Search

Lisa Schaaf,1 Sanita Ley,2 Allen Riegler,1 Amy Poetker,1 Stavra Xanthakos,3 Jennifer Sizemore,1 Nancy Crimmins,4 Michael Helmrath,5 Rebekah Tracy,6 Ana Catalina Arce-Clachar,3 Jennifer Crail,1 Nancy Morwessel,1 Kelsey Frenck,1 Fatima Tariq,1 Amy Sanghavi Shah4 1Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Department of Pediatrics, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 3Department of Pediatrics, Division of Gastroenterology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Department of Pediatrics, Cincinnati, OH, USA; 4Department of Pediatrics, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 5Department of Surgery, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 6Center for Better Health and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Lisa Schaaf, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA, Tel +1 610 291 6981, Fax +1 513 636 9677, Email lisa.schaaf@cchmc.orgIntroduction: Diabetes self-management education and lifestyle interventions are the cornerstones of type 2 diabetes (T2D) care; however, the higher risk of comorbidities among youth with T2D requires a comprehensive care model. Traditionally, sub-specialty care relies on a referral model placing the burden on patients/families. In response, we developed a pediatric T2D multidisciplinary clinic (MDC)-A single physical location where patients can access various sub-specialists. The goals of the MDC are to aid with lifestyle modifications and provide referral/access to sub-specialists within the MDC, as determined through screening labs and assessment tools.Methods: We conducted a retrospective chart review of youth seen in the T2D MDC clinic at Cincinnati Children’s Hospital from 1/2020 to 12/2021. We evaluated the frequency that youth met with each specialist and completion rates of annual screening labs.Results: The cohort consisted of 227 youth with T2D (mean age 17.6 years, mean BMI 40.9kg/m2, 64% female, 50% Black or African American, 65% public insurance). All patients met with a diabetes provider and 81.2% met with a registered dietitian/certified diabetes education specialist. Exercise physiology met with 51.5% of patients, gastroenterology met with 34.8% of patients, social work met with 44.1% of patients, clinical psychology met with 27.3% of patients, and bariatric surgery met with 9.7% of patients. Percent completion of annual labs were: 98.2% for HbA1c, 84.6% for urine microalbumin, 83.7% for lipids, 90% for liver function, 59.5% for retinopathy, and 45.4% for the Patient Health Questionnaire-9.Conclusion: The majority of patients received diabetes and nutrition education and annual screening labs. Exercise counseling and sub-specialty care remain below 60% in part due to services not being available at every MDC. Our goals are to increase access to subspecialty care within the MDC’s and consider additional care delivery methods to provide comprehensive care to youth with T2D.Keywords: pediatrics, type 2 diabetes, multidisciplinary, adolescent, comorbidities

Background: Studies on adults have shown an association between overt or subclinical hypothyroidism (SH) and metabolic dysfunction-associated steatotic liver disease (MASLD). The goal of this study was to assess the relationship between thyroid-stimulating hormone (TSH) levels and the histological characteristics of MASLD in youth., Methods: This observational study used prospectively collected liver biopsy and clinical data from youth enrolled in two pediatric clinical trials in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Thyroid assays were compared between youth with MASLD and population-based controls aged ≤18 years from the National Health and Nutrition Examination Survey (NHANES). Individuals with overt hypothyroidism, abnormal anti-thyroid antibody, or thyroid-related medications were excluded. SH was defined as TSH between 4.5-10.0 uIU/L. Multinomial logistic regression was used to test the association between TSH and MASLD histological changes at baseline, adjusting for age, sex, race/ethnicity, and body mass index. Mixed-effect models, including treatment and time, were used for the longitudinal analysis., Results: Mean TSH, total thyroxine (T4), total triiodothyronine (T3), and free T4 levels were higher ( p <0.001) in the NASH CRN cohort (n=218; 421 observations) than in the NHANES cohort (n=2,198). TSH levels were positively associated with increased steatosis over time ( p =0.03). SH was associated with borderline or definite metabolic-associated steatohepatitis on histology at baseline ( p =0.03) and with changes in fibrosis over time ( p =0.01)., Conclusion: The association between TSH and steatosis severity in individuals with normal thyroid hormone concentrations suggests an independent role of TSH in MASLD., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Objective: To investigate the relationship between longitudinal changes in body composition and liver disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD)., Study Design: This longitudinal, single-center, retrospective analysis included patients aged <20 years followed for MASLD who had had ≥2 bioelectrical impedance analyses (BIAs) performed. MASLD regression was defined as alanine aminotransferase (ALT) normalization or a decrease of >50% from baseline. Fat and skeletal muscle mass were adjusted for size by calculating respective indices (dividing by height 2 ). Logistic and linear regressions were used to determine the independent relationship between changes in body composition over time and serological markers of liver disease severity., Results: We included 258 patients (75% male, 50% Hispanic) with a median age of 14 years (IQR, 11-16 years) at the time of first BIA. Median body mass index (BMI) z-score at baseline was 2.33 (IQR, 2.04-2.62). Median time from first to last BIA was 12 months (IQR, 6-24 months). A decrease in fat mass index was independently associated with reductions in ALT and gamma glutamyl transferase and increased odds of MASLD regression (OR; 0.55; P < .001). Fat mass index reduction was superior to BMI z-score in predicting MASLD regression. Change in skeletal muscle mass index was not associated with change in ALT or gamma glutamyl transferase., Conclusions: Changes in fat mass, not skeletal muscle mass, are associated with serological markers of liver injury in youth with MASLD. Fat mass changes outperform BMI z-score changes in predicting MASLD regression. BIA can serve as an adjunct biomarker of liver disease progression., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.

Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate longitudinal changes in plasma-PFAS after the time of bariatric surgery. This study included 214 adolescents with severe obesity who had available longitudinal measures of plasma-PFAS and underwent bariatric surgery between 2007 and 2012. Underlying effects related to undergoing bariatric surgery were found to be associated with an initial increase or plateau in concentrations of circulating PFAS up to 6 months after surgery followed by a persistent decline in concentrations of 36 months (p < 0.001 for all plasma-PFAS). Bariatric surgery in adolescents was associated with a decline in circulating PFAS concentrations. Initially following bariatric surgery (0-6 months) concentrations were static followed by decline from 6 to 36 months following surgery. This may have large public health implications as PFAS are known to be associated with numerous metabolic related diseases and the significant reduction in circulating PFAS in individuals who have undergone bariatric surgery may be related to the improvement of such metabolic related diseases following bariatric surgery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas Inge reports a relationship with Standard Bariatrics, Teleflex, and Mediflex, and royalties from Wolters Kluwer (UpToDate) that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD., Methods: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG)., Results: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m 2 was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both)., Conclusions: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes., Methods: We included 63 participants from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort. We assessed 4,4'-DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4'-DDE via fluorescent staining and imaging., Results: A dose-response relationship was observed, with the low-exposure group having a greater reduction in BMI during the first year compared to higher-exposure groups and showing smaller regains compared to higher-exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4'-DDE during adipogenic differentiation for 12 days showed a concentration-dependent increase in lipid accumulation., Conclusions: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification., Competing Interests: Declaration of interests Manal F. Abdelmalek consults, advises, and received grants from Bristol Myers Squibb, Hanmi, Intercept, Inventiva, and Madrigal. She consults and advises 89Bio, Merck, NGM Bio, Novo Nordisk, Sonic Incytes, and Theratechnologies. She is on the speakers’ bureau for the Chronic Liver Disease Foundation, Clinical Care Options, Fishawack, Medscape, and Terra Firma. She received grants from Allergan, Boehringer Ingelheim, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Novo Nordisk, Poxel, Target NASH, and Viking. Quentin M. Anstee, on behalf of Newcastle University, consults for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, GENFIT, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Poxel, RTI, Resolution Therapeutics, Ridgeline Therapeutics, Roche, Shionogi, and Terns. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He holds intellectual property rights with Elsevier, Ltd. Ramon Bataller is on the speakers’ bureau for Abbvie and Gilead. Ulrich Beuers consults for CSL Behring. He is on the speakers’ bureau for Abacus and Zambon. Elisabetta Bugianesi advises Boehringer Ingelheim, MSD, and Novo Nordisk. Helena Cortez-Pinto consults and received grants from Novo Nordisk and Roche. She received grants from Eisai, Gilead, GMP-Orphan, and Intercept. Kenneth Cusi Consults for Aligos, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Covance, Lilly, Madrigal, Myovant, Novo Nordisk, Prosciento, Sagimet, and Siemens. He received grants from Echosens, Inventiva, LabCorp, Nordic Biosciences, and Target NASH. Sven M. Francque consults and received grants from Astellas, Falk, GENFIT, Gilead, Glympse Bio, Janssen, Inventiva, Merck, Pfizer, and Roche. He consults for AbbVie., Actelion, Aelin Therapeutics, Allergan, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Coherus, CSL Behring, Echosens, Eisai, ENYO, Galapagos, Galmed, Genetech, Intercept, Julius Clinical, Madrigal, Medimmune, NGM Bio, Novartis, Novo Nordisk, and Promethera. Samer Gawrieh consults for Pfizer and TransMedics. He received grants from LiverIncytes, Viking, and Zydus. Manuel Romero-Gómez advises and received grants from Novo Nordisk and Siemens. He advises AbbVie., Alpha-sigma, Allergan, AstraZeneca, Axcella, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Intercept, Inventia, Kaleido, MSD, Pfizer, Prosciento, Rubió, Shionogi, Sobi, and Zydus. He received grants from Echosens and Theratechnologies. Cynthia D. Guy consults for 89Bio, CymaBay, HistoIndex, Madrigal, and NGM. Stephen Harrison consults, advises, is involved with trials, received grants, and owns stock in Akero, Galectin, GENFIT, Hepion, and NGM Bio. He consults, advises, is involved with trials, and received grants from Axcella, Gilead, Intercept, Madrigal, and Poxel. He consults, advises, received grants, and owns stock in NorthSea Therapeutics. He consults, advises, and is involved with trials for Terns. He consults, advises, and received grants from HighTide, Novartis, Novo Nordisk, and Sagimet. He consults, advises, and owns stock in HistoIndex, Metacrine, and Sonic Incytes. He consults, received grants, and owns stock in Cirius. He consults, is involved with trials, and received grants from ENYO and Viking. He is involved with trials and received grants from Genentech. He consults and is involved with trials for Ionis. He consults and received grants from CiVi, CymaBay, Galmed, and Pfizer. He consults and owns stock in Hepta Bio. He consults and advises for Altimmune, Echosens North America, Foresite Labs, and Medpace. He advises and owns stock in ChronWell. He consults for AgomAb, Alentis, Aligos Therapeutics, Alimentiv, Blade, Bluejay, Boston Pharmaceuticals, Boxer Capital, CanFite BioPharma, the Chronic Liver Disease Foundation (CLDF), CohBar, Corcept, Fibronostics, Fortress Biotech, Galecto, Gelesis, GSK, GNS Healthcare, GRI Bio, Hepagene, Indalo, Inipharm, Innovate Biopharmaceuticals, Kowa Research Institute, Merck, MGGM, NeuroBo, Nutrasource, Perspectum, Piper Sandler, Prometic (now Liminal BioSciences), Ridgeline Therapeutics, Silverback, and Zafgen (now Larimar). He advises Arrowhead BVF Partners, Humana, and Pathai. He received grants from Bristol Myers Squibb, Conatus, Immuron, and Second Genome. Samuel Klein advises Alnylam, Altimmune, and Merck. Kris V. Kowdley advises, is on the speakers’ bureau, and received grants from Gilead and Intercept. He advises, received grants, and owns stock in Inipharm. He advises and received grants from 89bio, CymaBay, GENFIT, Ipsen, Madrigal, Mirum, NGM Bio, Pfizer, Pliant, and Zeds. He advises Enact, HighTide, and Protagonist. He is on the speakers’ bureau for AbbVie. He received grants from Boston Pharmaceuticals, Corcept, GSK, Hanmi, Janssen, Novo Nordisk, Terns, and Viking. Jeffrey V. Lazarus consults for Novavax. He received grants from AbbVie, Gilead, MSD, and Roche Diagnostics. Rohit Loomba consults and received grants from Arrowhead, AstraZeneca, Bristol Myers Squibb, Galmed, Gilead, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal, Merck, NGM Bio, Novo Nordisk, Pfizer, and Terns. He consults and owns stock in 89Bio and Sagimet. Consults for Altimmune, Anylam, Amgen, CohBar, Glympse Bio, HighTide, Inipharm, Metacrine, Novartis, Regeneron, Theratechnologies, and Viking. He received grants from Boehringer Ingelheim, Galectin Therapeutics, Hanmi, and Sonic Incytes. He cofounded and owns stock in LipoNexus. Phillip N. Newsome consults, advises, is on the speakers’ bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GSK, Intercept, Madrigal, Pfizer, Poxel, and Sun Pharma. He is on the speakers’ bureau for AiCME. Elizabeth E. Powell advises and received grants from Novo Nordisk. Vlad Ratziu consults and received grants from Intercept. He consults for Boehringer Ingelheim, Eny, Madrigal, NorthSea, Novo Nordisk, E. Poxel, and Sagimet. He received grants from Gilead. Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GSK, Novo Nordisk, HistoIndex, Intercept, Madrigal, NGM Bio, and Sonic Incytes. Michael Roden consults and received grants from Boehringer Ingelheim and Novo Nordisk. He consults for Lilly. He is on the speakers’ bureau for AstraZeneca. Arun J. Sanyal consults and advises Avant Santé and AstraZeneca. He consults and received grants from Akero, Bristol Myers Squibb, Intercept, Lilly, Madrigal, and Novo Nordisk. He consults and owns stock in Rivus. He consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelhiem, 89Bio, Echosense, Genentech, Gilead, GSK, HistoIndex, Malinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns, and Zydus. He owns stock in Durect, Exhalenz, GENFIT, Indalo, Inversago, and Tiziana. He received royalties from Elsevier and Wolters Kluwer. Marcelo Silva consults, advises, and received grants from Zydus. He received grants from Inventiva and MSD. Dina Tiniakos consults for Clinnovate Health, ICON, Ionis, Inventiva, Merck, and Verily. Luca Valenti consults and received grants from Gilead. He consults for AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, and Resalis Therapeutics. Miriam B. Vos consults and advises Thiogenesis. She consults and received grants from Target Real World Evidence. She consults and owns stock in Intercept. She consults for Albireo, Boehringer Ingelheim, Lilly, Novo Nordisk, and Takeda. She received grants from Bristol Myers Squibb, Quest, and Sonic Incytes. Vincent Wai-Sun Wong consults and received grants from Gilead. He consults for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet, and TARGET PharmaSolutions. He owns stock in Illuminatio Medical Technology. Yusuf Yilmaz consults for Zydus. He advises Novo Nordisk. He is on the speakers’ bureau for Echosens. Zobair Younossi consults for Bristol Myers Squibb, Gilead, Intercept, Madrigal, Merck, Novartis, Novo Nordisk, Quest, Siemens, and Terns. The remaining authors have no conflicts to report., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher D. Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome (senior), NAFLD Nomenclature consensus group. Published by Elsevier España, S.L.U. All rights reserved.)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome, NAFLD Nomenclature consensus group. Published by Elsevier B.V. All rights reserved.)

