Search

Aim: This study aimed to investigate the outcomes and effectiveness of various treatment strategies in patients with hepatic artery stenosis (HAS) after pediatric liver transplantation (pLT)., Methods: This is a single center observational cohort study between January 1st, 2004 and August 1st, 2023, including pLT recipients aged <18 years. The primary outcome was graft and patient survival. The secondary outcomes included incidence of biliary complications, technical success of surgery or endovascular therapy (EVT), and changes in liver function. The cut-off for early and late HAS was 14 days after pLT., Results: Among a total of 327 pLT patients, 4 % (n = 13) developed HAS (n = 3 early; n = 10 late). Treatments included surgical revascularization for one early HAS, conservative management with anticoagulation for one early and four late HAS, and EVT for one early and six late HAS. Over a median follow-up of 28.2 months after the diagnosis of HAS, graft survival was 100 % and 83 % in early and late HAS groups, and patient survival reached 100 % in both groups. One graft loss occurred in the conservative group. Conversely, graft survival in the EVT group was 100 %., Conclusion: The long-term outcomes of HAS after pLT are excellent. Both EVT and conservative management exhibited high graft survival rates for late HAS, with EVT achieving high technical success., Competing Interests: Conflict of interest All authors declare no conflicts of interest or industry support of the article entitled: ‘Hepatic artery stenosis after pediatric liver transplantation: the potential role of conservative management’., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications., Methods and Analysis: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC., Ethics and Dissemination: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals., Trial Registration Number: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to evaluate the effectiveness of different treatments for hepatic artery thrombosis (HAT) and hepatic artery stenosis (HAS) after pediatric liver transplantation. We systematically reviewed studies published since 2000 that investigated the management of HAT and/or HAS after pediatric liver transplantation. Studies with a minimum of 5 patients in one of the treatment methods were included. The primary outcomes were technical success rate and graft and patient survival. The secondary outcomes were hepatic artery patency, complications, and incidence of HAT and HAS. Of 3570 studies, we included 19 studies with 328 patients. The incidence was 6.2% for HAT and 4.1% for HAS. Patients with an early HAT treated with surgical revascularization had a median graft survival of 45.7% (interquartile range, 30.7%-60%) and a patient survival of 61.3% (interquartile range, 58.7%-66.9%) compared with the other treatments (conservative, endovascular revascularization, or retransplantation). As for HAS, endovascular and surgical revascularization groups had a patient survival of 85.7% and 100% (interquartile range, 85%-100%), respectively. Despite various treatment methods, HAT after pediatric liver transplantation remains a significant issue that has profound effects on the patient and graft survival. Current evidence is insufficient to determine the most effective treatment for preventing graft failure., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Children frequently undergo routine Doppler-ultrasound (DUS) after liver transplantation (LT) for which they are fasted, but this may cause hunger and discomfort., Objective: To determine if DUS measurements, with focus on the portal vein (PV), are affected by prandial changes, and if this affects distress and feasibility of the DUS., Materials and Methods: Children were prospectively included to undergo a pre- and postprandial DUS on the same day at 6 months after LT. Pre- and anastomotic PV peak systolic velocity (PSV), and hepatic artery and hepatic vein DUS measurements were obtained. Pre- and postprandial measurements, and relative postprandial change of PV velocity ratio (VR) compared to PV anastomotic PSV, were compared using paired-sample t-tests and intraclass correlation coefficients (ICC). Obscuration by bowel gas, difficulty of DUS, and impact of fasting were assessed using 5-point rating scales., Results: Twenty-eight children (median age 3.5 years, IQR 1.6-10.8) were included; four were subsequently excluded because they were not fasted (N = 2) or withdrew consent for the second DUS (N = 2). Measurements between pre- and postprandial DUS, and relative postprandial change of VR compared to PV anastomotic PSV, were not significantly different (p > .05). Test consistency was good (ICC = 0.69, 95% CI = 0.29-0.67) for PV anastomotic PSV, and excellent (95% CI = 0.61-0.93) for PV VR. Obscuration by bowel gas or ease of DUS did not