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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV‐related liver disease has advanced considerably thanks to development and improvements in therapy. Direct‐acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype‐specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age‐specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource‐limited settings. Direct‐acting antiviral drug regimens are highly effective and safe for treatment of adults, adolescents and children with chronic hepatitis C.Two combination regimens with pangenotypic activity (sofosbuvir/velpatasvir and glecaprevir/pibrentasvir) and two with genotype‐specific activity (sofosbuvir/ledipasvir and sofosbuvir plus ribavirin) have been approved by both the European Medicines Agency and the United States Food and Drug Administration for use in adolescents and children aged 3 years and older with chronic hepatitis C. Direct‐acting antiviral drug regimens are highly effective and safe for treatment of adults, adolescents and children with chronic hepatitis C. Two combination regimens with pangenotypic activity (sofosbuvir/velpatasvir and glecaprevir/pibrentasvir) and two with genotype‐specific activity (sofosbuvir/ledipasvir and sofosbuvir plus ribavirin) have been approved by both the European Medicines Agency and the United States Food and Drug Administration for use in adolescents and children aged 3 years and older with chronic hepatitis C. We recommend treatment using direct‐acting antiviral regimens for all adolescents and children 3 years of age and above with chronic hepatitis C, regardless of stage of disease.Pangenotypic and genotype‐specific direct‐acting antiviral regimens are equally recommended for treatment.Pangenotypic, ribavirin‐free and regimens with the shortest treatment duration are preferrable when available.Sofosbuvir plus daclatasvir may be considered for adolescents and children with chronic hepatitis C in resource‐limited settings, as it is highly effective and widely available as low‐cost generic formulations. We recommend treatment using direct‐acting antiviral regimens for all adolescents and children 3 years of age and above with chronic hepatitis C, regardless of stage of disease. Pangenotypic and genotype‐specific direct‐acting antiviral regimens are equally recommended for treatment. Pangenotypic, ribavirin‐free and regimens with the shortest treatment duration are preferrable when available. Sofosbuvir plus daclatasvir may be considered for adolescents and children with chronic hepatitis C in resource‐limited settings, as it is highly effective and widely available as low‐cost generic formulations.

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.

Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

Congenital portosystemic shunt (CPSS) in a growth‐restricted fetus may lead to cardiac overload and ultimately hemodynamic imbalance. The aim of the study was to describe the application of tricuspid annular plane systolic excursion (TAPSE) for surveillance of cardiac function in growth‐restricted fetuses diagnosed with CPSS. The study group consisted of 7 fetuses with growth restriction diagnosed with CPSS between 2018 and 2020. Patients were followed longitudinally every 2 weeks. Sonographic fetal‐TAPSE (f‐TAPSE) was performed every 2 weeks. At each visit, the following parameters were recorded: estimated fetal weight, biophysical profile, nonstress test, Doppler flow indices, and fetal cardiothoracic index. Postnatal laboratory and imaging tests were retrieved from the medical files. Mean gestational age at diagnosis of CPSS was 32 + 1 weeks. Cardiomegaly was observed in all cases. All portosystemic shunts were classified as intrahepatic. Values of f‐TAPSE were above the 95th percentile in 6/7 fetuses at presentation and throughout follow‐up. Gestational age at delivery ranged between 36 + 5 and 38 + 5 weeks. Postnatally, spontaneous closure of the shunt was noted in 2 infants. Transient hyperammonemia was diagnosed in 2 neonates, with no signs of the characteristic complication. In growth‐restricted fetuses diagnosed concomitantly with CPSS, f‐TAPSE offers a practical sonographic tool for assessment of cardiac function and may serve as an additional clinical marker for follow‐up. The appearance of cardiomegaly in growth‐restricted fetuses should prompt a dedicated sonographic evaluation of the fetal portal system.

Severe obesity in the pediatric population has lifelong consequences. Bariatric surgery has been suggested for selected adolescents with severe obesity after careful evaluation. The indications for preoperative esophagogastroduodenoscopy (EGD) in this age group are not clear, despite its established usefulness in adults. We aimed to assess the usefulness of EGD before bariatric surgery in pediatric patients with severe obesity and metabolic comorbidities. We conducted a retrospective chart review in a single tertiary pediatric medical center of adolescents treated during 2011 to 2018. Data collected from electronic medical records included patient demographics, endoscopic findings, and laboratory parameters. A total of 80 patients (40 boys) underwent evaluation. Macroscopic abnormalities were detected in 54% of the endoscopies, including gastritis, esophagitis, and duodenitis in 46%, 16%, and 13%, respectively. Forty-nine percentage of the biopsies showed histological abnormalities; in 35 (44%) patients, Helicobacter pyloriwas detected. Thirty-three patients (41%) received medical treatment and 2 (2.5%) required a second EGD. Metabolic comorbidities included hypertriglyceridemia (38% of the patients), low high-density lipoprotein (23%), and prediabetic (16%) or diabetic levels of HbA1C (4%). Fifty-five percentage of the cohort had elevated alanine aminotransferase (ALT), suggestive of nonalcoholic fatty liver disease (NAFLD). Endoscopies performed before bariatric surgeries suggest a higher prevalence of clinically significant findings, many of which required treatment. These findings support incorporating an EGD into the preoperative evaluation of this patient population.

