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.

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.

Food Insecurity and Pediatric Nonalcoholic Fatty Liver Disease Severity.

OBJECTIVE: To determine the association between food insecurity and pediatric nonalcoholic fatty liver disease (NAFLD). METHODS: Cross-sectional study of patients < 21 years of age with histologically confirmed NAFLD. The Household Food Security Survey Module was administered to determine food insecurity status. Skin lipidomics were performed to explore pathophysiologic mechanisms. RESULTS: Seventy-three patients with histologically confirmed NAFLD completed the Household Food Security Survey Module. Of these, the majority were male (81%) and non-Hispanic (53%), with a mean age at biopsy of 13 ± 3 years. Food insecurity was seen in 42% (n = 31). Comparison of features between food insecure and food secure subgroups revealed no differences in sex, ethnicity, BMI z-score, aminotransferases, or histologic severity. However, children experiencing food insecurity presented on average 2 years before their food secure counterparts (12.3 ± 3.0 vs 14.4 ± 3.6 years, P = .015). A subset of 31 patients provided skin samples. Skin lipidomics revealed that food insecurity was associated with down-regulated features from the lipoamino acid class of lipids, previously linked to inflammation and adipocyte differentiation. CONCLUSIONS: Food insecurity is highly prevalent in children with NAFLD and is associated with earlier presentation. Lipidomic analyses suggest a possible pathophysiologic link that warrants further exploration.

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.

Development of Fibro-PeN, a clinical prediction model for moderate-to-severe fibrosis in children with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Liver fibrosis is common in children with NAFLD and is an important determinant of outcomes. High-performing noninvasive models to assess fibrosis in children are needed. The objectives of this study were to evaluate the performance of existing pediatric and adult fibrosis prediction models and to develop a clinical prediction rule for identifying moderate-to-severe fibrosis in children with NAFLD. APPROACH AND RESULTS: We enrolled children with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis Clinical Research Network within 90 days of liver biopsy. We staged liver fibrosis in consensus using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. We evaluated existing pediatric and adult models for fibrosis and developed a new pediatric model using the least absolute shrinkage and selection operator with linear and spline terms for discriminating moderate-to-severe fibrosis from none or mild fibrosis. The model was internally validated with 10-fold cross-validation. We evaluated 1055 children with NAFLD, of whom 26% had moderate-to-severe fibrosis. Existing models performed poorly in classifying fibrosis in children, with area under the receiver operator curves (AUC) ranging from 0.57 to 0.64. In contrast, our new model, fibrosis in pediatric NAFLD was derived from fourteen common clinical variables and had an AUC of 0.79 (95% CI: 0.77-0.81) with 72% sensitivity and 76% specificity for identifying moderate-to-severe fibrosis. CONCLUSION: Existing fibrosis prediction models have limited clinical utility in children with NAFLD. Fibrosis in pediatric NAFLD offers improved performance characteristics for risk stratification by identifying moderate-to-severe fibrosis in children with NAFLD.

Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children.

BACKGROUND: Lower whole body bone mineral density (BMD) has been reported in children with nonalcoholic fatty liver disease (NAFLD), but potential mediators remain uncertain. AIMS: To assess BMD at multiple skeletal sites in children with confirmed NAFLD and controls with obesity, adjusting for known determinants of BMD, and examine potential mediators. METHODS: We assessed age-, sex-, and race-specific, and height-adjusted BMD z-scores of whole body, lumbar spine, hip, femoral neck and forearm by dual-energy-x-ray absorptiometry in 79 children, 8-19 years old: 46 with biopsy-confirmed NAFLD [29 steatohepatitis (NASH)/17 fatty liver (NAFL)] and 33 controls without liver disease. We compared BMD z-scores by multivariable regression, adjusting for known BMD determinants and potential mediators (inflammatory and insulin resistance measures). RESULTS: Unadjusted mean BMD z-scores in NAFLD were similar to controls, but significantly lower in NASH vs. NAFL at all sites. After covariate adjustment, mean forearm BMD z-score was higher in NAFL (ß 0.60 ± SE 0.30, p < 0.05) and lower in NASH (ß - 0.49 ± SE 0.26, p = 0.06) vs. controls (p = 0.002 for group), with similar trends at whole body and total hip; hs-CRP negatively associated with whole body and forearm BMD z-scores (p < 0.05), while visceral fat area negatively associated with femoral neck (p < 0.05). Only three children had clinically low whole body BMD z-scores (< - 2), one per group (control, NAFL and NASH). CONCLUSIONS: NASH, but not NAFL, may be associated with increased risk of reduced BMD in children. Systemic inflammation, independent of body composition and load bearing, may mediate reduction in BMD in NASH.

