Search

Introduction: Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including 'simple' steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults. Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints. The potential for the extension of adult treatments to children is discussed, as well as what limits the use of certain agents in children. Expert commentary: No drugs have yet to be licenced for NAFLD. Trial heterogeneity makes comparison of drugs between studies challenging. FXR agonists are yet to be trialled in children but may represent a safe and potentially efficacious therapy. Future treatments would likely encompass a multimodal approach that may include bariatric surgery.

Atherosclerosis origins early in childhood. Aim of the study was to investigate vascular signature and phenotypes of cardiovascular disease in obese children and adolescents identifying novel potential circulating markers of risk. Cross-sectional study of intima-media-thickness (IMT), pulse wave velocity (PWV), augmentation index (AIX@75), circulating markers (E-selectin, soluble-intercellular-adhesion-molecule1&#95;ICAM1, chemerin, fatty-acid-binding protein 4, sCD36, lipopolysaccharides&#95;LPS, oxLDL, fetuin) in 123 obese (body mass index, BMI z-score >1.645 SD) children (N=55, age ≤10 years-old) and adolescents (N=68, age >10 years-old). Adolescents had significantly higher uric acid ( p =0.002), non-HDL-cholesterol ( p =0.02), fasting glucose ( p =0.04), systolic blood pressure ( p =0.005) and PWV ( p =0.02) than children. Obese adolescent patients with metabolic syndrome (MetS) abnormalities had higher PWV ( p <0.05) than peers without. No differences were observed in circulating biomarkers in relationship to age and MetS status. oxLDL, sCD36 and LPS were correlated to AIX@75 and/or IMT M in children and adolescents (p ranging from <0.05 to <0.0001). Total cholesterol, non-HDL-cholesterol, TG/HDL ratio, oxLDL, sCD36, ICAM1, LPS were significantly different across AIX@75 tertiles ( p between 0.03 and 0.001). Early phenotypes of cardiovascular alterations in young severely obese patients encompass increased IMT, stiffness of intermediate size and resistance vasculature. Novel biomarkers investigated in the present study were associated to estimates of stiffness and thickness not differently from traditional risk factor such as non-HDL-cholesterol and TG/HDL ratio., Competing Interests: Competing Interests: A Handberg is the inventor of two patent applications on sCD36 as a biomarker of the metabolic syndrome. The patent IP rights are owned by the Idea's Clinic of Aalborg University Hospital. The remaining authors have indicated they have no potential conflicts of interest to disclose. Other authors have indicated they have no financial relationships relevant to this article to disclose.

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the most common form of chronic liver disease in children and adolescents. The histologic spectrum of NAFLD is broad ranging, from the relatively benign form of simple steatosis to the aggressive form of nonalcoholic steatohepatitis, eventually leading to fibrosis and cirrhosis. NAFLD has also been recognized as an independent risk factor for extrahepatic complications, such as cardiovascular disease, type 2 diabetes mellitus, sleep disorders, and osteoporosis. In this review, we discuss both the hepatic and extrahepatic complications of NAFLD in children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is evidence that nonalcoholic fatty liver disease (NAFLD) is affected by gut microbiota. Therefore, we investigated its modifications in pediatric NAFLD patients using targeted metagenomics and metabolomics. Stools were collected from 61 consecutive patients diagnosed with nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), or obesity and 54 healthy controls (CTRLs), matched in a case-control fashion. Operational taxonomic units were pyrosequenced targeting 16S ribosomal RNA and volatile organic compounds determined by solid-phase microextraction gas chromatography-mass spectrometry. The α-diversity was highest in CTRLs, followed by obese, NASH, and NAFL patients; and β-diversity distinguished between patients and CTRLs but not NAFL and NASH. Compared to CTRLs, in NAFLD patients Actinobacteria were significantly increased and Bacteroidetes reduced. There were no significant differences among the NAFL, NASH, and obese groups. Overall NAFLD patients had increased levels of Bradyrhizobium, Anaerococcus, Peptoniphilus, Propionibacterium acnes, Dorea, and Ruminococcus and reduced proportions of Oscillospira and Rikenellaceae compared to CTRLs. After reducing metagenomics and metabolomics data dimensionality, multivariate analyses indicated a decrease of Oscillospira in NAFL and NASH groups and increases of Ruminococcus, Blautia, and Dorea in NASH patients compared to CTRLs. Of the 292 volatile organic compounds, 26 were up-regulated and 2 down-regulated in NAFLD patients. Multivariate analyses found that combination of Oscillospira, Rickenellaceae, Parabacteroides, Bacteroides fragilis, Sutterella, Lachnospiraceae, 4-methyl-2-pentanone, 1-butanol, and 2-butanone could discriminate NAFLD patients from CTRLs. Univariate analyses found significantly lower levels of Oscillospira and higher levels of 1-pentanol and 2-butanone in NAFL patients compared to CTRLs. In NASH, lower levels of Oscillospira were associated with higher abundance of Dorea and Ruminococcus and higher levels of 2-butanone and 4-methyl-2-pentanone compared to CTRLs., Conclusion: An Oscillospira decrease coupled to a 2-butanone up-regulation and increases in Ruminococcus and Dorea were identified as gut microbiota signatures of NAFL onset and NAFL-NASH progression, respectively. (Hepatology 2017;65:451-464)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background/aims: Insulin-like growth factor (IGF)-I is related to cardiometabolic risk in adults, whereas the metabolic role of IGF-II is unclear. The aim of this study was to assess IGFs in obese children and correlate them with metabolic syndrome (MetS) components., Methods: This is a retrospective study including 574 obese children (11.34 ± 3.16 years). All subjects underwent complete anthropometry and biochemical assessment. In a subgroup of 136 subjects, body composition was evaluated. IGF-I was measured in 300 obese subjects and IGF-II in 77 obese and 15 lean children. 177 subjects were divided according to the presence of 1 or more MetS criteria: group 1, subjects with 1 MetS criterion; group 2, subjects with 2 components; and group 3, subjects with MetS diagnosis., Results: IGF-I, IGF-II, and IGF-I/insulin-like growth factor-binding protein-3 ratio were not different among subjects with an increasing number of MetS criteria and were not associated with single components of MetS as well as with body composition parameters. In children younger than 10 years, IGF-I directly correlated with high-density lipoprotein cholesterol (p < 0.005) even after controlling for confounders. IGF-II was significantly higher in obese children and correlated with parameters of insulin sensitivity (p < 0.05)., Conclusion: IGFs were neither related to MetS nor to body composition parameters in obese children. Further studies are needed to clarify the mechanisms underlying the relationship between IGF-II and insulin sensitivity., (© 2017 S. Karger AG, Basel.)

