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OBJECTIVE--To clarify the pathogenesis of diabetes associated with mutations of the hemochromatosis (HFE) gene, 17 carriers, 9 normal glucose tolerant (NGT) and 8 diabetic, were evaluated in an interventional trial. [...]

Intrauterine growth retardation is associated with the development of abnormalities in glucose tolerance in adulthood (1,2). Studies in adults and children born small for gestational age (SGA) (3-7) indicate that [...]

The aim of the study was to evaluate long-term nutritional outcomes and clinical characteristics in a cohort of children with pediatric intestinal pseudo-obstruction (PIPO) at neonatal-onset (NO-PIPO) and at later-onset (LO-PIPO). All children fulfilling new PIPO criteria over a 30-year period were reviewed. Baseline demographic and clinical features as well as nutritional outcomes were collected. Nutritional outcomes included overall survival, prevalence of enteral autonomy and parenteral nutrition (PN) dependency, rate of major PN complications, and growth course. Forty-four patients were still alive at the end of the follow-up. Twenty-five patients (57%) achieved enteral autonomy, whilst 18 remained on PN. Among the patients requiring PN at the beginning of the study period, we found that 55% (CI 34–70) has the probability of remaining on PN at the latest follow-up. Prevalence of gastrointestinal obstruction symptoms (P< 0.01), urinary involvement (P< 0.05), stoma placements [gastrostomy (P< 0.01), ileostomy P< 0.05)] and complex gastrointestinal surgery (P< 0.05) were significantly higher in NO-PIPO than in LO-PIPO. The number of patients requiring long-term PN (P< 0.001) and the number of PN days (P< 0.05) were significantly higher in NO-PIPO, whilst the number of patients achieving enteral autonomy was significantly higher in LO-PIPO (P< 0.05). In our study, we have reported the nutritional outcome of a cohort of children with PIPO over a 30-year period showing that about 20% of patients develop irreversible intestinal failure requiring life-long PN. Nutritional and clinical outcomes seem to be influenced by the time of onset of the disease.

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P< 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7missense variants were associated with circulating lipids. PCSK7was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P< 0.05). The rs236918 C allele was associated with upregulation of a new “intra-PCSK7” long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P< 0.01), which correlated with triglycerides (P= 0.04). In HepG2 cells, PCSK7deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7expression/activity.

Nonalcoholic fatty liver disease (NAFLD) is being increasingly diagnosed at younger ages, pointing toward an early-life origin.

We aimed to investigate national allocation policies for pediatric liver transplantation (LT). A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

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Supplemental Digital Content is available in the text

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

Background: An altered IL-18 pathway in heart failure (HF) has recently been described and this cytokine was shown to be of clinical and prognostic utility. Cardiomyocytes are a target of this cytokine which exerts inflammatory, hypertrophic, and profibrotic activities. B-type natriuretic peptide is a cardiac hormone produced in response to cardiac filling to regulate cardiovascular homeostasis. The aim of the study was to verify the ability of IL-18 to induce B-type natriuretic peptide synthesis in vitroand to analyse the relationship between these two molecules in plasma in vivofrom acute HF patients.Methods and Results: We demonstrated the ability of IL-18 to directly stimulate a murine cardiomyocyte cell line to express the B-type natriuretic peptide gene, synthesize the relative protein through a PI3K-AKT-dependent transduction, and induce a cell secretory phenotype with B-type natriuretic peptide release. A correlation between IL-18 and B-type natriuretic peptide plasma levels was found in non-overloaded acute HF patients, and in subgroups of acute HF patients with diabetes and coronary artery disease. Acute HF patients with renal failure had significantly higher IL-18 plasma levels than patients without. IL-18 plasma levels were correlated with C-reactive protein plasma levels.Conclusions: This study provides the first evidence of the ability of IL-18 to induce B-type natriuretic peptide synthesis in vitroand outlines the relationship between the two molecules in acute HF patients with an ongoing inflammatory status.

