Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

Autoimmune hepatitis: Brighton Collaboration case definition and guidelines for data collection, analysis, and presentation of immunisation safety data.

This report introduces a Brighton Collaboration (BC) case definition for autoimmune hepatitis (AIH), which has been classified as a priority adverse event of special interest (AESI), as there were possible cases seen following COVID-19 vaccination. The case definition was developed by a group of subject matter and BC process experts to facilitate safety data comparability across pre- and post-licensure clinical trials, as well as pharmacovigilance activities in multiple settings with diverse resources and healthcare access. The usual BC case definition development process was followed in an expedited manner, and took two months to complete, including finalising the manuscript for publication, instead of the usual 1 year development time. It includes a systematic review of the literature and an expert consensus to define levels of diagnostic certainty for AIH, and provides specific guidelines for data collection and analysis. Histology, serological and biochemical tests and exclusion of alternate diagnosis were considered necessary to define the levels of certainty (definitive, probable and possible). AEFI reports of suspected AIH were independently classified by the WG members to test its useability and these classifications were used to finalise the case definition. The document underwent peer review by external AIH experts and a Reference Group of vaccine safety stakeholders in high-, low- and middle-income countries to ensure case definition useability, applicability, and scientific integrity. The expedited process can be replicated for development of other standardised case definitions for priority AESIs for endemics and epidemics. While applicable to cases reported following immunisation, the case definition is independent of lapsed time following vaccination and, as such, can also be used to determine background incidence for vaccinated and unvaccinated control groups in studies of causal association. While use of this case definition is also appropriate for the study of safety of other products including drugs, it is not meant to guide clinical case management.

Galectin-3 in biliary atresia and other pediatric cholestatic liver diseases.

AIMS: Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin-3, a beta-galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin-3 levels in children with BA. METHODS: Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin-3 was measured using standard enzyme-linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. RESULTS: Plasma Galectin-3 in late BA was significantly higher than in early BA (20.82 [12.45-30.46] vs. 11.30 [8.74-16.83] ng/mL, p = 0.0096). Galectin-3 levels correlated with markers of disease severity and interleukin-6. There were significantly more Galectin-3+ M2 macrophages in late BA in comparison to late other CLD (162 [157-233] vs. 49 [33-59] cells/mm2 , p = 0.03). The number of Galectin-3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. CONCLUSIONS: Plasma Galectin-3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin-3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin-3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Cytomegalovirus in biliary atresia is associated with increased pretransplant death, but not decreased native liver survival.

BACKGROUND: Biliary atresia (BA) is likely caused by a common phenotypic response to various triggers; one proposed trigger, cytomegalovirus (CMV), may lead to worse outcomes. The aim of this study was to determine the severity of disease and pretransplant outcomes of infants with BA, who have evidence of CMV (CMV+) at diagnosis compared with CMV-negative (CMV-) infants. METHODS: The study used data and biospecimens from the Childhood Liver Disease Research Network PROBE study of cholestatic infants. Plasma obtained at the time of hepatic portoenterostomy (HPE) of 249 infants with BA was tested for CMV by DNA-PCR and CMV-IgM. Comparisons between CMV+ and CMV- infants were made using Wilcoxon rank sum, Student t test, chi-square, or Fisher exact test. Native liver survival (NLS) outcomes were analyzed using Kaplan-Meier and Cox regression adjusting for age at HPE; pretransplant patient survival outcomes were analyzed using a competing risk model and adjusting for age at HPE. RESULTS: CMV+ infants (n = 29, 12%) underwent HPE later (67.8±13.6 d vs. 55.1±18.5 d, p = 0.0005) and had higher baseline alkaline phosphatase and aminotransferases. There was no difference between groups in jaundice clearance or NLS. The subdistribution HR of pretransplant death for CMV+ infants adjusted for age at HPE was 3.8 (p = 0.034). CONCLUSIONS: CMV infection at the time of HPE in infants with BA is not associated with worse NLS despite the association with worse liver injury, older age at HPE, and increased risk of pretransplant death adjusted for age at HPE. Continued evaluation of the consequences of CMV infection and the effects of antiviral treatment should be explored.

