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.

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.

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 16.6 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 476 miRNAs in the Teen-LABs study and 13 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.

Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Type 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors. METHODS: Children with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection. RESULTS: This study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]). CONCLUSIONS: Children with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.

Randomized placebo-controlled trial of losartan for pediatric NAFLD.

BACKGROUND AND AIMS: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. APPROACH AND RESULTS: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. CONCLUSIONS: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

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.

Five-Year Outcomes of Gastric Bypass in Adolescents as Compared with Adults.

BACKGROUND: Bariatric surgery results in weight loss and health improvements in adults and adolescents. However, whether outcomes differ according to the age of the patient at the time of surgery is unclear. METHODS: We evaluated the health effects of Roux-en-Y gastric bypass in a cohort of adolescents (161 patients enrolled from 2006 through 2012) and a cohort of adults (396 patients enrolled from 2006 through 2009). The two cohorts were participants in two related but independent studies. Linear mixed and Poisson mixed models were used to compare outcomes with regard to weight and coexisting conditions between the cohorts 5 years after surgery. The rates of death and subsequent abdominal operations and selected micronutrient levels (up to 2 years after surgery) were also compared between the cohorts. RESULTS: There was no significant difference in percent weight change between adolescents (-26%; 95% confidence interval [CI], -29 to -23) and adults (-29%; 95% CI, -31 to -27) 5 years after surgery (P = 0.08). After surgery, adolescents were significantly more likely than adults to have remission of type 2 diabetes (86% vs. 53%; risk ratio, 1.27; 95% CI, 1.03 to 1.57) and of hypertension (68% vs. 41%; risk ratio, 1.51; 95% CI, 1.21 to 1.88). Three adolescents (1.9%) and seven adults (1.8%) died in the 5 years after surgery. The rate of abdominal reoperations was significantly higher among adolescents than among adults (19 vs. 10 reoperations per 500 person-years, P = 0.003). More adolescents than adults had low ferritin levels (72 of 132 patients [48%] vs. 54 of 179 patients [29%], P = 0.004). CONCLUSIONS: Adolescents and adults who underwent gastric bypass had marked weight loss that was similar in magnitude 5 years after surgery. Adolescents had remission of diabetes and hypertension more often than adults. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number, NCT00474318.).

Comparison of Quantitative Liver US and MRI in Patients with Liver Disease.

Background Quantitative US techniques can be used to identify changes of liver disease, but data regarding their diagnostic performance and relationship to MRI measures are sparse. Purpose To define associations between quantitative US and MRI measures of the liver in children, adolescents, and young adults with liver disease and to define the predictive ability of quantitative US measures to detect abnormal liver stiffening and steatosis defined with MRI. Materials and Methods In this prospective study, consecutive patients aged 8-21 years and known to have or suspected of having liver disease and body mass index less than 35 kg/m2 underwent 1.5-T MRI and quantitative liver US during the same visit at a pediatric academic medical center between April 2018 and December 2020. Acquired US parameters included shear-wave speed (SWS) and attenuation coefficient, among others. US parameters were compared with liver MR elastography and liver MRI proton density fat fraction (PDFF). Pearson correlation, multiple logistic regression, and receiver operating characteristic curve analyses were performed to assess associations and determine the performance of US relative to that of MRI. Results A total of 44 study participants (mean age, 16 years ± 4 [SD]; age range, 8-21 years; 23 male participants) were evaluated. There was a positive correlation between US SWS and MR elastography stiffness (r = 0.73, P < .001). US attenuation was positively correlated with MRI PDFF (r = 0.45, P = .001). For the prediction of abnormal (>2.8 kPa) liver shear stiffness, SWS (1.56 m/sec [7.3 kPa] cutoff) had an area under the receiver operating characteristic curve (AUC) of 0.95 with 91% sensitivity (95% CI: 71, 99) (20 of 22 participants) and 95% specificity (95% CI: 76, 99) (20 of 21 participants). For the prediction of abnormal (>5%) liver PDFF, US attenuation (0.55 dB/cm/MHz cutoff) had an AUC of 0.75 with a sensitivity of 73% (95% CI: 39, 94) (eight of 11 participants) and a specificity of 73% (95% CI: 55, 86) (24 of 33 participants). Conclusion In children, adolescents, and young adults with known or suspected liver disease, there was moderate to high correlation between US shear-wave speed (SWS) and MR elastography-derived stiffness. US SWS predicted an abnormal liver shear stiffness with high performance. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Khanna and Alazraki in this issue.