Celiac disease (CD) is a common intestinal autoimmune disorder with diverse presenting features. We aimed to determine age-dependent patterns in CD presentation, diagnosis and management at a large tertiary referral center. A retrospective review of electronic medical records of pediatric patients diagnosed with CD between January 1999 and December 2018 at Schneider Children's Medical Center of Israel. We compared demographics, clinical and laboratory parameters between four age groups at CD presentation. A cohort of 932 children was divided into four groups by age (in years) at diagnosis: 0–3 (17.9%), 3–6 (31.8%), 6–12 (34.5%), 12–18 (15.8%). The youngest age group presented more frequently with diarrhea, weight loss, abdominal distention, vomiting and lower weight zscores, P< 0.01. Hypoalbuminemia and zinc deficiency were also more frequent in this age group, compared to older patients (P< 0.05, each). Rates of anemia were higher in younger age groups (0–3 and 3–6 years), compared to older age groups, P< 0.05. Patients in the younger age groups (0–3 and 3–6 years) presented more frequently with tissue transglutaminase (TTG) levels above 10 times the upper limit of normal (ULN; P< 0.05), and more often normalized their CD serologies by 24 months of gluten-free diets (GFD) compared to older age groups (P< 0.05). There is an age-dependent variation in CD presentation during childhood. Younger patients present more often with malabsorptive features, and higher TTG levels, yet normalize TTG while on GFD more rapidly than older patients. Clinicians should be aware of the diversity in CD presentation and course at the various presentation age.

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Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children.

We describe the clinical and laboratory manifestations and outcomes of 25 pediatric solid organ transplant recipients who tested positive for severe acute respiratory coronavirus-2. Twenty-one (84%) developed a mild disease; 22 of 23 (96%) had a positive serologic response. Two patients (8%), both kidney transplant recipients with additional comorbidities, developed a severe disease. The findings emphasize the need for close monitoring of this population.

Although gluten-free diet (GFD) is the only proven therapy for celiac disease (CD), its effect on cardiovascular disease (CVD) risk factors is still unclear. Our aim was to determine whether adherence to GFD affects CVD risk factors among newly diagnosed pediatric CD subjects. We prospectively enrolled pediatric subjects undergoing upper gastrointestinal endoscopy for suspected CD. We collected anthropometric and laboratory parameters related to CVD risk factors at the time of CD diagnosis and 1 year after initiation of a GFD and evaluated changes in CVD risk factors. Paired ttests or Wilcoxon nonparametric tests were used, each when appropriate. One hundred ten newly diagnosed CD pediatric subjects were included in the analysis. There were 64 (58.2%) girls and the mean age at diagnosis was 6.8 ± 3.4 years. Median body mass index zscores (P= 0.84), rates of underweight or overweight (P= 0.32), and rates of elevated blood pressure (P= 0.78) remained unchanged. Although median fasting insulin levels increased (1.9 vs 5.4 µU/mL, P< 0.001), insulin resistance as measured by homeostatic model assessment did not increase after 1 year of GFD (P= 0.16). Although rates of dyslipidemia remained unchanged, median high-density lipoprotein levels increased on GFD (47 vs 51 mg/dL, P< 0.001). In this pediatric CD cohort, GFD for 1 year was not associated with increased CVD risk factors. The long-term significance of these mild changes is yet to be determined.

To compare the application of three standardized definitions of acute kidney injury (AKI), using corrected serum creatinine values, in children immediately after liver transplantation.

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In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12–17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children. A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique. The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin. This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection.

Data describing the incidence and risk factors for colectomy in pediatric ulcerative colitis (UC) is inconsistent. Our aim was to describe the colectomy rate and to identify risk factors associated with colectomy in a large cohort of children with UC with long-term follow-up. We performed a retrospective chart review of pediatric UC cases that were diagnosed at Schneider Children's Medical Center of Israel between 1981 and 2013. Potential predictors for colectomy including age at diagnosis, sex, disease extent, severity indices, and different therapeutic regimens during disease course were assessed. Of 188 patients with pediatric onset UC, 34 (18%) underwent colectomy. Median follow-up was 6.9 years (range, 1–30). Kaplan-Meier survival estimates of the cumulative probability for colectomy were 4% at 1 year and 17% at 10 years from diagnosis. Multivariate Cox models showed that male sex (hazard ratio 4.2, P= 0.001) and severe disease at diagnosis reflected by Pediatric Ulcerative Colitis Activity Index score =65 (hazard ratio 8.9, P< 0.001) were associated with increased risk for colectomy. Age, disease extent, ethnicity, family history of inflammatory bowel disease, early introduction of immunomodulators, or treatment with antitumor necrosis factor a agent did not affect the risk of colectomy. Male sex and higher Pediatric Ulcerative Colitis Activity Index score at diagnosis are independent risk factors for colectomy.

