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Background: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated., Methods: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group., Findings: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range., Interpretation: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Cystic fibrosis liver disease (CFLD) begins early in life. Symptoms may be vague, mild, or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of CFLD to determine the impact of early CFLD on general and disease-specific QOL., Methods: Ultrasound (US) patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age ≥5 years) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1 year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups., Results: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight., Conclusions: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement., Competing Interests: S.J.S. serves as a consultant for Nestle, UpToDate, and AbbVie. A.J.F. has grant/research support through Travere Therapeutics and Allergan; serves as an advisor for Abbvie and Takeda. W.K. has received research grants from Gilead Sciences and Albireo Pharma; serves as an advisor for Mirum and Travere Therapeutics. D.H.L. has grant/research support from Abbvie, Gilead, and Mirum; serves as a consultant for Gilead, Vertex, and Merck. S.C.L. receives research funding from Abbvie and Gilead and serves as a consultant for Abbvie JPM has research funding from Gillead, Abbvie, Albireo, Mirum. K.F.M. is a consultant for Albireo and Gilead. M.R.N. serves as a consultant for Vertex, has received research grants from Gilead, AbbVie, and has a family member with stock in Merck. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Ascites is a pathologic buildup of fluid in the peritoneal cavity. Knowledge is lacking in clinical outcome in pediatric patients with ascites. We aim to identify and assess clinical variables, associated with morbidity and mortality in pediatric patients who are hospitalized with ascites., Methods: A retrospective cohort study was performed on patients ages 0 to 21 hospitalized at Johns Hopkins Hospital between 1983 and 2010 with an ICD-9 discharge diagnosis of ascites (789.5, 789.51, 789.59). A total of 518 pediatric patients were studied, all with a diagnosis of ascites during hospitalization. Study outcomes included hospital length of stay (LOS) as a proxy for morbidity and death at hospital discharge for mortality. Variables analyzed included demographic data, ascites etiology and grade, comorbidities, and laboratory markers. Variables were analyzed by log-linear regression and competing risk model., Results: Among the 3 age groups (0-5, 6-12, and 13-21), the 0 to 5 age group experienced significantly increased LOS (P < 0.001) and mortality (P = 0.027). Ascites etiology of veno-occlusive disease (VOD) and the presence of hydrothorax or thrombocytopenia was also significantly associated with increased LOS. Ascites with the etiology of congestive hepatopathy and the presence of grade 3 ascites, hepatic encephalopathy, hepatorenal syndrome, hydrothorax, hyponatremia, and thrombocytopenia were associated with increased mortality. Additionally, black pediatric patients have an increased risk of mortality (P = 0.027). Other factors including sex, leukopenia, portal vein thrombosis, and splenomegaly were not associated with LOS or mortality., Conclusions: Morbidity and mortality in pediatric patients hospitalized with ascites are associated with specific demographic and clinical factors. Further studies are required to apply this knowledge to predict the clinical outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Early identification of children with cystic fibrosis (CF) at risk for severe liver disease (CFLD) would enable targeted study of preventative therapies. There is no gold standard test for CFLD. Ultrasonography (US) is used to identify CFLD, but with concerns for its diagnostic accuracy. We aim to determine if differences in standard blood tests, imaging variables and noninvasive liver fibrosis indices correlate with liver US patterns, and thus provide supportive evidence that a heterogeneous US liver pattern reflects clinically relevant liver disease., Methods: We studied baseline research abdominal US and bloodwork from 244 children with pancreatic insufficient CF, ages 3 to 12 years, enrolled in a prospective study of the ability of US to predict CF cirrhosis (PUSH study). Children with a heterogeneous (HTG) liver pattern on US (n = 62) were matched 1 : 2 in design with children with normal US (NL, n = 122). Analyses included children with nodular (NOD, n = 22) and homogeneous hyperechoic (HMG, n = 38) livers., Results: Univariate analysis showed significant differences between US groups for standard blood tests, spleen size, and noninvasive liver fibrosis indices. Multivariable models discriminated NOD versus NL with excellent accuracy (AUROC 0.96). Models also distinguish HTG versus NL (AUROC 0.76), NOD versus HTG (0.78), and HMG versus NL (0.79)., Conclusions: Liver US patterns in children with CF correlate with platelet count, spleen size and indices of liver fibrosis. Multivariable models of these biomarkers have excellent discriminating ability for NL versus NOD, and good ability to distinguish other US patterns, suggesting that US patterns correlate with clinically relevant liver disease.

Objectives: Cirrhosis occurs in 5% to 10% of cystic fibrosis (CF) patients, often accompanied by portal hypertension. We analyzed 3 adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver-related death (LD), and risk factors for these in CF Foundation Patient Registry subjects with reported cirrhosis., Methods: We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression., Results: From 2003 to 2012, 943 participants (41% females, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had previous pseudomonas. Seventy-three subjects had reported VB: 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. Ten-year cumulative VB, LT, and LD rates were 6.6% (95% confidence interval [CI]: 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (hazard ratio [HR] 1.10, 95% CI: 0.59, 2.08). CF-related diabetes (HR: 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk, whereas only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver., Conclusions: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report.