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, due to the increased worldwide incidence of obesity among children. It is now clear enough that of diet high in carbohydrates and simple sugars are associated with hepatic steatosis and non-alcoholic steatohepatitis (NASH). Several studies have shown that an increased consumption of simple sugars is also positively associated with overweight and obesity, and related co-morbidities, such as type 2 diabetes, metabolic syndrome and NAFLD. It is difficult to define the role of the various components of soft drinks and energy drinks in the pathogenesis of NAFLD and its progression in NASH, but the major role is played by high calorie and high sugar consumption, mainly fructose. In addition, other components of these beverages (e.g. xanthine) seem to have an important role in the pathogenesis of metabolic disorders, crucial pathways involved in NAFLD/NASH. The drastic reduction in the consumption of energy drinks and soft drinks is an appropriate intervention for the prevention of obesity and NAFLD in young people.

Background: Glucose derangement has been reported to increase oxidative stress, one of the most important factors underlying the progression of hepatic fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). To date, careful evaluation of the glucose profile in pediatric NAFLD has not been performed., Methods: A total of 30 severely obese children (15 males; mean age 12.87 ± 2.19 years) with biopsy-proven NAFLD were enrolled in this study from September to December 2013. All patients underwent anthropometric and laboratory evaluation, including the oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM)., Results: Our study reveals some differences between OGTT and CGM in detecting NAFLD children with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). OGTT showed 2 (6.67%) patients with IFG and 1 (3.34%) with IGT, while CGM showed 5 (16.67%) patients with IFG and 6 (20%) with IGT. The daily blood glucose profile positively correlated with the baseline blood glucose (r = 0.39, p = 0.04) and the homeostatic model assessment (r = 0.56, p = 0.05). A positive correlation between hyperglycemia and liver fibrosis was found (r = 0.65, p < 0.05). Mean glucose values (F3-F4 group: 163.2 ± 35.92 mg/dl vs. F1 group: 136.58 ± 46.83 mg/dl and F2 group: 154.12 ± 22.51 mg/dl) and the difference between the minimum and maximum blood glucose levels (F3-F4 group: 110.21 ± 25.26 mg/dl vs. F1 group: 91.67 ± 15.97 mg/dl and F2 group: 92 ± 15.48 mg/dl) were significantly (p < 0.05) higher in the F3-F4 group compared to the F1 and F2 groups., Conclusion: Glucose profile derangement as detected by CGM is associated with the severity of hepatic fibrosis in children with NAFLD., (© 2015 S. Karger AG, Basel.)