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained ( r 2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Background: Performance of vibration-controlled transient elastography (VCTE) is inadequately validated in pediatric nonalcoholic fatty liver disease (NAFLD). We aimed to assess the technical performance of VCTE in pediatric NAFLD and define the agreement between VCTE and reference standards of imaging and/or biopsy. Methods: This prospective study recruited participants with known or suspected NAFLD who underwent a research VCTE examination (FibroScan Mini 430). Ten valid VCTE liver stiffness measurements (kPa) and controlled attenuation parameter (CAP) (dB/m) measurements were obtained for each participant. Available clinically acquired MR elastography and magnetic resonance imaging proton density fat fraction (PDFF), liver ultrasound shear wave elastography, and biopsy served as references standards. Results: Eighty-four consecutive participants were included (55 males, mean age 15.0 ± 3.5 years, mean BMI 36.6 ± 9.4 kg/m 2 ). VCTE examinations were complete in 80/83 participants. 37/83 participants were examined with an XL probe. There was no significant correlation between CAP and PDFF [ n  = 16; r  = 0.17 (95% confidence interval [CI]: -0.34 to 0.61), p  = 0.5] or between VCTE liver stiffness and MR elastography stiffness [ n  = 27; r  = 0.31 (95% CI: -0.07 to 0.62), p  = 0.10]. For prediction of any fibrosis stage ≥1 on biopsy ( n  = 9/15 participants), VCTE median liver stiffness >5.1 kPA had an area under receiver operating characteristic curve of 0.52 (95% CI: 0.26-0.78) with a sensitivity of 88.9% and specificity of 16.6% ( p  > 0.99). Conclusions: Complete VCTE examinations could be obtained in most pediatric patients with NAFLD. Neither VCTE liver stiffness nor CAP correlated well with measures of liver fat or stiffness by established imaging modalities and biopsy.

