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.

Severe early-onset Wilson disease caused by a common pathogenic variant in the Bukharan Jewish population in Israel.

BACKGROUND: Wilson disease is caused by pathogenic variants in the ATP7B gene which encodes a copper-transporting ATPase. AIMS: Describe a common founder pathogenic variant among Bukharan Jews and to assess its prevalence, clinical features, and outcome. METHODS: The cohort consisted of patients of Bukharan Jewish descent diagnosed with Wilson disease at a tertiary pediatric medical center in 2013-2018. Clinical and genetic data were collected and analyzed. RESULTS: Six patients from 4 unrelated families who were homozygous for the c.3784G > T p.(Val1262Phe) pathogenic variant in ATP7B were identified. Five presented with elevated aminotransferase levels, and one, with acute liver failure. Mean age at diagnosis was 8.7 years (5-12.5). Serum ceruloplasmin level was extremely low in all patients (1.9-7 mg/dL; mean 3.2(. The variant was identified in a heterozygous state in 5/153 Bukharan Jews; 2/33 from our local exome database and 3/120 healthy unrelated Bukharan Jews in another cohort, for an estimated carrier frequency of ∼1:30. CONCLUSIONS: We report a common founder pathogenic variant in the ATP7B gene among Bukharan Jews associated with severe early-onset Wilson disease. Given the clinical severity, high frequency of the variant, and being a treatable disease, its inclusion in pre-symptomatic screening in the Bukharan Jewish community should be considered. Furthermore, WD should be part of future genetic newborn screening programs in Israel and worldwide, to enable early treatment and prevention of future life-threatening complications.

Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy.

AIM: Implementing genetic analyses have unraveled rare alterations causing early-onset obesity and complications, in whom treatment is challenging. We aimed to report on the effects of adjuvant off-label therapy with liraglutide, glucagon-like peptide-1 analogue (GLP-1a), in rare genetic diagnoses. METHODS: Case scenarios and review of the literature. RESULTS: Case 1: Nine-year-old boy with early-onset severe obesity and nonalcoholic fatty liver disease (NAFLD) due to a homozygous mutation in the MC4R gene deteriorated under lifestyle change and metformin therapy [at 10.5 years: body mass index (BMI) 51.2kg/m2, 226% of the 95th percentile, fat percentage (FP) 65% and muscle-to-fat ratio (MFR) z-score of -2.41]. One year of liraglutide treatment halted progressive weight gain [BMI 50.3kg/m2, 212% of the 95th percentile, 63.7% FP and MFR z-score of -2.34], with biochemical improvement. Case 2: Twelve-year-old boy with obesity presented with diabetes and progressive NAFLD. Exome analysis revealed two heterozygous mutations compatible with monogenic diabetes (HNF1A) and familial hypercholesterolemia (LDLR). Lifestyle modifications resulted in clinical and laboratory improvement (BMI 87th percentile, 32.8% FP, MFR z-score of -1.63, HbA1c 5.5%) without the expected recovery in liver transaminases. Liraglutide treatment augmented the improvement in weight status (BMI 68th percentile, 22.6% FP, MFR z-score of -1.13) with normalization of liver transaminases. Case 3: Nineteen-year-old male with spinal muscular atrophy type 3 presented with sarcopenic obesity and comorbidities. Treatment strategy included dietary counseling and multiple drug therapies (metformin, anti-hypertensive and statins). Liraglutide therapy led to a gradual recovery of metabolic complications allowing tapering-down other medications. CONCLUSIONS: Considering the pleiotropic effects of GLP1-a beyond BMI reduction, this treatment modality may serve as a game changer in challenging cases.

Bacterial resistance to commonly prescribed antibiotics was rare among children hospitalised for clinical dysentery.

