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Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent hepatic condition linked to metabolic alterations. It gradually causes liver damage and potentially progresses to cirrhosis. Despite its significance, research, especially in the pediatric population, is limited, leading to contradictory findings in diagnosis and treatment. This meta-analysis aims to synthesize existing literature on therapeutic interventions for MASLD in children and adolescents. Methods A comprehensive search of randomized controlled clinical trials yielded 634 entries from PubMed, Scopus, and Web of Science up to 2023. Interventions included medications, behavioral modifications, dietary changes, probiotics, supplements, surgical procedures, or combinations. The analysis focused on studies with treatment duration of at least 3 months, employing a random-effects REML meta-analysis model. Treatment effects on anthropometric measurements and biochemical components were examined and adjusted for heterogeneity factors analysis. A bibliometric analysis for insights into research contributors was performed. Results The systematic review incorporated 31 clinical trials, with 24 meeting criteria for meta-analysis. These comprised 3 medication studies, 20 with supplements, 4 focusing on lifestyle, and 4 centered on diets. Significant overall treatment effects were observed for ALT, AST, BMI, and HOMA-IR mainly by supplements and lifestyle. Meta-regression identified age, BMI changes, and treatment duration as factors modifying ALT concentrations. Bibliometric analysis involving 31 linked studies highlighted contributions from 13 countries, with the USA, Spain, and Chile being the most influential. Conclusions We conclude that supplementation and lifestyle changes can effectively impact ALT and AST levels, which can help address liver issues in obese children. However, the evaluation of risk bias, the high heterogeneity, and the bibliometric analysis emphasize the need for more high-quality studies and broader inclusion of diverse child populations to provide better therapeutic recommendations. Trial registration PROSPERO, CRD42023393952. Registered on January 25, 2023.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent hepatic condition linked to metabolic alterations. It gradually causes liver damage and potentially progresses to cirrhosis. Despite its significance, research, especially in the pediatric population, is limited, leading to contradictory findings in diagnosis and treatment. This meta-analysis aims to synthesize existing literature on therapeutic interventions for MASLD in children and adolescents. Methods: A comprehensive search of randomized controlled clinical trials yielded 634 entries from PubMed, Scopus, and Web of Science up to 2023. Interventions included medications, behavioral modifications, dietary changes, probiotics, supplements, surgical procedures, or combinations. The analysis focused on studies with treatment duration of at least 3 months, employing a random-effects REML meta-analysis model. Treatment effects on anthropometric measurements and biochemical components were examined and adjusted for heterogeneity factors analysis. A bibliometric analysis for insights into research contributors was performed. Results: The systematic review incorporated 31 clinical trials, with 24 meeting criteria for meta-analysis. These comprised 3 medication studies, 20 with supplements, 4 focusing on lifestyle, and 4 centered on diets. Significant overall treatment effects were observed for ALT, AST, BMI, and HOMA-IR mainly by supplements and lifestyle. Meta-regression identified age, BMI changes, and treatment duration as factors modifying ALT concentrations. Bibliometric analysis involving 31 linked studies highlighted contributions from 13 countries, with the USA, Spain, and Chile being the most influential. Conclusions: We conclude that supplementation and lifestyle changes can effectively impact ALT and AST levels, which can help address liver issues in obese children. However, the evaluation of risk bias, the high heterogeneity, and the bibliometric analysis emphasize the need for more high-quality studies and broader inclusion of diverse child populations to provide better therapeutic recommendations. Trial registration: PROSPERO, CRD42023393952. Registered on January 25, 2023. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Polycystic ovary syndrome (PCOS) increases non-alcoholic fatty liver disease (NAFLD) risk and severity in adults, but data in adolescents with diverse backgrounds are limited. We evaluated NAFLD prevalence and characterized NAFLD risk factors in overweight/obese adolescents by PCOS status. METHODS: Retrospective study of overweight (n=52)/obese (n=271) female adolescents (12-18 years old), evaluated clinically 2012-2020, was conducted comparing PCOS patients to age-matched non-PCOS controls. NAFLD was defined as ALT≥44U/L x2 and/or ≥80U/L x1, hepatic steatosis on imaging, or NAFLD on biopsy, in absence of other liver disease. Metabolic comorbidities were captured. Log-binomial regression models estimated prevalence risk ratios (PR). RESULTS: NAFLD prevalence was 19.1 % in adolescents with PCOS (n=161), similar to those without (n=162) (16.8 %, p=0.6). Adolescents with PCOS were more likely to have insulin resistance, hypercholesterolemia, and higher triglycerides (p

Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n - 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n - 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.

