Perspectives on youth-onset nonalcoholic fatty liver disease.

BACKGROUND: The prevalence and incidence of youth-onset nonalcoholic fatty liver disease (NAFLD) far exceeds other paediatric chronic liver diseases and represents a considerable public health issue globally. METHODS: Here, we performed a narrative review of current knowledge regarding the epidemiology of paediatric NAFLD, selected concepts in pathogenesis, comorbidities, diagnosis, and management, and issues related to the transition to adulthood. RESULTS: Paediatric NAFLD has become increasingly more prevalent, especially in certain subgroups, such as children with obesity and certain races/ethnicities. The pathophysiology of paediatric NAFLD is complex and multifactorial, driven by an interaction of environmental and genetic factors. Once developed, NAFLD in childhood is associated with type 2 diabetes, hypertension, increased cardiovascular disease risk, and end-stage liver disease. This predicts an increased burden of morbidity and mortality in adolescents and young adults. Early screening and diagnosis are therefore crucial, and the development of noninvasive biomarkers remains an active area of investigation. Currently, treatment strategies are focused on lifestyle changes, but there is also research interest in pharmacological and surgical options. In the transition from paediatric to adult care, there are several potential challenges/barriers to treatment and research is needed to understand how best to support patients during this time. CONCLUSIONS: Our understanding of the epidemiology and pathophysiology of paediatric NAFLD has increased considerably over recent decades, but several critical knowledge gaps remain and must be addressed in order to better mitigate the short-term and long-term risks of youth-onset NAFLD.

ALT Trends through Childhood and Adolescence Associated with Hepatic Steatosis at 24 Years: A Population-Based UK Cohort Study.

(1) Background: Alanine aminotransferase (ALT) is used to screen for non-alcoholic fatty liver disease (NAFLD) in children; however, the optimal age to commence screening is not determined. Our objective was to describe whether ALT trends from 9-24 years were associated with hepatic steatosis at 24 years in a population-based UK cohort. (2) Methods: The sample included 1156 participants who were assessed for hepatic steatosis at 24 years and had at least two ALT measurements at 9, 15, 17, and/or 24 years. Controlled attenuation parameter scores were used to assess steatosis (low (<248 dB/m), mild/moderate (248-279 dB/m), severe (>279 dB/m)). Sex-stratified mixed-effects models were constructed to assess the liver enzyme trends by steatosis level. (3) Results: The final sample was 41.4% male and 10.4% had severe steatosis. In both sexes, ALT trends from 9 to 24 years differed in those with low vs. severe steatosis at 24 years (p < 0.001). There was no evidence of differences prior to puberty. At 17 years, the low vs. severe geometric mean ratio (GMR) was 0.69, 95% CI: 0.57-0.85 in males and (0.81, 0.65-1.01) females. At 24 years, the GMR was (0.53, 0.42-0.66) in males and (0.67, 0.54-0.84) females. (4) Conclusions: Higher ALT concentration in adolescence was associated with hepatic steatosis at 24 years. The increased screening of adolescents could strengthen NAFLD prevention and treatment efforts.

Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth.

INTRODUCTION: Body fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution. RESEARCH DESIGN AND METHODS: This was a cross-sectional sub-study of 283 children/adolescents (7-19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot. RESULTS: The data divided into four communities of correlated variables (|r|>0.15, p<0.05) after integrative network analysis. In the largest community, hepatic fat was associated with eight clinical biomarkers, including measures of insulin resistance and dyslipidemia, and 878 metabolite features that were enriched predominantly in amino acid (AA) and lipid pathways in pathway enrichment analysis (p<0.05). Key metabolites associated with hepatic fat included branched-chain AAs (valine and isoleucine/leucine), aromatic AAs (tyrosine and tryptophan), serine, glycine, alanine, and pyruvate, as well as several acylcarnitines and glycerophospholipids (all q<0.05 in MLR adjusted for covariates). The other communities detected in integrative network analysis consisted of abdominal visceral, superficial subcutaneous, and deep subcutaneous fats, but no clinical variables, fewer metabolite features (280, 312, and 74, respectively), and limited findings in pathway analysis. CONCLUSIONS: These data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat-insulin resistance interface in youth.

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography-mass spectrometry was performed on plasma samples from a combined cross-sectional sample of children and adolescents ages 2-25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole-body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

Truncal-to-leg fat ratio and cardiometabolic disease risk factors in US adolescents: NHANES 2003-2006.