Non-alcoholic fatty liver disease (NAFLD) is currently considered the main cause of chronic liver disease worldwide. Mechanisms leading to the development and progression of this disease are topics of great interest for researchers and clinicians. The current multi-hit hypothesis has thrown the crosstalk between liver and adipose tissue into sharp focus. It is well known that adipose tissue produces circulating factors, known as adipocytokines, which exert several effects on liver cells, promoting the onset of NAFLD and its progression to non-alcoholic steatohepatitis in obese subjects. In a similar way, hepatocytes may also respond to obesogenic stimuli by producing and releasing hepatokines into the circulation. Here, the authors provide an overview of recent advances in our understanding of the role of the most relevant adipocytokines and hepatokines in NAFLD pathogenesis, highlighting their possible molecular and functional interactions.

Obesity is a major health concern. While some children develop comorbidities such as insulin resistance and low-grade systemic inflammation upon weight gain, others stay metabolically healthy. There is an urgent need for clinically relevant markers with prognostic value related to disease development and intervention success. MicroRNAs (miRNAs) are established biomarkers for several disease states. Herein, we give a brief overview of miRNA biogenesis and function and the potential role of circulating miRNA in the context of pediatric obesity., (© 2016 S. Karger AG, Basel.)

Objective: Obesity in childhood is associated with an inflammatory state in adipose tissue and liver, which elevates risk for diabetes and liver disease. No prior study has examined associations between pathologies occurring in adipose tissue and liver to identify elements of tissue damage associated with type 2 diabetes risk. This study sought to determine whether inflammation and fibrosis in abdominal subcutaneous adipose tissue (SAT) in obese/overweight children (BMI-z 2.3 ± 0.76) was related to the extent of observed liver disease or type 2 diabetes risk., Methods: Biopsy samples of abdominal (SAT) and liver were simultaneously collected from 33 Italian children (mean BMI 28.1 ± 5.1 kg/m(2) and mean age 11.6 ± 2.2 years) with confirmed NAFLD. Histology and immunohistochemistry were conducted on biopsies to assess inflammation and fibrosis in adipose tissue and fibrosis and inflammation in liver., Results: Presence vs. absence of crown-like structures (CLS) in SAT was significantly related to liver fibrosis scores (1.7 ± 0.7 vs. 1.2 ± 0.7, P = 0.04) independent of BMI. SAT fibrosis was significantly correlated with a lower disposition index (r = -0.48, P = 0.006). No other adipose measures were associated with liver disease parameters., Conclusion: Markers of subcutaneous white adipose tissue inflammation are associated with greater extent of liver fibrosis independent of obesity and SAT fibrosis may contribute to diabetes risk through reduced insulin secretion., (Copyright © 2014 The Obesity Society.)

Rationale: Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown., Objectives: To assess the relationship of OSAS with liver injury in pediatric NAFLD., Methods: Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h., Measurements and Main Results: Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis., Conclusions: In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.

Background/aims: Elevated thyroid-stimulating hormone (TSH) concentrations in association with normal/slightly elevated free triiodothyronine (fT(3)) and/or free thyroxine (fT(4)) have been consistently found in obese children. To examine relationships between adiposity, insulin sensitivity, and TSH, fT(3) and fT(4)., Methods: 240 overweight/obese prepubertal children were studied. Fasting TSH, fT(3), fT(4), glucose, insulin, C-peptide, lipids, leptin and adiponectin were evaluated. Insulin sensitivity and resistance were estimated [quantitative insulin check index (QUICKI), insulin sensitivity index (ISI), and hepatic insulin resistance index]. Body fat was measured by dual-energy X-ray absorptiometry. The central obesity index was calculated as the ratio of fat tissue in the trunk region to fat tissue in the leg region., Results: The multiple regression analysis with age, gender and measures of fatness as covariates showed that QUICKI was the only significant negative predictor of TSH and central obesity index the strongest positive predictor of fT(3), in association with either age or hepatic insulin resistance index, and that the only positive determinant of fT(4) was hepatic insulin resistance index., Conclusions: Reduced insulin sensitivity is associated with augmented TSH and fT(4), while progressive central fat accumulation is strictly related to a parallel increase in fT(3) levels, independently from total body fat. Further studies are needed to understand mechanisms linking thyroid function to insulin sensitivity and body composition in obese children., (Copyright © 2012 S. Karger AG, Basel.)

The aim of the present study was to build a predictive model of nonalcoholic fatty liver disease (NAFLD) in obese children. Fifty-six obese 10-year-old children underwent blood tests for biochemical measures and magnetic resonance imaging for NAFLD diagnosis. A model combining waist-to-height ratio, homeostasis model assessment of insulin resistance, adiponectin, and alanine aminotransferase was accurate in predicting NAFLD (AUROC = 0.94 [95% confidence interval 0.89-0.99], P < 10). When adiponectin was not included in the model, the discrimination accuracy was still good (AUROC = 0.88 [95% confidence interval 0.79-0.97], P < 10). In conclusion, a predictive equation combining routinely available variables may allow physicians to identify obese children at the highest risk of NAFLD.