change after eating (p > .05). The majority (16/28, 57.2%) found fasting difficult, and several (13/28, 46.4%) got upset when fasted., Conclusion: Children with an LT do not need to be fasted for routine DUS, which may decrease the burden of the examination., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Objectives: Doppler ultrasound (DUS) is the main imaging modality to evaluate vascular complications of pediatric liver transplants (LT). The current study aimed to determine reference values and their change over time., Methods: A consecutive cohort of pediatric patients undergoing an LT were retrospectively included between 2015 and 2020. Timepoints for standardized DUS were intra-operative and postoperative (day 0), days 1-7, months 1 and 3, and years 1 and 2. DUS measurements of the hepatic artery (HA), portal vein (PV), and hepatic vein(s) (HV) were included if there were no complications during 2 years follow-up. Measurements consisted of: peak systolic velocity (PSV) and resistive index (RI) for the HA, PSV for the PV, and venous pulsatility index (VPI) for the HV. Generalized estimating equations were used to analyze change over time., Results: One hundred twelve pediatric patients with 123 LTs were included (median age 3.3 years, interquartile range 0.7-10.1). Ninety-five HAs, 100 PVs, and 115 HVs without complications were included. Reference values for HA PSV and RI, PV PSV, and HV VPI were obtained for all timepoints (4043 included data points in total) and presented using 5 th -95 th percentiles and threshold values. All reference values changed significantly over time (p = 0.032 to p < 0.001)., Conclusions: DUS reference values of hepatic vessels in children after LT are presented, reference values change over time with specific vessel-dependent patterns. Timepoint-specific reference values improve the interpretation of DUS values and may help to better weigh their clinical significance., Key Points: • Doppler ultrasound reference values of pediatric liver transplantations are not static but change over time. Applying the correct reference values for the specific timepoint may further improve the interpretation of the measurements. • The pattern of change over time of Doppler ultrasound measurements differs between the hepatic vessel and measurement; knowledge of these patterns may help radiologists to better understand normal postoperative hemodynamic changes., (© 2023. The Author(s).)

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis., Competing Interests: VM consults for Mirum Pharmaceuticals, Albireo, and AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Albada, Shah, Derks, Fuchs, Jans, McLin and van der Doef.)

Introduction: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO., Methods and Analysis: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques., Ethics and Dissemination: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences., Trial Registration Number: Netherlands Trial Register (NL9261)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with severe acute low iliofemoral deep vein thrombosis (DVT), such as phlegmasia cerulea dolens, benefit from catheter-directed thrombolysis (CDT). This meta-analysis investigated the effectiveness and safety of adjuvant percutaneous mechanical thrombectomy (PMT) during CDT compared with CDT alone in the treatment of acute iliofemoral DVT., Methods: A meta-analysis was performed in accordance with the PRISMA guidelines. Medline, Embase, the Cochrane Library, China National Knowledge Internet, and Wanfang data were searched for studies on the management of acute iliofemoral DVT by means of CDT or CDT with adjuvant PMT. Randomized, controlled trials and nonrandomized studies were included. The primary outcomes were venous patency rate, major bleeding complications, and post-thrombotic syndrome occurrence within 2 years of the procedure. The secondary outcomes were thrombolytic time and volume, as well as the rates of thigh detumescence and iliac vein stenting., Results: The meta-analysis included 20 eligible studies with a total of 1686 patients. The rates of venous patency (mean difference, 10.11; 95% confidence interval [CI], 5.59-14.62) and thigh detumescence (mean difference, 3.64; 95% CI, 1.10-6.18) of the adjuvant PMT group were higher than those of the CDT alone group. Compared with CDT alone, the adjuvant PMT group experienced fewer incidences of major bleeding complications (odds ratio, 0.45; 95% CI, 0.26-0.77) and occurrences of post-thrombotic syndrome within 2 years of the procedure (odds ratio, 0.55; 95% CI, 0.33-0.92). Furthermore, the duration of thrombolytic therapy was shorter, and the total dose of administered thrombolytics was lower with adjuvant PMT., Conclusions: Adjuvant PMT during CDT is associated with improved clinical outcomes and a lower incidence of major bleeding