BACKGROUND: This study aims to describe patterns of truncal versus peripheral fat deposition measured by truncal-to-leg fat ratio (TLR) in adolescents and examine associations of TLR with cardiometabolic (CMD) risk factors. METHODS: Data were from 3810 adolescents (12-19 years old) in the National Health and Examination Survey (NHANES) 2003-2006. Body fat was assessed by dual-energy X-ray absorptiometry, and CMD risk factors were determined by blood samples and physical examination. Linear and logistic regressions adjusted for BMI z-score and other covariates were used to examine associations of TLR with CMD risk factors as continuous and dichotomized outcomes, respectively. RESULTS: Adolescents who were Mexican American, who have lower income, and with obesity had the highest mean TLR (all p < 0.05). In linear regression, increasing TLR was associated positively with homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, total cholesterol, systolic blood pressure (BP), c-reactive protein, and alanine aminotransferase (ALT), and negatively with high-density lipoprotein (HDL) cholesterol in both sexes (p < 0.05). TLR was also associated with diastolic BP in boys and low-density lipoprotein cholesterol in girls (p < 0.05). A similar pattern of findings resulted from logistic regression. When further stratified by race/ethnicity, TLR was positively associated with high triglycerides, total cholesterol, and ALT for White and/or Mexican American (p < 0.05), but not Black adolescents, while associations with HOMA-IR and HDL were significant for all race/ethnicities. CONCLUSIONS: In this cohort of adolescents, TLR was associated with several risk factors independent of BMI z-score, although some findings were sex or race/ethnicity specific. Body fat distribution may be an important determinant of future CMD.

Associations of Added Sugar from All Sources and Sugar-Sweetened Beverages with Regional Fat Deposition in US Adolescents: NHANES 1999-2006.

BACKGROUND: The relative distribution of upper- versus lower-body fat may be an important determinant of cardiometabolic disease risk in youths. Dietary components associated with adolescent regional body fat distribution require further investigation. OBJECTIVE: To evaluate associations of added sugar intake overall and from sugar-sweetened beverages (SSBs) with relative upper-body fat deposition in US adolescents. METHODS: This was a cross-sectional analysis of data from 6585 adolescents (aged 12-19 y) in the NHANES cycles 1999-2006. Trunk, leg, and total fat mass were assessed by DXA. Participants were grouped into categories of total and SSB added sugar intake as a percentage of total energy intake (TEI) in 5% increments. Stepwise multivariable linear regression was used to examine associations of added sugar intake with truncal-to-leg fat ratio (TLR) and truncal-to-total fat ratio (TTR). RESULTS: There were no associations of total added sugar intake with TLR or TTR. For SSB added sugar, compared with the lowest category of intake (<2% TEI), the highest category (>22% TEI) was associated with higher log-TLR [ß (95% CI): >22% TEI versus <2% TEI: 0.05 (0.01, 0.09)] and TTR [1.30 (0.53, 2.07)] in the partially adjusted model with sex, age, race/ethnicity, income, physical activity, and smoking status as covariates (P-trend = 0.0001 for both). When BMI z-score and TEI were added as covariates, the magnitude of the associations were attenuated, but remained significant [log-TLR ß (95% CI): 0.03 (0.005, 0.06), P-trend = 0.0018; TTR ß (95% CI): 0.75 (0.27, 1.23), P-trend = 0.0004]. CONCLUSIONS: These findings support that added sugar from beverages is associated with higher upper-body adiposity, though the magnitude and clinical significance of the associations may be small, especially when adjusted for BMI and TEI. Additional studies are needed to elucidate the underlying biological mechanisms to explain these findings.

Self-efficacy and diabetes prevention in overweight South Asians with pre-diabetes.

OBJECTIVE: We evaluated the effects of a diabetes prevention itervention on self-efficacy (SE) and the associations between SE and diabetes-related outcomes among overweight Asian Indian adults with pre-diabetes in a randomized controlled translational trial (the Diabetes Community Lifestyle Improvement Program, D-CLIP). RESEARCH DESIGN AND METHODS: Data were obtained from 550 adults who were randomized to a diabetes prevention program or standard of care. Dietary and exercise-related SEs were measured at baseline, core intervention completion (4 months), and annually until the end of follow-up (3 years or diabetes diagnosis). Mixed-effects regressions described changes in SE over time by treatment group. Among treatment participants, multivariable-adjusted models described associations of SE at baseline and intervention completion with diabetes incidence and other secondary outcomes (weight, waist circumference (WC), exercise, and energy intake). RESULTS: From baseline to 4 months, dietary (ß=10.3, p=0.04) and exercise (ß=0.49, p=0.04) SE increased significantly in the treatment arm only; however, this increase from baseline was no longer significant at later time points. Among treatment participants, there was no association of dietary or exercise SE with diabetes incidence, but baseline exercise SE was independently associated with improved weight, WC, and exercise at 4 months (p<0.05). Change in exercise SE from baseline to intervention completion also predicted increased exercise at 4, 12, and 24 months (p<0.05). CONCLUSIONS: Exposure to D-CLIP resulted in improved SE at treatment completion, but this effect was not sustained over longer follow-up. Several short-term and long-term secondary outcomes, but not diabetes risk, were significantly associated with exercise SE, suggesting this psychosocial trait may facilitate success in achieving certain health goals. TRIAL REGISTRATION NUMBER: NCT01283308.

