Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. Childhood NAFLD is associated with hepatic and nonhepatic morbidity and mortality. ...Nonhepatic associations include cardiovascular, metabolic, pulmonary, and psychological disorders. Cardiovascular conditions observed in childhood include left ventricular dysfunction. Furthermore, childhood obesity is associated with greater odds of having hepatocellular carcinoma as an adult. Evidence suggests that NAFLD may begin in utero in children of diabetic mothers. Thus rigorous efforts for structured diagnosis and follow-up are a priority to better develop the understanding of outcomes in pediatric NAFLD.
To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic ...accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity.
We evaluated children aged 9-17 years with obesity for the presence of NAFLD. Diseases other than NAFLD were excluded by history and laboratories. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction. The diagnostic accuracy of ALT for detecting NAFLD was evaluated.
The study included 408 children with obesity that had a mean age of 13.2 years and mean body mass index percentile of 98.0. The study population had a mean ALT of 32 U/L and median hepatic magnetic resonance imaging proton density fat fraction of 3.7%. The estimated prevalence of NAFLD was 26.0% (95% CI 24.2%-27.7%), 29.4% in male patients (CI 26.1%-32.7%) and 22.6% in female patients (CI 16.0%-29.1%). Optimal ALT cut-point was 42 U/L (47.8% sensitivity, 93.2% specificity) for male and 30 U/L (52.1% sensitivity, 88.8% specificity) for female patients. The classification and regression tree model with sex, ALT, and insulin had 80% diagnostic accuracy for NAFLD.
NAFLD is common in children with obesity, but NAFLD and obesity are not concomitant. In children with obesity, NAFLD is present in nearly one-third of boys and one-fourth of girls.
The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD.
We performed a ...prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis.
Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87).
In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.
Objectives:
Nonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator‐activated receptor α/δ agonist, has been proposed as a ...treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8–17 years and (2) assess changes in aminotransferases.
Methods:
Children with NASH were randomized to open‐label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent‐to‐treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed.
Results:
Ten males mean 15.1 years, standard deviation (SD) 2.2 with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9‐ and 1.3‐fold increase in median Cmax and AUC0–24, respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of −37.4% (SD 23.8%) at 12 weeks.
Conclusions:
Once daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH.
ABSTRACT
Objectives:
To determine the incidence of clinically diagnosed depression and anxiety in adolescents with nonalcoholic fatty liver disease (NAFLD).
Methods:
This was a prospective, ...longitudinal cohort study between January 1, 2012 and July 1, 2018 conducted in a Children's Hospital Pediatric Gastroenterology Clinic. Participants included adolescents 12 to 17 years old at baseline with biopsy‐confirmed NAFLD. The primary outcomes were having depression and/or anxiety based upon a clinical diagnosis established by a physician or psychologist. The rates of depression and anxiety were measured at baseline and longitudinally throughout follow‐up.
Results:
A total of 160 adolescents with NAFLD were followed for a mean of 3.8 years. At baseline, 8.1% had a diagnosis of depression. During follow‐up, an additional 9.5% (95% confidence interval, 4.7–14.3) developed depression. The incidence density of depression was 27 new cases per 1000 person‐years at risk. In adolescents with NAFLD, 6.3% had anxiety at baseline and 6.7% (95% confidence interval, 2.6–10.7) developed anxiety during follow‐up. The incidence density of anxiety was 18 new cases per 1000 person‐years at risk. The change in alanine aminotransferase was significantly worse for adolescents with NAFLD who developed depression compared to those who did not develop depression (P < 0.01).
Conclusions:
Adolescents with NAFLD had a high incidence of clinically diagnosed depression and anxiety. The rates were higher than expected relative to the available data in the general population. Addressing this mental health burden will require efforts at both the patient level and the systems level.
