Search

Background: Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system., Aim: The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services., Methods: Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique., Results: We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients., Conclusions: Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.

Chronic liver disease is a growing problem that has substantial effects on public health. Many paediatric liver conditions are precursors of adult chronic liver disease, cirrhosis, and hepatocellular carcinoma. Clinical management of Wilson's disease, autoimmune liver disease, and chronic biliary disorders, such as biliary atresia, which remains the most common paediatric chronic liver disease and indication for liver transplantation, is similar in children and adults. In the past 10 or so years, paediatric hepatology has expanded into neighbouring clinical areas, such as metabolic liver diseases and systemic conditions with liver involvement. We aim to describe some of these disorders, and outline their natural history and possible differences between management in adults and children to stimulate further debate on the optimal transition of care between paediatric and adult specialists., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic liver diseases in children represent a rising problem with significant effects on public health. In fact, several pediatric liver diseases are precursors of adult chronic hepatopathies, cirrhosis and hepatocellular carcinoma. The prevalence of liver diseases in children is unknown. In the USA, every year, 15,000 children are hospitalized for liver diseases, but these disorders continue to be under-recognized or diagnosed late. The main reason is due to the frequent absence of symptoms in the vast majority of liver diseases, especially in the early stages. In the last few decades several advances have been made in understanding the pathogenesis of liver diseases, permitting the discovery of new therapeutic targets to treat liver diseases, thus improving the natural history of these disorders. In this article we discuss the most recent advances in the understanding of the pathogenesis, diagnosis and treatment of the most frequent pediatric liver diseases.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Biliary atresia is a neonatal obstructive cholangiopathy characterized by a destructive, obliterative process affecting both the intrahepatic and extrahepatic ducts of the biliary tree that uniquely presents in the first months of life. The consequence of progressive inflammatory and sclerotic reaction is the development of obstructive jaundice. To determine the proinflammatory cytokine profile in children with biliary atresia, we measured circulating levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and IL-8., Methods: Twelve children, five males and seven females, with biliary atresia were studied. In addition, four patients with progressive familial intrahepatic cholestasis and three with Alagille syndrome were also included. Five patients with neonatal hepatitis were studied as controls of a liver disease without portal fibrosis. Serum concentration of total and conjugated bilirubin, gamma-glutamyl transferase and glutamic-pyruvic transaminase were measured by routine methods in all patients at time of sampling for the study. The degree of fibrosis in liver biopsies was scored using the histologic activity index., Results: In our study IL-8 was detectable in 11 of 12 patients with biliary atresia with a median level of 262 pg/ml and a highly statistically significant difference (P < 0.0001) from controls. In patients with progressive familial intrahepatic cholestasis or with Alagille syndrome serum IL-8 levels were similarly elevated. In patients with neonatal hepatitis, IL-8 levels were marginally increased. Serum IL-8 levels were significantly correlated (Rs = 0.725, P < 0.0001) with the histologic activity index., Conclusions: Although further studies are needed to determine the role of IL-8 in portal inflammation, our results suggest that increased production of IL-8 may be a mechanism leading to the progressive portal inflammation and fibrosis in patients with chronic liver disease.

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).

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]

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p<0.01), Endoplasmic Reticulum-localized DnaJ homologue (Erdj4) mRNA (p<0.05) and Bip/GRP78-glucose-regulated protein 78 (Bip) mRNA (p<0.05) was observed in the liver of IUGR rats at birth. Furthermore, the expression of gluconeogenesis genes and lipogenesis genes were significantly upregulated (p<0.05) in IUGR pups. At 105 d, IUGR male rats showed significantly reduced glucose tolerance (p<0.01). A significant decreased expression of XBP1s mRNA (p<0.01) and increased expression of double-stranded RNA-dependent protein kinase-like ER kinase (PERK) and Asparagine synthetase (ASNS) (p<0.05) was observed in the liver of IUGR male adult rats. Liver focal steatosis and periportal fibrosis were observed in IUGR rats. These findings show for the first time that fetal exposure to uteroplacental insufficiency is associated with the activation of hepatic UPR and suggest that UPR signaling may play a role in the metabolic risk. [ABSTRACT FROM AUTHOR]