Does High-Intensity Exercise Cause Acute Liver Injury in Patients with Fontan Circulation? A Prospective Pilot Study.

The Fontan procedure results in chronic hepatic congestion and Fontan-associated liver disease (FALD) characterized by progressive liver fibrosis and cirrhosis. Exercise is recommended in this population, but may accelerate the progression of FALD from abrupt elevations in central venous pressure. The aim of this study was to assess if acute liver injury occurs after high-intensity exercise in patients with Fontan physiology. Ten patients were enrolled. Nine had normal systolic ventricular function and one had an ejection fraction < 40%. During cardiopulmonary exercise testing, patients had near-infrared spectroscopy (NIRS) to measure oxygen saturation of multiple organs, including the liver, and underwent pre- and post-exercise testing with liver elastography, laboratory markers, and cytokines to assess liver injury. The hepatic and renal NIRS showed a statistically significant decrease in oxygenation during exercise, and the hepatic NIRS had the slowest recovery compared to renal, cerebral, and peripheral muscle NIRS. A clinically significant increase in shear wave velocity occurred after exercise testing only in the one patient with systolic dysfunction. There was a statistically significant, albeit trivial, increase in ALT and GGT after exercise. Fibrogenic cytokines traditionally associated with FALD did not increase significantly in our cohort; however, pro-inflammatory cytokines that predispose to fibrogenesis did significantly rise during exercise. Although patients with Fontan circulation demonstrated a significant reduction in hepatic tissue oxygenation based on NIRS saturations during exercise, there was no clinical evidence of acute increase in liver congestion or acute liver injury following high-intensity exercise.

Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.

Role of galectin-3 in the pathogenesis and progression of biliary atresia.

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HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives.

The strongest genetic association with autoimmunity is within chromosome 6p21, where the human leukocyte antigen (HLA) complex resides. This review will focus on the HLA associations within pediatric autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis. In general, there is considerable overlap in HLA genotypes conferring susceptibility to pediatric autoimmune liver diseases, however unique HLA associations and protective HLA genotypes exist. There are numerous areas for future research initiatives in pediatric autoimmune liver diseases and HLA associations with clinical outcomes, autoantigen discovery and novel therapeutics targeting the HLA- autoantigen- T cell pathway will be highlighted.

The discriminatory ability of FibroScan liver stiffness measurement, controlled attenuation parameter, and FibroScan-aspartate aminotransferase to predict severity of liver disease in children.

Vibration controlled transient elastography (FibroScan) is used to predict the severity of liver fibrosis and steatosis. In pediatrics, few studies have been performed directly comparing liver histologic features with FibroScan liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs). The FibroScan-aspartate aminotransferase (FAST) score, which predicts liver disease severity in adult nonalcoholic fatty liver disease (NAFLD), has not been analyzed in children. The aims of this study were to determine if LSM and CAP correlated with liver histologic fibrosis stage and steatosis grade, respectively, and to determine the predictive capacity of FAST in pediatric NAFLD. Research participants (n = 216) included those with FibroScan within 90 days of a liver biopsy. The ability of LSM, CAP, and FAST to predict severity of liver disease was analyzed by Spearman correlation, linear regression, and receiver operating characteristic and C statistic. Significant correlations were identified between LSM and Ishak fibrosis stages, with the strongest correlation occurring in the non-NAFLD group (Spearman r = 0.47, p < 0.0001). LSM adequately predicted Ishak stages F0-2 versus F3-F6 (area under the receiver operating characteristic curve [AUROC], 0.73 for all; 0.77 for non-NAFLD). CAP strongly predicted histologic steatosis grade (r = 0.84; p < 0.0001; AUROC, 0.98). FAST had acceptable discriminatory ability for significant liver disease (AUROC, 0.75). A FAST cutoff ≥0.67 had a sensitivity of 89% but a specificity of only 62% at determining significant liver disease. This study encompasses one of the largest pediatric cohorts describing the accuracy of FibroScan LSM and CAP to predict liver histologic fibrosis stage and steatosis grade, respectively. In order to determine specific LSM, CAP, and FAST cut-off values for fibrosis stages, steatosis grades, and significant liver disease, respectively, a much larger cohort is necessary and will likely entail the need for multicentered studies.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome.