Nonalcoholic fatty liver disease (NAFLD) is pediatrics' most common chronic liver disease. The incidence is high in children and adolescents with obesity, which is associated with an increased risk of disease progression. Currently, there is no effective drug therapy in pediatrics; therefore, lifestyle interventions remain the first line of treatment. This review aims to present an updated compilation of the scientific evidence for treating this pathology, including lifestyle modifications, such as exercise and dietary changes, highlighting specific nutritional strategies. The bibliographic review was carried out in different databases, including studies within the pediatric population where dietary and/or nutritional interventions were used to treat NAFLD. Main interventions include diets low in carbohydrates, free sugars, fructose, and lipids, in addition to healthy eating patterns and possible nutritional interventions with n-3 polyunsaturated fatty acids (EPA and DHA), amino acids (cysteine, L-carnitine), cysteamine, vitamins, and probiotics (one strain or multi-strain). Lifestyle changes remain the main recommendation for children with NAFLD. Nevertheless, more studies are required to elucidate the effectiveness of specific nutrients and bioactive compounds in this population. [ABSTRACT FROM AUTHOR]

Prateek Sharma,1 Jayachandran Nair,1 Anurag Sinh,1 Shivangi,1 Thirumurthy Velpandian,2 Ruchi Tripathi,1 Rajani Mathur1 1Department of Pharmacology, Delhi Institute of Pharmaceutical Science and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India; 2Department of Ocular Pharmacology, Dr. R.P. Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, 110029, IndiaCorrespondence: Rajani Mathur, Department of Pharmacology, Delhi Institute of Pharmaceutical Science and Research, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Sec III, New Delhi, 110017, India, Tel +91-011-29551490, Fax +91-011-29554503, Email mathurajani@gmail.comPurpose: Fructose is highly lipogenic, and its unhindered ingestion by children and adolescents is understood to induce hypertriglyceridemia and non-alcoholic fatty liver disease (ped-NAFLD) that is till date managed symptomatically or surgically. The aim of the present study was to investigate the potential of hydroethanolic extract of leaves of Guava (PG-HM) to suppress the alterations in the hepatic molecular signals due to unrestricted fructose (15%) drinking by growing rats.Methods: Weaned rats (4 weeks old) in control groups had ad libitum access to fructose drinking solution (15%) for four (4FDR) or eight (8FDR) weeks, ie, till puberty or early adulthood, respectively, while treatment groups (4PGR, 8PGR) additionally received PG-HM (500 mg/kg, po).Results: The PG-HM suppressed ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I–V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). Parri passu, the insulin sensitizing effect of PG-HM and its ethyl acetate fraction (PG-EA) was elucidated using HepG2 cells grown in media enhanced with fructose. Further, in murine hepatocytes cultured in fructose-rich media, PG-HM (35 μg mL-1) outperformed Pioglitazone (15 μM) and Metformin (5 mM), to suppress hepatic insulin resistance.Conclusion: This study established that hydroethanolic extract of leaves of Guava (PG-HM) has potential to suppress hepatic metabolic alteration for the management of the pediatric NAFLD.Graphical Abstract: Keywords: Psidium guajava, pediatric NAFLD, insulin sensitizer, mitochondrial function

Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD). This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966–2017; n = 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n = 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs. Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference = 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77–9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference = 6.6%; 95% CI 4.0–9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92–7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18–43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05–9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77–27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97–48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75–98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73–10.79). Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls. Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality. [Display omitted] • Biopsy-proven pediatric and young-adult NAFLD contributes to substantial excess mortality. • Mortality is increased with simple steatosis, and further amplified with steatohepatitis. • This excess mortality was primarily from cancer, cardiometabolic disease and liver disease. [ABSTRACT FROM AUTHOR]

Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low. Bariatric surgery, though effective, is invasive and can worsen NAFLD postoperatively. Thus, there is an evolving and underutilized role for pharmacotherapy in children, both for weight reduction and NAFLD management. In this perspective article, we provide an overview of the efficacy of weight reduction on pediatric NAFLD treatment, discuss the pros and cons of currently approved pharmacotherapy options, as well as drugs commonly used off-label for weight reduction in children and adolescents. We also highlight gaps in, and opportunities for, streamlining obesity trials to include NAFLD assessment as a valuable, secondary, therapeutic outcome measure, which may aid drug repurposing. Finally, we describe the already available, and emerging, minimally-invasive biomarkers of NAFLD that could offer a safe and convenient alternative to liver biopsy in pediatric obesity and NAFLD trials.

Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low. Bariatric surgery, though effective, is invasive and can worsen NAFLD postoperatively. Thus, there is an evolving and underutilized role for pharmacotherapy in children, both for weight reduction and NAFLD management. In this perspective article, we provide an overview of the efficacy of weight reduction on pediatric NAFLD treatment, discuss the pros and cons of currently approved pharmacotherapy options, as well as drugs commonly used off-label for weight reduction in children and adolescents. We also highlight gaps in, and opportunities for, streamlining obesity trials to include NAFLD assessment as a valuable, secondary, therapeutic outcome measure, which may aid drug repurposing. Finally, we describe the already available, and emerging, minimally-invasive biomarkers of NAFLD that could offer a safe and convenient alternative to liver biopsy in pediatric obesity and NAFLD trials. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents. About 30% of patients with NAFLD progress to the more severe condition of nonalcoholic steatohepatitis (NASH), which is typically diagnosed using liver biopsy. Liver stiffness (LS) quantified by elastography is a promising imaging marker for the noninvasive assessment of NAFLD and NASH in pediatric patients. However, the link between LS and specific histopathologic features used for clinical staging of NAFLD is not well defined. Furthermore, LS data reported in the literature can vary greatly due to the use of different measurement techniques. Uniquely, time-harmonic elastography (THE) based on ultrasound and magnetic resonance elastography (MRE) use the same mechanical stimulation, allowing us to compare LS in biopsy-proven NAFLD previously determined by THE and MRE in 67 and 50 adolescents, respectively. In the present work, we analyzed the influence of seven distinct histopathologic features on LS, including septal infiltration, bridging fibrosis, pericellular fibrosis, hepatocellular ballooning, portal inflammation, lobular inflammation, and steatosis. LS was highly correlated with periportal and lobular fibrosis as well as hepatocellular ballooning while no independent association was found for inflammation and steatosis. Based on this analysis, we propose a composite elastography score (CES) which includes the four key histopathologic features identified as mechanically relevant. Interestingly, CES-relevant histopathologic features were associated with zonal distribution patterns of pediatric NAFLD. Mechano-structural changes associated with NAFLD progression can be histopathologically staged using the CES, which is easily determined noninvasively based on LS measured by time-harmonic elastography. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Objective: Pediatric nonalcoholic fatty liver disease (NAFLD) is a growing problem, but its underlying mechanisms are poorly understood. We used transcriptomic reporter cell assays to investigate differences in transcriptional signatures induced in hepatocyte reporter cells by the sera of children with and without NAFLD., Methods: We studied serum samples from 45 children with NAFLD and 28 children without NAFLD. The sera were used to induce gene expression in cultured HepaRG cells and RNA-sequencing was used to determine gene expression. Computational techniques were used to compare gene expression patterns., Results: Sera from children with NAFLD induced the expression of 195 genes that were significantly differentially expressed in hepatocytes compared to controls with obesity. NAFLD was associated with increased expression of genes promoting inflammation, collagen synthesis, and extracellular matrix remodeling. Additionally, there was lower expression of genes involved in endobiotic and xenobiotic metabolism, and downregulation of peroxisome function, oxidative phosphorylation, and xenobiotic, bile acid, and fatty acid metabolism. A 13-gene signature, including upregulation of TREM1 and MMP1 and downregulation of CYP2C9, was consistently associated with all diagnostic categories of pediatric NAFLD., Conclusion: The extracellular milieu of sera from children with NAFLD induced specific gene profiles distinguishable by a hepatocyte reporter system. Circulating factors may contribute to inflammation and extracellular matrix remodeling and impair xenobiotic and endobiotic metabolism in pediatric NAFLD., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose of Review: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA, affecting over 7 million children. In this article, we provide an update on pediatric NAFLD by briefly reviewing the recent publications in diagnosis, screening, therapy, and follow-up.Recent Findings: NAFLD remains a diagnosis of exclusion and liver biopsy is the most accurate test to assess severity of the disease in children. There is a growing collection of studies testing noninvasive tests for hepatic steatosis and fibrosis, several of which have become available in more recent years, such as fibrosis scores, imaging and serum biomarkers. The mainstay of NAFLD treatment remains weight loss through dietary modifications and exercise. There is substantial interest in pharmacological therapies for NAFLD given the frequent failure of lifestyle and behavior modification to resolve the disease. Certain medications of interest target mechanisms involved in the pathogenesis of NAFLD such as insulin resistance, oxidative stress, and dyslipidemia.Summary: Research within the field of NAFLD has advanced substantially, yet critical gaps remain including lack of accurate noninvasive tests for NAFLD, effective prevention, and treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess liver disease progression using paired magnetic resonance imaging (MRI) measurements of liver fat fraction (FF) and stiffness.Study Design: Retrospective cohort study including patients with nonalcoholic fatty liver disease who had undergone repeat MRI studies. Descriptive statistics were used, as well as Pearson or Spearman correlation when appropriate. Mixed model analyses were used to determine relationships between liver FF/stiffness and predictor variables.Results: Sixty-five patients (80% non-Hispanic, mean age 14 ± 3 years) were included. Time from first to last MRI was 27 ± 14 months. Over time, body mass index z score remained stable, and there were no significant differences in mean serum aminotransferases, insulin, glucose, triglycerides, low-density lipoprotein, and high-density lipoprotein (HDL) levels. However, the proportion of patients with alanine aminotransferase (ALT) < 50 U/L increased. MRI FF and stiffness decreased in 29% and 20% of patients, respectively, and increased in 25% and 22% of patients, respectively. There was a weak positive correlation between FF change and ALT change (r = 0.41, P = .053) and a moderate negative correlation between change in FF and change in serum HDL levels (r = -0.58, P = .004). After adjusting for HDL, increase in serum insulin was the only variable predictive of increase in FF (P = .061). There was no correlation between change in liver stiffness and change in ALT (r = .02, P = .910).Conclusions: MRI-determined hepatic FF and stiffness improved in a minority of patients overtime. ALT levels were not reflective of the change in FF or stiffness. MRI-based imaging is complementary in the assessment of NAFLD progression. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: Lifestyle modification has been the mainstay of controlling childhood obesity and has proved to be effective in reducing cardiovascular risk factors. However, it is currently unknown whether the subclinical atherosclerotic changes associated with nonalcoholic fatty liver disease (NAFLD) in such population are reversible. Methods and results: We analyzed changes of brachial flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), clinical, laboratory, and imaging data in 120 obese children with NAFLD, at the end of a 1-year intervention program with diet and physical exercise. The lifestyle intervention led to a significant mean decrease of body mass index (BMI)–standard deviation score (SDS), waist circumference (WC) and fat mass, along with diastolic blood pressure, triglycerides, liver enzymes, insulin, insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR), and high-sensitivity C-reactive protein. At the end of the study, FMD improved (P < 0.0001), while cIMT did not change significantly (P = 0.20). A significant decrease in hepatic fat content as measured by magnetic resonance imaging was also observed. Changes in FMD were inversely associated with changes in BMI–SDS, WC, total cholesterol, non-HDL cholesterol, liver enzymes, HOMA-IR, physical activity, and hepatic fat content. After including in the model all the significant variables as well as age, gender, pubertal status, and baseline FMD values, changes in FMD were significantly and independently associated with changes in WC and total cholesterol. Conclusion: Also in obese children with NAFLD arterial function may be restored by improving metabolic risk factors and reducing visceral adiposity following a 1-year lifestyle intervention. [Copyright &y& Elsevier]