Objective: The aim of the present study was to evaluate the association between the type of early feeding and indices of insulin metabolism in 8-year-old overweight and obese children., Methods: The sample included 350 overweight (body mass index [BMI] ≥1.036 standard deviation score [SDS]) and obese (BMI ≥1.645 SDS) children and 33 normal-weight control subjects who had been exclusively breast-fed or formula-fed for 4 months or longer. Parameters of insulin sensitivity and secretion were derived from 120-minute oral glucose tolerance tests., Results: Overweight and obese formula-fed children (N = 165) were more insulin resistant than breast-fed individuals (N = 185; Whole-Body Insulin Sensitivity Index 5.1 ± 2.3 vs 6.6 ± 2; p < 0.0001) despite having the same degree of obesity (BMI z-score 1.8 ± 0.4 vs 1.7 ± 0.4 SDS; p = 0.5). They compensated for enhanced insulin resistance by augmenting insulin secretion (Insulinogenic Index 6.8 ± 3.6 vs 5.2 ± 2.5 μIU/mL × mg/mL(-1); p < 0.0001). Thus, they presented with a disposition index similar to that of breast-fed children (34.6 ± 15 vs 30.8 ± 19.2; p = 0.4), Formula feeding was associated with greater catch-up growth in the first month (odds ratio 2.49, 95% confidence interval 1.97 to 3.01; p < 0.0001) and between months 6 and 12 of life (odds ratio 4.62, 95% confidence interval 3.58 to 5.67; p < 0.0001)., Conclusions: In comparison with breast-feeding, formula feeding seems to be associated with reduced insulin sensitivity and increased insulin secretion in overweight and obese children.

Purpose of Review: The intent of this review is to provide a concise overview of all recent acquisitions in terms of therapies and early noninvasive diagnostic approaches for nonalcoholic fatty liver disease (NAFLD) in children., Recent Findings: NAFLD is increasingly being diagnosed in children. If undiscovered and if certain risks are present (i.e. obesity), nonalcoholic steatohepatitis, the most severe form of NAFLD, may silently progress to cirrhosis, hepatocarcinoma and liver-related death in adulthood. Current therapies include approaches for reducing the incidence of risk factors (i.e. weight reduction), drugs targeting the major molecular mechanisms thought essential in the pathogenesis of the disease (insulin resistance and oxidative stress) or both, but other novel treatments are under investigation., Summary: Although weight reduction, achieved through a combination of diet and exercise, makes it possible to modify the natural course of simple steatosis, the addition of adequate drugs might also provide a therapeutic action on nonalcoholic steatohepatitis. Moreover, preventive strategies and the design and translation into clinical practice of indices that integrate noninvasive diagnostic tools and serum biomarkers might be a winning approach for improving management of paediatric NAFLD/nonalcoholic steatohepatitis in the coming years.

Objective: To evaluate the relationship between biopsy-proven non-alcoholic fatty liver disease (NAFLD) and carotid artery intima-media thickness (CIMT) in children and adolescents., Methods: A case-control study was performed. Cases were 31 mostly obese children and adolescents, with NAFLD detected at ultrasonography, and confirmed by liver biopsy. Controls were 49 mostly obese children matched for gender, age and BMI without NAFLD at ultrasonography and with normal levels of aminotransferases. Besides standard laboratory measurements, subjects underwent an oral glucose tolerance test to evaluate glucose tolerance and to estimate whole body insulin sensitivity (ISI)., Results: CIMT was similar in cases and controls on the right side but higher in cases on the left side. Although statistically significant, this difference is unlikely to be clinically relevant because of substantial overlap of CIMT values between cases and controls. Moreover, there was no association between CIMT and the severity of steatosis, ballooning, fibrosis, and the non-alcoholic steato-hepatitis score in cases. At multivariable analysis in the pooled sample (n=80), age and the z-score of BMI but not NAFLD, gender, blood pressure and triglycerides, were associated with CIMT., Conclusions: We found no association between CIMT and NAFLD in children and adolescents. More importantly, there was no association between histological severity and CIMT in children with NAFLD., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Insulin resistance (IR) and obesity may be associated with impaired response to physical exercise. We aimed at assessing physical capacity in obese children with biopsy proven non-alcoholic fatty liver disease (NAFLD) as compared to normal weight and obese children without fatty liver disease. All male subjects, 20 NAFLD and 31 control individuals (20 obese, without NAFLD and 11 normal weight children) took part in the study. We evaluated changes in cardiovascular parameters during a bicycle-ergometer exercise test (James' test). Duration, power of exercise, heart rate (HR), blood pressure (BP), pulse pressure, cardiac output ((I)CO) and total peripheral vascular resistance indexed for height ((I)TPVR) were recorded at rest ((r)) and peak ((p)) exercise. The homeostatic model assessment was used to determine insulin resistance (HOMA-IR) and beta-cell action (HOMA-beta cell). In NAFLD and obese subjects, fasting leptin, insulin secretion, insulinogenic index (IGI), muscle insulin sensitivity (MISI) and hepatic insulin resistance index (HIRI) were assayed. Children with NAFLD were the most insulin-resistant (P = 0.001), and showed higher HIRI than obese controls (P = 0.05). At rest, they had the lowest values of SBP(r) (P = 0.001 vs. controls and P < or = 0.05 vs. obese controls); during the test, the highest values of (I)CO(p) (P = 0.005), Delta(I)CO (P = 0.003) and DeltaTRVP(p) (P < or = 0.0001). NAFLD and obese controls both had impaired DeltaHR(p) (P < or = 0.0001). However, obese controls were not able to reduce peripheral resistance during the test. HOMA-IR explained 28% of variance in Delta(I)CO of the whole sample, (P < or = 0.0001). In obese children with or without NAFLD, increased IR and body weight may induce cardiovascular compensatory changes in response to physical exercise with fairly different pathogenetic mechanisms, which are likely to be dependent on the different degree of IR.

