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Nonalcoholic steatohepatitis, a progressive form of nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in children who present with particular risk factors including obesity, sedentary lifestyle, and/or a predisposing genetic background. The worldwide prevalence of NAFLD in children is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. To date, the etiopathogenesis of primary NAFLD in children is unknown. Understanding the pathogenetic mechanisms provides the basis to characterize early predictors of the disease and noninvasive diagnostic tools and to design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD, no treatment exists for children with NAFLD. In this review, the authors provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis, and treatment of NAFLD in pediatric population.

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Background & Aims A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02–0.05], p z = 4.8×10 –5 ) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05–1.3], p z = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03–1.45], p z = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT ( p z = 0.002) and lower serum triglycerides ( p z = 1.5×10 –4 ). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene ( ‘MBOAT7’ ) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

ObjectivesTo explore the relationship between academic performance, extracurricular activity, and quality of life at medical school in the UK to aid our understanding of students’ work-life balance. MethodsA cross-sectional study, using an electronic questionnaire distributed to UK final year medical students across 20 medical schools (4478 students). Participants reported the hours of self-regulated learning and extracurricular activities undertaken each year at medical school; along with their academic decile (1 = highest, 10 = lowest). Self-reported quality of life (QoL) was assessed using an established screening tool (7 = highest, 1 = lowest). ResultsSeven hundred responses were obtained, across 20 participating medical schools, response rate 16% (700/4478). Factors associated with higher academic achievement were: graduate entry course students (2 deciles higher, p< 0.0001), more hours academic study during term and revision periods (rho=-0.1, p< 0.01), and involvement in teaching or research. Increased hours of study was associated with lower QoL (rho = -0.13, p<0.01). ConclusionsStudy skills may be more important than duration spent studying, for academic achievement and QoL. Graduate-entry students attain higher decile scores despite similar self-reported duration of study.

Animal models of human disease are a key component of translational hepatology research, and yet, there is no consensus on which model is optimal for non-alcoholic fatty liver disease (NAFLD). Here, we generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous and, therefore, few models had been cited more than once.Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high fat, high fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the fields of hepatology and beyond. In conclusion, this systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.

Pediatric nonalcoholic fatty liver disease (NAFLD) histology demonstrates variable amounts of portal inflammation, which may be associated with more severe liver disease and fibrosis. We assessed the relationship between portal inflammation, hepatic fibrosis, and the metabolic syndrome in pediatric NAFLD. Children with biopsy-proven NAFLD were eligible for inclusion. Histology was assessed using Kleiner fibrosis stage and the Nonalcoholic Steatohepatitis Clinical Research Network system for portal inflammation. Patients were divided by histology into type 1, type 2, and overlap NAFLD. Multivariable ordinal logistic regression was used to determine factors associated with fibrosis and portal inflammation. The 430 Caucasian children were divided into 52 with type 1, 95 with type 2, and 283 with overlap NAFLD. Those with type 2 had a more severe metabolic phenotype, with higher body mass index z score (2.0 versus 1.6, P < 0.0001), waist circumference centile (96th versus 90th, P < 0.0001), and triglycerides (84 versus 77 mg/dL, P 5 0.01) and lower high-density lipoprotein (46 versus 60 mg/dL, P 5 0.004) than those with type 1. Similarly, those with overlap NAFLD had a more severe phenotype. Stage 2-3 fibrosis was present in 69/283 (24%) with overlap NAFLD. Portal inflammation was associated with stage 2-3 fibrosis on multivariable analysis (95% confidence interval 1.4-5.2, odds ratio 5 3.7). Waist circumference centile was associated with portal inflammation (95% confidence interval 1.2-3.4, odds ratio 5 2.0). Conclusion: Portal inflammation is associated with more advanced pediatric NAFLD and features of the metabolic syndrome. (HEPATOLOGY 2016;63:745-753)