 mg/dL predicted jaundice-free after HPE (P = 0.02). BA patients with a post-HPE 1-week T-bil ≤4.85 mg/dL were more likely to be jaundice-free within 3 months of HPE (odds ratio = 3.53; P = 0.006). Kaplan–Meier plot analysis showed that the likelihood of native liver survival and jaundice-free native liver survival were significantly higher in BA subjects with a post-HPE 1-week T-bil ≤4.85 mg/dL than in other subjects (P = 0.01 and 0.01, respectively). The serum post-HPE 1-week T-bil level may predict the long-term outcome in BA patients. A post-HPE 1-week T-bil ≤4.85 mg/dL correlated with better native liver survival and jaundice-free native liver survival in BA patients.

Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T‐ and B‐cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen‐DR isotype [HLA‐DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA‐DR+CD38+ NK cells and expression of NK cell activation markers CD69 and HLA‐DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)‐8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA‐DR+CD38+ NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL‐8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.

Biliary atresia is a progressive obliterative cholangiopathy of neonates, which causes jaundice and can lead to end stage liver disease. Despite recent improvements, Kasai hepatoportoenterostomy remains the standard surgical procedure to re-establish bile flow in these patients to date. Nevertheless, the majority of children with biliary atresia ultimately undergo liver transplantation. Herein, technical notes and perioperative therapies in children undergoing Kasai operation are reported.

Background Biliary atresia (BA) causes progressive fibrosis and obliteration of the biliary tree, resulting in bile stasis and eventual liver dysfunction. It affects 1 in 10,000–18,000 infants, and if left untreated, universally leads to liver failure. The Kasai hepatoportoenterostomy (KPE) was developed as an effective surgical therapy for BA and can restore bile drainage into the intestine. Traditionally, the KPE procedure extra-corporealizes the liver to expose the portal plate. Here, we describe modifications to the procedure via a smaller incision in which the liver remains within the abdominal cavity and we compare the outcomes of this technique to previous institutional outcomes and to contemporary international series. Materials and methods We identified all patients who underwent KPE for BA at a single institution between 1994 and 2012. Patient outcomes after the modified KPE performed from 2004 to 2012 were compared to data from infants who underwent the traditional KPE from 1994 to 2003. Results Ninety-nine patients were identified. Fifty-two were in the traditional KPE group and 47 in the modified KPE group. There was no difference in mean age at surgery. Median follow-up was 64 months (traditional KPE) and 46 months (modified KPE). The rate of native liver survival (39.1% vs 48.5%), overall survival (89.2% vs 97.8%), liver transplant occurring under one year of age (36.5% vs 40.4%) and median time to liver transplant (188 vs 172 days) were not statistically different between groups (p > 0.05 for all comparisons). The results of the modified KPE compared favorably to published outcomes. Conclusion The described modifications to the KPE appear to yield equivalent outcomes when compared to the traditional KPE procedure and compare well with published outcomes in the literature. It is possible that the procedure described here results in less scarring and technically easier liver transplant procedures. Level of Evidence Level III.

Background Cholecystoduodenostomy is a surgical procedure that bypasses the extrahepatic biliary tree and connects the gallbladder directly to the duodenum. This case describes the successful use of this procedure in a novel situation. Case presentation A premature (34 weeks gestation) female infant with cystic fibrosis required a laparotomy on day 1 of life due to an intrauterine small bowel perforation. Resection of small bowel and ileostomy formation resulted in short gut syndrome, with 82 cm residual small bowel and intact ileocaecal valve. Post-ileostomy reversal at 2 months old, she developed conjugated hyperbilirubinaemia. Despite conservative management including increased enteral feeding, ursodeoxycholic acid, cholecystostomy drain insertion and flushes, her cholestatic jaundice persisted. A liver biopsy revealed an “obstructive/cholestatic” picture with fibrosis. To avoid further shortening her gut with an hepatoportoenterostomy, cholecystoduodenostomy was performed at 3 months of age with subsequent post-operative improvement and eventual normalisation of her clinical jaundice and liver biochemistry. Conclusions This is the first reported case of a cholecystoduodenostomy being used successfully to treat an infant with persistent conjugated hyperbilirubinemia, cystic fibrosis and short gut syndrome. Cholecystoduodenostomy is a treatment option that with further study, may be considered for obstruction of the common bile duct in patients with short gut and/or where a shorter operating time with minimal intervention is preferred.

