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• The prevalence of abnormal glucose tolerance is uncertain in children with biopsy-proven NAFLD. • Children with NAFLD have a higher prevalence of abnormal glucose tolerance than those without NAFLD. • Children with NAFLD and abnormal glucose tolerance have a higher prevalence of NASH than those with normal glucose tolerance. • Central adiposity is the factor that is most strongly associated with NASH. We undertook a cross-sectional study of children/adolescents with and without non-alcoholic fatty liver disease (NAFLD) to compare the prevalence of prediabetes and diabetes, and to examine the role of abnormal glucose tolerance as a predictor of liver disease severity. We recruited a cohort of 599 Caucasian children/adolescents with biopsy-proven NAFLD, and 118 children/adolescents without NAFLD, who were selected to be similar for age, sex, body mass index and waist circumference to those with NAFLD. The diagnosis of prediabetes and diabetes was based on either hemoglobin A1c, fasting plasma glucose or 2 h post-load glucose concentrations. Children/adolescents with NAFLD had a significantly higher prevalence of abnormal glucose tolerance (prediabetes or diabetes) than those without NAFLD (20.6% vs. 11%, p = 0.02). In particular, 124 (20.6%) children/adolescents with NAFLD had abnormal glucose tolerance, with 19.8% (n = 119) satisfying the diagnostic criteria for prediabetes and 0.8% (n = 5) satisfying the criteria for diabetes. The combined presence of prediabetes and diabetes was associated with a nearly 2.2-fold increased risk of non-alcoholic steatohepatitis (NASH; unadjusted odds ratio 2.19; 95% CI 1.47–3.29; p <0.001). However, this association was attenuated (but remained significant) after adjustment for age, sex, waist circumference (adjusted odds ratio 1.69, 95% CI 1.06–2.69, p = 0.032), and the PNPLA3 rs738409 polymorphism. Both this PNPLA3 polymorphism and waist circumference were strongly associated with NASH. Abnormal glucose tolerance (especially prediabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. These children also have a higher risk of NASH, though central adiposity is the factor that is most strongly associated with NASH. Children with biopsy-proven non-alcoholic fatty liver disease (NAFLD) have a higher prevalence of abnormal glucose tolerance (prediabetes or type 2 diabetes) than children without NAFLD. Children with biopsy-proven NAFLD and abnormal glucose tolerance also have a higher prevalence of the progressive form of disease, non-alcoholic steatohepatitis, than those with normal glucose tolerance, though central adiposity is the factor that is most strongly associated with non-alcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Several studies suggest that the improvement of oxidative stress is suggested as a possible therapeutic strategy for pediatric nonalcoholic steatohepatitis. We performed a randomized, double-blind placebo-controlled trial to test the potential efficacy, assessed by improvement of oxidative stress parameters and liver ultrasound, and tolerability of a mixture of vitamin E and hydroxytyrosol (HXT) in adolescents with biopsy-proven NAFLD. Four hundred forty consecutive patients were screened, 80 of these with biopsy-proven NAFLD were enrolled. Forty patients received an oral dose of HXT and vitamin E and 40 children received the capsules of placebo for 4 months. Seventy patients completed the study. Patients in the treatment arm showed a decrease of insulin resistance (IR), triglyceride levels, oxidative stress parameters, and steatosis grade. Noteworthy, the steatosis improvement correlates with the levels of advanced glycation end products and carbonylated proteins. The HXT and vitamin E treatment improved the main oxidative stress parameters, IR, and steatosis in children with NAFLD. The use of two natural molecules that may have antioxidant effects seems a promising strategy that could be easily diet integrated to improve NAFLD-related liver damage in children. [ABSTRACT FROM AUTHOR]