ObjectivesAn association between coeliac disease (CD) and eosinophilic oesophagitis (EoE)/oesophageal eosinophilia (EE) has been suggested. We sought to characterise children with CD+EE in-depth and assess the contribution of each condition to the clinical presentation and treatment response.Study designMedical records of children with both CD+EE, or isolated EoE diagnosed between 2000 and 2014, were retrospectively reviewed and compared with patients with isolated CD or epigastric pain. Frequency of EE was calculated from endoscopy results of patients with suspected CD or epigastric pain between 2011 and 2014. Missing data were obtained via a telephone questionnaire.SettingSingle large, tertiary paediatric centre.Patients17 CD+EE, 46 EoE, 302 isolated CD and 247 epigastric pain.ResultsThe patients with CD+EE shared characteristics of both individual conditions. While age at diagnosis, family history of autoimmunity/CD and anaemia were similar to patients with CD, other characteristics such as male gender, personal/family history of atopy, peripheral eosinophilia and oesophageal white papules were more similar to patients with EoE. Combined patients (CD+EE) tended to present with CD-associated symptoms; the majority (63%) later developed typical EoE symptoms. Only a minority (21%) of combined patients had EE that resolved after a gluten-free diet; another 21% had normalisation of EE upon proton pump inhibitor treatment. The remainder required EoE-specific treatment.ConclusionPatients with CD found to have EE share characteristics with both isolated CD and EoE. It appears that these are two coexisting entities presenting in the same patient rather than eosinophilia associated with CD, and therefore, interventions separately addressing each condition may be considered.

Diet assessment is essential in the care of patients with inflammatory bowel disease (IBD). We aimed to study food intake in children with IBD and evaluated the relation of dietary intake with disease activity and nutritional status in these children. This cross-sectional study investigated 68 children and adolescents with IBD (57 Crohn disease, 11 ulcerative colitis). Evaluation included clinical, laboratory, and nutritional assessment including 3 days diet record. Compared with recommended daily allowance, the intake of patients with IBD was significantly poor for carbohydrates (75%, P= 0.016), calcium (49%, P< 0.05), magnesium (76%, P< 0.05), vitamin A (72%, P< 0.05), vitamin E (57%, P< 0.05), and fiber (44%, P< 0.05) and higher for protein (175%, P< 0.05), iron (112%, P< 0.05), and water-soluble vitamins (118%–189% P< 0.05). Compared with the intakes of healthy children from National Nutritional Survey, the intake of IBD group was lower for calories (78%, P= 0.012), carbohydrates (61% P< 0.05), magnesium (67% P< 0.05), vitamin C (34%, P< 0.05), and fiber (54%, P< 0.05) and high for B12 (141%, P< 0.05). Fifty subjects ate ordinary diets, 7 of 68 children were on exclusive enteral nutrition and 11 of 68 consumed regular food with different polymeric formulas supplements. Compared with children without supplements, children on exclusive enteral nutrition and nutritional supplements (18/68) had significantly better intakes of energy (1870 ± 755 vs 2267 ± 432, P< 0.05), carbohydrates (223 ± 97 vs 292 ± 99, P< 0.05), and all minerals (P< 0.05) and micronutrients (P< 0.05). Dietary intake was not different by disease status (remission or relapse). In the absence of nutritional supplements, food intake is inadequate for many nutrients in many children with IBD.

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AbstractBackground:We previously demonstrated that children with Type 1 Diabetes Mellitus (T1DM) may have transiently elevated tissue transglutaminase antibodies (TTG) on a gluten-containing diet. This study aimed to examine if the presence of autoantibodies in newly diagnosed T1DM differs between patients with celiac disease and those with transient celiac serology.Methods:Forty children were identified who had been diagnosed with T1DM between 2003 and 2009 and who had elevated serum IgA-TTG antibody levels at diagnosis. Blood samples were collected for measurement of insulin (IA-2A) antibodies, islet cell antigen (ICA) antibodies, glutamic acid decarboxylase (GAD) antibodies, thyroglobulin (TgAb) antibodies, and thyroid peroxidase (TPO) antibodies. Children diagnosed with celiac disease (CD; group 1, n=23) and children in whom TTG antibody levels spontaneously normalized over time (group 2, n=17) were compared.Results:No significant differences in positivity rates between groups 1 and 2 were found for any of the autoantibodies tested. The respective findings were as follows: IA-2A 50% and 47.1% (p=0.855); ICA 77.3% and 76.5% (p=0.953); GAD 27.3% and 52.9% (p=0.102). Thyroid antibodies were found positive in a limited number of patients: TgAb 4.5% and 11.8%; TPO 4.5% and 11.8%. In addition, antibody titer levels did not differ significantly for all autoantibodies. Difference in occurrence of clinical or subclinical thyroid disease did not reach significance (4.3% vs. 29.4%; p=0.07). Age was positively correlated with the presence of thyroglobulin and thyroid peroxidase antibodies, and negatively correlated with the presence of insulin antibody.Conclusion:Neither the number of concomitant autoantibodies nor their titers in newly diagnosed T1DM differed between patients with proven CD and those with transient TTG serology.