Background: Among adults with nonalcoholic fatty liver disease (NAFLD), alpha-1-antitrypsin (A1AT) heterozygosity has been linked to advanced liver disease; pediatric data remain unclear., Objective: The objective of this study is to determine whether A1AT PiZ or PiS variants are associated with liver disease severity in youth with NAFLD., Methods: Retrospective study of youth with confirmed NAFLD. Multivariable logistic regression used to determine independent associations between A1AT risk variants and histologic severity [NAFLD activity score (NAS) ≥5 and/or significant fibrosis (stage ≥2)]., Results: The cohort included 269 patients, mean age 12 [±3] years with NAFLD and A1AT phenotyping (n = 260) and/or A1AT levels (n = 261). The mean NAS of the cohort was 4.2 [±1.5]; 50% had any, and 18% had significant fibrosis. Most (86%) had the MM A1AT phenotype, while 7% had the MS and 3% the MZ phenotype (the rest had other, nonpathogenic variants). Mean A1AT level was 123 mg/dL [±20]. A1AT levels did not differ by low versus high NAS (122 ± 2 vs 126 ± 19 mg/dL, P = 0.12) or by no/mild versus significant fibrosis (123 ± 20 vs 126 ± 20 mg/dL, P = 0.23, respectively). Carriers and noncarriers of the PiS or PiZ variants had similar NAS (mean NAS 3.8 ± 1.6 vs 4.2 ± 1.4; P = 0.25, respectively). Fibrosis severity did not differ by carrier vs noncarrier group: 38% versus 52% had any fibrosis ( P = 0.17) and 14% versus 18% had significant fibrosis ( P = 0.80, respectively). Multivariable modeling showed no association between A1AT risk variants and histologic severity., Conclusion: While not uncommon, carriage of the A1AT PiZ or PiS risk variants was not associated with histologic severity in children with NAFLD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: To evaluate the prevalence of suspected nonalcoholic fatty liver disease (NAFLD) in young children with obesity and determine associated risk factors. Methods: Retrospective single-center study of children with obesity, ages 2-6 years. Suspected NAFLD was defined as an alanine aminotransferase (ALT) >30 U/L. Multivariable analyses were performed to determine predictors of elevated ALT. Results: Among 237 children 2-6 years old, 35% had elevated ALT. Multivariable analysis showed that higher BMI z score [odds ratio (OR): 1.5 confidence interval (95% CI: 1.04-1.92)] and higher gamma-glutamyl transferase (GGT) [OR: 21.3 (95% CI: 3.7-121.1)] predicted elevated ALT. Of those with ≥2 ALT levels, 38% ( n  = 33/86) had a persistently elevated ALT (median ALT >30 U/L). Only 7% of patients with ALT >30 U/L underwent further testing to evaluate for alternative causes of liver disease. Conclusion: Suspected NAFLD is common in young children with obesity and predicted by obesity severity and GGT. Other cardiometabolic markers were equivalent between those with normal vs. elevated ALT, suggesting NAFLD onset may precede development of comorbidities. Earlier screening will enable prompt diagnosis and intervention, which may prevent or delay the onset of cardiometabolic diseases commonly associated with NAFLD in adolescence and adulthood.

Introduction: To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups., Methods: Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5., Results: In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences., Conclusions: There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.

