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BACKGROUND AND AIMS: NAFLD is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity. APPROACH AND RESULTS: Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele-specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. A total of 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk ( p = 2.24 × 10 -14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis ( p = 0.005), lobular ( p = 0.03) and portal inflammation ( p = 0.002). Steatosis grade associated with TM6SF2 ( p = 0.0009), GCKR ( p = 0.0032), PNPLA3 rs738409 ( p = 0.0053), and MTTP ( p = 0.0051). Fibrosis stage associated with PARVB rs6006473 ( p = 0.0001), NR1I2 ( p = 0.0021), ADIPOR2 ( p = 0.0038), and OXTR ( p = 0.0065). PNPLA3 rs738409 ( p = 0.0002) associated with borderline zone 1 NASH. CONCLUSIONS: This study demonstrated disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Niño , Adolescente , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/patología , Genotipo , Fibrosis , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Obesity and its associated comorbidities are major public health concerns for which nutrition is central to disease prevention and management. Pentadecanoic acid (C15:0) has the potential for beneficial effects on obesity, but supplementation has not been studied in humans. OBJECTIVES: The primary objective was to investigate changes in plasma C15:0 levels after daily supplementation for 12 wk. Additionally, the study aimed to assess safety and tolerability as well as measure potential markers of physiologic response. METHODS: This was a single-center, double-blind, randomized, controlled, 2-arm trial of 200 mg C15:0 or placebo daily for 12 wk in young adults with overweight or obesity. RESULTS: A total of 30 participants with a mean age of 20.0 ± 2.1 y and a mean body mass index of 33.4 ± 5.3 kg/m2 were included. In total, 20 participants received C15:0 supplement and 10 received placebo. The mean increase in circulating C15:0 for the treatment group was 1.88 µg/mL greater than that of the placebo group (P = 0.003). No significant adverse events occurred. Half of the participants in the treatment group had a posttreatment C15:0 level >5 µg/mL. In these individuals, there were significantly greater decreases in alanine aminotransferase (-29 U/L, P = 0.001) and aspartate aminotransferase (-6 U/L, P = 0.014), as well as a greater increase in hemoglobin (0.60 g/dL, P = 0.010), as compared with participants that did not reach a posttreatment level >5 µg/mL. CONCLUSIONS: Daily C15:0 supplementation increased circulating C15:0 levels in young adults with overweight or obesity. End-of-treatment C15:0 >5 µg/mL was associated with potentially relevant improvements in clinical indices, warranting further study. This trial was registered at clinicaltrials.gov as NCT04947176.
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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 AUC 0-24 , 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.
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Chalconas , Enfermedad del Hígado Graso no Alcohólico , Masculino , Humanos , Niño , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Chalconas/efectos adversos , Propionatos/efectos adversosRESUMEN
OBJECTIVES: Early-phase pediatric nonalcoholic fatty liver disease (NAFLD) clinical trials are designed with noninvasive parameters to assess potential efficacy. Increasingly, these parameters include magnetic resonance imaging (MRI)-derived proton density fat fraction (PDFF) and MR elastography (MRE)-derived shear stiffness as biomarkers of hepatic steatosis and fibrosis, respectively. Understanding fluctuations in these measures is essential for calculating trial sample sizes, interpreting results, and planning clinical drug trials in children with NAFLD. Lack of such data in children constitutes a critical knowledge gap. Therefore, the primary aim of this study was to assess whole-liver MRI-PDFF change in adolescents with nonalcoholic steatohepatitis (NASH) over 12 weeks. METHODS: Adolescents 12 to 19 years with biopsy-proven NASH undergoing standard-of-care treatment were enrolled. Baseline and week-12 assessments of anthropometrics, transaminases, MRI-PDFF, and MRE stiffness were obtained. RESULTS: Fifteen adolescents were included (mean age 15.7 [SD 2.9] years). Hepatic MRI-PDFF was stable over 12 weeks (mean absolute change -0.8%, Pâ=â0.24). Correlation between baseline and week-12 values of MRI-PDFF was high (ICCâ=â0.97, 95% CI 0.90-0.99). MRE stiffness was stable (mean percentage change 2.7%, Pâ=â0.44); correlation between baseline and week-12 values was moderate (ICCâ=â0.47; 95% CI 0-0.79). Changes in weight, BMI, and aminotransferases were not statistically significant. CONCLUSION: In adolescents with NASH, fluctuations in hepatic MRI-PDFF and MRE stiffness over 12 weeks of standard-of-care were small. These data on the natural fluctuations in quantitative imaging biomarkers can serve as a reference for interventional trials in pediatric NASH and inform the interpretation and planning of clinical trials.