Non-Invasive Approaches to Estimate Liver Steatosis and Stiffness in Children With Non-Alcoholic Fatty Liver Disease.

OBJECTIVES: To develop pediatric-specific models that predict liver stiffness and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD), based on clinical and laboratory data. METHODS: Children with NAFLD, who had undergone magnetic resonance imaging with proton density fat fraction (MRI-PDFF) for steatosis quantification and/or magnetic resonance elastography (MRE) for liver stiffness assessment were included. We used data from patients imaged between April 2009 to July 2018 to develop a predictive model for fat fraction and stiffness. We validated the performance of the models using data from a second cohort, imaged between 2018 and 2019. RESULTS: The first cohort (n = 344) consisted of predominantly non-Hispanic (80%), male (67%) adolescents. MRE data were available for 343 children, while PDFF data were available for 130. In multivariable regression, ethnicity, insulin levels, platelet count, and aspartate aminotransferase independently predicted liver stiffness and these variables were used to develop the predictive model. Similarly, sex, ethnicity, alanine aminotransferase, and triglycerides levels independently predicted liver PDFF and were used in the PDFF model. The AUC of the optimal cutoff for the model that predicted a stiffness of >2.71 kPa was 0.70 and for the model that predicted PDFF >5% was 0.78. The validation group (n = 110) had similar characteristics. The correlation coefficient of the model with the measured liver stiffness was 0.30 and with the measured liver PDFF was 0.26. CONCLUSIONS: Pediatric-specific models perform poorly at predicting exact liver stiffness and steatosis; however, in the absence of magnetic resonance imaging can be used to predict the presence of significant steatosis (>5%) and/or significant stiffness (>2.71). Thus, imaging remains an invaluable adjunct to laboratory investigations in determining disease severity.

Insight Into the Adolescent Patient Experience With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease in youth, yet little is known about the adolescent patient's experience with NAFLD, which is key for treatment engagement. We examined adolescents' experiences with NAFLD diagnosis, thoughts on how NAFLD affects their daily life, understanding and perceptions of diagnosis and treatment, and impressions of how to improve care. METHODS: Utilizing a mixed-method design, adolescents with NAFLD (N = 16; Mean age = 15.8 years; Mean BMI = 37 kg/m 2 ) participated in focus groups. To supplement qualitative data, adolescents and their caregiver completed measures assessing illness perceptions, adolescent quality of life, and eating/activity behaviors. RESULTS: Focus group themes suggested reactions to diagnosis varied from unconcerned to anxious. NAFLD diagnosis occurred within the context of other psychological/medical concerns and was not perceived to affect most adolescents' daily lives. Although adolescents understood general contributors to NAFLD, comprehension of their diagnosis varied. Adolescents were more likely to make lifestyle changes when families were supportive, and they preferred tailored recommendations for health behavior change from the healthcare team. Notably, 62.5% of adolescents were more concerned about their weight than NAFLD. Almost half (43.8%) identified as food insecure. CONCLUSIONS: Adolescents with NAFLD may benefit from personalized treatment. Care could be enhanced by ensuring comprehension of diagnosis, problem-solving personal, and family barriers and increasing family support. Harnessing adolescents' desire for weight loss may be a more salient driver for change in disease status. Interventions should also address systemic barriers such as food insecurity to ensure equitable care.

