Objective

To generate and report standardized growth curves for weight, length, head circumference, weight/length, and BMI for non-growth hormone-treated white infants (boys and girls) with Prader-Willi syndrome (PWS) between 0 and 36 months of age. The goal was to monitor growth and compare data with other infants with PWS.

Methods

Anthropometric measures (N = 758) were obtained according to standard methods and analyzed from 186 non-growth hormone-treated white infants (108 boys and 78 girls) with PWS between 0 and 36 months of age. Standardized growth curves were developed and the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles were calculated by using the LMS (refers to λ, μ, and σ) smoothing procedure method for weight, length, head circumference, weight/length, and BMI along with the normative 50th percentile using Centers for Disease Control and Prevention national growth data from 2003. The data were plotted for comparison purposes.

Results

Five separate standardized growth curves (weight, length, head circumference, weight/length, and BMI) representing 7 percentile ranges were developed from 186 non-growth hormone-treated white male and female infants with PWS aged 0 to 36 months, and the normative 50th percentile was plotted on each standardized infant growth curve.

Conclusions

We encourage the use of these growth standards when examining infants with PWS and evaluating growth for comparison purposes, monitoring for growth patterns, nutritional assessment, and recording responses to growth hormone therapy, commonly used in infants and children with PWS.

Objective

To investigate the histological spectrum of nonalcoholic fatty liver disease (NAFLD) in children with normal, mildly elevated (26-50 U/L boys, 23-44 U/L girls), or elevated (>50 U/L in boys, >44 U/L in girls) serum alanine aminotransferase (ALT) levels.

Study design

The Nonalcoholic Steatohepatitis Clinical Research Network enrolls children aged 5-18 years with NAFLD. We analyzed baseline clinical and histological data from 91 children with suspected NAFLD and normal or mildly elevated ALT and liver biopsy analysis within 180 days of ALT measurement, and compared them with data from 392 children with elevated ALT.

Results

Seventeen of the 91 children with suspected NAFLD (19%) had a normal ALT level, and 74 (81%) had a mildly elevated ALT level. Overall, 45% of the biopsy specimens analyzed had steatosis ≥33%, 22% had grade ≥2 lobular inflammation, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had "suspicious/borderline" steatohepatitis, 8% had definite nonalcoholic steatohepatitis, 34% had an NAFLD activity score ≥4, and 46% had fibrosis (38% mild/moderate and 8% bridging/cirrhosis). Marked steatosis (50% vs 24%) and fibrosis (54% vs 12%) were significantly more common in the patients with mildly elevated ALT compared with those with normal ALT, with no difference in ballooning, inflammation, or NAFLD activity score ≥4 between the 2 groups. Fibrosis stage 3/4 was seen in none of the children with normal ALT, in 9% of those with mildly elevated ALT, and in 15% of those with elevated ALT.

Conclusion

Liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis in children with mildly elevated ALT. Thus, measurement of ALT may underestimate liver injury in NAFLD. The use of appropriate ALT cutoff levels can help identify children at risk for more severe disease.

Aims

There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.

Materials and methods

Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151.

Results

One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo.

Conclusions

MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Background

Reliable non-invasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving NASH and to identify potential non-invasive discriminators of NAFLD severity and pattern.

Methods

Cytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike Information Criterion (AIC) was used to determine cytokines retained in multivariable models.

Results

Of 235 subjects, 31% had "Definite NASH" on liver histology, 43% had "Borderline NASH", and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL-8) was higher in those with stage 3-4 fibrosis and lobular inflammation. sIL-2rα was higher in children with stage 3-4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, definite NASH, lobular inflammation and ballooning. IL-8 increased with steatosis and fibrosis severity; sIL-2rα increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity.

Conclusions

Plasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. Future, more targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as non-invasive discriminators of disease severity.

OBJECTIVE:The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. METHODS:A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. RESULTS:Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). CONCLUSION:Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

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.

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.

Background & aims

No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD.

Methods

We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis.

Results

There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005).

Conclusions

In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Background

Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.

Methods

Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components.

Results

In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04).

Conclusions

In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.

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.