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.

Paralleling the growing prevalence of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) is emerging as the most frequent hepatopathy in adults and children. The true prevalence of pediatric NAFLD is still unknown, because of the heterogeneity of diagnostic methods used for diagnosis in the available studies and the different characteristics of the populations evaluated. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome. Age, gender and race/ethnicity are significant determinants of risk, and sex hormones, insulin sensitivity and adipocytokines are implicated in the pathogenesis of pediatric NAFLD. The natural history of NAFLD in children is still poorly understood, because of its complex nature and the scarcity of prospective studies, especially in pediatric populations. Both genetic and environmental factors seem to be implicated in the development and progression of the disease via multiple mechanisms that involve liver crosstalk with other organs and tissues, especially gut and adipose tissue. To evaluate and effectively treat pediatric NAFLD, the pathophysiology and natural history of the disease should be clarified and noninvasive methods for screening, diagnosis, and longitudinal assessment developed.

Non-alcoholic fatty liver disease (NAFLD) is recognized as an emerging health risk in obese children and adolescents. NAFLD represents a wide spectrum of liver conditions, ranging from asymptomatic steatosis to steatohepatitis. The growing prevalence of fatty liver disease in children is associated with an increased risk of metabolic and cardiovascular complications. NAFLD is considered the hepatic manifestation of Metabolic Syndrome (MetS) and several lines of evidence have reported that children with NAFLD present one or more features of MetS. The pathogenetic mechanisms explaining the interrelationships between fatty liver disease and MetS are not clearly understood. Altough central obesity and insulin resistance seem to represent the core of the pathophysiology in both diseases, genetic susceptibility and enviromental triggers are emerging as crucial components promoting the development of NAFLD and MetS in children. In the present review we have identified and summarizied studies discussing current pathogenetic data of the association between NAFLD and MetS in children. [ABSTRACT FROM AUTHOR]

Background and aims: Nonalcoholic fatty liver disease is one of the major complications of obesity, occurring already in pediatric age. Insulin like growth factor-I has been proposed as a potential therapeutic agent for its beneficial effect in experimental liver fibrosis. The aim of this work was to investigate the expression of insulin-like growth factor-I and its receptor in the liver of children with biopsy-proven nonalcoholic fatty liver disease and relate it to liver histological features. Methods: 45 obese children and adolescents (14 females and 31 males) with nonalcoholic fatty liver disease were included. Insulin like growth factor-I and its receptor expression was evaluated in liver tissue by immunofluorescence and qPCR. Results: The expression of insulin like growth factor-I and its receptor were significantly related to fibrosis and were higher in children with stage 3 fibrosis compared to stage 1 and 2 (p<0.001 and p = 0.007 respectively). mRNA of insulin like growth factor-I receptor was higher in more advanced stages of fibrosis (p<0.001). Furthermore, the expression of insulin like growth factor-I and its receptor in hepatic stellate cells, the cell type mostly involved in fibrosis progression, was significantly increased in stage 3 fibrosis compared to stage 1 (p = 0.01 and p = 0.008 respectively). Conclusions: We demonstrated for the first time that insulin like growth factor-I and its receptor are upregulated in children with nonalcoholic fatty liver disease. These findings give a new hint for the potential therapeutic use of insulin like growth factor-I in pediatric nonalcoholic fatty liver disease complicated by liver fibrosis. [ABSTRACT FROM AUTHOR]