Background & Aims: It is uncertain whether non‐alcoholic steatohepatitis (NASH) is a risk factor for low bone mineral density (BMD). Our aim was to investigate: (a) associations between NASH and BMD values and (b) associations between PNPLA3 I148M genotypes and BMD, in children with histologically proven non‐alcoholic fatty liver disease (NAFLD). Methods: BMD area (g/cm2) was measured using dual‐energy X‐ray absorptiometry (DEXA). NASH was diagnosed by a Steatosis, Activity and Fibrosis (SAF) score and FLIP algorithm. Genotyping for patatin‐like phospholipase domain containing‐3 (PNPLA3) I148M genotype (rs738409) (CC, CG and GG) was undertaken using the TaqMan SNP genotyping allelic discrimination method. Logistic regression was used to test associations [OR (95% CIs)] between low BMD, and both NASH and PNPLA3 I148M genotypes. Results: Thirty‐four adolescents (mean age 13.8 ± 1.1 years) with histologically confirmed NAFLD were studied. Subjects with NASH (n = 25) had a lower BMD (means (SDs) 0.87 ± 0.06 vs 0.97 ± 0.12, P = 0.005), compared to subjects without NASH. Subjects with PNPLA3 CG+GG genotypes had a lower BMD compared with subjects with PNPLA3‐CC genotype (means (SDs) 0.79 ± 0.20 vs 0.92 ± 0.10, P = 0.009). PNPLA3 CG+GG genotypes were independently associated with NASH [OR (95% CIs 1.78, 1.24, 2.99)], and low BMD was associated with both PNPLA3 CG+GG (OR 3.62 (95% CIs 1.21, 5.53), P = 0.028) and with SAF score (OR 2.76 (95% CIs 1.12, 5.41), P = 0.045). Conclusions: Taken together the independent associations between: (a) low BMD and PNPLA3 CG+GG genotype; (b) low BMD and NASH; and (c) PNPLA3 CG+GG genotype and NASH, provide support for a causal relationship between NASH and low BMD. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: As dietary components are delivered directly to the periportal zone of the liver lobule, there is the potential for greater injury in this zone (zone 1) compared to the perivenous zone (zone 3). We investigated the associations between dietary fructose consumption and uric acid concentrations and differential zonal injury in periportal and perivenous zones. Methods: A total of 271 children's histological images were scored in 5 periportal and 5 perivenous zones for steatosis, ballooning, inflammation and fibrosis severity. Dietary fructose consumption (g/d) was assessed and uric acid measured in serum. Logistic regression was undertaken to test associations between both high fructose consumption and hyperuricaemia, and histological disease in periportal and perivenous zones. Results: Children with a mean age of 12.5 years were included in the study. Inflammation (mean ± SD) was increased in the periportal vs perivenous zones (0.78 ± 0.43 vs 0.41 ± 0.48, P = .041). There were non‐significant trends towards greater steatosis, ballooning and fibrosis in the periportal zone. In the fully adjusted models, high fructose intake was associated with disease in both zones. Example for periportal and perivenous zones, respectively, steatosis 1.56 (1.12, 2.49) and 1.21 (1.09, 2.73); inflammation 4.29 (2.31, 5.88) and 3.69 (2.14, 4.56); and fibrosis 2.72 (1.43, 3.76) and 1.96 (1.24, 2.37). Hyperuricaemia (uric acid ≥5.9 mg/dL) was associated with inflammation in the periportal zone 1.71 (1.17, 2.35); and was associated with steatosis and fibrosis in both zones; for example, for periportal and perivenous zones, respectively, steatosis 2.98 (1.65, 3.23) and 1.14 (1.05, 1.99); and fibrosis, 2.65 (1.35, 2.99) and 1.31 (1.13, 2.17). Conclusions: High fructose consumption is associated with disease severity in both lobular zones and hyperuricaemia may be associated with more severe disease in the periportal zone. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver diseases, and is closely related to metabolic syndrome and its related conditions, diabetes mellitus and dyslipidemia. On the other hand, NAFLD as a multisystem disease increases the risk of several chronic diseases include type 2 diabetes mellitus, cardiovascular disease (CVD), and chronic kidney disease. The main objective was to review the efficacy of bioactive natural compounds assessed by clinical trials. Search literature using four databases (PubMed, EBSCO, Web of Science, and Ovid Medline) to review publications that focused on the impact of bioactive natural compounds in NAFLD treatment. Due to the lack of effective pharmacological treatments available for NAFLD, lifestyle modifications such as following a healthy diet, vigorous physical activity, and weight reduction remain the first line of treatment for NAFLD. However, due to the poor adherence to this type of treatment, especially for long-term weight loss diets some of which may have harmful effects on the liver, finding novel therapeutic agents for NAFLD treatment and/or preventing NAFLD progression has garnered significant interest. Although the therapeutic agents of NAFLD treatment have been reviewed previously, to date, no summary has been conducted of clinical trials examining the effects of herbal compounds on NAFLD-related biomarkers. This review highlights the beneficial role of herbal bioactives and medicinal plants in NAFLD treatment, particularly as complementary to a healthy lifestyle. All natural products described in this review seem to have some benefits to improve oxidative stress, cellular inflammation and insulin-resistance, which always remain as the “primum movens” of NAFLD pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non‐alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. Methods: 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analysed in five control subjects with proven normal liver histology. NASH was defined by the Paediatric NAFLD Histological Score (PNHS). Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with: a) NASH and b) hepatic FXR protein levels. Results: Mean ± SD age was 13.7 ± 1.9 years. Nineteen patients had NASH (PNHS ≥ 85) and 14 did not have NASH (PNHS < 85). Hepatic FXR level and plasma FGF19 concentration varied ~10‐fold and 5‐fold, respectively, between groups, and was highest in control subjects, intermediate in NAFLD without NASH, and lowest in NASH (between group differences P < .001 and P < .01 respectively). NASH was independently associated with both FXR protein levels (OR = 0.18, 95% CI 0.09, 0.38) and FGF19 concentration (OR = 0.55, 95% CI 0.20, 0.89). Conclusions: FXR protein levels vary markedly between normal liver, NAFLD without NASH, and NASH. Low levels of FXR are independently associated with NASH. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD), considered the leading cause of chronic liver disease in children, can often progress from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It is clear that obesity is one of the main risk factors involved in NAFLD pathogenesis, even if specific mechanisms have yet to be elucidated. We investigated the distribution of intestinal bifidobacteria and lactobacilli in the stools of four groups of children: obese, obese with NAFL, obese with NASH, and healthy, age-matched controls (CTRLs).Material and Methods: Sixty-one obese, NAFL and NASH children and 54 CTRLs were enrolled in the study. Anthropometric and metabolic parameters were measured for all subjects. All children with suspected NASH underwent liver biopsy. Bifidobacteria and lactobacilli were analysed in children's faecal samples, during a broader, 16S rRNA-based pyrosequencing analysis of the gut microbiome.Results: Three Bifidobacterium spp. (Bifidobacterium longum, Bifidobacterium bifidum, and Bifidobacterium adolescentis) and five Lactobacillus spp. (L. zeae, L. vaginalis, L. brevis, L. ruminis, and L. mucosae) frequently recurred in metagenomic analyses. Lactobacillus spp. increased in NAFL, NASH, or obese children compared to CTRLs. Particularly, L. mucosae was significantly higher in obese (p = 0.02426), NAFLD (p = 0.01313) and NASH (p = 0.01079) than in CTRLs. In contrast, Bifidobacterium spp. were more abundant in CTRLs, suggesting a protective and beneficial role of these microorganisms against the aforementioned diseases.Conclusions: Bifidobacteria seem to have a protective role against the development of NAFLD and obesity, highlighting their possible use in developing novel, targeted and effective probiotics. [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]

Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. [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]

Background Mechanism(s) connecting obstructive sleep apnoea syndrome (OSAS) to liver injury in paediatric non-alcoholic fatty liver disease (NAFLD) are unknown. We hypothesised alterations in gut-liver axis and in the pool and phenotype of hepatic progenitor cells (HPCs) may be involved in OSAS-associated liver injury in NAFLD. Methods Eighty biopsy-proven NAFLD children (age, mean±SD, 11.4±2.0 years, 56% males, body mass index z-score 1.95±0.57) underwent a clinical- biochemical assessment, with measurement of insulin sensitivity, plasma cytokines, lipopolysaccharide (LPS), an intestinal permeability test and a standard polysomnography. Hepatic toll-like receptor (TLR)-4 expression by liver-resident cells and overall number and expression of resistin and adiponectin by HPCs were assessed by immunofluorescence and immunohistochemistry. OSAS was defined by an apnoea/ hypopnoea index =1. Results OSAS was characterised by an increased intestinal permeability and endotoxemia, coupled with TLR-4 upregulation in hepatocytes, Kupffer and hepatic stellate cells (HSCs) and by an expansion of an adiponectin-deficient HPC pool, key features of steatohepatitis and fibrosis. The duration of haemoglobin desaturation (SaO2 <90%) independently predicted intestinal permeability (ß: 0.396; p=0.026), plasma LPS (ß: 0.358; p=0.008) and TLR-4 expression by hepatocytes (ß: 0.332; p=0.009), Kupffer cells (ß: 0.357; p=0.006) and HSCs (ß:0.445; p=0.002). SaO2 <90% predicted also HPC number (ß: 0.471; p=0.001) and impaired adiponectin expression by HPC pool (ß: -0.532; p=0.0009). These relationships were observed in obese and nonobese children. Conclusions In paediatric NAFLD, OSAS is associated with increased endotoxemia coupled with impaired gut barrier function, with increased TLR-4-mediated hepatic susceptibility to endotoxemia and with an expansion of an adiponectin-deficient HPC pool. These alterations may represent a novel pathogenic link and a potential therapeutic target for OSAS-associated liver injury in NAFLD. [ABSTRACT FROM AUTHOR]

The article discusses issues associated with Non-Alcoholic Fatty Liver Disease (NAFLD), which is currently the most common cause of chronic liver disease in children. Topics discussed include prevalence of NAFLD due to unhealthy diet and sedentary lifestyle, pathogenesis of NAFLD involving both genetic and environmental factors and single nucleotide polymorphisms (SNPs) in genes involved in lipid metabolism.

Although a rather benign course of chronic hepatitis B virus ( HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included 'Hepatitis B virus infection,' 'children,' ' HBV,' 'interferon,' 'lamivudine,' 'adefovir,' 'entecavir,' and 'tenofovir.' Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies. [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]

Introduction: Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool. Patients and Methods: 20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters. Results: GPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines. Conclusions: DHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival. [ABSTRACT FROM AUTHOR]

The aim of this secondary analysis of a randomized controlled trial was to test whether the I148M variant of Patatin-like phospholipase domain-containing protein-3 (PNPLA3) is associated with the response to docosahexaenoic acid (DHA) in children with non-alcoholic fatty liver disease (NAFLD). Sixty children with NAFLD were randomized in equal numbers to DHA 250 mg/day, DHA 500 mg/day or placebo. Coherently with the primary analysis, the probability of more severe steatosis after 24 months of DHA supplementation was 50% lower [95% confidence interval (CI) −59% to −42%)] in the combined DHA 250 and 500 mg/day groups versus placebo. The present secondary analysis revealed an independent effect of PNPLA3 status on the response to DHA. In fact, the probability of more severe steatosis was higher (37%, 95% CI 26-48%) for the PNPLA3 M/M versus I/M genotype and lower (−12%, 95% CI −21% to −3%) for the I/I versus I/M genotype (Somers' D for repeated measures). We conclude that the 148M allele of PNPLA3 is associated with lower response, and the 148I allele with greater response, to DHA supplementation in children with NAFLD. [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]

Liver transplantation (LT) is a standard treatment for children with end-stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so-called post-transplant metabolic syndrome (PTMS). During the post-transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non-alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long-term health outcomes and acceptable graft survival can be achieved. [ABSTRACT FROM AUTHOR]

Abstract: Over the past decade, non-alcoholic fatty liver disease (NAFLD) has become one of most common chronic liver diseases in children. A greater understanding about the risk factors and molecular pathogenesis of NAFLD suggests that lifestyle interventions aiming to decrease obesity/body mass index and metabolic derangement are the first line of treatments adopted in children affected by this disease. However, because these therapeutic options are often at the beginning misjudged by the patients and their parents, the use of pharmacologic agents may help to protect the liver and other organs from further irreversible tissue damage. Pharmacologic therapies against one or more specific factors and/or molecules involved in the development of NAFLD (i.e., insulin resistance, free fatty acid lipid toxicity, and oxidative stress) also might slow the progression of this increasingly prevalent pediatric disorder. On this basis, insulin sensitizers, antioxidants, cytoprotective agents, and dietary supplementations have been evaluated in pediatric clinical trials. In this review, we discuss the efficacy of the dietary approaches, possibly coupled with regular exercise, on decreasing the metabolic and histologic damage in pediatric NAFLD. We also emphasize several advantages of the pharmacologic treatments adopted or adoptable in combination with lifestyle interventions in children with NAFLD. [Copyright &y& Elsevier]

