Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease.

ObjectiveNonalcoholic fatty liver disease (NAFLD) affects 9.6% of children and may put these children at elevated risk of high blood pressure and subsequent cardiovascular morbidity and mortality. Therefore, we sought to determine the prevalence of and risk factors for high blood pressure in children with NAFLD.MethodsCohort study performed by the NIDDK NASH Clinical Research Network. There were 484 children with NAFLD ages 2 to 17 at enrollment; 382 children were assessed both at enrollment and 48 weeks afterwards. The main outcomes were high blood pressure at baseline and persistent high blood pressure at both baseline and 48 weeks.ResultsPrevalence of high blood pressure at baseline was 35.8% and prevalence of persistent high blood pressure was 21.4%. Children with high blood pressure were significantly more likely to have worse steatosis than children without high blood pressure (mild 19.8% vs. 34.2%, moderate 35.0% vs. 30.7%, severe 45.2% vs. 35.1%; P = 0.003). Higher body mass index, low-density lipoprotein, and uric acid were independent risk factors for high blood pressure (Odds Ratios: 1.10 per kg/m2, 1.09 per 10 mg/dL, 1.25 per mg/dL, respectively). Compared to boys, girls with NAFLD were significantly more likely to have persistent high blood pressure (28.4% vs.18.9%; P = 0.05).ConclusionsIn conclusion, NAFLD is a common clinical problem that places children at substantial risk for high blood pressure, which may often go undiagnosed. Thus blood pressure evaluation, control, and monitoring should be an integral component of the clinical management of children with NAFLD

Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease.

BackgroundReliable 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.MethodsCytokines 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.ResultsOf 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.ConclusionsPlasma 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

Histologic Abnormalities in Children with Nonalcoholic Fatty Liver Disease and Normal or Mildly Elevated Alanine Aminotransferase Levels.

Objectives: 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 boys, > 44 girls) serum alanine aminotransferase (ALT) levels. Study design: The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) enrolls children 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 within 180 days of ALT, and compared them with 392 children with elevated ALT. Results: Of 91 children, 17 (19%) had normal and 74 (81%) had mildly elevated ALT levels. Overall, 45% of biopsies had ≥ 33% steatosis, lobular inflammation grade was ≥ 2 in 22%, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had “suspicious/borderline” steatohepatitis, and 8% had definite NASH, 34% had NAFLD activity score (NAS) ≥ 4. Overall, 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 mildly elevated vs normal, with no difference in ballooning, inflammation, or NAS ≥ 4. Fibrosis stage 3/4 was seen in none of the children with normal ALT, and in 9% of the mildly elevated and 15% of the elevated. Conclusions: Liver biopsies of children with NAFLD with normal or mildly elevated ALT levels show significant histologic abnormalities, including advanced fibrosis in children with mildly elevated ALT. ALT thus may underestimate liver injury in NAFLD. Appropriate ALT cut-off levels can help identify children at risk for more severe disease

Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children

OBJECTIVES: To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD. STUDY DESIGN: A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category. RESULTS: Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P < .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62). CONCLUSION: Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease

An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis

ObjectivesNonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8-17 years and (2) assess changes in aminotransferases.MethodsChildren with NASH were randomized to open-label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent-to-treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed.ResultsTen males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9- and 1.3-fold increase in median Cmax and AUC 0-24 , respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of -37.4% (SD 23.8%) at 12 weeks.ConclusionsOnce daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH

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

Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis

Background: Haptoglobin (Hp) genotype has been linked to oxidative stress and response to vitamin E (VitE) in patients with dyslipidemia. Its effect on histological response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. Goals: Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. Study: A post hoc analysis of 228 patients receiving VitE or placebo in two clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1–1, 2–1, or 2–2), on histologic features and laboratory markers of liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. Results: Hp 2–2 patients treated with VitE versus placebo showed significant histologic improvement (51% versus 20%, OR=4·2, p=0·006), resolution of steatohepatitis (44% versus 12%, OR=6.2, p=0·009), decrease in NAFLD Activity Score (NAS) (−2·2 versus −0·6, p=0·001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase. Hp 2–1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1–1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2–2 or 2–1 versus 1–1 for all liver enzymes. Conclusion: Hp 2 allele is associated with greater histological and biological improvement in NASH with VitE treatment compared to the Hp 1 allele

Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease

Background &amp; aimsType 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors.MethodsChildren with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike's Information Criteria selection.ResultsThis study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0-2.8]), associated with BMI z-score (HR, 1.8 [1.0-3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0-1.7]), and fibrosis stage (HR, 1.3 [1.0-1.5]).ConclusionsChildren with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed

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