Nonalcoholic Steatohepatitis in Children.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Although environmental factors are major contributors to early onset, children have both shared and unique genetic risk alleles as compared with adults with NAFLD. Treatment relies on reducing environmental risk factors, but many children have persistent diseases. No medications are approved specifically for the treatment of NAFLD, but some anti-obesity or diabetes treatments may be beneficial. Pediatric NAFLD increases the risk of diabetes and other cardiovascular risk factors. Long-term prospective studies are needed to determine the long-term risk of hepatic and non-hepatic morbidity and mortality in adulthood.

Variation in Alanine Aminotransferase in Children with Non-Alcoholic Fatty Liver Disease.

Background: Pediatric non-alcoholic fatty liver disease (NAFLD) is a major public health concern. Aminotransferase (ALT) is frequently used for screening and monitoring, but few studies have reported typical patterns of ALT elevation in children. Methods: TARGET-NASH is a real-world longitudinal observational cohort of patients with NAFLD receiving care across the United States. Analyses included children enrolled between 1 August 2016, and 12 October 2020, with at least one ALT measurement after enrollment. Peak ALT was based on the first and last available record and categorized into clinical cut points: <70 IU/L, >70−<250 IU/L, and >250 IU/L. A chi-squared test was used to compare differences in proportions, and a Kruskal−Wallis test was used to compare the medians and distributions of continuous responses. Results: Analyses included 660 children with a median age of 13 years. Of the 660, a total of 187 had undergone a biopsy and were more likely to be Hispanic or Latino (67% vs. 57%, p = 0.02) and to have cirrhosis (10% vs. 1%, p < 0.001). The highest ALT scores ranged from 28 U/L to 929 U/L; however, these scores varied across time. The prevalence of cirrhosis or any liver fibrosis stage was most common among children with a peak ALT > 70 U/L. Conclusions: Large variability was seen in ALT among children, including many values > 250 U/L. Higher levels of ALT were associated with increased prevalence of comorbidities and more advanced stages of NAFLD. These findings support an increased need for therapeutics and disease severity assessment in children with peak ALT > 70 U/L.

Intestinal Guanylate Cyclase-C mRNA Expression in Duodenum and Colon of Children.

OBJECTIVES: Guanylate cyclase-C (GC-C) agonists, which increase intestinal secretion and accelerate transit, are used to treat chronic constipation and constipation-predominant irritable bowel syndrome and are being evaluated for pediatric use. Prior studies suggest GC-C receptor density may be higher in young children, potentially amplifying GC-C agonism with treatment implications. We aimed to quantitate duodenal and colonic GC-C mRNA expression in children. METHODS: Mucosal biopsies were obtained from subjects aged 6 months to 18 years during clinically indicated upper, that is, esophago-gastro-duodenal, and/or colonic endoscopy. Tissue samples without histologic abnormalities were grouped by subject age (<24 months, 24 months to <6 years, 6 to <12 years, and 12 to <18 years) and analyzed for GC-C mRNA expression by qPCR. The relationship between GC-C mRNA levels and age was modeled using regression analyses. RESULTS: Ninety-nine subjects underwent upper endoscopy/colonoscopy; 93 had evaluable samples. Mean relative GC-C mRNA expression was 2.36 (range 2.21-2.46) for duodenal samples and 1.56 (range 1.22-1.91) for colonic samples. Predicted and observed normalized GC-C mRNA expression in each region were comparable among age groups. Pooled expression by region demonstrated lower expression in colonic versus duodenal samples. CONCLUSIONS: Uniform levels of GC-C mRNA expression were detected in children aged >6 months in the duodenum and >12 months in the colon. Higher expression was observed in all age groups in duodenal versus colonic samples, indicating regional variability in GC-C receptor density. These data are reassuring for further studies of GC-C agonists in children.