Objectives:Small for gestational age (SGA) is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the correlation of birthweight with the severity of liver damage in a large cohort of children with NAFLD.Methods:Two hundred and eighty-eight consecutive Caucasian Italian overweight/obese children with biopsy-proven NAFLD were included in the study. We examined the relative association of each histological feature of NAFLD with metabolic alterations, insulin-resistance, I148M polymorphism in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, and birthweight relative to gestational age.Results:In the whole NAFLD cohort, 12.2% of patients were SGA, 62.8% appropriate for gestational age (AGA), and 25% large for gestational age (LGA). SGA children had a higher prevalence of severe steatosis (69%) and severe portal inflammation (14%) compared with the AGA and LGA groups. Notably, severe steatosis (>66%) was decreasing from SGA to AGA and LGA, whereas the prevalence of moderate steatosis (33–66%) was similar in three groups. The prevalence of type 1 NAFLD is higher in the LGA group with respect to the other two groups (25% vs.5.2% vs.9.4%), whereas the SGA group shows a higher prevalence of overlap type (85.8%) with respect to the LGA group (51.4%) but not compared with the AGA group (75%). At multivariable regression analysis, SGA at birth increased fourfold the likelihood of severe steatosis (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.43–10.9, P=0.008) and threefold the likelihood of NAFLD Activity Score (NAS)≥5 (OR 2.98, 95% CI 1.06–8.33, P=0.037) independently of homeostasis model assessment of insulin resistance and PNPLA3 genotype. The PNPLA3-CC wild-type genotype was the strongest independent predictor of the absence of significant fibrosis (OR 0.26, 95% CI 0.13–0.52, P=<0.001).Conclusions:In children with NAFLD, the risk of severe steatosis is increased by SGA at birth, independent of and in addition to other powerful risk factors (insulin-resistance and I148M variant of the PNPLA3 gene).

Hemoglobin (Hb) and red blood cell distribution width (RDW) have been reported to be a risk marker of metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). No study exists on pediatric populations. We aimed to determine the association between hematological parameters, and the severity of disease in children with biopsy-proven NAFLD. A total of 117 children (85 boys, mean age 12 years) with ultrasound evidence of NAFLD undergoing liver biopsy for diagnosis of nonalcoholic steatohepatitis (NASH), were prospectively enrolled between January 2011 and May 2013 in the setting of a tertiary care center. Children were screened for routine hematological and metabolic parameters, and causes of liver steatosis other than nonalcoholic were excluded, before liver biopsy was performed. A total of 41 NAFLD (boys 29, mean age 11.2 years) and 76 NASH (boys 56, mean age 12.8 years) children were studied. Alanine transaminase levels were significantly higher in NASH group compared with NAFLD group (P=0.05), and homeostatic model assessment of insulin resistance and triglycerides levels (P=0.03 and 0.02, respectively). Regarding hematological components: red cell count, Hb, hematocrit, and RDW values were all significantly higher in NASH group compared with NAFLD group (P< 0.05 for each parameter). Children with NASH were more likely to have high levels of RDW compared to those with steatosis only. Moreover, NASH was associated with higher red cell count, Hb, and hematocrit. If confirmed in future follow-up studies, hematological parameters may be introduced in algorithms for NASH risk prediction.

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

Shear-wave elastography is an accurate and reproducible noninvasive technique for efficiently detecting significant liver fibrosis and, less accurately, mild liver fibrosis in children with nonalcoholic steatohepatitis.

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.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies.

Background: During recent years, treatment with statins has been suggested to induce several effect on bone status and vitamin D metabolism, interpreted as statins pleiotropic effects. Actually, the available data are not conclusive and the characteristics of this association remains unclear. Aim: The purpose of this meta-analysis was therefore to investigate the possible effect of statins therapy on vitamin D serum levels based on the reported results from RCTs and observational studies. Methods: PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched to identify studies evaluating the impact of statins on plasma vitamin D concentrations from inception to September 16, 2015. A systematic assessment of bias in the included randomized controlled trials was performed using the Cochrane criteria. A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used for the heterogeneity of studies in terms of demographic characteristics of populations being studied and also differences in study design and type of statin being studied. Sensitivity analysis was conducted using the leave-one-out method. Results: Following a multiple database search, 1422 published studies were identified; among these, 7 studies were found to be eligible and included in the systematic review and meta-analysis. Our meta-analysis of data from seven studies (including 5 RCTs) did not indicate any significant effect of statins treatment on plasma vitamin D levels. Conclusion: Further well-designed trials are necessary to confirm these results and to define better a possible relationship between statins and vitamin D levels.