Objective: To investigate the prevalence and characteristics of children with nonalcoholic fatty liver disease (NAFLD) who reduce their body mass index (BMI) z-score (BMIz) by >.25, a goal in obesity medicine, and to determine the BMIz decrease needed for serum aminotransferase normalization., Study Design: This retrospective, single-center study included patients aged <18 years followed for NAFLD. Patients who had undergone weight loss surgery or had other reasons for weight loss/gain were excluded. Logistic regression was used to determine the odds of achieving a BMIz change of >-.25, as well as predictors of this outcome., Results: Of the 784 children who met the study criteria (median age, 13 years; 66% male; 24% Hispanic), 541 had a lowest BMIz at >90 days following the baseline clinic visit. Of these children, 168 (31%) had a BMIz change of >-.25 from baseline over a median of 367 days (IQR, 201-678 days). Decreases in serum aminotransferase and lipid levels were seen in both groups (with and without a BMIz change of >-.25); however, these decreases were more pronounced in children who achieved a BMIz drop of >.25. Hemoglobin A1c concentration did not change in either group. Young age (OR, .861; 95% CI, .81-.92; P < .01) and non-Hispanic ethnicity (OR of non-Hispanic vs Hispanic, .61; 95% CI, .38-.97; P < .04) were predictors of a BMIz change >-.25. The BMIz decrease associated with normalization of serum alanine aminotransferase was .27., Conclusions: A BMIz reduction of >.25 is associated with significant changes in serum aminotransferase levels. These findings can further guide the clinical management of children with NAFLD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The objective of this study was to identify the prevalence of health-related social needs among youth with nonalcoholic fatty liver disease (NAFLD)., Methods: Retrospective review of prospectively administered health-related social needs questionnaires from Steatohepatitis Clinics., Results: Patients with NAFLD (n=271) were predominantly male (72%), and non-Hispanic (68%). The most common unmet need was food insecurity (13%, n=36). Families who endorsed food insecurity at the first visit were 27-fold more likely to have unmet health-related social needs persist at subsequent visits than those who were food-secure at their first visit (95% CI: 6.7-111)., Conclusion: Screening for social, economic, and environmental needs may identify previously unrecognized family challenges and may enhance intervention delivery, inform resource allocation, and improve outcomes., Competing Interests: Financial Disclosure: The authors have no conflicts of interest relevant to this article to disclose

Objectives: Little is known about the behavioral and psychosocial correlates of pediatric nonalcoholic fatty liver disease (NAFLD). Given diet contributes to the development and persistence of NAFLD, we examined (1) the prevalence of unhealthy eating behaviors (UEB), (2) whether these varied by NAFLD or nonalcoholic steatohepatitis (NASH) presence, and explored (3) the association of psychopathology with NAFLD., Methods: Before metabolic and bariatric surgery (MBS), adolescents (N = 159; Mage = 16.4; MBMI = 53.7 kg/m2, 73% girls, 62.3% white) self-reported presence/absence of 10 UEB (Questionnaire on Eating and Weight Patterns-Revised, Night Eating Questionnaire, Look AHEAD). NAFLD and NASH presence was assessed by intraoperative liver biopsy. Height/weight, blood pressure, and blood specimens were obtained. A medical comorbidity index was created (prediabetes/diabetes, dyslipidemia, elevated blood pressure). Psychopathology was assessed in a subgroup completing the Youth Self-Report (N = 98)., Results: Binge eating disorder symptomatology was associated with higher odds of NAFLD whereas frequent eating out was associated with lower odds of NAFLD. Among those with NAFLD frequent eating out was associated with higher odds of NASH while nocturnal eating was associated with lower odds of NASH. Separate models identified internalizing psychopathology as associated with higher odds of NAFLD after controlling for demographics, number of UEB, and medical comorbidities., Conclusions: Results suggest potential phenotypical differences between adolescents presenting for MBS with/without NAFLD, with implications for behavioral/psychosocial targets for screening and intervention. Replication should occur in a sample with greater gender and ethnic diversity to improve generalizability. Understanding differences in the context of surgical weight loss and comorbidity resolution is indicated., Competing Interests: The Teen-LABS consortium is funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), through grants UM1DK072493 (PI, Dr Thomas Inge, University of Colorado, Denver, CO), and UM1DK095710 (PI, Dr Changchun Xie, University of Cincinnati, OH). The TeenView ancillary was supported by grant R01DK080020 (PI: M.H.Z.). Dr S.X's effort was supported by the NIDDK K23 grant DK080888 (PI S.X.). Dr S.L.L.'s effort, in part, was supported by an NIH postdoctoral training grant (T32 DK063929). The aforementioned funding sources played no role in study design, data collection, analysis and interpretation of data, report writing, or in the decision to submit the article for publication. For the remaining authors, no conflicts of interest or funding sources are declared., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Abstract: To investigate the effect of high fructose diet on ultrastructure and content of hepatic mitochondria, we randomized 6-8 weeks old male C57Bl6/J mice to ad lib chow or high-fat-high-fructose (HF2) diet for 32 weeks. HF2-fed mice gained more weight, had higher plasma alanine aminotransferase, and fasting glucose levels and increased hepatic triglyceride content at all time points compared to chow-fed mice. HF2-fed mice had lower mitochondrial to nuclear DNA ratio compared to chow-fed mice. HF2-fed mice had lower average mitochondrial surface area and the number of mitochondria compared to chow-fed mice. HF2-fed mice had higher expression of the hepatic endoplasmic reticulum stress marker Chop, compared to chow-fed mice. A diet high in fat and fructose leads to enhanced hepatic mitochondrial aging, depletion, and dysfunction, which may be important determinants of nonalcoholic steatohepatitis pathogenesis., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Competing Interests: Declaration of competing interest SAP, ESK, EAT, SK, AL, AM, HT, IC, AG, MWG, DAV, AA and FC have no competing interests. ME is a member of the advisory board for AMRA-Medical. SX has received research funding from Target RWE, restricted research funding from Axcella Health and consulting with Intercept Pharmaceuticals. CSM has been a shareholder of and reports grants through his institution and personal consulting fees from Coherus Incand Pangea Inc., reports grants through his institution and personal consulting fees from Novo Nordisk, reports personal consulting fees and in kind support with research reagents from Ansh -Ιnc., reports personal consulting fees from Genfit, P.E.S., Amgen, Intercept, Astra Zeneca, Aegerion and Regeneron, reports in kind support (meals during educational activities) from Amarin, Jansen, Boehringer Ingelheim and travel support and fees from TMIOA, the California Walnut Commission and the cardio metabolic health conference.