Celiac disease (CD) is defined as a permanent intolerance to ingested wheat gliadins and other cereal prolamins, occurring in genetically susceptible people. Persistent elevation of serum aminotransferase activity is expression of liver damage related to CD, which occurs in two distinctive forms. The most frequent is a mild asymptomatic liver injury, with a moderate increase of serum aminotransferase activities and a mild inflammatory portal and lobular infiltrate on liver biopsy (celiac hepatitis), reversible on a gluten-free diet (GFD). More rarely, severe and progressive inflammatory liver damage, induced by an autoimmune process and identified as autoimmune hepatitis (AIH), can develop and it is generally unaffected by gluten withdrawal. Surveys that included only pediatric patients report a wide range of prevalence of CD in AIH of 11.5-46% (mean 21.5%). CD and AIH share selected combinations of genes coding for class II human leukocyte antigens, which could explain their coexistence. Increased intestinal permeability and circulation of antitissue transglutaminase (tTG) have also been considered as further potential causes of liver damage in CD patients. tTG in the liver and in other extraintestinal tissues could modify other externalor self-antigens and generate different neo-antigens, which are responsible for liver injury in patients with CD. Patients with AIH represent a population at high risk for developing CD; screening for CD should be integrated into the diagnostic routine of all patients with AIH, with or without gastrointestinal manifestations, before starting immunosuppressive treatments. The only currently available treatment for CD is the GFD and the supportive nutritional care for iron, calcium, and vitamin deficiencies. Due to the difficulties of a GFD, in the past decade researchers have become increasingly interested in therapeutic alternatives to continuous or intermittent use of a GFD in patients with CD. Interventions addressed to correct the defect in the intestinal barrier are currently at the most advanced stage of clinical trials. The impact of a GFD on the outcome of AIH is not clear but it seems to be ineffective in the treatment of AIH. The early detection and treatment CD, however, may prevent progression to end-stage liver failure. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease encompasses a spectrum of disease from asymptomatic steatosis, with or without elevated aminotransferases, to cirrhosis with relative complications and hepatocellular carcinoma. Owing to the increasing prevalence of nonalcoholic fatty liver disease and the potential for nonalcoholic steatohepatitis to progress to cirrhosis and liver-related mortality, more research has been focused on therapy of this important liver disease over the last two decades. To date, weight loss and physical activity represent the cornerstone of treatment, with interventions being limited to subjects at risk of disease progression, but the type of treatment remains a matter of debate. A few medications have shown promising results in preliminary pilot studies, but few agents have been tested rigorously. Today, multiple therapeutic approaches are considered the way to go in treating nonalcoholic steatohepatitis patients. In this paper we review the status of current and emerging therapeutic strategies for children and adult patients with nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Background & Aims: The T-455C and C-482T APOC3 promoter region polymorphisms (SNPs) have recently been reported to predispose to dyslipidemia, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) in Indian subjects, but the association with liver damage has not been evaluated so far. The aim was to assess the association between APOC3 SNPs and liver damage in Caucasian patients. Methods: We considered 437 Italian patients with histological diagnosis of NAFLD (including 137 children, 120 morbid obese) and 316 healthy controls, 71 Italian family trios, and 321 patients from the UK. APOC3 SNPs were determined by sequencing, allele-specific oligonucleotide probes and PCR–restriction fragment length polymorphism analysis, hepatic APOC3 mRNA levels by real-time PCR. Results: APOC3 SNPs were not associated with NAFLD in Italian subjects, although a borderline significance for the transmission of the −455T allele was observed in the family study. Homozygosity for the APOC3 wild-type genotype (APOC3 WT) was associated with a more favorable lipid profile in control subjects, and consistently with lower hepatic APOC3 mRNA levels in obese patients without diabetes. However, APOC3 SNPs, alone or in combination, were not associated with insulin resistance, altered lipid levels, liver enzymes, and with liver damage (severity of steatosis, nonalcoholic steatohepatitis, and moderate/severe fibrosis) in Italian as well as in UK patients, and in the whole cohort. Stratification for the I148M PNPLA3 mutation, associated with the susceptibility to NASH, did not alter the results. Conclusions: APOC3 genotype is not associated with progressive liver damage in Caucasian patients with NAFLD. [ABSTRACT FROM AUTHOR]