Introduction: Surgical treatment of biliary atresia (BA) is still based on sequential strategy with Kasai hepatoportoenterostomy (KP) followed by liver transplantation (LT), in case of complicated secondary biliary cirrhosis. Concerns have been expressed regarding the risks of LT related to previous KP, suggesting primary LT as an exclusive treatment of BA.Methods: Single-center retrospective analysis including 393 pediatric patients who underwent LT for BA from 1993 to 2018, categorized into two groups: with (KP) or without (NoKP) previous KP. Pre-LT clinical condition was estimated considering age at LT, time on waiting list, pediatric end-stage liver disease score (PELD), and presence of portal vein hypoplasia. Post-LT outcome was evaluated considering patient and graft survival rates, and need for early reoperation due to abdominal or graft-related complications (Results: Two-hundred ninety-six patients (75.3%) were categorized in the KP group, and 97 (24.7%) in the NoKP group. Median age at LT was 1.14 years in the KP group and 0.85 years in the NoKP group (p < 0.0001). PELD score was significantly less severe in KP patients (p < 0.05). One-year patient survival rates were 96.9 and 96.8% in the KP and NoKP groups, respectively (p = 0.43), and the corresponding graft survival was 92.5 and 94.8% (p = 0.97). The need for early reoperation was more frequent in the KP group (29.8%) vs. NoKP group (12.4%, p = 0.01). The rate of bowel perforation was non-significantly higher in the KP group (8.1%) vs. NoKP group (3.1%, p = 0.11).Conclusions: The sequential strategy including KP and LT allowed performing LT in patients with significant older age and better clinical conditions, when compared to those transplanted without previous KP. Patient and graft survivals were not impacted by previous KP. Although previous KP was associated with an increased rate of post-LT surgical complications, bowel perforation and bleeding did not occur significantly more frequently. Such results support the current strategy based on sequential treatment.

Background: Although Kasai portoenterostomy (KPE) is performed timely for most children with biliary atresia (BA), the native liver survival (NLS) is still poor due to the progressive liver fibrosis. Many children have to receive liver transplantation (LT) within 2 years after KPE. Early prediction of the prognosis permits the implementation of prophylactic treatments for BA children. However, studies about the prediction are limited.Objective: The purpose of this study is to establish a nomogram to predict the prognosis of BA children within 2 years after KPE.Methods: The follow-up data of 151 BA children were retrospectively reviewed, and were randomly divided into a training cohort for constructing a nomogram (n = 103) and a validation cohort (n = 48). In the training cohort, patients were divided into Group A and Group B according to whether death or LT were observed within 2 years post-KPE. Multivariate Cox regression based on the baseline characteristics, liver function indicators and LSM (liver stiffness measurement) values at KPE and 3 months after KPE was utilized for the establishment of the nomogram in predicting the prognosis of BA within 2 years after KPE. The discrimination and calibration of the nomogram were internally and externally validated.Results: Fifty-six BA children were included in Group A and 47 were included in group B. Age at KPE, METAVIR score F4, LSM at 3 months, first onset of cholangitis within 3 months, and jaundice clearance time were the independent predictors for the prognosis of BA children within 2 years after KPE (all P < 0.05). The developed nomogram based on these independent predictors showed good discrimination and calibration by the internal and external validation. Its performance was better than each predictor in predicting the prognosis (all P < 0.05).Conclusions: The established nomogram based on the indicators from the first 3 months after KPE may be useful for predicting the prognosis of BA children within 2 years post-KPE and helpful for the consideration of LT.

Background The role of microbiota in biliary atresia (BA) remains unclear. The aim of our study was to assess efficacy and safety of LGG treatment in children with BA after HPE with special focus on bacterial cholangitis (BCH) and quantitative assessment of the gut microbiota composition and metabolism. Methods We performed double-blind placebo controlled trial with patients randomized into treatment group who received LGG (n = 14) and placebo (n = 16). The gut microbiota and short-chain fatty acids (SCFA) were assessed at baseline and after 6 months of treatment. Clinical and laboratory parameters including episodes of bacterial cholangitis (BCH) were collected during the study period and after 2-year follow-up. Additionally, stool composition of BA patients was compared with healthy age-matched control group. Results There were lower concentration of SCFA in children with BA compared to control group and significant increase in the number of Enterococcus bacteria. After 6 months of treatment, neither laboratory parameters nor gut microbiota composition differed between LGG group and placebo. PP analysis results were similar to ITT analysis, no significant differences between study and control group. Overall, there were 11 (36%) patients who developed at least one episode of bacterial cholangitis; 3 (21%) in the LGG group compared to 8 (50%) placebo group (p = 0.14). Bacterial cultures were positive in 22% of cases and recurrence after the first episode was observed in 27% of patients. The level of total bilirubin decreased below 2 mg/dl after 6 months of the study in 6 (42.8%) patients in the LGG group and in 8 (50%) patients in the placebo group (p = 0.73). During 2-year follow-up 6 out of 14 patients (42.8%) in the LGG group and 11 out of 16 placebo patients (68.7%) underwent liver transplantation (p = 0.27). Conclusions Patients with BA present with specific microbiota profiles and decreased SCFA what gives opportunities to implement novel therapeutic options based on modulation of microbiota. Whether LGG is an effective therapy needs to be studied in a larger group with similar outcome parameters.