Background and Objectives: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity., Methods: Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases)., Results: Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups., Conclusions: Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Background: Paediatric non-alcoholic fatty liver disease (NAFLD) is highly prevalent among children with obesity. The primary objective of this study was determining whether obesity severity is associated with NAFLD severity. By using paediatric classifications for severe obesity, clinicians may be able to better risk stratify patients, which in turn would guide more effective management and treatment., Methods: Retrospective cohort study including patients followed at Cincinnati Children's Medical Center for NAFLD. Patients were categorized as overweight or class I, II, III obese based on established body mass index (BMI) cut-offs. Liver disease severity was determined using biochemical, imaging (magnetic resonance elastography [MRE]), and histologic evidence of liver injury., Results: Three cohorts were studied individually based on the method used to assess disease severity (biochemical n = 767, imaging n = 366, and histology n = 249). Between the three cohorts, there were significant differences in age, proportion of patients with class II and class III obesity, and serum alanine transaminase (ALT) levels. In the biochemistry cohort, the odds of having ALT > 80 U/L were highest in patients with class III obesity (P = .026). In the imaging cohort, liver stiffness was significantly different between BMI groups of patients (P = .001). In the histology cohort, those with class III obesity had significantly higher odds of NAFLD activity score (NAS) ≥ 5 (P = .012)., Discussion: Obesity severity is associated with liver disease severity. Patients with more severe obesity are more likely to have more advanced liver disease, a finding that can assist in risk stratification, as well as monitoring and treatment approaches., (© 2019 World Obesity Federation.)

Shared decision-making (SDM) is a best practice for delivering high-quality, patient-centered care when there are multiple options from which to choose. A patient decision aid (PDA) to promote SDM for the treatment of adolescent severe obesity was piloted among 12-17-year-olds ( n = 31) from six pediatric weight management programs within the Childhood Obesity Multi Program Analysis and Study System (COMPASS). Medical providers used a brochure that described indications, risks, and benefits of intensive lifestyle management alone versus bariatric surgery plus lifestyle. Immediately after, patients/families completed a survey. Patient/family perceptions of provider effort to promote understanding of health issues, to listen to what mattered most to them, and to include what mattered most to them in choosing next steps averaged 8.6, 8.8, and 8.7, respectively (0 = no effort, 9 = every effort). Nearly all (96%) reported knowing the risks/benefits of each treatment option and feeling clear about which risks/benefits mattered most to them. Most (93%) reported having enough support/advice to make a choice, and 89% felt sure about what the best choice was. Providers largely found the PDA to be feasible and acceptable. This pilot will guide a more rigorous study to determine the PDA's effectiveness to support decision-making for adolescent severe obesity treatment.