Introduction: Oxidative stress is central to the pathogenesis of non-alcoholic steatohepatitis. The reactive oxygen species (ROS) that characterise oxidative stress are generated in several cellular sites and their production is influence by multi-organ interactions. Areas covered: Mitochondrial dysfunction is the main source of ROS in fatty liver and is closely related to endoplasmic reticulum stress. Both are caused by lipotoxicity and together these three factors form a cycle of progressive organelle damage, resulting in sterile inflammation and apoptosis. Adipose tissue inflammation and intestinal dysbiosis provide substrates for ROS formation and trigger immune activation. Obstructive sleep apnea and abnormal divalent metal metabolism may also play a role. Expert commentary: The majority of available high-quality data originates from studies in adults and there are fewer therapeutic trials performed in pediatric cohorts, therefore conclusions are generalised to children. Establishing the role of organelle interactions, and its relationship with oxidative stress in steatohepatitis, is a rapidly evolving area of research. [ABSTRACT FROM PUBLISHER]

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 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]

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.)

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.

Background: Noninvasive hepatic fibrosis scores that predict the presence of advanced fibrosis have been developed and validated in adult patients with NAFLD. The aims of our study were to assess the utility of commonly used adult fibrosis scores in pediatric NAFLD and to develop a pediatric specific fibrosis score that can predict advanced fibrosis. Methods: Consecutive children with biopsy-proven NAFLD were included. Fibrosis was determined by an experienced pathologist (F0–4). Advanced fibrosis was defined as fibrosis stage ≥3. The following adult fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 Index. Multivariable logistic regression analysis was performed to build a new pediatric model for predicting advanced fibrosis. Results: Our cohort consisted of 242 children with a mean age of 12.4±3.1 years and 63% were female. 36 (15%) subjects had advanced fibrosis. APRI and FIB-4 were higher in patients with advanced fibrosis compared to those with fibrosis stage 0–2; however, AST/ALT ratio and NFS were not different between the two groups. We used our data to develop a new model to predict advanced fibrosis which included: ALT, alkaline phosphatase, platelet counts and GGT. The multivariable logistic regression model (z) was defined as follows: z = 1.1+(0.34*sqrt(ALT))+(0.002*alkaline phosphatase) – (1.1*log(platelets) – (0.02*GGT). This value was then converted into a probability distribution (p) with a value between 0 to 100 by the following formula: p = 100×exp(z)/[1+exp(z)]. The AUCROC for this model was 0.74 (95% CI: 0.66, 0.82). This was found to be significantly better than APRI, NAFLD Fibrosis Score and FIB-4 Index. Conclusion: Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing advanced fibrosis in children with NAFLD. We developed a new pediatric NAFLD fibrosis score with improved performance characteristics. [ABSTRACT FROM AUTHOR]

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/m2 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. [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]