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Diagnóstico por Imagen de Elasticidad/métodos , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Selección de Paciente , Adolescente , Biomarcadores/análisis , Niño , Ensayos Clínicos como Asunto , Femenino , Humanos , Hígado/patología , Masculino , Adulto JovenRESUMEN
Importance: Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment. Objective: To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD. Design, Setting, and Participants: An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017. Interventions: The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet. Main Outcomes and Measures: The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence. Results: Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was -6.23% (95% CI, -9.45% to -3.02%; P < .001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L; P < .001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study. Conclusions and Relevance: In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02513121.
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Dieta Baja en Carbohidratos , Azúcares de la Dieta , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Adolescente , Glucemia/análisis , Índice de Masa Corporal , Niño , Hispánicos o Latinos , Humanos , Lípidos/sangre , Pruebas de Función Hepática , Masculino , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etnología , Resultado del Tratamiento , Pérdida de PesoAsunto(s)
Enfermedad del Hígado Graso no Alcohólico , Adolescente , Dieta , Humanos , Masculino , AzúcaresRESUMEN
Background: Pediatric studies have shown associations between hepatic steatosis and total body fat, visceral fat, and lean mass. However, these associations have not been assessed simultaneously, leaving their relative importance unknown. Objective: To evaluate associations between hepatic steatosis and total-body adiposity, visceral adiposity, and lean mass in children. Method: In children at risk for fatty liver, hepatic steatosis, adipose, and lean mass were estimated with magnetic resonance imaging and dual-energy X-ray absorptiometry. Results: Two hundred twenty-seven children with mean age 12.1 years had mean percent body fat of 38.9% and mean liver fat of 8.4%. Liver fat was positively associated with total-body adiposity, visceral adiposity, and lean mass (P < 0.001), and negatively associated with lean mass percentage (P < 0.001). After weight adjustment, liver fat was only positively associated with measures of central adiposity (P < 0.001). Visceral adiposity also had the strongest association with liver fat (P < 0.001). Conclusions: In children, hepatic steatosis is more strongly associated with visceral adiposity than total adiposity, and the association of lean mass is not independent of weight or fat mass. These relationships may help guide the choice of future interventions to target hepatic steatosis.
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Adiposidad , Hígado Graso , Humanos , Niño , Hígado Graso/diagnóstico por imagen , Hígado Graso/epidemiología , Hígado/metabolismo , Obesidad/metabolismo , Grasa Intraabdominal/metabolismo , Imagen por Resonancia Magnética , Obesidad Abdominal/complicaciones , Obesidad Abdominal/diagnóstico por imagen , Obesidad Abdominal/metabolismo , Músculos/patologíaRESUMEN
Dietary sugar reduction is one therapeutic strategy for improving nonalcoholic fatty liver disease (NAFLD), and the underlying mechanisms for this effect warrant further investigation. Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic fat reductions in youth with NAFLD. Data/samples were from a randomized controlled trial in adolescent boys (11-16 years, mean ± SD: 13.0 ± 1.9 years) with biopsy-proven NAFLD who were either provided a low free-sugar diet (LFSD) (n = 20) or consumed their usual diet (n = 20) for 8 weeks. Plasma metabolomics was performed on samples from all 40 participants by coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with mass spectrometry. In a sub-sample (n = 8 LFSD group and n = 10 usual diet group), 16S ribosomal RNA (rRNA) sequencing was performed on stool to examine changes in microbial composition/diversity. The diet treatment was associated with differential expression of 419 HILIC and 205 C18 metabolite features (p < 0.05), which were enriched in amino acid pathways, including methionine/cysteine and serine/glycine/alanine metabolism (p < 0.05), and lipid pathways, including omega-3 and linoleate metabolism (p < 0.05). Quantified metabolites that were differentially changed in the LFSD group, compared to usual diet group, and representative of these enriched metabolic pathways included increased serine (p = 0.001), glycine (p = 0.004), 2-aminobutyric acid (p = 0.012), and 3-hydroxybutyric acid (p = 0.005), and decreased linolenic acid (p = 0.006). Microbiome changes included an increase in richness at the phylum level and changes in a few genera within Firmicutes. In conclusion, the LFSD treatment, compared to usual diet, was associated with metabolome and microbiome changes that may reflect biological mechanisms linking dietary sugar restriction to a therapeutic decrease in hepatic fat. Studies are needed to validate our findings and test the utility of these "omics" changes as response biomarkers.
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BACKGROUNDHepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODSAdolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging-proton density fat fraction.RESULTSHepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: -10.6% [95% CI: -19.1%, -2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 µIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSIONOur results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRYClinicalTrials.gov NCT02513121.FUNDINGThe Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core, Children's Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.