The prognosis and management of chronic liver diseases in children largely depend on the extent and progression of liver fibrosis, which is often the most important predictor of disease outcome, and thus influences the indication for potential therapy. Unfortunately, liver biopsy continues to be the gold standard for the staging and grading of fibrosis. Liver biopsy is an invasive and painful technique with several limitations. These limitations have led to the development of alternative noninvasive methods for the accurate assessment of fibrosis and for the maintenance of an acceptable risk/benefit ratio. In the last decades, transient elastography (TE) has received increasing consideration as a means of evaluating disease progression in paediatric chronic liver disease. TE is an accurate and reproducible methodology for identifying subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In this review, we provide an outline of liver fibrosis in paediatric liver diseases, including fibrogenesis, and noninvasive techniques for the diagnosis and follow-up of fibrosis, and then focus on the characteristics of TE and on its strength in the assessment of liver fibrosis, paying particular attention to studies conducted in children. [ABSTRACT FROM AUTHOR]

Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, Monti L, Gennari F, Torre G, de Ville de Goyet J, Bartuli A. Preemptive liver transplantation in a child with familial hypercholesterolemia. Pediatr Transplantation 2011: 15:E25-E29. © 2010 John Wiley & Sons A/S. Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL-cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life-long recurrent apheresis to reduce plasma LDL-cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5-yr-old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low-fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL-cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications. [ABSTRACT FROM AUTHOR]

The prevalence of obesity worldwide has dramatically increased during the last three decades. With obesity comes a variety of adverse health outcomes which are grouped under the umbrella of metabolic syndrome. The liver in particular seems to be significantly impacted by fat deposition in the presence of obesity. In this article we discuss several liver conditions which are directly affected by overweight and obese status, including non-alcoholic fatty liver disease, chronic infection with hepatitis C virus and post-liver transplant status. The deleterious effects of obesity on liver disease and overall health can be significantly impacted by a culture that fosters sustained nutritional improvement and regular physical activity. Here we summarize the current evidence supporting non-pharmacological, lifestyle interventions that lead to weight reduction, improved physical activity and better nutrition as part of the management and treatment of these liver conditions. [ABSTRACT FROM AUTHOR]

The article reflects on steatosis and fibrosis in paediatric liver transplant. It is said that post-transplant complications are the development of steatosis and fibrosis, which are observed in patients with recurrent hepatitis C infection. It is said that the pathogenesis of steatosis and fibrosis may influence the graft response to the new and different environment.

The article discusses the non-alcoholic fatty liver disease (NAFLD) in children. It mentions that NAFLD has become the common liver disease in children as well as adolescents due to overweight and obesity during their childhood. It states that NAFLD is associated with type 2 diabetes mellitus. It adds that NAFLD causes insulin resistance.