complications. The studies investigated were, however, single-center cohort studies, and future randomized controlled trials are needed to substantiate these findings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST ( p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization ( p = 0.001), whereas LDLT increased from 55% to 74% ( p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST ( p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose Doppler ultrasound (DUS) is widely used to detect vascular complications after pediatric liver transplantation (LT). This study aimed to assess the moment of first detection of vascular complications with DUS, and to determine the positive predictive value (PPV) of DUS. Materials and Methods Patients aged 0-18 years who underwent LT between 2015 and 2019 were retrospectively included. 92 LTs in 83 patients were included (median age: 3.9 years, interquartile range: 0.7-10.5). Patients underwent perioperative (intra-operative and immediately postoperative) and daily DUS surveillance during the first postoperative week, and at 1, 3, and 12 months. Vascular complications were categorized for the hepatic artery, portal vein, and hepatic veins. DUS findings were compared to surgical or radiological findings during the 1-year follow-up. Results 52 vascular complications were diagnosed by DUS in 35/92 LTs (38%). 15 out of 52 (28.8%) were diagnosed perioperatively, 29/52 (55.8%) were diagnosed on postoperative days 1-7, and 8/52 (15.4%) after day 7. The PPV for all vascular complications diagnosed with DUS was 92.3%. During the 1-year follow-up, 18/19 (94.7%) hepatic artery complications, 19/26 (73.1%) portal vein complications, and 7/7 (100%) hepatic vein complications were diagnosed perioperatively or during the first week. Conclusion The majority of vascular complications during the first year after pediatric LT were diagnosed by DUS perioperatively or during the first week, with a high PPV. Our findings provide important information regarding when to expect different types of vascular complications on DUS, which might improve DUS post-LT surveillance protocols., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Inborn errors of metabolism (IEMs) comprise a diverse group of individually rare monogenic disorders that affect metabolic pathways. Mutations lead to enzymatic deficiency or dysfunction, which results in intermediate metabolite accumulation or deficit leading to disease phenotypes. Currently, treatment options for many IEMs are insufficient. Rarity of individual IEMs hampers therapy development and phenotypic and genetic heterogeneity suggest beneficial effects of personalized approaches. Recently, cultures of patient-own liver-derived intrahepatic cholangiocyte organoids (ICOs) have been established. Since most metabolic genes are expressed in the liver, patient-derived ICOs represent exciting possibilities for in vitro modeling and personalized drug testing for IEMs. However, the exact application range of ICOs remains unclear. To address this, we examined which metabolic pathways can be studied with ICOs and what the potential and limitations of patient-derived ICOs are to model metabolic functions. We present functional assays in patient ICOs with defects in branched-chain amino acid metabolism (methylmalonic acidemia), copper metabolism (Wilson disease), and transporter defects (cystic fibrosis). We discuss the broad range of functional assays that can be applied to ICOs, but also address the limitations of these patient-specific cell models. In doing so, we aim to guide the selection of the appropriate cell model for studies of a specific disease or metabolic process., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Prime editing is a versatile genome-editing technique that shows great promise for the generation and repair of patient mutations. However, some genomic sites are difficult to edit and optimal design of prime-editing tools remains elusive. Here we present a fluorescent prime editing and enrichment reporter (fluoPEER), which can be tailored to any genomic target site. This system rapidly and faithfully ranks the efficiency of prime edit guide RNAs (pegRNAs) combined with any prime editor variant. We apply fluoPEER to instruct correction of pathogenic variants in patient cells and find that plasmid editing enriches for genomic editing up to 3-fold compared to conventional enrichment strategies. DNA repair and cell cycle-related genes are enriched in the transcriptome of edited cells. Stalling cells in the G1/S boundary increases prime editing efficiency up to 30%. Together, our results show that fluoPEER can be employed for rapid and efficient correction of patient cells, selection of gene-edited cells, and elucidation of cellular mechanisms needed for successful prime editing., (© 2022. The Author(s).)