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.

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.

Nutritional Risks in Adolescents After Bariatric Surgery.

BACKGROUND & AIMS: Little is known about prevalence and risk factors for nutritional deficiencies in adolescents after metabolic bariatric surgery. We performed a 5-year prospective cohort study of these. METHODS: Adolescents who had Roux-en-Y gastric bypass (RYGB, n = 161) or vertical sleeve gastrectomy (VSG, n = 67) were enrolled at 5 tertiary-care centers from March 2007 through February 2012. The final analysis cohort included 226 participants (161 who had RYGB and 65 who had VSG). We measured serum levels of ferritin; red blood cell folate; vitamins A, D, B1, B12; and parathyroid hormone at baseline and annually for 5 years. General linear mixed models were used to examine changes over time and identify factors associated with nutritional deficiencies. RESULTS: The participants were 75% female and 72% white, with a mean age of 16.5 ± 1.6 years and mean body mass index of 52.7 ± 9.4 kg/m2 at surgery. Mean body mass index decreased 23% at 5 years, and did not differ significantly between procedures. After RYGB, but not VSG, serum concentrations of vitamin B12 significantly decreased whereas serum levels of transferrin and parathyroid hormone increased. Ferritin levels decreased significantly after both procedures. Hypo-ferritinemia was observed in 2.5% of patients before RYGB and 71% at 5 y after RYGB (P < .0001), and 11% of patients before VSG and 45% 5 y after VSG (P = .002). No significant changes in serum levels of folate or vitamins A, B1, or D were found between baseline and 5 y after either procedure. By 5 y, 59% of RYGB and 27% of VSG recipients had 2 or more nutritional deficiencies. Risk factors associated with specific deficiencies included surgery type, female sex, black race, supplementation intake, weight regain, and for females, pregnancy. CONCLUSIONS: In a prospective study of adolescents who underwent RYGB or VSG, we observed nutritional deficiencies by 5 y after the procedures-particularly in iron and B12 after RYGB. Ongoing nutrient monitoring and supplementation are recommended for all patients, but surgery type, supplementation intake, sex, and race might affect risk. (Clinical trial registration: Adolescent Bariatrics: Assessing Health Benefits and Risk [also known as Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS)], NCT00474318.).

Normal Liver Stiffness Measured with MR Elastography in Children.

Background Stiffness thresholds for liver MR elastography in children vary between studies and may differ from thresholds in adults. Normative liver stiffness data are needed to optimize diagnostic thresholds for children. Purpose To determine normal liver stiffness, and associated normal ranges for children, as measured with MR elastography across vendors and field strengths. Materials and Methods This was a prospective multicenter cohort study (ClinicalTrials.gov identifier: NCT03235414). Volunteers aged 7-17.9 years without a known history of liver disease were recruited at four sites for a research MRI and blood draw between February 2018 and October 2019. MRI was performed on three vendor platforms and at two field strengths (1.5 T and 3.0 T). All MRI scans were centrally analyzed; stiffness, proton density fat fraction (PDFF), and R2* values were expressed as means of means. Mean and 95% confidence intervals (CIs) for liver stiffness were calculated. Pearson correlation coefficient (r), two-sample t test, or analysis of variance was used to assess univariable associations. Results Seventy-one volunteers had complete data and no documented exclusion criterion (median age, 12 years; interquartile range [IQR], 10-15 years; 39 female participants). Median body mass index percentile was 54% (IQR, 32.5%-69.5%). Mean liver stiffness was 2.1 kPa (95% CI: 2.0, 2.2 kPa) with mean ± 1.96 kPa standard deviation of 1.5-2.8 kPa. Median liver PDFF was 2.0% (IQR, 1.7%-2.6%). There was no association between liver stiffness and any patient variable or MRI scanner factor. Conclusion Mean liver stiffness measured with MR elastography in children without liver disease was 2.1 kPa (similar to that in adults). The 95th percentile of normal liver stiffness was 2.8 kPa. Liver stiffness was independent of sex, age, or body mass index and did not vary with MRI scanner vendor or field strength. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Yin in this issue.