Study protocol: a prospective controlled clinical trial to assess surgical or medical treatment for paediatric type 2 diabetes (ST2OMP).

INTRODUCTION: The pathophysiology of type 2 diabetes (T2D) in youth differs from adults and conventional medical treatment approaches with lifestyle change, metformin, thiazolidinediones or insulin are inadequate. Metabolic bariatric surgery (MBS) improves multiple health outcomes in adults with T2D. Initial small, uncontrolled studies of Roux-en-Y gastric bypass have also suggested beneficial effects in adolescents. Definitive studies in youth with T2D are lacking, especially with the now more common form of MBS, vertical sleeve gastrectomy (VSG). The surgical or medical treatment for paediatric type 2 diabetes (ST2OMP) clinical trial was designed to test the hypothesis that VSG will more effectively reduce hyperglycaemic and diabetes comorbidities than the best currently available medical treatment incorporating state of the art pharmacotherapies. ST2OMP is also designed to better understand the pancreatic and enterohepatic mechanisms by which MBS improves diabetes and its associated comorbidities. METHODS AND ANALYSIS: ST2OMP is a prospective, open-label, controlled clinical trial that will recruit 90 postpubertal participants, age range 13-19.9 years, with body mass index ≥35 kg/m2 or >120% of 95th percentile and youth-onset T2D. The primary outcome is the per cent of youth achieving haemoglobin A1c <6.0% at 12 months postgroup allocation (post-VSG vs postmedical group allocation). Secondary outcomes include remission of comorbidities and measures of ß-cell and incretin responses at 12 and 24 months post VSG versus AMT. ETHICS AND DISSEMINATION: The ST2OMP protocol was approved by the Cincinnati Children's Hospital Medical Center and the University of Colorado Institutional Review Boards. Written informed consent is obtained prior to study enrolment. Study findings will be widely disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov NCT04128995.

Alternative Etiologies of Liver Disease in Children With Suspected NAFLD.

OBJECTIVES: To determine the prevalence of alternative causes of liver disease in a cohort of youth with overweight and obesity undergoing evaluation for suspected nonalcoholic fatty liver disease (NAFLD). METHODS: Multicenter, retrospective cohort study of patients aged ≤18 years with overweight and obesity and evidence of elevated serum aminotransferases and/or hepatic steatosis on imaging, referred for suspected NAFLD to Cincinnati Children's Hospital Medical Center (2009-2017) or Yale New Haven Children's Hospital (2012-2017). Testing was performed to exclude the following: autoimmune hepatitis (AIH), Wilson disease, viral hepatitis (B and C), thyroid dysfunction, celiac disease, α-1 antitrypsin deficiency, and hemochromatosis. RESULTS: A total of 900 children with overweight and obesity (63% boys, 26% Hispanic ethnicity) were referred, with a median age of 13 years (range: 2-18). Most had severe obesity (n = 666; 76%) with a median BMI z score of 2.45 (interquartile range [IQR]: 2.2-2.7). Median alanine aminotransferase level at presentation was 64 U/L (IQR: 42-95). A clinically indicated liver biopsy was performed in 358 children (40%) at a median of 6 months (IQR: 1-14) post initial visit; of those, 46% had confirmed nonalcoholic steatohepatitis. Positive autoantibodies were observed in 13% of the cohort, but none met criteria for AIH. Only 19 (2%) were found to have other causes of liver disease, with no cases of viral hepatitis or Wilson disease detected. CONCLUSIONS: In a large, multicenter cohort, the vast majority of children with overweight and obesity with presumed or confirmed NAFLD tested negative for other causes of liver disease. In contrast to a previous pediatric report, no patient was diagnosed with AIH.

Significance of autoantibody seropositivity in children with obesity and non-alcoholic fatty liver disease.