Computed tomography (CT)-derived body metrics such as skeletal muscle index (SMI), psoas muscle index (PMI), and subcutaneous fat area index (ScFI) are measurable components of sarcopenia, frailty, and nutrition. While these body metrics are advocated in adults for predicting postoperative outcomes after liver transplantation (LT), little is known about their value in pediatric populations. This study assessed the relation between preoperative CT-based body metrics and postoperative short-term outcomes in pediatric LT recipients. Patients aged 0-18 years who underwent a primary LT were retrospectively included (n = 101; median age 0.5 years; range 0.2-17.1). SMI, PMI, and ScFI were derived from preoperative axial CT slices. Postoperative outcomes and complications within 90 days were correlated with the CT-based body metrics. To classify postoperative infections, the Clavien-Dindo (CD) classification was used. Subgroup analyses were performed for age groups (<1, 1-10, and >10 years old). An optimal threshold for test performance was defined using Youden's J-statistic and receiver operating characteristic curve as appropriate. ScFI was significantly (P = 0.001) correlated with moderate to severe postoperative infections (CD grade 3-5) in children aged <1 year, with the optimal ScFI threshold being ≤27.1 cm 2 /m 2 (sensitivity 80.4% and specificity 77.8%). A weak negative correlation between SMI and the total duration of hospital stay (R = -0.3; P = 0.01) and intensive care unit (ICU) stay (R = -0.3; P = 0.01) was observed in children aged <1 year. No other associations between CT-based body metrics and postoperative outcomes were shown. In children aged <1 year with cirrhotic liver disease undergoing LT, preoperative CT-based body metrics were correlated with moderate to severe postoperative infections (ScFI) and with longer duration of hospital and ICU stay (SMI), and thus can be considered important tools for pre-LT risk assessment., (Copyright © 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Introduction: Portal vein obstruction (PVO) is a significant vascular complication after liver transplantation (LT) in pediatric patients. Current treatment strategies include percutaneous transluminal angioplasty (PTA), with or without stent placement, mesorex bypass (MRB), splenorenal shunt, mesocaval shunt, endovascular recanalization (EVR), splenic artery embolization and splenectomy. However, specific characteristics of patients undergoing intervention and selection of individual treatment and its efficacy have remained unclear. This review systematically analyzed biochemical and clinical characteristics, selection of treatment, efficacy, and post-procedural complications., Methods: We systematically searched PubMed and Embase between January 1995 and March 2021 for studies on the management of PVO after LT. We analyzed the reports for biochemical and clinical characteristics at the timing of the intervention in different patients, selection of treatment, and reported efficacies., Results: We found 22 cohort studies with 362 patients who had the following characteristics: biliary atresia (83%), living-donor LT (85%), thrombocytopenia (73%), splenomegaly (40%), ascites (16%), or gastrointestinal bleeding (26%). The 3-year primary patency of PTA without stent placement was similar to that with stent placement (70%-80% and 43%-94%, respectively). MRB was used as an initial treatment with a 3-year patency of 75% to 100%. One study showed that 5-year primary patency of EVR was 80%. Secondary patency was 90% to 100% after 3 years in all studies with PTA alone, PTA/stent placement, and stent placement alone., Conclusion: This is the first review of all treatment protocols in PVO after pediatric LT. We showed that an important group of patients has severe symptoms of portal hypertension. Efficacy of all treatment modalities was high in the included studies which make them important modalities for these patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During LT screening, children undergo CTA to determine hepatic artery anatomy. However, CTA imparts radiation, unlike MRA. The aim was to compare MRA to CTA in assessing hepatic artery anatomy in pediatric LT recipients. Twenty-one children (median age 8.9 years) who underwent both CTA and fl3D-ce MRA before LT were retrospectively included. Interreader variability between 2 radiologists, image quality, movement artifacts, and confidence scores, were used to compare MRA to CTA. Subgroup analyses for ages <6 years and ≥6 years were performed. Interreader variability for MRA and CTA in children <6 years was comparable (k = 0.839 and k = 0.757, respectively), while in children ≥6 years CTA was superior to MRA (k 1.000 and k 0.000, respectively). Overall image quality and confidence scores of CTA were significantly higher compared to MRA at all ages (2.8/3 vs. 2.3/3, p = .001; and 2.9/3 vs. 2.5/3, p = .003, respectively). Movement artifacts were significantly lower in CTA compared to MRA in children ≥6 years (1.0/3 vs. 1.7/3, p = .010, respectively). CTA is preferred over fl3D-ce MRA for the preoperative assessment of hepatic artery anatomy in children receiving LT, both at ages <6 years and ≥6 years., (© 2021 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.