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

Hepatitis E virus (HEV) is endemic in large parts of the developing world. Waterborne transmission of genotypes 1 or 2 commonly causes acute hepatitis, which is usually self-limited in healthy individuals. In addition, acute HEV infections also occur outside endemic areas, mostly related to foodborne transmission of HEV genotype 3. A growing number of publications in the last decade have reported chronic infection progressing to cirrhosis in immunosuppressed patients. It has also been suggested that HEV transmission may occur via contaminated blood products. This publication aims to provide recommendations for diagnosis, prevention, and treatment of HEV infection, particularly in children after solid organ transplantation. A systematic PubMed literature search on HEV infection from 1990 to January 2016 was performed focusing on pediatric studies. The existing body of evidence was reviewed and recommendations were agreed upon following discussion and unanimous agreement by all members of the ESPGHAN Hepatology Committee during a consensus meeting in January 2016. In the absence of randomized controlled studies these recommendations were considered to be expert opinions. Immunocompetent children with increased transaminases and/or extrahepatic manifestations should be considered for testing for evidence of HEV infection. Immunocompromised children with increased aminotransferases should be repeatedly tested for HEV and may require therapeutic intervention.

Solid tumors account for approximately 30% of all pediatric cancers. Although chemotherapy has largely contributed to strongly improve patient outcome, multidrug resistance (MDR) remains one of the major mechanisms limiting the overall survival. The enhanced efflux rate of chemotherapeutic drugs from tumor cells through drug transporters is one of the most important mechanisms of MDR. Drug transporters play a pivotal role in preserving the balance between sensitivity and resistance of tumor cells to anti-neoplastic drugs. Their functional activities have been barely investigated in pediatric solid malignancies. Here, we provide evidence from the current literatures on drug transporters and MDR in the most common types of pediatric solid tumors, including neuroblastoma, Wilms’ tumor, rhabdomyosarcoma, retinoblastoma, medulloblastoma and hepatoblastoma.

Because the prevalence of obesity in children is increasing, the frequency of pediatric nonalcoholic fatty liver disease (NAFLD) is growing. A reliable noninvasive biomarker for monitoring progression of liver fibrosis would be useful. In cirrhotic persons serum bile acid (BA) levels are significantly elevated. We hypothesized that BA levels and composition in pediatric NAFLD vary depending on the stage of fibrosis. Children with NAFLD were compared with controls and classified by stages of fibrosis (NAFLD-F0, n = 27; NAFLD-F=1, n = 65) based on liver-biopsy findings. Fasted metabolic and cholestasis status was assessed by several blood tests. BA profiles were measured by tandem mass spectrometry and compared with healthy controls (n = 105). Compared with controls, all of the NAFLD patients were overweight and showed significantly elevated glucose, insulin, aspartate transaminase, and alanine transaminase levels. Total serum BAs were lower in nonfibrotic NAFLD children than in a control cohort (1.73 vs 3.6 µmol/L) because low glycine-conjugated BA levels were incompletely compensated by increases in taurine-conjugated or unconjugated BA. In patients with fibrotic NAFLD, BA levels were lower than in controls (2.45 vs 3.6 µmol/L) but higher than in nonfibrotic patients (2.45 vs 1.73 µmol/L), and the BA pattern resembled that of healthy controls. Fibroblast growth factor 19 levels were significantly lower in both NAFLD groups than in controls (P= 0.001) and were positively correlated with ursodeoxycholic acid levels. Our data indicate that serum BA levels decrease in early NAFLD and increase during progression to fibrosis. Given that BA levels are increased in cirrhotic adults, we postulate a continuous rise as NAFLD advances. BA may have a value as a noninvasive biomarker in pediatric NAFLD progression.

Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD), which is one of the most common causes of chronic liver disease worldwide. The present best treatment for NAFLD and nonalcoholic steatohepatitis (NASH) is weight reduction through lifestyle modification. Because of frustrating inefficiency of such a therapeutic approach, bariatric surgery is increasingly performed in adolescents as an alternative option for weight reduction. Standards of care and consensus for indications are, however, scarce. We explore the indications and limitations of bariatric surgery in children with severe obesity with and without NASH and aim to provide guidance for the exceptional indications for adolescents with extreme obesity with major comorbidity that may benefit from these controversial interventions. Present evidence suggests that bariatric surgery can decrease the grade of steatosis, hepatic inflammation, and fibrosis in NASH. Uncomplicated NAFLD is not an indication for bariatric surgery. Roux-en-Y gastric bypass is considered a safe and effective option for adolescents with extreme obesity, as long as an appropriate long-term follow-up is provided. Laparoscopic adjustable gastric banding has not been approved by the Food and Drug Administration for use in adolescents and therefore should be considered investigational. Finally, sleeve gastrectomy and other types of weight loss surgery that have grown increasingly common in adults, still need to be considered investigational. Temporary devices may be increasingly being used in pediatrics; however, future studies, including a long-term risk analysis of patients who undergo surgery, are much needed to clarify the exact indications for bariatric surgery in adolescents.

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.

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.

Introduction:In the past decade, nonalcoholic fatty liver disease (NAFLD) had rapidly become one of the most common liver diseases. If efficient therapeutic strategies will not reduce the prevalence of NAFLD in children soon, serious deleterious effects on the quality of life of these patients in adulthood are expected. Lifestyle modification is the current first-line therapy for pediatric NAFLD, even though it is difficult to obtain and to maintain. Therefore, lifestyle changes are usually ineffective and long-lasting improvement of the NAFLD-associated liver damage is rarely observed. As guidelines for the management of NAFLD in children are still lacking, the identification of effective treatments represents a challenge for pediatric hepatologists in the near future.Areas covered:Here, we review the existing therapeutic approaches for treating NAFLD in children and overview all ongoing clinical trials for new promising drugs in pediatric setting.Expert opinion:Considering the multifactorial pathogenesis and the wide spectrum of histological and clinical features of NAFLD, we believe that a drug mix, containing agents that are effective against the principal pathogenetic factors, associated with lifestyle modification, could represent the winning choice of treatment for pediatric NAFLD.

Central obesity represents the major factor responsible for NAFLD, but several immunological and endocrinological mechanisms are involved in fatty infiltration in the liver, inflammation and fibrosis. Gut microbiota and genetic factors were recently indicated as major players in liver injury. Loss of weight and physical activity represent till now the cornerstone of treatment, but they are very difficult to obtain and to maintain. Several pharamocotherapeutic approaches including insulin sensitizers, omega-3 fatty acids and vitamin E have been extensively studied in randomized trials, but final conclusions still could not be formulated. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish the effective pharmacological therapy of this disorder.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in industrialized countries in adults and children, following the trail of the epidemic diffusion of obesity. Nonalcoholic steatohepatitis (NASH) is a potentially serious form of NAFLD linked with a significant increase in overall and liver-related morbidity and mortality. Because diagnosis still requires liver biopsy, there is urgent need of developing noninvasive early markers. The aim of the present study was to assess whether the simultaneous detection of genetic risk factors could predict NASH.

Oxidative stress has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and progression to the more severe form, nonalcoholic steatohepatitis (NASH), in children. We aimed to study the clinical correlation between bilirubin, a potent endogenous antioxidant with cytoprotective properties, and histopathological findings in pediatric patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) in adolescents and children is rapidly becoming one of the most common causes of chronic liver disease worldwide. NAFLD varies from simple fatty liver to nonalcoholic steatohepatitis (NASH) with possible fibrosis. Several studies suggest that oxidative stress plays a central role in several metabolic abnormalities and cellular damage that characterize NAFLD. We investigated whether transition metals and their related proteins were related to NAFLD symptoms and their underlying processes.