AIM: Temporal changes in common pathogens that cause clinical dysentery have been described in Europe. We aimed to describe the distribution of pathogens and their antibiotic resistance in hospitalised Israeli children. METHODS: This study retrospectively studied children hospitalised for clinical dysentery, with or without a positive stool culture, from 1 January 2016 to 31 December 2019. RESULTS: We diagnosed 137 patients (65% males), with clinical dysentery at a median age of 3.7 (interquartile range 1.5-8.2) years. Stools were cultured in 135 patients (99%), and the results were positive in 101 (76%). These comprised Campylobacter (44%), Shigella sonnei (27%), non-typhoid Salmonella (18%) and enteropathogenic Escherichia coli (12%). Only one of the 44 Campylobacter cultures was resistant to erythromycin and one of the 12 enteropathogenic Escherichia coli cultures was resistant to ceftriaxone. None of the Salmonella and Shigella cultures were resistant to ceftriaxone or erythromycin. We did not find any pathogens that were associated with a typical clinical presentation or laboratory results on admission. CONCLUSION: The most common pathogen was Campylobacter, in line with recent European trends. Bacterial resistance for commonly prescribed antibiotics was rare, and these findings support the current European recommendations.

The Yield of Routine Tissue Sampling in Pediatric Gastrointestinal Endoscopy.

OBJECTIVES: Societies' guidelines suggest routine tissue sampling in all children undergoing esophagogastroduodenoscopy and ileocolonoscopy, even in the absence of visible endoscopy abnormalities. We aimed to determine the agreement between endoscopic and histopathological findings in pediatric endoscopy and to assess the yield of routine biopsies from all sites. METHODS: Since January 2019, our endoscopy institute protocol has included routine biopsies sampling from the esophagus, stomach, duodenum, ileum, and colon in all diagnostic procedures. Agreement between tests was done using the kappa coefficient ( κ ). The study included all endoscopies performed during 2019. RESULTS: In total, 541 diagnostic endoscopies were done during the study period with 434 (80%) esophagogastroduodenoscopy and 107 (20%) were ileocolonoscopy. Compared to histology, endoscopic findings performance were: esophagus-sensitivity 33%, specificity 98%; stomach-sensitivity 60%, specificity 89%; duodenum-sensitivity 50%, specificity 97%; duodenal bulb-sensitivity 47%, specificity 89%; terminal ileum-sensitivity 82%, specificity 100%; colon-sensitivity 84%, specificity 96%. Assessment of concordance between endoscopic and histopathologic findings reveals an overall low level of agreement in esophagogastroduodenoscopy ( κ of 0.39, 0.51, 0.53, and 0.24 for the esophagus, stomach, duodenal second part, and bulb, respectively), and good agreement in ileocolonoscopy ( κ of 0.88 and 0.81 for the ileum and colon, respectively). CONCLUSIONS: Endoscopy findings are highly specific for histologic pathology, whereas the absence of findings correlates poorly with histologic findings. Ileocolonoscopy shows better agreement than esophagogastroduodenoscopy. Our data support routine tissue sampling in pediatric endoscopy.

Elevated liver enzymes of newly diagnosed pediatric celiac patients-a prospective-observational study.

Celiac disease clinical presentation is constantly changing. We set to determine the prevalence of elevated transaminases in newly diagnosed celiac patients and to evaluate this sub-group of patients for associated clinical and laboratory findings and assess their natural course of disease following therapeutic diet initiation. We conducted a prospective-observational study of all newly diagnosed pediatric celiac patients, between August 2016 and April 2018, in a pediatric gastroenterology clinic. Clinical data, anthropometrics, and blood test results were recorded at diagnosis and at 3, 6, and 12 months, respectively, of follow-up. We compared patients with normal and elevated transaminases at diagnosis. ALT threshold was set at 24 U/l. Of 125 newly diagnosed celiac patients, 31 (24.8%) had elevated ALT at diagnosis; two (1.6%) with over 3 × ULN. Patients with elevated ALT at diagnosis were significantly younger (mean age 5.5 (SD 3.4) vs. 7.3 (SD 3.7) years, p < 0.01) and more commonly presented with diarrhea (32.3% vs. 14.9%, p = 0.03). Eighty percent of patients with elevated ALT levels normalized their ALT within 3 months and all within 1 year. Following gluten-free diet initiation, patients with elevated ALT had similar clinical course, growth, serology normalization rate, and laboratory results, compared to patients with normal ALT over a 1-year follow-up. A single patient was simultaneously co-diagnosed with celiac disease and autoimmune hepatitis.Conclusion: Clinically significant ALT abnormalities are rare among newly diagnosed pediatric celiac patients. Significant elevations failing to normalize on a gluten-free diet should raise concern of a concomitant primary liver disease and warrant further investigations. What is Known: • Elevated liver enzymes may be an extra-intestinal manifestation of celiac disease. • Reported prevalences of ALT elevations among children with a new diagnosis of celiac disease ranges between 5 and 40%. What is New: • ALT elevations are present in 25% of children with a new diagnosis of celiac disease. • Significant elevations (>3 × ULN) are rare (1.6%). • Elevated liver enzymes are associated with earlier age at diagnosis. • The natural history of patients with elevated liver enzymes at diagnosis is comparable to those without.