BACKGROUND: Autoantibodies are frequently positive in adults with nonalcoholic fatty liver disease (NAFLD) without concurrent autoimmune hepatitis (AIH). The clinical significance of this is unknown in children. OBJECTIVE: To determine the prevalence of autoantibody positivity in pediatric NAFLD and to evaluate its association with disease severity. METHODS: Multicenter, retrospective study of patients ≤18 years of age with biopsy-confirmed NAFLD. Descriptive statistics were used and groups were compared using Wilcoxon-Mann Whitney or χ2 testing, and multivariable logistic regression was used for binary or ordinal outcomes. RESULTS: One hundred and thirty six patients with a median age of 14 years were included. The median body mass index Z-score was 2.5 (interquartile range 2.2, 2.6). Positive antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal antibody, or any combination of autoantibodies were observed in 22%, 14%, 0%, and 33% of patients, respectively. The proportion of patients with a steatosis score ≥2 was significantly higher in those with positive ANA (P = .045). In the multivariable regression analysis, positive ANA was associated with increased odds of steatosis score ≥2 (odds ratio, 5.91; 95% confidential interval, 1.50-23.26), after controlling for potential confounders. No other significant histology differences were seen between the groups. CONCLUSIONS: Positive ANA and ASMA are common in children with NAFLD; however, anti-LKM positivity is not. ANA positivity is associated with more severe steatosis.

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. METHODS: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. RESULTS: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (<0.05), and over follow-up time, with increasing level of alanine aminotransferase, hemoglobin A1C (P<.05), gamma-glutamyl transferase and development of type 2 diabetes (P<.01). Increasing level of gamma-glutamyl transferase was also associated with reduced odds of any improvement (P = .003). CONCLUSIONS: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.

Glomerular Hyperfiltration Is Associated with Liver Disease Severity in Children with Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To determine the prevalence of renal impairment in a large cohort of youths with histologically confirmed nonalcoholic fatty liver disease (NAFLD), and to determine its association with liver disease severity. STUDY DESIGN: Clinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD at a tertiary care center between 2010 and 2017. Histological NAFLD severity was scored using validated criteria. Glomerular filtration rate (GFR) was calculated and categorized as low (<90 mL/min/1.73 m2), normal (90-136 mL/min/1.73 m2), or high (>136 mL/min/1.73 m2). Univariate and multivariate modeling were used to determine differences between the GFR groups and to control for confounders. RESULTS: The cohort comprised 179 patients (82% non-Hispanic; median age; 14 years; IQR, 12-16 years). One-third of the patients had abnormal renal function, including 36 (20%) with glomerular hyperfiltration and 26 (15%) with low GFR. In multivariable logistic regression, compared with normal GFR, hyperfiltration was independently associated with higher NAFLD activity score (aOR, 2.96; 95% CI, 1.49-5.87; P = .002), after adjusting for age, sex, ethnicity, obesity severity, presence of type 2 diabetes mellitus, and medications. CONCLUSIONS: In this large cohort with histologically confirmed NAFLD, renal impairment was highly prevalent and associated with liver disease severity, independent of obesity severity. Screening patients with confirmed NAFLD for renal complication is recommended.

Metabolic outcomes of surgery in youth with type 2 diabetes.

Youth-onset type 2 diabetes (T2D) is a formidable threat to the health of obese adolescents because of its potential for early-onset and aggressive co-morbidities and complications. The physiology of youth-onset T2D differs from T2D in adults and is associated with a greater degree of insulin resistance, a more rapid decline in pancreatic ß-cell function, and a poorer response to medications. Medical management in youth is focused on combining lifestyle intervention and pharmacological treatment, but these therapies have yet to demonstrate improvements in disease progression. Metabolic bariatric surgery (MBS) is now recommended for the treatment of T2D in adults largely because of the beneficial effects on weight, ability to improve glycemic control, and, in a large proportion of people, induce diabetes remission. MBS is now being performed in adolescents with severe obesity and T2D, with initial results also showing high rates of T2D remission. Here, we review the state of medical management of youth-onset T2D and the outcomes of MBS studies in youth with T2D published to date.

Correction to: Understanding the Bariatric Patient Perspective in the National Patient-Centered Clinical Research Network (PCORnet) Bariatric Study.

In the original article the list of author names and affiliations were incorrect.

Understanding the Bariatric Patient Perspective in the National Patient-Centered Clinical Research Network (PCORnet) Bariatric Study.

