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.

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 and Implementation of a Multidisciplinary Clinic Focused on the Care of Adolescents with Youth-Onset Type 2 Diabetes.

Introduction: 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.

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.

Clinical Performance of Transient Elastography With Comparison to Quantitative Magnetic Resonance Imaging, Ultrasound, and Biopsy in Children and Adolescents With Known or Suspected Fatty Liver Disease.

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/m2). 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.

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.

Health-Related Social Needs Facing Youth with NonAlcoholic Fatty Liver Disease.

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.

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.

Body composition measured by bioelectrical impedance analysis is a viable alternative to magnetic resonance imaging in children with nonalcoholic fatty liver disease.

OBJECTIVE: To determine the relationship between bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) obtained measures of body composition in children with nonalcoholic fatty liver disease (NAFLD). METHODS: Youth with obesity and NAFLD who had BIA and abdominal MRI testing were included. BIA measured skeletal muscle mass (SMM), appendicular lean mass (ALM), trunk muscle mass (TMM), and percent body fat. MRI measured total psoas muscle surface area (tPMSA) and fat compartments. Univariate analysis described the relationship between BIA- and MRI-derived measurements. Multivariable regression analyses built a model with body composition measured via MRI. RESULTS: 115 patients (82 (71%) male, 38 (33%) Hispanic, median age14 years) were included. There was a strong correlation between tPMSA and SMM, ALM, and TMM (correlation coefficients [CCs]: 0.701, 0.689, 0.708, respectively; all P < .001). Higher SMM, ALM, and TMM were associated with higher tPMSA. This association remained after controlling for age, sex, ethnicity, type 2 diabetes mellitus status, and body mass index z-score. Total fat mass by BIA and MRI-determined total, subcutaneous, and intraperitoneal fat area correlated significantly (CCs: 0.813, 0.808, 0.515, respectively; all P < .001). In univariate regression, higher total fat mass by BIA was associated with increased total fat area and increased fat in each of the four regions measured by MRI. After controlling for confounders, the association between total fat mass by BIA and total fat area by MRI persisted. CONCLUSIONS: BIA measures of muscle and fat mass correlate strongly with MRI measures of tPMSA and fat areas in children with obesity and 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.

Alternative Etiologies of Liver Disease in Children With Suspected NAFLD.

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

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

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

Can Baseline Characteristics be Used to Predict Liver Disease Outcomes in Pediatric Nonalcoholic Fatty Liver Disease?

OBJECTIVE: Longitudinal studies on childhood predictors of nonalcoholic fatty liver disease (NAFLD) progression are lacking. The objective of this study was to determine whether baseline clinical or laboratory measures predict liver disease outcomes in a pediatric NAFLD cohort. METHODS: A retrospective study of patients with presumed NAFLD was conducted using baseline and follow-up clinical and laboratory measures. Disease outcomes were defined using the mean serum alanine aminotransferase (ALT) levels from 24 to 36 months after the first visit. Logistic regression assessed the relationship between ALT progression/regression and predictor variables. Multivariable regression determined the best model for predicting the ALT outcome. Markov process modeling explored the likelihood for a patient to transition between ALT states. RESULTS: Of a total of 816 patients identified, 144 had sufficient data. Regression was seen in 26%, whereas 30% progressed. No baseline clinical or laboratory measurements had a significant effect on disease outcomes. Markov modeling demonstrated that subjects were more likely to either remain in their baseline ALT group or worsen rather than improve. CONCLUSIONS: Routinely obtained baseline clinical or laboratory measures cannot help risk-stratify youth with presumed NAFLD in terms of long-term outcomes. Close clinical, radiographic, and histologic evaluation of patients is warranted to determine those at risk of progression.

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

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

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

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

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

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

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

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

Severe obesity is associated with liver disease severity in pediatric non-alcoholic fatty liver disease.

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.

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

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.