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

Targeted Hepatic Sonography During Clinic Visits for Detection of Fatty Liver in Overweight Children

ObjectivesThe purpose of this study was to assess the feasibility and utility of targeted hepatic sonography to evaluate for hepatic steatosis during a subspecialty clinic visit.MethodsIn this pilot study, we performed targeted hepatic sonography on 25 overweight children aged 7 to 17 years consecutively seen in a pediatric obesity clinic. Long-axis images of the right lobe of the liver and a split-screen image of liver and spleen were taken. Images were interpreted in real time by the radiologist and shown to the family. Demographics, clinical measurements, and laboratory parameters were also collected from the specialty clinic visit on the same day.ResultsSonography required a median of 4 minutes during the visit (interquartile range, 3-5 minutes). All consented patients completed the study. The median alanine aminotransferase (ALT) level was 23 U/L in those with no steatosis (n = 14), 26 U/L with mild steatosis (n = 6), and 41 U/L with moderate/marked steatosis (n = 5). Children with ALT levels of 25 to 50 U/L had very variable sonographic measures of hepatic steatosis. When the participants were categorized by the overall degree of fatty liver, hepatic steatosis was significantly associated with the aspartate aminotransferase level (P = .028), ALT level (P = .003), and diastolic blood pressure (P = .05) but did not correlate with age, sex, Latino race, or insulin resistance.ConclusionsTargeted hepatic sonography added information not apparent from routine ALT screening and provided immediate feedback to clinicians and families about the effect of obesity on end organs. This examination could be a feasible, informative addition to screening for children at high risk for nonalcoholic fatty liver disease who are seen in clinics that specialize in obesity

Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls

Although body composition, insulin sensitivity, and lipids are markedly altered in overweight adolescents, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. We hypothesized that low-peak GH on the GH-releasing hormone (GHRH)-arginine stimulation test and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance, and lipids. We examined the following parameters in 15 overweight and 15 bone age-matched control 12- to 18-yr-old girls: 1) body composition using dual-energy X-ray absorptiometry and MR [visceral and subcutaneous adipose tissue at L4–L5 and soleus intramyocellular lipid (1H-MR spectroscopy)], 2) peak GH on the GHRH-arginine stimulation test, 3) mean overnight GH and cortisol, 4) 24-h urinary free cortisol (UFC), 5) fasting lipids, and 6) an oral glucose tolerance test. Stepwise regression was the major tool employed to determine relationships between measured parameters. Log peak GH on the GHRH-arginine test was lower (P = 0.03) and log UFC was higher (P = 0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with subcutaneous adipose tissue and, with body mass index standard deviation score, accounted for 92% of its variability, whereas log peak GH and body mass index standard deviation score accounted for 88% of visceral adipose tissue variability and log peak GH for 34% of the intramyocellular lipid variability. Log mean cortisol was independently associated with log homeostasis model assessment of insulin resistance, LDL, and HDL and explained 49–59% of the variability. Our data indicate that lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance, and lipids

Nutrient intake in community-dwelling adolescent girls with anorexia nervosa and in healthy adolescents

BACKGROUND: Adolescence is a common time for the onset of anorexia nervosa (AN), a condition associated with long-term medical and hormonal consequences. OBJECTIVE: The objective was to compare the nutrient intakes of community-dwelling girls with AN with those of healthy adolescents and to describe the associations between specific nutrient intakes and nutritionally dependent hormones. DESIGN: Nutrient intakes in 39 community-dwelling girls with AN and 39 healthy adolescents aged 12.1-18.7 y were determined by using 4-d food records. Fasting adiponectin, leptin, ghrelin, insulin, and insulin-like growth factor I (IGF-I) concentrations were measured. Indirect calorimetry was used to assess respiratory quotient and resting energy expenditure. RESULTS: In contrast with the control group, the AN group consumed fewer calories from fats (P \u3c 0.0001) and more from carbohydrates (P = 0.0009) and proteins (P \u3c 0.0001). Intake of individual fat components was lower and of dietary fiber higher in the AN group. No significant between-group differences were observed in dietary intakes of calcium, zinc, and iron; however, total intake was greater in the AN group because of greater supplement use (P = 0.006, 0.02, and 0.01, respectively). The AN group had greater intakes of vitamins A, D, and K and of most of the B vitamins, and significantly more girls with AN met the Dietary Reference Intake for calcium (P = 0.01) and vitamin D (P = 0.02) from supplement use. Fat intake predicted ghrelin, insulin, and IGF-I concentrations; carbohydrate intake predicted adiponectin. Resting energy expenditure was lower (P \u3c 0.0001) and leisure activity levels higher in the AN group. CONCLUSIONS: Despite outpatient follow-up, community-dwelling girls with AN continue to have lower fat and higher fiber intakes than do healthy adolescents, which results in lower calorie intakes. Nutritionally related hormones are associated with specific nutrient intakes

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice

Background &amp; aimsNonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth.MethodsWe 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.ResultsAt 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 (&lt;0.05), and over follow-up time, with increasing level of alanine aminotransferase, hemoglobin A1C (P&lt;.05), gamma-glutamyl transferase and development of type 2 diabetes (P&lt;.01). Increasing level of gamma-glutamyl transferase was also associated with reduced odds of any improvement (P&nbsp;= .003).ConclusionsOne-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