Objectives: The aim of our study was to describe the changing prevalence, demographic features, etiologies, and treatment of ascites in children hospitalized during a 27-year period at the Johns Hopkins Hospital (Baltimore, MD)., Methods: We retrospectively reviewed discharges from 1983 to 2010 to select patients whose records included a diagnosis of ascites. We assessed the etiologies and degrees of ascites (ascites grade 1 detectable only by radiologic tests; ascites grades 2 and 3 recognized by moderate and marked abdominal distension by physical examinations)., Results: We classified 518 children into 9 etiology groups: intrahepatic disease (IH) (105), hepatic vein outflow obstruction (HVOO) (45), congestive heart disease (CH) (33), nephrotic syndrome (NS) (36), pancreatitis (26), inflammatory and infectious diseases (77), malignancy (49), idiopathic (71), and miscellaneous (76). IH and CH were predominant in the younger age group (0-5 years) versus HVOO, pancreatitis, and malignancy in the older age group (13-21 years) (P < 0.001). The prevalence of ascites increased over time from 1983 to 2006 and declined thereafter. Ascites grade 1 was more common than ascites grades 2 and 3 in all the groups (P = 0.048). IH and NS were more likely to have ascites grade 2 and 3 (P = 0.02). Although spironolactone was more frequently used in the IH group versus other etiologies, furosemide was used more frequently in NS and CH versus other etiologies (P < 0.001)., Conclusions: The increased prevalence of ascites during the initial study period could reflect improved detection radiologic detection. The proportion of severe ascites and the various medical treatments differed among the etiologic groups.

Objectives: α-1-Antitrypsin (A1AT) deficiency is a common genetic disease with an unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network is a National Institutes of Health, multicenter, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers., Methods: Longitudinal, cohort study of A1AT patients' birth through 25 years diagnosed as having liver disease, type PIZZ or PISZ. Medical history, physical examination, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care., Results: In the present report of the cohort at baseline, 269 subjects were enrolled between November 2008 and October 2012 (208 with their native livers and 61 postliver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or postliver transplant) were not different in age at presentation. A total of 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (P = 0.0024). A total of 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no-PHT and PHT groups (P > 0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no-PHT group (P << 0.001), but overlap was large. Chemistries alone could not identify PHT., Conclusions: Many subjects with A1AT presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow-up will identify genetic and environmental disease modifiers.

Background: Multiple enzyme deficiencies have been reported in some cases of congenital glucoamylase, sucrase, or lactase deficiency. Here we describe such a case and the investigations that we have made to determine the cause of this deficiency., Methods and Results: A 2.5 month-old infant, admitted with congenital lactase deficiency, failed to gain weight on a glucose oligomer formula (Nutramigen). Jejunal mucosal biopsy at 4 and 12 months revealed normal histology with decreased maltase-glucoamylase, sucrase-isomaltase, and lactase-phlorizin hydrolase activities. Testing with a C-starch/breath CO loading test confirmed proximal starch malabsorption. Sequencing of maltase-glucoamylase cDNA revealed homozygosity for a nucleotide change (C1673T) in the infant, which causes an amino acid substitution (S542L) 12 amino acids after the N-terminal catalytic aspartic acid. The introduction of this mutation into "wildtype" N-terminus maltase-glucoamylase cDNA was not associated with obvious loss of maltase-glucoamylase enzyme activities when expressed in COS 1 cells and this amino-acid change was subsequently found in other people. Sequencing of the promoter region revealed no nucleotide changes. Maltase-glucoamylase, lactase, and sucrase-isomaltase were each normally synthesized and processed in organ culture., Conclusions: The lack of evidence for a causal nucleotide change in the maltase-glucoamylase gene in this patient, and the concomitant low levels of lactase and sucrase activity, suggest that the depletion of mucosal maltase-glucoamylase activity and starch digestion was caused by shared, pleiotropic regulatory factors.

Background: Maltase-glucoamylase enzyme plays an important role in starch digestion. Glucoamylase deficiency is reported to cause chronic diarrhea in infants, but its role in dyspeptic children is unknown., Methods: Glucoamylase and other disaccharidase specific activities were assayed from duodenal biopsy specimens in 44 children aged 0.5-18 years (mean, 10 +/- 5 years) undergoing endoscopy to evaluate dyspeptic symptoms. All subjects had normal duodenal histology. Intestinal organ culture was used to evaluate synthesis and processing of maltase-glucoamylase. Sequencing of the maltase-glucoamylase coding region was performed in subjects with low activity or variation of isoform in organ culture., Results: Twenty-two of the dyspeptic children had one or more disaccharidases with low specific activity. Twelve subjects (28%) had low activity of glucoamylase. Eight subjects had low activities of glucoamylase, sucrase, and lactase. Low glucoamylase activity was not correlated with the isoform phenotype of maltase-glucoamylase as described by metabolic labeling and sodium dodecyl sulfate electrophoresis. Novel nucleotide changes were not detected in one subject with low glucoamylase activity or in two subjects with variant isoforms of maltase-glucoamylase peptides., Conclusion: Twelve of 44 dyspeptic children had low specific activity of duodenal maltase-glucoamylase. Eight of these children had low specific activity of all measured disaccharidases.