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent, chronic liver diseases, worldwide. It is a multifactorial disease caused by complex interactions between genetic, epigenetic and environmental factors. Recently, several microRNAs, some of which epigenetically regulated, have been found to be up- and/or down-regulated during NAFLD development. However, in NAFLD, the essential role of the Polycomb Group protein Enhancer of Zeste Homolog 2 (EZH2), which controls the epigenetic silencing of specific genes and/or microRNAs by trimethylating Lys27 on histone H3, still remains unknown. In this study, we demonstrate that the nuclear expression/activity of the EZH2 protein is down-regulated both in livers from NAFLD rats and in the free fatty acid-treated HepG2. The drop in EZH2 is inversely correlated with: (i) lipid accumulation; (ii) the expression of pro-inflammatory markers including TNF-a and TGF-ß; and (iii) the expression of miR-200b and miR-155. Consistently, the pharmacological inhibition of EZH2 by 3-Deazaneplanocin A (DZNep) significantly reduces EZH2 expression/activity, while it increases lipid accumulation, inflammatory molecules and microRNAs. In conclusion, the results of this study suggest that the defective activity of EZH2 can enhance the NAFLD development by favouring steatosis and the de-repression of the inflammatory genes and that of specific microRNAs. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Nonalcoholic steatohepatitis (NASH) is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). Noninvasive methods to identify children with NASH are urgently needed. The aim of this study was to evaluate the use of plasma cytokeratin-18 (CK18) fragment levels, a marker of increased hepatocyte apoptosis, as a non-invasive biomarker for pediatric NASH.METHODS:Consecutive children with biopsy-proven NAFLD were included and blood samples were collected at the time of the biopsy. The diagnosis of NASH was based on Brunt's criteria. Histological features were scored: steatosis (0-3), lobular inflammation (0-3), ballooning (0-2), and portal inflammation (0-2). NAFLD activity score was calculated (0-8) and fibrosis stage was scored (0-4). We measured plasma CK18 levels using the M30-Apoptosense enzyme-linked immunosorbent assay kit.RESULTS:A total of 201 subjects were included in the study. The mean age was 10.7±2.5 years and 37% were male. NASH was diagnosed in 140 patients with a mean NAFLD activity scoring of 4.4±1.3. CK18 levels were significantly higher in subjects with NASH compared with not NASH (322.1 U/l±104.8 vs. 164.2 U/l±62, respectively; P<0.001). The risk of having NASH on liver biopsy increased with increased CK18 levels (P<0.001). For every 10 U/l increase in CK18 levels, the likelihood of having NASH increased by 70% after adjusting for multiple confounders. The performance of CK18 level for the diagnosis of NASH was excellent with an area under the receiver operating characteristics curve of 0.933.CONCLUSIONS:CK18 is a promising non-invasive biomarker for NASH in children with fatty liver disease. [ABSTRACT FROM AUTHOR]

Atypical fibroblast growth factors (FGF) 21 and 19 play a central role in energy metabolism through the mediation of Klotho coreceptor. Contradictory findings are available about the association of FGF21 and FGF19 with nonalcoholic fatty liver disease (NAFLD) in humans. We investigated the association of serum FGF21, FGF19 and liver Klotho coreceptor with non-alcoholic steatohepatitis (NASH) and fibrosis in children with NAFLD. Serum FGF21 and FGF19 were measured in 84 children with biopsy-proven NAFLD and 23 controls (CTRL). The hepatic expression of Klotho coreceptor was measured in 7 CTRL, 9 patients with NASH (NASH+) and 11 patients without NASH (NASH−). FGF21 and FGF19 showed a tendency to decrease from CTRL (median FGF21 = 196 pg/mL; median FGF19 = 201 pg/mL) to NASH− (FGF21 = 89 pg/mL; FGF19 = 81 pg/mL) to NASH+ patients (FGF21 = 54 pg/mL; FGF19 = 41 pg/mL) (p<0.001 for all comparisons) and were inversely associated with the probability of NASH and fibrosis in children with NAFLD. The hepatic expression of Klotho coreceptor was inversely associated with NASH (R2 = 0.87, p<0.0001) and directly associated with serum FGF21 (R2 = 0.57, p<0.0001) and FGF19 (R2 = 0.67, p<0.0001). In conclusion, serum FGF19 and FGF21 and hepatic Klotho expression are inversely associated with hepatic damage in children with NAFLD and these findings may have important implications for understanding the mechanisms of NAFLD progression. [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]

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]

The authors discuss gut microbiota's causative role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The authors explore several observations suggesting microbiota's potential role in the developmen of NAFLD. Meanwhile, the authors suggest that promising therapeutic agents may be represented by probiotic impact on gut flora in connection to tolerability for reverting liver damage related to non-alcoholic steatohepatitis (NASH).