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.

Muscle Mass Is Linked to Liver Disease Severity in Pediatric Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To investigate the association between muscle mass and liver disease severity in pediatric patients with non-alcoholic fatty liver disease (NAFLD). STUDY DESIGN: This was a retrospective study of patients aged <20 years followed from 2009 to 2018. Muscle mass was estimated in all patients by measuring magnetic resonance imaging-based total psoas muscle surface area (tPMSA) and correcting for height (tPMSA index = tPMSA/height2). Two cohorts were studied, one with histological confirmation of NAFLD (n = 100) and the other with magnetic resonance imaging (MRI) evidence of hepatic steatosis (n = 236). Histology was scored using Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) criteria. MRI-measured proton density fat fraction (PDFF) and liver stiffness were collected. Demographic, clinical, and socioeconomic status (using a validated Community Deprivation Index [CDI]) were assessed as covariates. Univariate regression analyses, followed by multivariable regression analyses, were used to determine the relationships between tPMSA index and NAS, MRI-PDFF, and liver stiffness, adjusting for clinical, demographic, and CDI variables. RESULTS: In the multivariable regression analyses, higher steatosis score was associated with a lower tPMSA index (OR, 0.73; 95% CI, 0.56-0.96) and younger age (OR, 0.84; 95% CI, 0.73-0.97). Liver PDFF was also significantly associated with the tPMSA index (P = .029), sex (P = .019), and CDI (P = .005). In contrast, liver stiffness was not associated with tPMSA in multivariable analyses. CONCLUSIONS: tPMSA index was independently associated with both imaging and histological features of hepatic steatosis severity in children. Future studies should directly explore the presence and directionality of causative links between muscle mass and steatosis, as well as whether interventions that enhance muscle mass can reduce disease severity in children with NAFLD.

Liver Shear Wave Speed and Other Quantitative Ultrasound Measures of Liver Parenchyma: Prospective Evaluation in Healthy Children and Adults.

OBJECTIVE. The purpose of this study was to use 2D ultrasound shear wave elastography (SWE) to define expected ranges for liver shear wave speed and shear wave dispersion in children and adults without a known history of liver disease. The study also sought to define liver attenuation in adults. SUBJECTS AND METHODS. This was an institutional review board-approved prospective study of 128 children (younger than 18 years old) and 32 adults without liver disease who underwent 2D SWE of the liver with a Canon Aplio i800 ultrasound system (i8CX1 transducer). Ten shear wave speed and shear wave dispersion measurements were obtained. In adults, five attenuation measurements were also obtained. Pearson correlation and t tests were used to define relationships between shear wave speed and dispersion values and predictor variables. Multivariable logistic regression with forward selection was used to generate models. RESULTS. Median age was 5.04 years old for the pediatric participants and 48.92 years old for the adult participants. Mean median shear wave speed and shear wave dispersion were 1.29 ± 0.13 m/s and 11.43 ± 1.75 (m/s)/kHz, respectively, for the pediatric participants and 1.32 ± 0.13 m/s and 10.24 ± 1.65 (m/s)/kHz, respectively, for the adults. Mean median attenuation in adults was 0.52 ± 0.11 dB/cm/MHz. On multivariable modeling, height was the only significant predictor of shear wave speed in children (0.0012 m/s per cm, p < 0.0001) and abdominal wall thickness was the only predictor of shear wave speed in adults (0.12 m/s per cm, p = 0.0008). CONCLUSION. Liver shear wave speed and shear wave dispersion data for children and adults without liver disease provides data against which results from patients with liver disease can be compared. Liver shear wave speed increases during childhood associated with increases in height and shear wave speed increases in adulthood with increasing abdominal wall thickness.

