Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.

In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis.

BACKGROUND & AIMS: Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. METHODS: We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. RESULTS: Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P < .001) and a significantly higher proportion had any fibrosis (81% vs 51%; P < .001) or advanced fibrosis (13% vs 5%; P < .001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P < .001). CONCLUSIONS: Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis.

Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease.

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two-dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross-validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross-validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%-81.1%). Overall cross-validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%-94.5%) for center 1, 90.0% (95% CI, 81.9%-95.3%) for center 2, and 86.7% (95% CI, 77.9%-92.9%) for automated analysis. CONCLUSION: 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (Hepatology 2017;66:1474-1485).

Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease.

IMPORTANCE: Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. OBJECTIVE: To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. MAIN OUTCOMES AND MEASURES: The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. RESULTS: There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P < .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose. CONCLUSIONS AND RELEVANCE: In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes. These children had greater odds of having NASH and thus were at greater long-term risk for adverse hepatic outcomes.

Lifestyle Interventions Including Nutrition, Exercise, and Supplements for Nonalcoholic Fatty Liver Disease in Children.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease among children. Lifestyle interventions, such as diet and exercise, are frequently recommended. Children with NAFLD have a distinct physiology that is different from obesity alone and has the potential to influence lifestyle treatments. Studies of diet alone in the treatment of pediatric NAFLD have focused on sugar and carbohydrate, but did not indicate any one dietary approach that was superior to another. For children who are obese and have NAFLD, weight loss may have a beneficial effect regardless of the diet used. Exercise is widely believed to improve NAFLD because a sedentary lifestyle, poor aerobic fitness, and low muscle mass are all risk factors for NAFLD. However, there have been no randomized controlled trials of exercise as a treatment for children with NAFLD. Studies of the combination of diet and exercise suggest a potential for improvement in serum alanine aminotransferase activity and/or magnetic resonance imaging liver fat fraction with intervention. There is also enthusiasm for the use of dietary supplements; however, studies in children have shown inconsistent effects of vitamin E, fish oil, and probiotics. This review presents the available data from studies of lifestyle intervention and dietary supplements published to date and highlights challenges that must be addressed in order to advance the evidence base for the treatment of pediatric NAFLD.