Obesity levels, especially in children, have dramatically increased over the last few decades. Recently, several studies highlighted the involvement of gut microbiota in the pathophysiology of obesity. We investigated the composition of gut microbiota in obese adolescents and adults compared to age-matched normal weight (NW) volunteers in order to assemble age- and obesity-related microbiota profiles. The composition of gut microbiota was analyzed by 16S rRNA-based metagenomics. Ecological representations of microbial communities were computed, and univariate, multivariate, and correlation analyses performed on bacterial profiles. The prediction of metagenome functional content from 16S rRNA gene surveys was carried out. Ecological analyses revealed a dissimilarity among the subgroups, and resultant microbiota profiles differed between obese adolescents and adults. Using statistical analyses, we assigned, as microbial markers, Faecaiibacterium prausnitzii and Actinomyces to the microbiota of obese adolescents, and Parabacteroides, Rikenellaceae, Bacteroides caccae, Barnesiellaceae, and Osciiiospira to the microbiota of NW adolescents. The predicted metabolic profiles resulted different in adolescent groups. Particularly, biosynthesis of primary bile acid and steroid acids, metabolism of fructose, mannose, galactose, butanoate, and pentose phosphate and glycolysis/gluconeogenesis were for the majority associated to obese, while biosynthesis and metabolism of glycan, biosynthesis of secondary bile acid, metabolism of steroid hormone and lipoic acid were associated to NW adolescents. Our study revealed unique features of gut microbiota in terms of ecological patterns, microbial composition and metabolism in obese patients. The assignment of novel obesity bacterial markers may open avenues for the development of patient-tailored treatments dependent on age-related microbiota profiles. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background & Aims Recent research has suggested that dietary fructose intake may increase serum uric acid (UA) concentrations. Both UA concentration and fructose consumption maybe also increase in NAFLD. It is not known whether dietary fructose consumption and UA concentration are independently associated with non-alcoholic steatohepatitis (NASH). Our aim was to investigate the factors associated with NASH in children and adolescents with proven NAFLD, and to test whether UA concentrations and fructose consumption are independently associated with NASH. Methods Obese children with NAFLD were studied (n = 271). NASH was diagnosed by a NAFLD activity score ~5 and the fatty liver inhibition of progression (FLIP) algorithm. Fructose consumption (g/day) was assessed by food frequency questionnaire, and UA (mg/dl) was measured in serum. Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with NASH. Results NASH occurred in 37.6% of patients. Hyperuricaemia (UA ~5.9 mg/dl) was present in 47% of patients with NASH compared with 29.7% of non-NASH patients (p = 0.003). Both UA concentration (OR = 2.488, 95% CI: 1.87-2.83, p = 0.004) and fructose consumption (OR = 1.612, 95% CI 1.25-1.86, p = 0.001) were independently associated with NASH, after adjustment for multiple (and all) measured confounders. Fructose consumption was independently associated with hyperuricaemia (OR = 2.021, 95% CI: 1.66-2.78, p = 0.01). These data were confirmed using the FLIP algorithm. Conclusions Both dietary fructose consumption and serum UA concentrations are independently associated with NASH. Fructose consumption was the only factor independently associated with serum UA concentration. Lay summary Currently, it is not known whether dietary fructose consumption and uric acid (UA) concentration are linked with non-alcoholic steatohepatitis (NASH) in children and adolescents. Our aim was to test whether UA concentrations and fructose consumption are independently associated with NASH in children and adolescents with proven non-alcoholic fatty liver disease (NAFLD). We show that both dietary fructose consumption and serum UA concentrations are independently associated with NASH and fructose consumption was independently linked with high serum UA concentrations. [ABSTRACT FROM AUTHOR]