This study aimed to determine whether circulating levels of clusterin (CLU), an extracellular chaperone implicated in cholestatic and fibrotic processes, are associated with clinical parameters of post-operative BA patients and could serve as a BA biomarker. Ninety-six BA patients and 56 healthy controls were recruited. Circulating CLU levels were measured using enzyme-linked immunosorbent assay. Circulating CLU levels were significantly reduced in BA patients – especially those with worse outcomes including jaundice, severe liver fibrosis, and late-stage of hepatic dysfunction. Multivariate linear regression analysis revealed that circulating CLU levels were negatively associated with outcome parameters indicating jaundice status, degree of fibrosis, and liver dysfunction, but positively correlated with serum albumin and platelet number of BA patients. Lower circulating CLU levels were considerably associated with poor survival of post-operative BA patients. Receiver-operating characteristic curve analysis demonstrated a diagnostic value of circulating CLU as a non-invasive indicator for poor outcomes of BA patients (AUC = 0.85), with a sensitivity of 81.5% and a specificity of 73.5%. All findings indicate that reduced circulating CLU might reflect poor outcomes of BA patients and have potential as a novel biomarker for the disease severity following Kasai-operation.

Aim of the study Biliary atresia (BA) is a fibro-inflammatory cholangiopathy of intra- and extrahepatic biliary radicles. The standard-of-care treatment is surgical restoration of bile flow by Kasai hepatoportoenterostomy (HPE). We aimed to identify the predictors of short-term outcome of the Kasai operation three months postoperatively. Material and methods This retrospective study included 107 infants diagnosed with BA by intraoperative cholangiography. All underwent a Kasai operation. The surgical outcome was classified after 3 months post-operatively as successful (bilirubin ≤ 2 mg/dl) or failed (bilirubin > 2 mg/dl). The two groups were compared according to basic clinical, ultrasonographic and histopathological characteristics. Results Of the studied patients 29 (27.1%) had a successful outcome while 78 (72.9%) had failed Kasai HPE. Of the preoperative characteristics, lower age and lower serum alkaline phosphatase (ALP) were significantly associated with successful surgical outcome (p = 0.009 and < 0.0001, respectively). In addition, surgical type of BA affected the short-term outcome (p = 0.017), while there was no statistically significant difference regarding the other studied parameters between groups. Age of 69.5 days or less was predictive of successful outcome with 74.4% specificity but with low sensitivity (58.6%), and ALP at a cutoff level of 532.5 U/l or less was predictive of successful outcome with 75.9% sensitivity and 74.4% specificity. Conclusions Younger age at the time of surgery and lower ALP are good predictors for the short-term outcome of Kasai HPE with better performance of ALP. This may help to anticipate those who can benefit from surgical correction and those who should be given high priority for transplant referral.