There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.

Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study.

Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiencies, suffer debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open-label, Phase 2, international, long-term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty-three patients, ranging from 12 months to 18 years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)-BSEP, and 19 had ≥ 1 nontruncating mutation (nt)-BSEP. Patients received maralixibat 266 µg/kg orally, once daily, from baseline to Week 72, with twice-daily dosing permitted from Week 72. Long-term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of > 75% from baseline or concentrations <102.0 µmol/L) was achieved in 7 patients with nt-BSEP, 6 during once-daily dosing, and 1 after switching to twice-daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant-free after > 5 years. No patients with FIC1 deficiency or t-BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well-tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt-BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well-tolerated alternative to surgical intervention.

Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.

Diagnostic Tools for Early Detection of Biliary Atresia: Is a Newborn Screen Attainable?

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Cholangitis Definition and Treatment after Kasai Hepatoportoenterostomy for Biliary Atresia: A Delphi Process and International Expert Panel.

(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.

Primary vs. salvage liver transplantation for biliary atresia: A retrospective cohort study.

INTRODUCTION: Kasai hepatoportoenterostomy is the standard of care for children with biliary atresia, but a majority of patients progress to end-stage liver disease and require a salvage liver transplant. Given the high failure rates of the hepatoportoenterostomy operation, some have advocated for primary liver transplantation as a superior treatment approach. The aim of this study was to compare outcomes of pediatric candidates with biliary atresia listed for primary vs. salvage liver transplantation. METHODS: The SRTR/OPTN database was retrospectively reviewed for all children with biliary atresia listed for liver transplant between March 2002 and February 2021. Candidates were categorized as primary liver transplant if they had not undergone previous abdominal surgery prior to listing and salvage liver transplant if they had. Salvage transplants were further categorized as early failure if listed within the first year of life or late failure if listed at an older age. RESULTS: 3438 children with biliary atresia were listed for transplant during the study period, with 15% of them listed for a primary transplant, 17% for salvage transplant after early failure, and 67% after late failure. Recipients of salvage liver transplant with late failure had lower bilirubin levels and were less critically ill as demonstrated by MELD/PELD scores and hospitalization status. Correspondingly, these recipients had higher waiting list and graft survival, though this did not remain statistically significant after adjustment in multivariable models. There were no differences in waiting list, recipient, or graft survival with primary vs. salvage liver transplant after early failure. CONCLUSION: Kasai hepatoportoenterostomy should remain the standard of care in biliary atresia as it may delay need for transplant beyond the first year of life in a subset of recipients and does not jeopardize subsequent transplant outcomes, even with early failure. LEVELS OF EVIDENCE: Retrospective cohort study (Level III).

Malnutrition in Biliary Atresia: Assessment, Management, and Outcomes.

Children with biliary atresia (BA), particularly infants, are at high risk for malnutrition attributed to a multitude of factors, including poor oral intake and intolerance of enteral feeding, fat malabsorption, abnormal nutrient metabolism, and increased caloric demand. Malnutrition and sarcopenia negatively impact outcomes in BA, leading to higher pretransplant and posttransplant morbidity and mortality. This review summarizes factors contributing to nutritional deficiencies in BA and offers an organized approach to the assessment and management of malnutrition in this vulnerable population.