Added Sugar Intake among Pregnant Women in the United States: National Health and Nutrition Examination Survey 2003-2012.

BACKGROUND: Despite associations of dietary added sugar with excess weight gain and chronic disease risk, intake among most Americans exceeds the recommended limits (<10% total energy). Maternal diet plays an important role in pregnancy-related outcomes, but little is known about the extent of added sugar intake during pregnancy. OBJECTIVE: To assess intake and identify the top sources of added sugars in the diets of pregnant vs nonpregnant women in the United States. DESIGN: Cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES), 2003-2004 to 2011-2012. PARTICIPANTS: Four thousand one hundred seventy-nine pregnant and nonpregnant women (aged 20 to 39 years) who completed a dietary recall. STATISTICAL ANALYSES PERFORMED: Survey-weighted analyses were used to estimate means (95% CIs) in total grams and as percentage of total energy for added sugar intake by pregnancy status and by demographic subgroup and to identify leading sources of added sugar. RESULTS: Added sugar intake trended toward being higher in pregnant compared with nonpregnant women in absolute grams, 85.1 g (95% CI: 77.4 to 92.7) vs 76.7 g (95% CI: 73.6 to 79.9), respectively (P=0.06), but was lower among pregnant women when total energy intake was accounted for, 14.8% (95% CI: 13.8 to 15.7) vs 15.9% (95% CI: 15.2 to 16.6) of total energy, respectively (P=0.03). Among pregnant women, added sugar intake was similar among demographic subgroups. However, in multivariable regression, pregnancy status significantly modified the associations of education and income with added sugar intake, whereby less educated and lower-income women who were pregnant had lower added sugar intakes compared with those who were not pregnant, but more educated or higher-income women did not exhibit this pattern. The top five sources of added sugar for all women were sugar-sweetened beverages; cakes, cookies, and pastries; sugars and sweets; juice drinks and smoothies; and milk-based desserts. CONCLUSIONS: Although pregnant women had higher energy intakes, this was not attributed to higher intakes of added sugar. Although education and income affected consumption during pregnancy, intake of added sugar among all women, regardless of pregnancy status, exceeded recommendations.

Natural History of NAFLD Diagnosed in Childhood: A Single-Center Study.

Little is known regarding the subsequent course of non-alcoholic fatty liver disease (NAFLD) diagnosed in childhood. The objectives of this single-center study were to gather data on long-term health outcomes and to assess the feasibility of contacting former pediatric patients. In a large pediatric medical center, electronic records were searched to initially identify 162 former patients who had a liver biopsy between 2000 and 2010. Of these, 44 subjects met the criteria for age at follow-up (≥18 year) and biopsy-proven NAFLD, and were recruited via postal and electronic mail. Participants were invited to complete a brief telephone survey on current health status. Supplemental data was also obtained from pediatric medical charts of all subjects. At NAFLD diagnosis, 18% of subjects had diabetes, 91% were obese, 61% had NASH, and 56% had fibrosis on biopsy. At follow-up, 10 subjects (23%) responded to the survey. Based on the survey and chart review, after a mean follow-up of 4.5 years, 5 additional subjects developed diabetes for a period prevalence of 30%, and most subjects (78%) remained obese at last follow-up. Additional prospective studies are needed to fully describe the longitudinal risks associated with pediatric NAFLD, and will require multi-dimensional strategies to successfully recruit former patients.

A nudge in a healthy direction. The effect of nutrition labels on food purchasing behaviors in university dining facilities.

BACKGROUND: Despite legislation that requires restaurants to post nutritional labels on their products or menu items, the scientific literature provides inconsistent support for the idea that adding labels to foods will change buying patterns. Lack of success of previous research may be that sample sizes have been too small and durations of studies too short. OBJECTIVE: To assess the effect of nutrition labeling on pre-packaged food purchases in university dining facilities. DESIGN: Weekly sales data for a sample of pre-packaged food items were obtained and analyzed, spanning three semesters before and three semesters after nutritional labels were introduced on to the sample of foods. The labels summarized caloric content and nutrient composition information. Mean nutrient composition purchased were calculated for the sample of foods. Labeled food items were categorized as high-calorie, low-calorie, high-fat, or low-fat foods and analyzed for change as a function of the introduction of the labels. SETTING: Data were obtained from all retail dining units located at Cornell University, Ithaca, NY where the pre-packaged food items were sold. RESULTS: Results indicated that the introduction of food labels resulted in a 7% reduction of the mean total kcals purchased per week (p < 0.001) from the labeled foods. Total fat purchased per week were also reduced by 7% (p < 0.001). Percent of sales from "low-calorie" and "low-fat" foods (p < 0.001) increased, while percent of sales from "high-calorie" and "high-fat" foods decreased (p < 0.001). CONCLUSIONS: The results suggest that nutrition labels on pre-packaged foods in a large university dining hall produces a small but significant reduction of labeled high calorie and high fat foods purchased and an increase in low calorie, low fat foods.