La crescita esponenziale dell’eccesso ponderale registratasi nelle ultime decadi anche in età pediatrica ha fatto drammaticamente aumentare l’incidenza di complicanze metaboliche quali sindrome metabolica (SM) ed epatopatia steatosica (NAFLD). Recenti evidenze dimostrano l’esistenza di una stretta correlazione tra SM e NAFLD, suggerendo che esse rappresentino l’espressione clinica di un comune disarray metabolico, nel quale l’insulino-resistenza e l’accumulo di grasso intraepatocitario svolgerebbero un ruolo chiave.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease and nowadays it is recognized as one of main leading cause of liver fibrosis worldwide. Because of the high risk to develop cirrhosis and hepatocellular carcinoma, the early assessment of liver fibrosis is an important part of the management of NAFLD patients. To date, histological evaluation of liver biopsy represents the cornerstone for staging and grading liver fibrosis. However, due to the several drawbacks of this approach, during the last decade clinicians and researchers are dedicating their efforts to the identification of novel, safe and effective non-invasive tools to assess liver fibrosis. As due to their accuracy degree, transient elastography (TE) and serum biomarkers seem to be able to replace liver biopsy to determine at least the presence of significant liver fibrosis. The combination of these tools may greatly enhance their diagnostic power. Nevertheless, investigations of new imaging techniques and the molecular pathogenesis of NAFLD are necessary to develop reliable non-invasive alternative approaches to liver biopsy. Here, the authors discuss the salient aspects of diagnostic performance of TE and serum biomarkers available for detecting hepatic fibrosis in NAFLD and provide suggestions as to how these non-invasive techniques can be incorporated into diagnostic management of patients affected by this disease.

The aim of the present study was to evaluate whether the lipin1 rs13412852 C>T polymorphism is associated with nonalcoholic steatohepatitis and fibrosis in pediatric Italian patients with nonalcoholic fatty liver disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world. As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis. NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment. Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents.

The aim of the present study was to build a predictive model of nonalcoholic fatty liver disease (NAFLD) in obese children. Fifty-six obese 10-year-old children underwent blood tests for biochemical measures and magnetic resonance imaging for NAFLD diagnosis. A model combining waist-to-height ratio, homeostasis model assessment of insulin resistance, adiponectin, and alanine aminotransferase was accurate in predicting NAFLD (AUROC=0.94 95 confidence interval 0.89–0.99, P<10−5). When adiponectin was not included in the model, the discrimination accuracy was still good (AUROC=0.88 95 confidence interval 0.79–0.97, P<10−5). In conclusion, a predictive equation combining routinely available variables may allow physicians to identify obese children at the highest risk of NAFLD.

The diagnostic accuracy of hepatic ultrasonography (US) for detection and grading of hepatic steatosis in children with suspected nonalcoholic fatty liver disease (NAFLD) remains poorly characterized. The aim of this study was to prospectively evaluate the clinical utility of ultrasonographic quantification of hepatic steatosis. Our cohort consisted of 208 consecutive pediatric patients with biopsy-proven NAFLD. Hepatic US was performed within 1 month of the liver biopsy procedure. Steatosis identified by US was scored using a 0 to 3 scale based on echogenicity and visualization of vasculature, parenchyma, and diaphragm, and compared to histological features based on Brunt's classification. The median age at time of first visit was 10.8 years and 64% were boys. Sixty-nine percent had moderate to severe steatosis on histology. Ultrasonographic steatosis score (USS) had an excellent correlation with histological grade of steatosis (with a Spearman's coefficient of 0.80). The area under the receiver operating characteristic curve for ultrasonographic detection of moderate-to-severe steatosis was 0.87. The USS did not correlate significantly with inflammatory activity or fibrosis stage; however, there was significant correlation with the NAFLD activity score (NAS), albeit this was in large part the result of the strong correlation with the steatosis component of NAS. Serum alanine transaminase and aspartate transaminase were not associated with histological grade of steatosis and showed no correlation with USS. Our results, which represent the largest prospective pediatric study evaluating the role of hepatic US in children with biopsy-proven NAFLD, demonstrate the utility of this technique for noninvasive diagnosis and estimation of hepatic steatosis in children.