Prime editing is a recent genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority of genetic defects. Here, we develop prime editing for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions in the gene encoding β-catenin (CTNNB1) that result in proliferation independent of Wnt-stimuli, mimicking a mechanism of the development of liver cancer. Moreover, prime editing functionally recovers disease-causing mutations in intestinal organoids from patients with DGAT1-deficiency and liver organoids from a patient with Wilson disease (ATP7B). Prime editing is as efficient in 3D grown organoids as in 2D grown cell lines and offers greater precision than Cas9-mediated homology directed repair (HDR). Base editing remains more reliable than prime editing but is restricted to a subgroup of pathogenic mutations. Whole-genome sequencing of four prime-edited clonal organoid lines reveals absence of genome-wide off-target effects underscoring therapeutic potential of this versatile and precise gene editing strategy.

Objectives: Treatment targets in inflammatory bowel disease (IBD) move away from controlling symptoms towards complete recovery of the intestinal mucosa. Currently, the most frequently used noninvasive surrogate marker of mucosal healing is a faecal calprotectin concentration in the target range. This study tested if there was a relation between time-to-reach target calprotectin and first flare., Methods: We prospectively included new-onset IBD patients ages 17 and younger in a cloud-based registry (FastForwardCare) and followed them for at least 52 weeks. They were treated according to Dutch national guidelines that advocate a step-up approach. Time-to-reach target was defined as the first calprotectin measurement below 250 μg/g after the start of induction therapy. Time-to-first flare was the time from the first calprotectin measurement below 250 μg/g until reappearance of symptoms with calprotectin values above 250 μg/g., Results: We included 76 patients (luminal Crohn disease [CD] 43); ulcerative colitis [UC] 33). Median age at diagnosis was, respectively 14.5 and 14.1 years. Median time-to-reach target calprotectin was 37 weeks in CD and 11 weeks in UC patients (Log-rank test, P = 0.001). Once the calprotectin target was reached, time-to-first flare was significantly longer in CD than in UC patients (Log-rank test, P = 0.001). CD patients with time-to-reach target calprotectin ≤12 weeks after conventional induction therapy (ie, exclusive enteral nutrition or steroids) had a more favorable disease course in the first year than those with time-to-reach target calprotectin >12 weeks (Log-rank test, P = 0.057). In UC patients, time-to-reach target calprotectin ≤12 weeks is not associated with a favorable disease course in the first year., Conclusions: The findings of this prospective registry suggest that a quick response to conventional therapy predicts a favorable disease course in new-onset paediatric CD, but not in UC. The concept "time-to-reach target calprotectin level" rationalizes the indefinite term "response to treatment" and is well suited for studying treatment effectiveness in real-world practices.