Relative Accuracy of Bioelectrical Impedance Analysis for Assessing Body Composition in Children With Severe Obesity.

OBJECTIVES: The accuracy of different bioelectrical impedance analysis (BIA) devices for assessing body composition in children with obesity is unclear. We determined the relative accuracy of 2 BIA devices compared to dual x-ray absorptiometry (DXA) in obese and severely obese children. METHODS: We measured body composition in a cross-sectional study of 78 obese children by a handheld single frequency tetrapolar BIA device (Omron), a stationary multifrequency octopolar BIA device (InBody 370) and DXA. Intermethod agreement was assessed by intraclass correlations, paired t tests, and Bland-Altman analyses. RESULTS: Participants (37% female, age 14.8 ±â€Š2.7 years) had mean (±standard deviation) body mass index of 36.7 ±â€Š7.5 kg/m, body fat percentage of 46.4% ±â€Š5.2%, and appendicular lean mass of 22.5 ±â€Š6.0 kg by DXA. Intraclass correlations with DXA for body fat percentage were 0.39 and 0.87 for single frequency tetrapolar and multifrequency octopolar BIA devices, respectively. The single frequency tetrapolar BIA underestimated body fat percentage by 5.5% ±â€Š2.9% (P < 0.0001). Differences between the multifrequency octopolar BIA and DXA for body fat percentage (-1.1% ±â€Š2.8%) and appendicular lean mass (-0.3 ±â€Š1.4 kg) were small, and 95% limits of agreement were approximately ±5%. CONCLUSIONS: BIA machines vary in relative accuracy in measuring body composition in children who are obese and severely obese. The multifrequency octopolar BIA device accurately estimated body fat percentage and appendicular lean mass relative to DXA and has the advantage of point of care performance.

Weight Loss and Health Status 3 Years after Bariatric Surgery in Adolescents.

BACKGROUND: Bariatric surgery is increasingly considered for the treatment of adolescents with severe obesity, but few prospective adolescent-specific studies examining the efficacy and safety of weight-loss surgery are available to support clinical decision making. METHODS: We prospectively enrolled 242 adolescents undergoing weight-loss surgery at five U.S. centers. Patients undergoing Roux-en-Y gastric bypass (161 participants) or sleeve gastrectomy (67) were included in the analysis. Changes in body weight, coexisting conditions, cardiometabolic risk factors, and weight-related quality of life and postoperative complications were evaluated through 3 years after the procedure. RESULTS: The mean (±SD) baseline age of the participants was 17±1.6 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 53; 75% of the participants were female, and 72% were white. At 3 years after the procedure, the mean weight had decreased by 27% (95% confidence interval [CI], 25 to 29) in the total cohort, by 28% (95% CI, 25 to 30) among participants who underwent gastric bypass, and by 26% (95% CI, 22 to 30) among those who underwent sleeve gastrectomy. By 3 years after the procedure, remission of type 2 diabetes occurred in 95% (95% CI, 85 to 100) of participants who had had the condition at baseline, remission of abnormal kidney function occurred in 86% (95% CI, 72 to 100), remission of prediabetes in 76% (95% CI, 56 to 97), remission of elevated blood pressure in 74% (95% CI, 64 to 84), and remission of dyslipidemia in 66% (95% CI, 57 to 74). Weight-related quality of life also improved significantly. However, at 3 years after the bariatric procedure, hypoferritinemia was found in 57% (95% CI, 50 to 65) of the participants, and 13% (95% CI, 9 to 18) of the participants had undergone one or more additional intraabdominal procedures. CONCLUSIONS: In this multicenter, prospective study of bariatric surgery in adolescents, we found significant improvements in weight, cardiometabolic health, and weight-related quality of life at 3 years after the procedure. Risks associated with surgery included specific micronutrient deficiencies and the need for additional abdominal procedures. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; Teen-LABS ClinicalTrials.gov number, NCT00474318.).