Objective: To assess liver disease progression using paired magnetic resonance imaging (MRI) measurements of liver fat fraction (FF) and stiffness., Study Design: Retrospective cohort study including patients with nonalcoholic fatty liver disease who had undergone repeat MRI studies. Descriptive statistics were used, as well as Pearson or Spearman correlation when appropriate. Mixed model analyses were used to determine relationships between liver FF/stiffness and predictor variables., Results: Sixty-five patients (80% non-Hispanic, mean age 14 ± 3 years) were included. Time from first to last MRI was 27 ± 14 months. Over time, body mass index z score remained stable, and there were no significant differences in mean serum aminotransferases, insulin, glucose, triglycerides, low-density lipoprotein, and high-density lipoprotein (HDL) levels. However, the proportion of patients with alanine aminotransferase (ALT) < 50 U/L increased. MRI FF and stiffness decreased in 29% and 20% of patients, respectively, and increased in 25% and 22% of patients, respectively. There was a weak positive correlation between FF change and ALT change (r = 0.41, P = .053) and a moderate negative correlation between change in FF and change in serum HDL levels (r = -0.58, P = .004). After adjusting for HDL, increase in serum insulin was the only variable predictive of increase in FF (P = .061). There was no correlation between change in liver stiffness and change in ALT (r = .02, P = .910)., Conclusions: MRI-determined hepatic FF and stiffness improved in a minority of patients overtime. ALT levels were not reflective of the change in FF or stiffness. MRI-based imaging is complementary in the assessment of NAFLD progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Magnetic resonance imaging (MRI) techniques are increasingly used to quantify and monitor liver tissue characteristics including fat fraction, stiffness, and liver volume. The purpose of this study was to assess the inter-relationships between multiple quantitative liver metrics and patient-specific factors in a large pediatric cohort with known or suspected fatty liver disease., Materials and Methods: In this IRB-approved, HIPAA-compliant study, we retrospectively reviewed patient data and quantitative liver MRI results in children with known/suspected fatty liver disease. Relationships between liver MRI tissue characteristics and patient variables [sex, age, body mass index (BMI), diabetic status (no diabetes mellitus, insulin resistance/"prediabetes" diagnosis, or confirmed diabetes mellitus), and serum alanine transaminase (ALT)] were assessed using linear mixed models., Results: 294 quantitative liver MRI examinations were performed in 202 patients [128/202 (63.4%) boys], with a mean age of 13.4 ± 2.9 years. Based on linear mixed models, liver fat fraction was influenced by age (-0.71%/+1 year, p = 0.0002), liver volume (+0.006%/+1 mL, p < 0.0001), liver stiffness (-2.80%/+1 kPa, p = 0.0006), and serum ALT (+0.02%/+1 U/L, p = 0.0019). Liver stiffness was influenced by liver volume (+0.0003 kPa/+1 mL, p = 0.001), fat fraction (-0.02 kPa/+1% fat, p = 0.0006), and ALT (0.002 kPa/+1 U/L, p = 0.0002). Liver volume was influenced by sex (-262.1 mL for girls, p = 0.0003), age (+51.8 mL/+1 year, p = 0.0001), BMI (+49.1 mL/+1 kg/m 2 , p < 0.0001), fat fraction (+30.5 mL/+1% fat, p < 0.0001), stiffness (+192.6 mL/+1 kPa, p = 0.001), and diabetic status (+518.94 mL for diabetics, p = 0.0009)., Conclusions: Liver volume, fat fraction, and stiffness are inter-related and associated with multiple patient-specific factors. These relationships warrant further study as MRI is increasingly used as a non-invasive biomarker for fatty liver disease diagnosis and monitoring.

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score. An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values. Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27years, age range: 4-67years). The median GD-DS3 score was 4 (range: 1-10.1) and median MRE value was 2.43kPa (range: 1.30-5.20kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r=0.47, p<0.001 for all scores, r=0.68, p<0.001 for complete scores and r=0.46, p<0.07 for incomplete scores. The inter-observer variation of bone marrow burden showed only fair agreement with a Kappa coefficient of 0.26. There is a significant positive correlation between increasing liver stiffness and increasing composite GD-DS3 scores. This supports the use of MRE, a non-invasive reproducible quantitative test, as both an additional assessment and independent marker for monitoring disease severity and progression in GD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [M age 16.9 ± 0.4 yr, body mass index (BMI) z-score 2.7 ± 0.1] undergoing bariatric surgery and liver biopsy categorized into three groups: no steatosis (normal, n = 8), steatosis only (n = 13), or NASH (n = 10) by liver histology. Age, body weight, and BMI did not differ among groups, but subjects with NASH were more insulin resistant (increased homeostatic model assessment/insulin resistance, P < 0.05 vs. other groups). RNA-Seq revealed 175 up- and 492 downregulated mRNA transcripts (≥±1.5-fold, false discovery rate <0.10) in IAT between NASH vs. Normal, with "mitochondrial dysfunction, P = 4.19E-7" being the top regulated canonical pathway identified by Ingenuity Pathway Analysis; only 19 mRNA transcripts were up- and 148 downregulated when comparing Steatosis vs. Normal, with suppression of "EIF2 signaling, P = 1.79E-27" being the top regulated pathway indicating increased cellular stress. A comparison of IAT between NASH vs. Steatosis found 515 up- and 175 downregulated genes, with "antigen presentation, P = 6.03E-18" being the top regulated canonical pathway and "inflammatory response" the top diseases and disorders function. Unique transcriptomic differences exist in IAT from severely obese adolescents with distinct stages of NAFLD, providing an important resource for identifying potential novel therapeutic targets for childhood NASH.