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.

PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. METHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. RESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. CONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.

Colorectal Dysplasia and Cancer in Pediatric-Onset Ulcerative Colitis Associated With Primary Sclerosing Cholangitis.

Inflammatory bowel disease (IBD), especially when associated with primary sclerosing cholangitis (PSC), is a risk factor for developing colorectal cancer (CRC).1-3 We aimed to determine the incidence of CRC in a large cohort of pediatric-onset PSC-ulcerative colitis (UC) patients.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis.

BACKGROUND AND AIMS: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

BACKGROUND: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

Young Age Predicts Acute Pancreatitis Severity in Children.

OBJECTIVES: The course and evolution of pediatric acute pancreatitis (AP) is poorly understood. Prognostication models in children perform poorly and lack consensus. We aimed to identify predictors of AP severity, and the risk for AP recurrence. METHODS: We retrospectively studied all patients hospitalized with AP at a single tertiary center, between January 1995 and June 2016. Patient demographics and admission laboratory data were assessed for severity and recurrence prediction. RESULTS: A total of 68 patients accounting for a total of 117 (15 moderate-severe) AP episodes were reviewed. Patients with moderate-severe disease were significantly younger (median [interquartile range (IQR)] of 8.3 [4.0-14.4] vs 13.8 [8.1-16.0] years, P = 0.02). Young age at presentation was associated with odds ratio of 3.8 (confidence interval [CI] 1.2-12.1) for children younger than 12 years and 5.8 (CI 1.6-21.4) for children younger than 6 years for developing moderate-severe disease.Further subanalysis of the 59 patients with first-time AP episodes, demonstrated younger age (median [IQR] of 5.3 [2.9-10.4] vs 12.0 [6.3-15.8] years, P = 0.03) and elevated white blood cell count (median [IQR] of 22.8 [11.8-31.3] vs 11.0 [8.1-14.6] 10/L, P < 0.01) of patients with moderate-severe disease, conferring a risk for moderate-severe disease with odds ratio of 7.5 (CI 1.5-38.2) for children younger than 6 years and 5.3 (CI 1.1-25.4) for patients with white blood cell count >15 × 10/L, respectively. Fourteen (23.7%) of 59 patients with first-time episodes had recurrent AP. Analysis of the data at the primary episode failed to identify predictors to indicate future recurrence. CONCLUSIONS: In our cohort, only young age (<12 years) predicted AP severity. No parameters were identified to predict future development of AP recurrence.

De Novo Allergy and Immune-Mediated Disorders Following Solid-Organ Transplantation-Prevalence, Natural History, and Risk Factors.

OBJECTIVES: To describe the prevalence, natural course, outcome, and risk factors of post-transplant de novo allergy and autoimmunity. STUDY DESIGN: A cross-sectional, cohort study of all children (<18 years) who underwent a solid-organ transplantation, between 2000 and 2012, in a single transplant center, with a follow-up period of 6 months or more post-transplant and without history of allergy or immune-mediated disorder pretransplant. RESULTS: A total of 626 eligible patients were screened, and 273 patients (160 males; 59%) met the inclusion criteria; this included 111 liver, 103 heart, 52 kidney, and 7 multivisceral recipients. Patients were followed for a median period of 3.6 years. A total of 92 (34%) patients (42 males, 46%) developed allergy or autoimmune disease after transplantation, with a high prevalence among liver (41%), heart (40%), and multivisceral (57%) transplant recipients compared with kidney recipients (4%; P < .001). Post-transplant allergies included eczema (n = 44), food allergy (22), eosinophilic gastrointestinal disease (11), and asthma (28). Autoimmunity occurred in 18 (6.6%) patients, presenting mainly as autoimmune cytopenia (n = 10). In a multivariate analysis, female sex, young age at transplantation, family history of allergy, Epstein-Barr virus infection, and elevated eosinophil count >6 months post-transplantation were associated with an increased risk for allergy or autoimmunity. Two patients (0.7%) died from autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis, and 52 episodes of post-transplant allergy, autoimmunity, and immune-mediated disorders (37%) did not improve over time. CONCLUSIONS: Allergy and autoimmunity are common in pediatric liver, heart, and multivisceral transplant recipients and pose a significant health burden. Further studies are required to clarify the mechanisms behind this post-transplant immune dysregulation.