Bilijarna atrezija rijetka je bolest neutvrđene etiologije koju karakterizira postojanje neprohodnih žučnih vodova, a može se javiti zasebno ili uz poremećaje drugih organskih sustava. Najčešće se manifestira u novorođenačkoj ili dojenačkoj dobi pojavom žutice, aholičnih stolica i tamnog urina, što upućuje na opstrukciju koja onemogućava fiziološki protok žuči u crijevo. U kasno prepoznatih slučajeva mogu biti prisutni znakovi uznapredovalog oštećenja jetre poput ascitesa, venskih varikoziteta i portalne encefalopatije. Kao primarni terapijski zahvat u većine oboljele djece izvodi se HPE po Kasaiju pri kojoj se anastomoziranjem slobodne vijuge tankog crijeva i portalnog dijela jetre formira put za protok žuči te se u slučaju uspješnog zahvata postiže nestanak znakova kolestaze. Unatoč ovoj operaciji, najvećem je broju oboljelih nakon određenog vremena ipak potrebna transplantacija jetre. Najčešća postoperativna komplikacija, kao i jedan od najznačajnijih faktora koji utječu na ishod bolesti nakon HPE, jest upala žučnih vodova ili kolangitis, za kojeg se smatra da nastaje kombinacijom više čimbenika koji pogoduju translokaciji i perzistenciji crijevnih bakterija u bilijarnom stablu. Ranija pojava i češće ponavljanje epizoda upale povezani su sa bržim propadanjem nativne jetre i ranijom potrebom za transplantacijom. U prevenciji kolangitisa koriste se različite kombinacije i režimi davanja antibiotika djelotvornih protiv najčešće izoliranih uzročnika, a primjenjuju se i kortikosteroidi zbog protuupalnih svojstava i povoljnog utjecaja na protok žuči te ursodeoksikolična kiselina koja također pokazuje koleretski efekt. Liječenje akutne upale temelji se na intravenskoj primjeni antibiotika širokog spektra uz eventualnu upotrebu intravenskih imunoglobulina., Biliary atresia is a rare disease of undetermined etiology, characterized by the presence of impenetrable bile ducts, which may be found separately or joined with disruptions of other organ systems. It is most commonly presented in the newborn or infants by appearance of jaundice, acholic stools and dark urine, suggestive of an obstruction which disables the physiological flow of bile into the intestine. In tardy recognized cases, signs of advanced liver damage can be detected, such as ascites, venous varices and portal encephalopathy. In most patients Kasai HPE is performed as a primary intervention. By creating an anastomosis between an isolated intestinal loop and the liver hilum, a pathway allowing the flow of bile is established, which, in case of success, leads to disappearance of signs of cholestasis. In spite of the operation, the majority of patients eventually require a liver transplant. The most common postoperative complication, as well as one of the most significant factors affecting the outcome after HPE, is the inflammation of bile ducts or cholangitis, believed to develop as a consequence of multiple factors favoring translocation of bacteria from the intestine and their persistence in the biliary tree. Earlier and more common episodes of inflammation are associated with a more rapid native liver deterioration and an earlier need for transplantation. Various combinations and administration regimes of antibiotics effective towards most commonly isolated causative bacteria are used in order to prevent cholangitis. Additionally, corticosteroids are administered due to their anti-inflammatory nature and positive effect on bile flow, and ursodeoxycholic acid shows a choleretic effect as well. The treatment of acute inflammation is based on intravenous administration of wide-range antibiotics and possibly intravenous immunoglobulins.

Background/purpose: Biliary atresia is the most common reason for newborn cholestasis and pediatric liver transplantation. Even after normalization of serum bilirubin after portoenterostomy, most patients require liver transplantation by adulthood due to expanding fibrosis. We addressed contemporary outcomes of biliary atresia in the Nordic countries. Methods: Data on center and patients characteristics, diagnostic practices, surgical treatment, adjuvant medical therapy after portoenterostomy, follow-up and outcomes were collected from all the Nordic centers involved with biliary atresia care during 2005-2016. Results: Of the 154 patients, 148 underwent portoenterostomy mostly by assigned surgical teams at median age of 64 (interquartile range 37-79) days, and 95 patients (64%) normalized their serum bilirubin concentration while living with native liver. Postoperative adjuvant medical therapy, including steroids, ursodeoxycholic acid and antibiotics was given to 137 (93%) patients. Clearance of jaundice associated with young age at surgery and favorable anatomic type of biliary atresia, whereas annual center caseload >3 patients and diagnostic protocol without routine liver biopsy predicted early performance of portoenterostomy. The cumulative 5-year native liver and overall survival estimate was 53% (95% CI 45-62) and 88% (95% CI 83-94), respectively. Portoenterostomy age 3 patients were predictive for long-term native liver survival, while normalization of serum bilirubin after portoenterostomy was the major predictor of both native liver and overall 5-year survival. Conclusions: The outcomes of biliary atresia in the Nordic countries compared well with previous European studies. Further improvement should be pursued by active measures to reduce patient age at portoenterostomy. Retrospective prognosis study: Level II. (C) 2017 Elsevier Inc. All rights reserved.