Background: Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD) which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for noninvasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center. Methods: The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69%) of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI), which varies between 0 and 10. Results: The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI) with bias correction 0.80 to 0.90) for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0) could be used to rule in liver fibrosis without performing liver biopsy. Conclusion: PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is no consensus on the treatment of pediatric nonalcoholic fatty liver disease (NAFLD). However, in a small pilot study conducted in 10 children, metformin has been proposed to be effective. Objective: We aimed to determine the effect of metformin in addition to lifestyle intervention/modification in children with NAFLD. Methods: Overweight or obese children aged 9 to 18 years with biopsy-proven NAFLD or nonalcoholic steatohepatitis were enrolled in an observational pilot study, initially planned for 12 months, which aimed to estimate the effect of metformin on liver enzymes. The study was extended to 24 months to estimate outcomes on liver histology. All subjects received lifestyle intervention (nutritional counseling and a physical exercise regimen) and metformin 1.5 g/d (MET group). To serve as the control in this study, we selected a control group from a separate but parallel study (N = 30) that had identical inclusion criteria on the use of antioxidants in NAFLD. End points were changes in liver enzymes and histology. Insulin resistance (IR) was estimated by the Homeostasis Model Assessment of IR (HOMA-IR) and liver biopsy was determined by the NAFLD activity score (NAS). Results: Sixty patients were assessed for inclusion in this study. However, 2 patients in the MET group dropped out of the study during the first year because they relocated abroad, and 1 patient in the control group refused follow-up after 12 months. Thus, study data is based on the findings in the 57 remaining patients. Alanine aminotransferase significantly improved from baseline with decreasing body weight in both groups (MET: 35 [range, 21–43] to 32 [20–46] U/L; control: 66 [28–121] to 33 [14–45] U/L; P ≤ 0.01). HOMA-IR significantly improved in both groups from baseline with decreasing body weight as well (MET: 1.4 [range, 0.5–5.11] to 1.3 [0.13–4.21]; control: 2.29 [0.86–5.76] to 1.5 [0.70–4.23]; P ≤ 0.01). Steatosis was reduced in both the MET (P = 0.02) and control (P = 0.02) groups as well as ballooning (both, P = 0.008). Lobular inflammation improved from baseline in the MET group (P = 0.003). The NAS score decreased from baseline (both, P = 0.001), but no significant changes in fibrosis were detected. Conclusion: In this small, 24-month observational study, metformin did not appear more effective than lifestyle intervention in ameliorating levels of aminotransferases, steatosis, and liver histology in these children with NAFLD. [Copyright &y& Elsevier]

Progressive familial intrahepatic cholestasis (PFIC) syndromes are characterized by defects in transporters of conjugated bile acids into the bile canaliculus. Three genes ( ATP8B1, ABCB11, ABCB4) are associated with the different forms, but no easy genotype–phenotype correlations help in the prioritization for gene testing. We developed a denaturing high-performance liquid chromatography (DHPLC) method to screen patients with PFIC for mutations in ATP8B1 and ABCB11, and combined genetic analyses with immunolabeling in liver for the ABCB11 and ABCB4 gene products. Used in combination with commercially available antibodies on liver specimens, the DHPLC approach allowed us to confirm the clinical diagnosis in two Italian sisters and to identify a novel missesnse mutation in ABCB11. Our findings are expected to facilitate detection of the molecular cause of PFIC in affected families. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oxidative stress and accumulation of excessive fat in the liver may underlie the pathophysiology of nonalcoholic steatohepatitis (NASH). Given that glutathione blood metabolism may represent an indicator of tissue oxidative status, we analysed the blood profile of various forms of glutathione in children with NASH, and we evaluated the presence of systemic oxidative stress by calculating the oxidised/reduced glutathione ratio (GSSG/GSH). Furthermore, we analysed the catalytic activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione transferase (GST), and glutathione reductase (GR) in blood of patients. Methods: Blood samples were obtained from 21 children with NASH and 28 controls. Total, reduced, oxidised, and protein-bound glutathione concentrations were determined by reversed-phase liquid chromatography with fluorescence detection. Antioxidant enzymes were spectrophotometrically assayed by using specific substrates. Results: Our findings showed a 1.5-fold increase of GSSG in patients, resulting in a significant rise of the GSSG/GSH ratio. SOD, GPx, and GR activities were not significantly different in NASH respect to controls, whereas GST, which provides the second defence line against oxidative stress, was 17.8% increased. Conclusions: Our data demonstrate an impairment of glutathione metabolism and antioxidant enzyme activities in blood of patients with NASH, supporting a consistent role of free radical cytotoxicity in the pathophysiology of the disease. [Copyright &y& Elsevier]