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]

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 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]

This article looks at pediatric Non Alcoholic Fatty Liver Disease (NAFLD) among co-morbidities. It reviews the concepts about pediatric NAFLD, its pathogenesis, diagnosis and treatment, with particular regard to lifestyle and food habits. It also indicates the possible causes of pediatric NAFLD. It highlights the association of NAFLD with abdominal obesity, insulin resistance and features of metabolic syndrome.

Background & Aims: Although nonalcoholic fatty liver disease (NAFLD) is increasingly common, only a minority of affected individuals develop fibrotic liver disease. Based on its role in liver growth and repair, we explored whether Kruppel-like factor 6 (KLF6) plays a role in NAFLD progression. Methods: KLF6 expression in 31 fibrosis scored NAFLD liver biopsy specimens was assessed by real-time polymerase chain reaction. Transfected minigene constructs were used to study the effect of a polymorphism, KLF6-IVS1-27G>A, that promotes KLF6 alternative splicing in vitro. We genotyped KLF6-IVS1-27G>A in 3 groups of patients (UK group 1, n = 306; Italian group 2, n = 109; trio group 3, n = 61 children and parents). Results: KLF6 expression was increased in association with increased steatosis, inflammation, and fibrosis in NAFLD livers. KLF6-IVS1-27G>A promoted alternative splicing of KLF6 and abrogated the up-regulation of both α-smooth muscle actin and collagen 1 in LX-2 cells. Group 1 genotyping identified KLF6-IVS1-27G>A in 44 of 306 (14.4%) patients. Notably, KLF6-IVS1-27G>A was associated significantly with milder NAFLD, with only 25% having more advanced fibrosis compared with 45% of wild-type (wt) individuals. This trend was confirmed in group 2. A linear regression analysis including all 415 patients, adjusted for age, sex, body mass index, and blood glucose level, confirmed that presence of the wt KLF6 allele was an independent predictor of fibrotic NAFLD. Furthermore, we have shown preferential transmission of the wt allele to children with fibrotic NAFLD. Conclusions: We report a functional polymorphism in the KLF6 gene associated with advanced NAFLD and believe further study of KLF6 may enhance our understanding of this disease process. [Copyright &y& Elsevier]

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide, affecting 20-30% of adults and 3-10% of children in Western countries. The pathogenesis of NAFLD is considered to be multifactorial and factors such as insulin resistance, intrahepatic fat accumulation, oxidative stress, mitochondrial alterations, and stellate cell activation appear to substantially contribute to the development and progression of the disease. In this Editorial, we highlight some evidence suggesting a close link between NAFLD and growth hormone (GH)-IGF (insulin-like growth factor) axis. [ABSTRACT FROM AUTHOR]

Percutaneous needle biopsy of the liver is the most common procedure used in clinical hepatology for histopathological examination and assessment of liver disease, and remains the cornerstone in the evaluation and management of parenchymal liver diseases. Liver biopsy is generally regarded as a safe procedure, but mortality rates up to 1:10,000 have been reported. In 2003, our group showed that routine use of US as a guide to liver biopsy reduces the rate of complications and provides a higher diagnostic yield. To report our experience of US-guided liver biopsy in children. We retrospectively reviewed all 421 liver biopsies performed in our department from October 2003 to December 2008. All samples had been obtained by the US-guided technique. All patients had a liver US examination performed prior to the procedure by the same radiologist performing the biopsy. US guidance allowed constant visualization of the needle leading to appropriate tissue sampling in all 421 children (including 221 obese children), and in 79% of children with only one pass. Pain in the right upper quadrant after liver biopsy was experienced by 36% of patients. US-guided percutaneous biopsy of the liver in children, performed in a specialized tertiary care paediatric centre by experienced and skilled physicians, can be considered safe and effective. [ABSTRACT FROM AUTHOR]