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Severe fibrosis and cirrhosis are potential consequences of pediatric NAFLD and can occur within a ...few years of diagnosis. Observations suggest that genetics may be a strong modifying factor in the presentation, severity, and natural history of the disease. There is increasing interest in determining at-risk populations based on genetics in the hope of finding genotypes that correlate to NAFLD phenotype. Ultimately, the hope is to be able to tailor therapeutics to genetic predispositions and decrease disease morbidity in children with NAFLD.
Osteoarthritis (OA) is a common degenerative disorder of the articular cartilage, which is associated with hypertrophic changes in the bone, synovial inflammation, subchondral sclerosis, and joint ...space narrowing (JSN). Radiography remains the first line of imaging till now. Due to the lack of soft-tissue depiction in radiography, researchers are exploring various imaging techniques to detect OA at an early stage and understand its pathophysiology to restrict its progression and discover disease-modifying agents in OA. As the OA relates to the degradation of articular cartilage and remodeling of the underlying bone, an optimal imaging tool must be sensitive to the bone and soft tissue health. In that line, many non-invasive imaging and minimally invasive techniques have been explored. Out of these, the non-invasive compositional magnetic resonance imaging (MRI) for evaluation of the integrity of articular cartilage and positron emission tomography (PET) scan with fluorodeoxyglucose (FDG) and more specific bone-seeking tracer like sodium fluoride (18F-NaF) for bone cartilage interface are some of the leading areas of ongoing work. Integrated PET-MRI system, a new hybrid modality that combines the virtues of the above two individual modalities, allows detailed imaging of the entire joint, including soft tissue cartilage and bone, and holds great potential to research complex disease processes of OA. This narrative review attempts to signify individual characteristics of MRI, PET, the fusion of these characteristics in PET-MRI, and the ongoing research on PET-MRI as a potential tool to understand the pathophysiology of OA.
Background
Magnetic resonance elastography (MRE) can determine the presence and stage of liver fibrosis. Data on normative MRE values, while reported in adults, are limited in children.
Purpose
To ...determine the distribution of MRE‐measured liver stiffness in children without liver disease.
Study Type
Prospective, observational.
Population
Eighty‐one healthy children (mean 12.6 ± 2.6 years, range 8–17 years).
Field Strength/Sequence
3.0T Signa HDxt, General Electric MR Scanner; 2D GRE MRE sequence.
Assessment
History, examination, laboratory evaluation, and (MR) exams (proton density fat fraction, PDFF, and MRE) were performed. MR elastograms were analyzed manually at two reading centers and compared with each other for agreement and with published values in healthy adults and thresholds for fibrosis in adult and pediatric patients.
Statistical Tests
Descriptive statistics, Bland–Altman analysis, t‐test to compare hepatic stiffness values with reference standards.
Results
Stiffness values obtained at both reading centers were similar, without significant bias (P = 0.362) and with excellent correlation (intraclass correlation coefficient ICC = 0.782). Mean hepatic stiffness value for the study population was 2.45 ± 0.35 kPa (95th percentile 3.19 kPa), which was significantly higher than reported values for healthy adult subjects (2.10 ± 0.23 kPa, P < 0.001). In all, 74–85% of subjects had stiffness measurements suggestive of no fibrosis.
Data Conclusion
Mean liver stiffness measured with MRE in this cohort was significantly higher than that reported in healthy adults. Despite rigorous screening, some healthy children had stiffness measurements suggestive of liver fibrosis using current published thresholds. Although MRE has the potential to provide noninvasive assessment in patients with suspected hepatic disease, further refinement of this technology will help advance its use as a diagnostic tool for evidence of fibrosis in pediatric populations.
Level of Evidence: 1
Technical Efficacy: 5
J. Magn. Reson. Imaging 2020;51:919–927.
Summary Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. ...We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. Methods We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6–7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6–7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry–India (CTRI/2010/091/000102) and ClinicalTrials.gov ( NCT01305109 ). Findings 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0–66·9; p=0·0013) and 56·4% (36·6–70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37–97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33–0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. Interpretation Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. Funding Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.
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