Pediatric experience with biliary tract injuries (BTI) is limited and mostly consists of case presentations. The purpose of this study is to evaluate clinical and radiological findings of possible BTI, treatment strategies, and results. The records of nine patients with the diagnosis of BTI between July 2009 and November 2017 were reviewed retrospectively. There were seven boys and two girls (mean 8.05 ± 4.39 years). The mechanisms were motor vehicle occupant, fall, crush and gunshot wound. Hepatic laceration routes that extended into the porta hepatis and contracted the gall bladder were demonstrated on computerized tomography (CT). Bile duct injury was diagnosed with bile leakage from the thoracic tube (n = 2), from the abdominal drain (n = 2) and by paracentesis (n = 5). Extrahepatic (n = 8) and intrahepatic (n = 1) bile duct injuries were diagnosed by cholangiography. Endoscopic retrograde cholangiography, sphincterotomy, and stent placement were successfully completed in five patients. Peritoneal drainage stopped after 3–17 days of procedure in four patients. The fifth patient was operated with the diagnosis of cystic duct avulsion. Cholecystectomies, primary repair of laceration, cystic duct ligation, and Roux-en-Y hepatoportoenterostomy were performed in the remaining four patients. All patients presented with clinically normal findings, normal liver functions, and normal ultrasonographic findings in the follow-up period. The presentation of the parenchymal injury extending to the porta hepatis with contracted gall bladder on CT and diffuse homogenous abdominal fluid should be considered as signs of BTI. We suggest a multi-disciplinary approach for the diagnosis and treatment of BTIs. Surgery may be indicated according to the patient’s clinical condition, radiological findings and failure of non-operative treatment.

We investigated the utility of transient elastography (TE) for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty-eight cholestatic infants (9-87 days of age) with direct bilirubin level1 mg/dL were enrolled. Liver stiffness measurement (LSM) by TE was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non-BA cholestatic infants. A receiver operating characteristic (ROC) curve analysis showed that an LSM7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%; specificity = 97%; area under the curve [AUC] = 85.3%; P = 0.0001). Cholestatic infants with an LSM7.7 kPa were more likely to be diagnosed with BA (odds ratio [OR] = 128; P0.001). Very early measurement of LSM after hepatoportoenterostomy (HPE) is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months post-HPE. Five of the BA subjects were awaiting or had received liver transplantation (LT), and they had a significantly higher LSM measured 1 week post-HPE than that in the other BA subjects (26.0 vs. 10.8 kPa; P = 0.006). A Cox proportional analysis demonstrated that the need for LT was significantly higher in BA subjects with LSM16 kPa measured 1 week post-HPE than other BA subjects (hazard ratio [HR] = 10.16; P = 0.04).LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM post-HPE may predict complications and the need for early LT in infants with BA. (Hepatology 2018).

Background Alagille Syndrome (AGS) and Progressive Familial Intrahepatic Cholestasis (PFIC) are rare pediatric biliary disorders that lead to progressive liver disease. This study reviews our experience with the surgical management of these disorders over the last 20 years. Methods We retrospectively reviewed the records of children diagnosed with AGS or PFIC from January 1996 to December 2016. Data collected included demographics, surgical intervention (liver transplant or biliary diversion), and complications. Results Of 37 patients identified with these disorders, 17 patients (8 AGS,9 PFIC) underwent surgical intervention. Mean postsurgical follow-up was 6.9 ± 4.7 years. Liver transplantation was the most common procedure (n = 14). Two patients who were initially thought to have biliary atresia underwent hepatoportoenterostomy, but were subsequently shown to have Alagille syndrome. Biliary diversion procedures were performed in 3 patients (external n = 1, internal n = 2). PFIC patients tended to be older at the time of liver transplant compared to AGS (4.3 ± 3.9 years vs. 2.4 ± 1.1 years, p = 0.25). The AGS patient with external diversion had resolution of symptoms and no complications (follow-up: 12.5 years). Both PFIC patients with internal diversion (conduit between gallbladder and transverse colon) had resolution of pruritus and no progression of liver disease (follow-up: 3.8 and 4.5 years). Conclusions AGS and PFIC are rare biliary disorders in children which result in pruritus and progressive liver failure. Three patients in this series (8%) benefited from biliary diversion for control of pruritus and have not to date required transplantation for progressive liver disease. 38% underwent transplantation owing to pruritus and severe liver dysfunction. Level of Evidence 2b

Bile lakes may be present at time of diagnosis or develop later following hepatoportoenterostomy (HPE) in patients with biliary atresia (BA). We report a patient with recurrent cholangitis following HPE who developed multiple large biliary cystic lesions. Percutaneous drainage resulted in resolution of jaundice and cholangitis but capping of drains resulted in recurrence of symptoms. Therefore, internal drainage of the bile lakes was accomplished using cystjejunostomy to the roux limb of the previous portoenterostomy. At 18 months of follow-up, the patient has remained jaundice free with only one recurrent cholangitis episode which occurred after stopping her antibiotic prophylaxis. Although this patient will likely require liver transplantation in the next few years, this case suggests that cystjejunostomy may be a viable surgical option to improve bile flow and prevent cholangitis in patients who develop bile lakes following HPE. Keywords: Bile lake, Biliary atresia, Cystjejunostomy