Background: There are no licensed treatments for non alcoholic fatty liver disease (NAFLD) in adults or children. In NAFLD, several studies have shown a benefit of omega-3 fatty acid treatment on lipid profile, insulin-sensitivity and hepatic steatosis and it has also been suggested that Vitamin D treatment has potential antifibrotic properties in liver disease. Trial Design: To date, however, there are no studies that have tested the combination of Docosahexanoic acid (DHA) and vitamin D treatment which may benefit the whole spectrum of disease in NAFLD. Our aim therefore, was to test the effect of daily DHA (500 mg) plus vitamin D (800 IU) treatment, in obese children with biopsy-proven NAFLD and vitamin D deficiency, in a randomized, double-blind placebo-controlled trial. Methods: The 41/43 patients completed the study (18-treatment, 23-placebo). At 12 months: i) the main outcome was liver histology improvement, defined by NAS; ii) the secondary outcome was amelioration of metabolic parameters. Results: DHA plus vitamin D treatment reduced the NAFLD Activity Score (NAS), in the treatment group (5.4 v1.92; p<0.001 for baseline versus end of study). There was no change in fibrosis score, but a reduction of the activation of hepatic stellate cells (HSC) and fibrillar collagen content was noted (3.51±1.66 v. 1.59±1.37; p = 0.003) in treatment group. Moreover, the triglycerides (174.5 vs. 102.15 mg/dl), ALT (40.25 vs. 24.5 UI/l) and HOMA-IR (4.59 vs. 3.42) were all decreased with treatment. Conclusion: DHA plus vitamin D treatment improved insulin-resistance, lipid profile, ALT and NAS. There was also decreased HSC activation and collagen content with treatment. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common liver disease in industrialized countries, and it is estimated that it will become the most frequent indication for liver transplantation in the next decade. NAFLD may be associated with moderate (i.e. steatosis) to severe (i.e. steatohepatitis and fibrosis) liver damage and affects all age groups. Furthermore, subjects with NAFLD may be at a greater risk of other obesity-related complications later in life, and people with obesity and obesity-related complications (e.g. metabolic syndrome, type 2 diabetes and cardiovascular disease) are at increased risk of developing NAFLD. To date, there is no licensed treatment for NAFLD and therapy has been mainly centered on weight loss and increased physical activity. Unfortunately, it is often difficult for patients to adhere to the advised lifestyle changes. Therefore, based on the known pathogenesis of NAFLD, several clinical trials with different nutritional supplementation and prescribed drugs have been undertaken or are currently underway. Experimental evidence has emerged about the health benefits of omega-3 fatty acids, a group of polyunsaturated fatty acids that are important for a number of health-related functions. Omega-3 fatty acids are present in some foods (oils, nuts and seeds) that also contain omega-6 fatty acids, and the best sources of exclusively omega-3 fatty acids are oily fish, krill oil and algae. In this review, we provide a brief overview of the pathogenesis of NAFLD, and we also discuss the molecular and clinical evidence for the benefits of different omega-3 fatty acid preparations in NAFLD. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Medical Biochemistry is the property of Society of Medical Biochemists of Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

During the last decade, paediatricians have observed a dramatic increase of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Evidence relating dietary patterns to obesity and related disorders such as non-alcoholic fatty liver disease (NAFLD) is limited in pediatric age. Aim of this study was to analyze the association between dietary patterns, obesity and development of severe steatosis and the metabolic syndrome in a series of children and adolescents referred for suspected NAFLD, and the interaction with the rs738409 I148M PNPLA3 polymorphism. Two hundred patients (112 females) had completed a food frequency and demographic questionnaire. Nearly 58 % were obese, and 32 % were overweight. Mild, moderate, and severe fatty liver was present in 60 (30 %), 87 (44 %), and 51 (26 %) participants, respectively. A great proportion of overweight/obese children and adolescents reported a correct dietary pattern. At multivariate ordinal regression analysis considering demographic, anthropometric, genetic, and behavioral determinants, the major determinant of steatosis severity was PNPLA3 I148M genotype ( p < 0.0001), followed by older age ( p = 0.017), higher waist circumference ( p = 0.016), and less time spent practising physical exercise ( p = 0.034). Furthermore, there was a significant interaction between PNPLA3 I148M and intake of sweetened beverages ( p = 0.033) and of vegetables ( p = 0.038). In conclusion, although dietary pattern was reportedly correct in at-risk overweight adolescents with NAFLD, we report a novel interaction between PNPLA3 I148M and dietary components with the severity of steatosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between plasma vitamin D (VD) levels and histological liver damage in children with nonalcoholic fatty liver disease (NAFLD). Subjects and methods: In this cross-sectional study, carried out in a tertiary care center for obesity, 73 consecutive overweight and obese children with persistently elevated serum aminotransferase levels and diffusely hyperechogenic liver on ultrasonography were selected for liver biopsy. Nonalcoholic steatohepatitis (NASH) and fibrosis were histologically diagnosed using NAFLD Clinical Research Network (CRN) criteria. The plasma levels of 25-OH-VD were measured by HPLC. Bone mineral density (BMD) of lumbar spine was evaluated by dual-energy X-ray absorptiometry. Multiple linear regression analysis was used to evaluate the association between 25-OH-VD levels and the predictors of interest after correction for age, gender, waist circumference, BMI, and other potential confounders. Results: The children (64% males) were aged 8-18 years, and their median BMI was 2.45 SDS. Both parathyroid hormone levels and BMD were within the normal range. All cases of fibrosis were detected in children with NASH. On multivariable linear regression with correction for age, gender, and BMI, 25-OH-VD levels were found to be 9 (95% CI 12-6) ng/ml lower in children with NASH than in those without NASH (P<0.001) and 9 (12-6) ng/ml lower in children with stage 1 fibrosis than in those with stage 0 fibrosis and 9 (13-6) ng/ml lower in children with stage 2 than in those with stage 0 fibrosis (P<0.001 for both). Conclusion: VD levels are inversely associated with NASH and fibrosis in children with NAFLD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide as a result of the increasing prevalence of obesity, starting from early life stages. It is characterized by a spectrum of liver diseases ranging from simple fatty liver (NAFL) to steatohepatitis (NASH), with a possible progression to fibrosis, thus increasing liver-related morbidity and mortality. NAFLD development is driven by the co-action of several risk factors, including obesity and metabolic syndrome, which may be both genetically induced and diet-related. Recently, particular attention has been paid to the gut-liver axis, which may play a physio-pathological role in the onset and progression of the disease. The gut microbiota is intended to act as a bioreactor that can guarantee autonomous metabolic and immunological functions and that can drive functional strategies within the environment of the body in response to external stimuli. The complexity of the gut microbiota suggests that it behaves as an organ. Therefore, the concept of the gut-liver axis must be complemented with the gut-microbiota-liver network due to the high intricacy of the microbiota components and metabolic activities; these activities form the active diet-driven power plant of the host. Such complexity can only be revealed using systems biology, which can integrate clinical phenomics and gut microbiota data. [ABSTRACT FROM AUTHOR]