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.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) encompasses diseases from simple steatosis, to steatohepatitis, to fibrosis, and cirrhosis. The pediatric NAFLD fibrosis index (PNFI) and the enhanced liver fibrosis (ELF) test are potential noninvasive markers for fibrosis. We prospectively evaluated the performance of PNFI and ELF in assessing fibrosis in children with biopsy-proven NAFLD. Methods: We analyzed 111 consecutive children with NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. PNFI was calculated based on age, waist circumference, and levels of triglycerides. The ELF test was used to determine levels of hyaluronic acid, the amino-terminal propeptide of type III collagen, and tissue inhibitor of metalloproteinase-1. Results: Some degree of fibrosis was detected in 68.5% of patients (62 had stage 1, 5 had stage 2, and 9 had stage 3). PNFI and ELF test values was higher among patients with fibrosis (P < .001). The area under the receiver operating characteristic (ROC) curve for predicting fibrosis using the PNFI and ELF test was 0.761 and 0.924, respectively. The best performance was obtained by combining PNFI and ELF test with (area under the receiver operating characteristic curve = 0.944). The combined results from the PNFI and ELF test predicted the presence or absence of fibrosis in 86.4% of children with NAFLD. Conclusions: In children with NAFLD, the combined results from the PNFI and ELF test can accurately assess the presence of liver fibrosis and identify patients that should be evaluated by liver biopsy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in regard to case management in children affected by non-alcoholic fatty liver disease.

A letter to the editor is presented in response to the article "Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio (APRI): Usefulness in patients with chronic liver disease," by Y. Yilmaz and colleagues in the 2011 issue.

Background & Aims Excess hepatic free cholesterol contributes to the pathogenesis of non-alcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis. Methods The relationship between statin use, genetic risk factors, and liver damage was assessed in a multi-center cohort of 1201 European individuals, who underwent liver biopsy for suspected non-alcoholic steatohepatitis. Results Statin use was recorded in 107 subjects, and was associated with protection from steatosis, NASH, and fibrosis stage F2-F4, in a dose-dependent manner (adjusted p <0.05 for all). In 100 treated patients matched 1:1 for modality of recruitment, gender, presence of IFG or type 2 diabetes, PNPLA3 I148M risk alleles, TM6SF2 E167K variant, age, and BMI, statin use remained associated with protection from steatosis (OR 0.09, 95% C.I. 0.01–0.32; p = 0.004), steatohepatitis (OR 0.25, 95% C.I. 0.13–0.47; p <0.001), and fibrosis stage F2-F4 (OR 0.42, 95% C.I. 0.20–0.8; p = 0.017). Results were confirmed in a second analysis, where individuals were matched within recruitment center ( p <0.05 for all). The protective effect of statins on steatohepatitis was stronger in subjects not carrying the I148M PNPLA3 risk variant ( p = 0.02 for interaction), as statins were negatively associated with steatohepatitis in patients negative ( p <0.001), but not in those positive for the I148M variant ( p = n.s.). Conclusions Statin use was associated with protection towards the full spectrum of liver damage in individuals at risk of non-alcoholic steatohepatitis. However, the I148M PNPLA3 risk variant limited this beneficial effect. [ABSTRACT FROM AUTHOR]

Abstract: In the last years numerous reports describing a possible association between administration of vaccines and development of autoimmune phenomena and overt autoimmune disease were published. Possible mechanisms of induction of autoimmune phenomena by vaccines and their excipients are probably similar to those implicated in induction by infectious agents. Here we report the case of an 11-year-old girl who developed autoimmune hepatitis type II after four weeks from vaccination against human papillomavirus. The possible relationships between the use of adjuvated vaccine against papillomavirus and autoimmune hepatitis are discussed. Although we do not provide evidence for a causal link, we suggest that the occurrence of the autoimmune hepatitis may be related to the stimulation of immune system by adjuvated-vaccine, that could have triggered the disease in a genetically predisposed individual. Therefore a monitoring of liver function test following administration of vaccine against papillomavirus may be useful in adolescent girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to early identify and to promptly treat autoimmune liver disorders. [Copyright &y& Elsevier]