Introduction:Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of most common liver diseases in industrialized countries owing to the increasing prevalence of obesity and being overweight. Until now, loss of weight and physical activity have represented the cornerstone of treatment, but they are very difficult to achieve and to maintain. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish an effective pharmacological therapy for this disorder.Areas covered:An overview of current therapeutic interventions to treat NAFLD is given. This review provides evidence of the efficacy of natural and pharmacological agents used so far in the treatment of both adult and pediatric NAFLD, on the basis of clinical trials published in the last 10 years.Expert opinion:In the last 10 years, many pharmacological agents on the basis of the pathogenetic mechanism of NAFLD have been attempted, but so far guidelines for the management of NAFLD are lacking. We believe that the advance in the understanding of pathogenesis and factors involved in the progression of the disease may disclose the way to defining new, solid, therapeutic strategies. A multidisciplinary approach considering the risk factors and comorbidities of fatty liver will represent in the future a successful therapeutic strategy for NAFLD.

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

The intent of this review is to provide a concise overview of all recent acquisitions in terms of therapies and early noninvasive diagnostic approaches for nonalcoholic fatty liver disease (NAFLD) in children.

Recent evidence supports a role for endotoxemia in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). We investigated the association between serum levels of endotoxin, proinflammatory molecules, and histology in children with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The aim of this study was to assess the relationship between severity of liver injury and atherogenic lipid profile in a large group of children with NAFLD. A total of 118 consecutive children with biopsy-proven NAFLD were included. Patients underwent extensive metabolic profiling. The NAFLD activity and fibrosis scores showed a significant positive correlation with triglyceride/HDL, total cholesterol/HDL, and LDL/HDL ratios (p <0.05) but not with apolipoprotein B/apolipoprotein A-1 ratio (p = 0.58). After adjusting for BMI, homeostatic model assessment, impaired glucose tolerance, and presence of metabolic syndrome, both the NAFLD activity score and stage of fibrosis remained independent predictors of proatherogenic lipid profile. All lipid ratios, except for apolipoprotein B/apolipoprotein A-1, were found to be markedly higher in children with nonalcoholic steatohepatitis compared with those with simple steatosis or borderline disease (p <0.05). This study shows for the first time that in children with NAFLD, the severity of liver injury is strongly associated with the presence of a more atherogenic lipid profile, having potential significant diagnostic and therapeutic implications.

Clinical evidence of the use of probiotics in pediatric NAFLD, framed within gut microbiota response, is herein discussed. The assistance of a new microbiological approach in probiotics’ design is playing a central role in NAFLD clinical management. Experimental studies demonstrated the effect of gut microbiota manipulation in NAFLD and recent clinical evidence reported their beneficial effect in pediatric patients. Epidemiology suggests that NAFLD is the most frequent pediatric chronic liver disease evolving from simple steatosis to a more severe form that may progress toward fibrosis. The goal of pharmacological treatment of NAFLD‐related fibrosis is to stop and eventually to reverse liver damage, but no drug tested so far seem to be able to reach this endpoint. A few encouraging clinical studies demonstrated an improvement of hepato‐metabolic milieu under probiotic treatment suggesting that they could exert an anti‐fibrotic activity. Currently, new insights onto probiotics can be deduced by ad hocgenerated NAFLD gut microbiota profiles. These functional maps may unveil gut ecosystem dynamics under probiotics’ treatment, selecting the most appropriate for NAFLD gut microbiota amelioration.