Background: Percutaneous biopsy of the liver is the most commonly used procedure to obtain tissue for histopathological assessment of liver disease. Although, intuitively, image-guided liver biopsy might be expected to reduce the risk of bleeding, haematoma caused by a penetrating injury of a branch of the hepatic artery or portal vein, and puncture of the gallbladder, no trial has been large enough to show reduced mortality or morbidity with US guidance, and the mechanisms by which the use of US can reduce the risk of bleeding remain speculative.Objective: To compare the mortality and morbidity of blind liver biopsy with that of US-guided liver biopsy.Materials and Methods: A retrospective review of our experience of 140 procedures over a 16-month period.Results: In the blind group, biopsy was unsuccessful in ten children (95% CL 7.3-25.4); no tissue was obtained in eight children and an inadequate sample was obtained in two. Three children (95% CL 9.2-14.7) suffered significant haemorrhage (indicated by a drop in haemoglobin of >20 g/l) with intrahepatic ( n=1) and subcapsular ( n=2) haematomas detectable by US after biopsy. An adequate sample was obtained in all children in the US-guided group. There were no complications requiring treatment in either group.Conclusions: Our results showed a significant difference in the complication rate between liver biopsy undertaken with US guidance and liver biopsy performed blind ( P=0.002). [ABSTRACT FROM AUTHOR]

The article focuses on the relationship of liver damage with alcohol abuse and obesity. It states that the convergence of Non-alcoholic Fatty Liver Disease (NAFLD) and alcohol abuse is much relevance in adolescents. It says that binge drinking is the most common pattern in adolescents that leads to alcohol abuse. It argues that alcohol abuse and obesity must be addressed as one.

A letter to the editor is presented in response to an article about the association between the C-428T and T-455C single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) and the risk of insulin resistance and nonalcoholic fatty liver disease among 258 healthy Indian men.

The article focuses on the occurrence/recurrence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) after liver transplantation in children. It describes the difference in the causes of fatty liver disease in children and adults. Steroids are used by majority of liver transplant centers as a long-term maintenance therapy.

The article offers information on the results of a study on the association of nonalcoholic fatty liver disease (NAFLD) in children with intrauterine growth retardation independent of and in addition to insulin resistance. It says that small for gestational age (SGA) with NAFLD represent a subset with a higher prevalence of both metabolic abnormalities and Non-Alcoholic Steatohepatitis (NASH). It states that factors known to affect insulin sensitivity may also independently contribute to liver disease progression.

A letter to the editor is presented in response to the article "Fatal Fulminant Hepatitis in an Infant With Human Herpesvirus-6 Infection," by Y. Asano, T. Yoshikawa, S. Suga and colleagues in the 1990 issue.

The article focuses on Pediatric Transplantation. Topics discussed include pediatric liver transplant that provide practices in screening and managing Post‐transplant metabolic syndrome (PTMS); mentions the role of potential genetic in the post‐transplant setting; and information on the impact of genetic variants like PNPLA3 on adipose tissue and adiponectin secretion.

In this article, the author offers views on the treatment of Vitamin D and liver fibrosis. He mentions that liver fibrosis is a reversible wound-healing response caused by the hepatic stellate cell (HSC)-mediated excessive accumulation of extracellular matrix proteins. He also mentions that demonstration of the antifibrotic effect of Vitamin D in liver fibrosis providing additional support to previous pivotal studies.

A response from the author of the article "Non-alcoholic fatty pancreas disease and Non-alcoholic fatty liver disease: more than ectopic fat" is presented.

The author comments on several studies suggesting that aminotransferases enzymes could be used as identifying markers to predict mortality. The relationship high concentrations of these enzymes have with such maladies as liver damage, increased heart disease risk via metabolic syndrome, and atherosclerosis, is examined. The many factors that can affect aminotransferase values are discussed.

The article reports on two cases of autoimmune sclerosing cholangitis (ASC) occurring in sisters. The first patient was a 12-year-old girl who was admitted to the hospital because of symptoms and signs of abdominal pain and fatigue. Another patient was a 17-year-old sister who was asymptomatic. These cases suggest a genetic predisposition to autoimmune sclerosing cholangitis.

The article reflects the opinion of the author on the significance of the measurement of advanced glycation end products (AGEs) in the changes on the management of non-alcoholic steatohepatitis. The author stressed that the discovery of nonenzygmatic AGEs and its receptors paved the way to new researches in medicine . Meanwhile, the author suggests that measurement of circulating AGEs can be a beneficial tool for discriminating patients with NASH.

The author reflects on the occurrence of multiple food allergies in children with the use of tacrolimus after heart and liver transplantation. It is stated that the causes of food allergies after liver transplantation is unclear. The author suggests that there is a need to study the possible role of immunosuppressive drug therapy related allergy in children who underwent liver transplantation.