Secondary protein-losing enteropathy (PLE) is a rare complication following pediatric liver transplantation (LT), mostly related to venous outflow obstruction of the liver. Here, we discuss a thus far unknown cause of secondary PLE following pediatric LT. A 7-month-old boy underwent LT with biliary anastomosis using a Roux-en-Y jejunal loop. Eleven months later he developed PLE. Routine diagnostic workup was negative. No hepatic outflow obstruction was detected during catheterization. Although the hepatic venous pressure gradient was slightly increased (10 mm Hg), there were no clinical signs of portal hypertension. Albumin scintigraphy with specific early recordings suggested focal albumin intestinal entry in the jejunal Roux-en-Y loop. Local bacterial overgrowth or local lymphangiectasia, possibly due to (venous) congestion, was considered. Treatment with metronidazole did not improve albumin loss. Next, surgical revision of the jejunal Roux-en-Y loop was performed. The explanted loop contained a small abnormal area with a thin hyperemic mucosa, near the former anastomosis. Histopathological analysis showed changes both in the blood vessels and the lymphatic vessels with focal deeper chronic active inflammation resulting in congestion of vessels, hampering lymphatic outflow leading to lymphangiectasia and patchy distortion of lymphatic vessels. Following surgical revision, secondary PLE disappeared, up to now, 1.5 year post revision., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background & Aims: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids., Methods: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7., Results: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids., Conclusions: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Serious and fatal complications after button battery ingestion are increasing worldwide. The aim of this study is to describe serious complications after battery ingestion in children in the Netherlands.All pediatric gastroenterologists in the Netherlands performing upper endoscopies were asked to report all serious complications after battery ingestion in children (0-18 years) between 2008 and 2016 retrospectively.Sixteen serious complications were reported: death after massive bleeding through esophageal-aortal fistula (n = 1), esophageal-tracheal fistula (n = 5), stenosis after (suspected) perforation and mediastinitis (n = 5), (suspected) perforation and mediastinitis (n = 3), vocal cord paralysis (n = 1), and required reintubation for dyspnea and stridor (n = 1). The median time interval between ingestion and presentation was 5 (IQR 2-258) h. All children were ≤ 5 (median 1.4; IQR 0.9-2.1) years. Vomiting (31.3%), swallowing/feeding problems (31.3%), and fever (31.3%) were the most common presenting symptoms; however, 18.8% of the patients were asymptomatic (n = 1 missing). All batteries were button batteries (75% ≥ 20 mm; 18.8% < 20 mm; n = 1 missing). The batteries were removed by esophagogastroduodenoscopy (50%) and rigid endoscopy (37.5%) or surgically (12.5%)., Conclusion: Sixteen serious complications occurred after small and large button batteries ingestion between 2008 and 2016 in both symptomatic and asymptomatic children in the Netherlands. Therefore, immediate intervention after (suspected) button battery ingestion is required. What is Known: • Button battery ingestion may result in serious and fatal complications. • Serious and fatal complications after button battery ingestion are increasing worldwide. What is New: • Sixteen serious complications after button battery ingestion occurred during 2008-2016 in children in the Netherlands. • Serious complications were also caused by small batteries (< 20 mm) in the Netherlands and also occurred in asymptomatic Dutch children.

Liver transplantation (LT) is the standard treatment for biliary atresia (BA) patients with end-stage liver disease. The prognosis after LT has steadily improved, but overall prognosis of BA patients is also determined by mortality before LT. We aimed to quantify mortality in young BA patients on the Eurotransplant waiting list and to determine the effect of disease severity and age at time of listing on pretransplant mortality. We used a cohort study design, which incorporated data from the Eurotransplant registry. Participants were 711 BA patients who were below 5 years of age from 5 countries and listed for LT between 2001 and 2014. We applied a competing risk analysis to evaluate simultaneously the outcomes death, LT, and still waiting for a suitable organ. We used Cox proportional hazards regression to assess 2-year mortality. In a subcohort of 416 children, we performed multivariate analyses between 2-year mortality and disease severity or age, each at listing. Disease severity at listing was quantified by the Model for End-Stage Liver Disease (MELD) score, which assesses bilirubin, creatinine, albumin, and international normalized ratio as continuous variables. Two-year wait-list mortality was 7.9%. Age below 6 months and MELD score above 20 points, each at listing, were strongly and independently associated with 2-year mortality (each P < 0.001). A total of 21% of infants who fulfilled both criteria did not survive the first 6 months on the waiting list. In conclusion, our findings quantify mortality among young BA patients on the waiting list and the relative importance of risk factors (age and severity of disease at listing). Our results provide both an evidence base to rationally address high mortality in subgroups and a methodology to assess effects of implemented changes, for example, in allocation rules. Liver Transplantation 24 810-819 2018 AASLD., (© 2018 by the American Association for the Study of Liver Diseases.)