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518-527).

Hepatoblastoma in Explanted Livers of Patients With Biliary Atresia.

OBJECTIVES: Surveillance of hepatic nodules for malignant transformation to hepatocellular carcinoma is important in the monitoring of patients with biliary atresia (BA). To date, only 2 published case reports describe the finding of hepatoblastoma (HB) in this setting. The present study aimed to investigate this association of HB and BA, and to assess the utility of alpha-fetoprotein (aFP) as a marker in the diagnosis. METHODS: A retrospective study of all patients who underwent isolated liver transplantation (LTx) for the primary diagnosis of BA at a single center, between January 1999 and June 2014, was conducted. Patient demographics, pre-LTx aFP levels, and histologic examination of native liver explants were reviewed. RESULTS: One hundred two (44% men, median age 11 months) patients underwent LTx for BA. Two (2%) explants examinations were confirmatory for concomitant HB; both patients had abnormally elevated aFP. Overall, 56 (55%) patients had available pre-LTx aFP levels. Recipients with persistently abnormal aFP levels (n = 20, 36%) were older at hepatoportoenterostomy (107 vs 68 days, P = 0.02) and younger at LTx surgery (359 vs 1713 days, P < 0.01), compared to patients with constantly normal levels (n = 24, 43%). CONCLUSIONS: In our cohort, HB was found to coexist in approximately 2% of patients with BA undergoing LTx, far exceeding the hypothetical anticipated incidence of 1:10 billion for the concomitant diagnoses. Elevated serum aFP levels may be sensitive but not specific for HB in this context. Further research is required to identify specific mechanisms and risk factors.

Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD.

The regulatory T cell effector molecule fibrinogen-like protein 2 is necessary for the development of rapamycin-induced tolerance to fully MHC-mismatched murine cardiac allografts.

Therapies that promote tolerance in solid organ transplantation will improve patient outcomes by eliminating the need for long-term immunosuppression. To investigate mechanisms of rapamycin-induced tolerance, C3H/HeJ mice were heterotopically transplanted with MHC-mismatched hearts from BALB/cJ mice and were monitored for rejection after a short course of rapamycin treatment. Mice that had received rapamycin developed tolerance with indefinite graft survival, whereas untreated mice all rejected their grafts within 9 days. In vitro, splenic mononuclear cells from tolerant mice maintained primary CD4(+) and CD8(+) immune responses to donor antigens consistent with a mechanism that involves active suppression of immune responses. Furthermore, infection with lymphocytic choriomeningitis virus strain WE led to loss of tolerance suggesting that tolerance could be overcome by infection. Rapamycin-induced, donor-specific tolerance was associated with an expansion of regulatory T (Treg) cells in both the spleen and allograft and elevated plasma levels of fibrinogen-like protein 2 (FGL2). Depletion of Treg cells with anti-CD25 (PC61) and treatment with anti-FGL2 antibody both prevented tolerance induction. Tolerant allografts were populated with Treg cells that co-expressed FGL2 and FoxP3, whereas rejecting allografts and syngeneic grafts were nearly devoid of dual-staining cells. We examined the utility of an immunoregulatory gene panel to discriminate between tolerance and rejection. We observed that Treg-associated genes (foxp3, lag3, tgf-ß and fgl2) had increased expression and pro-inflammatory genes (ifn-γ and gzmb) had decreased expression in tolerant compared with rejecting allografts. Taken together, these data strongly suggest that Treg cells expressing FGL2 mediate rapamycin-induced tolerance. Furthermore, a gene biomarker panel that includes fgl2 can distinguish between rejecting and tolerant grafts.