Purpose of Review: This review summarizes the current state of knowledge on non-alcoholic fatty liver disease (NAFLD) and the hepatitis C virus (HCV)-associated liver fibrosis, and provides insight into the role of dysmetabolism in hepatic fibrogenesis. Clinical relevance of drugs correcting these metabolic disturbances in the reversion of liver fibrosis will also be discussed. Recent Findings: Liver fibrosis affects more than ten millions of people worldwide and may lead to cirrhosis, liver failure, and death. Recent epidemiological data indicate that the incidence of liver fibrosis is expected to triple during the next 10 to 15 years as a result of the HCV infection and NAFLD escalation. In accordance with the modern view of liver fibrogenesis, the pathways involved in the pathogenesis of hepatic fibrosis appear to be broadly similar regardless of the etiology. Summary: Some features of metabolic syndrome, including obesity, insulin resistance, and type 2 diabetes represent a strong risk factor in development and progression of hepatic fibrosis. However, whatever the cause, fibrosis culminates in cirrhosis and results in liver failure, thus, a potent anti-fibrotic therapy is urgently needed to reverse scarring and eliminate progression to cirrhosis.

In view of the epidemic obesity in childhood, facing the disease and its associated morbidities early at this age becomes crucial for public health researchers and care givers. The present review focuses on pediatric Non Alcoholic Fatty Liver Disease (NAFLD) among co-morbidities, being the disease yet under diagnosed and under treated despite a prevalence growing exponentially.Evidences suggest that the environmental background for the development of NAFLD may be established in early life, and that the duration of the disease affects probably the likelihood of progression to more severe disease (necro-inflammation or Non Alcoholic SteatoHepatitis, also termed, NASH; fibrosis and cirrhosis).NAFLD associates with abdominal obesity, insulin resistance and features of metabolic syndrome. In genetically prone individuals, malnutrition (i.e., excessive consumption of saturated fats and refined sugars) leads to the derangement of the adipose tissue architecture and homeostasis, the peripheral and hepatic resistance to insulin-stimulated glucose uptake, thus favoring a condition of chronic low-grade inflammation. Excessive nutrients cannot be stored in the adipose tissue and overflow elsewhere, mainly to the muscle tissue and liver. Fat deposition in both sites enhances insulin resistance and further deposition of fats in a vicious manner.What is of special interest comparing NAFLD in children and adults is that the histological appearance of the disease differs significantly, likely representing a yet physiological response to environmental stressors in children and a long-term adaptation in adults.In this article, we review the current concepts about paediatric NAFLD, its pathogenesis, diagnosis and treatment, with particular regard to lifestyle and foods habits.

Objective: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children.Design and methods: In 72 biopsy-proven NAFLD children (aged 9–18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients.Results: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 ± 1.39 and 4.4 ± 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 ± 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 ± 6.3 in score 1 to 17.4 ± 6.9 in score 2 (P= 0.01) and 22.2 ± 6.8 ng/ml in score 3 (P< 0.001); FLI 2.56 ± 1.40, 3.57 ± 0.34, 4.45 ± 0.64 respectively (P= 0.05)); ballooning (from 13.7 ± 6.7 in score 1 to 17 ± 7.5 in score 2 (P= 0.001) and 22.1 ± 7.1 ng/ml in score 3 (P= 0.01); FLI 2.81 ± 1.50, 3.40 ± 1.65, 4.57 ± 1.67 (P= 0.01 between 0 and 2)); fibrosis (from 14.3 ± 7 to18.3 ± 6.9; P= 0.03; FLI 3.03 ± 1.57 vs 3.92 ± 077; P< 0.05) and NAS score (score 1–2: 12.9 ± 6.9; score 3–4: 17 ± 6.9 (P= 0.01); score 5–7: 22.9 ± 7.5 ng/ml (P= 0.03); FLI 2.70 ± 1.53, 3.12 ± 1.53, 4.58 ± 1.57 P= 0.01 and P= 0.05 between 1–2 vs 3–4 and 3–4 vs 5–7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r0= 0.6, 0.4 and 0.6 respectively; for all P< 0.001); FLI with ballooning (r0= 0.4, P< 0.0001), steatosis (r0= 0.5, P< 0.0001) and NAS score (r0= 0.5, P< 0.0001).Conclusions: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.