Renal impairment is prevalent in pediatric NAFLD/MASLD and associated with disease severity.

OBJECTIVES: Renal impairment is prevalent in adults with nonalcoholic fatty liver disease (NAFLD/metabolic dysfunction associated steatotic liver disease [MASLD]) and is associated with increased mortality. Pediatric data are limited. Our objective was to determine the prevalence of hyperfiltration or chronic kidney disease (CKD) in children with NAFLD/MASLD and determine links with liver disease severity. METHODS: Data from children who had previously participated in prospective, multicenter, pediatric studies by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) were collected. Renal function was determined using the calculated glomerular filtration rate (cGFR). Hyperfiltration was defined as cGFR > 135 mL/min/1.73m2, while CKD stage 2 or higher as cGFR < 90 mL/min/1.73 m2. Renal dysfunction progression was defined as transition from normal to hyperfiltration or to CKD stage ≥ 2, or change in CKD by ≥1 stage. Multinomial logistic regression models were used to determine the prevalence of CKD and independent associations between CKD and liver disease severity. RESULTS: The study included 1164 children (age 13 ± 3 years, 72% male, 71% Hispanic). The median cGFR was 121 mL/min/1.73 m2; 12% had CKD stage 2-5, while 27% had hyperfiltration. Hyperfiltration was independently associated with significant liver fibrosis (odds ratio: 1.45). Baseline renal function was not associated with progression in liver disease over a 2-year period (n = 145). Renal dysfunction worsened in 19% independently of other clinical risk factors. Progression of renal impairment was not associated with change in liver disease severity. CONCLUSIONS: Renal impairment is prevalent in children with NAFLD/MASLD and hyperfiltration is independently associated with significant liver fibrosis. Almost 1/5 children have evidence of progression in renal dysfunction over 2 years, not associated with change in liver disease severity. Future assessments including additional renal impairment biomarkers are needed.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Prognostic factors in resolution of nonalcoholic fatty liver disease post bariatric surgery in adolescents.

BACKGROUND: The long-term effect of bariatric surgery on adolescent non-alcoholic fatty liver disease is not clear. OBJECTIVES: To evaluate longitudinal change in serum alanine aminotransferase (ALT) levels and to determine the factors independently associated with this change over 2 years after bariatric surgery in adolescents with severe obesity. SETTING: An observational prospective cohort from the Teen-LABS Consortium. METHODS: We examined the relationship of longitudinal change in serum ALT (% change and normalization) to change in body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), high- (HDL) and low-density lipoprotein cholesterol, A1C and fasting glucose, accounting for age, sex, race-ethnicity, blood pressure, and baseline BMI in 219 adolescents during the first 2 years post-surgery. RESULTS: Mean BMI declined from a baseline of 52.6 to 37.2 kg/m2 at 2 years (P < .01). Alanine aminotransferase decreased significantly from baseline (36.5 [95% CI: 31.4, 41.7]) to 6 months (30.5 [95% CI: 25.4, 35.6]), and remained stable at 12 and 24 months, all P < .01 versus baseline. After adjustment, improvement in BMI, fasting glucose, HOMA-IR, triglycerides, TG/HDL ratio, and HDL were independently associated with reduced ALT at 6 months. These remained significantly associated with a decline in ALT after adjusting for BMI change. The %participants with elevated ALT decreased from 71% at baseline to 42% and 36% at 1 and 2 years post-surgery. CONCLUSIONS: Bariatric surgery resulted in significant and sustained improvement in ALT levels over 2 years. Although associated with weight loss, this decline was also associated with improved metabolic indices, independent of weight loss.

Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

Background and Aims: Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis. Methods: Whole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction. Results: No genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants in PNPLA3 or TM6SF2 was observed across phenotypes. Conclusion: In a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults: PNPLA3 and TM6SF2, though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.

Presurgery health influences outcomes following vertical sleeve gastrectomy in adolescents.

OBJECTIVE: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG. METHODS: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG. RESULTS: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m2. Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m2 (35.3%) versus the BAWL group, who lost 8.8 kg/m2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities. CONCLUSIONS: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.