Non-alcoholic fatty liver disease (NAFLD) is the number one chronic liver disease worldwide and is estimated to affect nearly 40% of obese youth and up to 10% of the general pediatric population without any obvious signs or symptoms. Although the early stages of NAFLD are reversible with diet and lifestyle modifications, detecting such stages is hindered by a lack of non-invasive methods of risk assessment and diagnosis. This absence of non-invasive means of diagnosis is directly related to the scarcity of long-term prospective studies of pediatric NAFLD in children and adolescents. In the majority of pediatric NAFLD cases, the mechanisms driving the origin and rapid progression of NAFLD remain unknown. The progression from NAFLD to non-alcoholic steatohepatitis (NASH) in youth is associated with unique histological features and possible immune processes and metabolic pathways that may reflect different mechanisms compared with adults. Recent data suggest that circulating microRNAs (miRNAs) are important new biomarkers underlying pathways of liver injury. Several factors may contribute to pediatric NAFLD development, including high-sugar diets, in utero exposures via epigenetic alterations, changes in the neonatal microbiome, and altered immune system development and mitochondrial function. This review focuses on the unique aspects of pediatric NAFLD and how nutritional exposures impact the immune system, mitochondria, and liver/gastrointestinal metabolic health. These factors highlight the need for answers to how NAFLD develops in children and for early stage-specific interventions. [ABSTRACT FROM AUTHOR]

Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig's seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of "NAFLD as a manifestation of the Metabolic Syndrome", to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research. [ABSTRACT FROM AUTHOR]

Pediatric nonalcoholic fatty liver disease is an increasingly prevalent disease, but its pathophysiology is not fully elucidated, diagnosis is difficult and invasive, and therapeutic options are limited. This article addresses the recent advancements made in understanding the pathophysiology of nonalcoholic fatty liver disease, the development of less invasive diagnostic modalities, and emerging therapeutic options, including ongoing clinical trials in children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic. Recent studies have clearly shown that the stage of fibrosis in adults with NAFLD is the most important histological feature in long-term outcomes and the development of liver-related complications. Despite the paucity of data regarding the natural history of pediatric NAFLD, its progression to cirrhosis and end-stage liver disease requiring liver transplantation is well documented. Given the high prevalence of NAFLD in children and adults, there is an urgent need to find safe and cost-effective alternatives to biopsy to determine the stage of liver fibrosis. In this review, we provide a concise overview of different noninvasive methods for diagnosing and staging liver fibrosis in children with NAFLD.