Purpose To evaluate the correlation between ultrasonographic (US) point shear-wave elastography (SWE) and magnetic resonance (MR) elastography liver shear-wave speed (SWS) measurements in a pediatric population and to determine if US data dispersion affects this relationship. Materials and Methods Institutional review board approval was obtained for this HIPAA-compliant investigation; informed consent and patient assent (as indicated) were obtained. Patients (age range, 0-21 years) undergoing clinical liver MR elastography between July 2014 and November 2015 were prospectively enrolled. Patients underwent two-dimensional gradient-recalled-echo 1.5-T MR elastography with point SWE performed immediately before or immediately after MR elastography. Spearman rank correlation coefficients were calculated to assess the relationship and agreement between point SWE and MR elastography SWS measurements. Uni- and multivariate logistic regression were performed to identify predictors of US data dispersion, with the best multivariate model selected based on Akaike information criterion. Results A total of 55 patients (24 female) were enrolled (mean age, 14.0 years ± 3.9 (standard deviation) (range, 3.5-21.4 years). There was fair correlation between point SWE and MR elastography SWS values for all patients (ρ = 0.33, P = .016). Correlation was substantial, however, when including only patients with minimal US data dispersion (n = 26, ρ = 0.61, P = .001). Mean body mass index (BMI) was significantly lower in patients with minimal US data dispersion than in those with substantial US data dispersion (25.4 kg/m 2 ± 7.8 vs 32.3 kg/m 2 ± 8.3, P = .003). At univariate analysis, BMI (odds ratio, 1.12; 95% confidence interval [CI]: 1.03, 1.21; P = .006) and abdominal wall thickness (odds ratio, 2.50; 95% CI: 1.32, 4.74; P = .005) were significant predictors of US data dispersion. In the best multivariate model, BMI was the only significant predictor (odds ratio, 1.11; 95% CI: 1.03, 1.20; P = .009). Conclusion Point SWE and MR elastography liver SWS measurements correlate well in patients with a BMI of less than 30 kg/m 2 and minimal US data dispersion; increasing US data dispersion is directly related to a higher BMI. © RSNA, 2016.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in children and can progress to liver cirrhosis during childhood. Patients with more advanced fibrosis on biopsy tend to have more liver complications. Noninvasive hepatic fibrosis scores have been developed for adult patients with NAFLD; however, these scores have not been validated in children. The aim of our study was to evaluate some of these scores in assessing the presence of fibrosis in children with biopsy-proven NAFLD., Methods: Our study consisted of 92 biopsy-proven NAFLD children from five major US centers. Fibrosis was determined by an experienced pathologist (F0-4). Clinically significant fibrosis was defined as fibrosis stage ≥ 2, and advanced fibrosis was defined as F3-4. The following fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 index. ROC was performed to assess the performance of different scores for prediction of presence of any, significant, or advanced fibrosis. A p value < 0.05 was considered statistically significant., Results: Mean age was 13.3 ± 3 years, and 33 % were females. Eleven (12 %) subjects had no fibrosis, 35 (38 %) had fibrosis score of 1, 26 (28 %) had fibrosis score of 2, and 20 (22 %) had a score of 3. APRI had a fair diagnostic accuracy for the presence of any fibrosis (AUC of 0.80) and poor diagnostic accuracy for significant or advanced fibrosis. AST/ALT, NFS, and FIB-4 index all either had poor diagnostic accuracy or failed to diagnose the presence of any, significant, or advanced fibrosis., Conclusion: Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing significant fibrosis in children with NAFLD. Our results highlight the urgent need to develop a reliable pediatric fibrosis score.

Objectives: Gender equality in the workplace has not been described in pediatric gastroenterology., Methods: An electronic survey that explored perceptions of career parity, work-life balance, and workplace harassment was sent to all members of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Reponses were anonymous., Results: Of the 303 respondents (21%), there was an even distribution across geographic region, age, and gender (54% men). Gender affected perception of salary and promotion; 46% of men but only 9% of women feel that "women earn the same as men" (P < 0.001). Similarly, 48% of men but only 12% of women feel that "women rise at the same rate as men" (P < 0.001). Both genders of academic practice respondents, compared with other practice models, perceived men were promoted more quickly than women (P = 0.008). Women had higher dissatisfaction with mentoring than men (29% vs 13%, P = 0.03). Significantly more men than women reported spouses with "flexible jobs" (35% vs 14%, P < 0.001). Having a spouse with "flexible job" or having children (preschool or school age), however, did not affect satisfaction with work-life balance for either gender. Overall, women are more likely to be dissatisfied with work-life balance than men (P = 0.046)., Conclusions: Satisfaction with work-life balance is lower among women versus men pediatric gastroenterologists, but does not correlate with flexibility of spouse's job or caring for young children. Gender-divergent perception of promotion, parity of compensation, and mentoring requires further investigation.

Background & Aims: To characterize the spectrum of nonalcoholic fatty liver disease (NAFLD) in morbidly obese adolescents, we correlated liver histology with clinical features and compared findings with reported adult data. We hypothesized that NAFLD would be less severe as a result of younger age and shorter duration of obesity, but portal inflammation and fibrosis would be more prevalent., Methods: Cross-sectional study was made of 41 adolescent subjects, 13-19 years old (mean, 16 years), 61% female, 83% non-Hispanic white, mean body mass index 59 kg/m(2), undergoing gastric bypass with liver biopsy. Liver biopsies were graded and staged as proposed by the NASH Clinical Research Network. Data were analyzed by using descriptive statistics, analysis of variance, and Fisher exact tests., Results: Eighty-three percent had NAFLD: 24% steatosis alone, 7% isolated fibrosis with steatosis, 32% nonspecific inflammation and steatosis, and 20% nonalcoholic steatohepatitis (NASH). Twenty-nine percent had fibrosis; none had cirrhosis. Abnormal ALT (P = .05) and AST (P = .01) were more prevalent in NASH. Mean fasting glucose was significantly higher in NASH (P = .05), but prevalence of the metabolic syndrome was not significantly different., Conclusions: NAFLD was very prevalent in morbidly obese adolescents, but severe NASH was uncommon. In contrast to morbidly obese adults, lobular inflammation, significant ballooning, and perisinusoidal fibrosis were rare, whereas portal inflammation and portal fibrosis were more prevalent, even in those who did not meet criteria for NASH. These findings might support use of a modified scoring system for pediatric NASH. Presence of the metabolic syndrome in morbidly obese adolescents did not distinguish NASH from steatosis alone.