Evaluation of: Oddy WH, Herbison CE, Jacoby P et al. The western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am. J. Gastroenterol. 108, 778-785 (2013). The prevalence of overweight and obesity in childhood is a major public health concern. According to the obesity trend, the prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is also increasing. Nonalcoholic fatty liver disease is characterized by a spectrum of hepatic lesions (i.e., steatosis, ballooning, necroinflammation and fibrosis) that can progress to cirrhosis, hepatocellular carcinoma and liver failure with the consequent need for liver transplantation. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome such as obesity, insulin resistance, dyslipidemia and Type 2 diabetes. The evaluated article reports the prospective relationship between dietary patterns at age 14 years and the presence of NAFLD at age 17 years. A total of 995 adolescents completed a food frequency questionnaire at 14 years and had liver ultrasound at 17 years. Prospective associations between the dietary pattern scores and the risk of NAFLD were analyzed using multiple logistic regression analyses. Nonalcoholic fatty liver disease was present in 15.2% of adolescents. A healthy dietary pattern at 14 years appeared protective against NAFLD at 17 years in centrally obese adolescents. On the contrary, a western dietary pattern at 14 years in this cohort was associated with an increased risk of NAFLD at 17 years, particularly in obese adolescents. [ABSTRACT FROM AUTHOR]

Summary: Non-alcoholic fatty liver disease (NAFLD) is a multi-faceted disorder, which ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) with/without fibrosis. The effects of specific risk factors, such as obesity and sedentary lifestyle, on predisposing genetic settings eventually lead to the development of NAFLD in children. The complex interplay between genes and environment in NAFLD pathogenesis is sustained by multiple mechanisms that involve liver crosstalk with other organs and tissues, especially gut and adipose tissue. Unfortunately, natural history of paediatric NAFLD is lacking, and the etiopathogenesis is still in the process of being defined. Potential early predictors and suitable non-invasive diagnostic tools can be discovered based on the pathogenetic mechanisms and histological patterns. This will also help design novel treatments and a comprehensive and successful management strategy for patients. In this review, we discuss the recent advances made in genetics, etiopathogenesis, diagnosis, and therapeutic management of NAFLD, focusing especially on the obesity-related steatotic liver condition. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Abstract: Nonalcoholic fatty liver disease is rapidly becoming one of the most common liver diseases in the pediatric population in industrialized countries because of the growing prevalence of obesity and overweight. For this reason, there is a keen and broad interest among researchers to identify new diagnostic noninvasive tools and novel treatment modalities for this condition. Unfortunately, to date, liver biopsy remains the imperfect gold standard for diagnosis. In addition, available noninvasive markers are not fully satisfactory for the diagnosis of fatty liver. Although in recent years many pharmacological agents, on the basis of pathogenetic mechanism of the disease, have been attempted, to date, the guidelines for the management of fatty liver are still lacking. Establishing effective therapeutic strategies to treat the disease represents the challenge for pediatric hepatologists in the near future. In this article, we briefly review the current knowledge and ideas concerning pediatric nonalcoholic fatty liver disease, and discuss the new perspective therapies. [Copyright &y& Elsevier]