Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.

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/m2 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.

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.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

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.

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

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

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

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

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

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.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

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.

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.

Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

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 (r2 > 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.

Presence of Alpha 1 Antitrypsin Risk Variants is Not Associated With Histologic Severity of Pediatric NAFLD.

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.

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.

Clinically Meaningful Body Mass Index Change Impacts Pediatric Nonalcoholic Fatty Liver Disease.

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.

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.

Unhealthy Eating, Psychopathology, and Nonalcoholic Fatty Liver Disease in Youth Presenting for Bariatric Surgery.

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.