BACKGROUND: In 2016, the Patient-Centered Outcomes Research Institute funded the National Patient Centered Clinical Research Network (PCORnet) Bariatric Study (PBS). Understanding the experience of postoperative patients was a key component of this study. METHODS: Nine focus groups were conducted in Southern California, Louisiana, Pennsylvania, and Ohio and in a national advocacy conference for patients with obesity. Participants were identified and recruited in both clinical and community settings. Focus group transcripts were analyzed using an iterative inductive-deductive approach to identify global overarching themes. RESULTS: There were 76 focus group participants. Participants were mostly women (81.4%), had primarily undergone gastric sleeve (47.0%), were non-Hispanic white (51.4%), had some college education (44.3%), and made $100,000 annual income or less (65.7%). Qualitative findings included negative reactions patients received from friends, family, and co-workers once they disclosed that they had bariatric surgery to lose weight; and barriers to follow-up care included insurance coverage, emotional and situational challenges, and physical pain limiting mobility. CONCLUSIONS: These findings confirm the other qualitative findings in this area. The approach to bariatric surgery should be expanded to provide long-term comprehensive care that includes in-depth postoperative lifetime monitoring of emotional and physical health.

Identifying Predictors of Response to Vitamin E for the Treatment of Pediatric Nonalcoholic Steatohepatitis.

BACKGROUND: A subset of patients with nonalcoholic steatohepatitis (NASH) respond to treatment with vitamin E. The characteristics of responders are not known. The objective of this study was to investigate the outcomes of vitamin E use in clinical practice and to determine factors associated with response to treatment. METHODS: A pediatric cohort with NASH treated with vitamin E for 6-24 months was studied retrospectively. Vitamin E response was defined as alanine aminotransferase (ALT) normalization or >50% ALT reduction from baseline. Univariate and multivariate logistic regression was used to determine the predictors of response to vitamin E. Available paired liver biopsy data were analyzed to determine histologic response. RESULTS: Of the 151 children prescribed vitamin E, 73 met inclusion/exclusion criteria. Of those, 28 (38%) were vitamin E responders. Higher baseline serum alkaline phosphatase (ALP) levels, steatosis grade, and Nonalcoholic Fatty Liver Disease Activity Score (NAS) were associated with response to vitamin E (ALP: odds ratio [OR], 14.1; 95% CI, 1.7-118.6; steatosis: OR 2.5; 95% CI, 1.2-5.0; NAS: OR 1.6; 95% CI, 1.1-2.4). In a multivariate logistic regression model, ALP and steatosis grade rendered an area under the curve of 0.75 (P < .001) for the prediction of response to treatment. Ballooning, NAS, and portal inflammation improved significantly with vitamin E in the subcohort (n = 15) with paired liver biopsies. CONCLUSIONS: Vitamin E treatment was associated with significant ALT response in 38% of children. Baseline serum ALP levels and steatosis grade were associated with response to treatment.

Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease.

BACKGROUND/OBJECTIVES: To determine associations between serum 25-hydroxyvitamin D (25(OH)-D) concentrations and histologic nonalcoholic fatty liver disease (NAFLD) severity. SUBJECTS/METHODS: Clinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD. Serum 25(OH)-D concentrations were used to define vitamin D deficiency (≤20 ng/ml), insufficiency (21-30 ng/ml), and sufficiency (≥31 ng/ml). RESULTS: In all, 234 patients (78% non-Hispanic, median age 14 years) were included. The majority (n = 193) were either vitamin D insufficient (50%) or deficient (32%). Eighty-four patients (36%) reported taking vitamin D supplements at the time of biopsy; serum 25(OH)-D concentrations were not higher in those supplemented. There were no differences in the demographic, clinical, and laboratory characteristics of the three vitamin D status groups. Severity of steatosis, ballooning, lobular/portal inflammation, and NAFLD activity score were also not different between the groups. The proportion of patients with significant fibrosis (stage ≥ 2) was higher in those with insufficiency (29%) compared to those who were sufficient (17%) or deficient (15%, p = 0.04). After controlling for important covariates selected from age, body mass index, ethnicity, vitamin D supplementation, and season, the insufficient group had increased odds of a higher fibrosis score compared to the sufficient group (adjusted OR, 2.04; 95%CI, 1.02-4.08). CONCLUSIONS: Vitamin D deficiency and insufficiency are common in children with NAFLD, but not consistently related with histologic disease severity. Prospective longitudinal studies are needed to determine optimal dosing strategies to achieve sufficiency and to determine whether adequate supplementation has an impact on histology.