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      Non-Alcoholic Fatty Liver and Metabolic Syndrome in Children: A Vicious Circle

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          Abstract

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

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          Most cited references 41

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          Pathology of nonalcoholic fatty liver disease.

          Nonalcoholic fatty liver disease (NAFLD) is a significant complication of obesity and is recognized as the hepatic manifestation of the metabolic syndrome. The process occurs in adults and children and is characterized by the presence of increased amounts of fat in the liver (steatosis). With inflammation, cell death and scarring (fibrosis), the process may result in end-stage liver disease, or be a precursor for hepatocellular carcinoma. Excess hepatic fat is now recognized as an independent marker for increased cardiovascular risk. Even though imaging studies and laboratory-based tests are accurate at detecting significant steatosis and/or advanced fibrosis, respectively, the diagnosis and characterization of NAFLD ultimately depend on histopathologic evaluation, as the parenchymal alterations that comprise the spectrum of injury in NAFLD include patterns as well as specific lesions. Histologic findings in children may differ from those in adults. In this Review, the histologic features that are diagnostic and discriminatory between steatosis and steatohepatitis, the significance of the distinction between steatosis and steatohepatitis, the types and locations of fibrosis, and the histologic variances between adult and pediatric NAFLD are discussed. Clinical advantages as well as potential drawbacks of liver biopsy are presented. Current pathophysiologic concepts relevant to histologic findings are discussed.
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            The role of hepatokines in metabolism.

            The liver is known to be involved in the natural history of the ongoing epidemics of type 2 diabetes mellitus and cardiovascular disease. In particular, the liver has a role in increased glucose production and dysregulated lipoprotein metabolism, conditions that are often found in patients with nonalcoholic fatty liver disease. Additionally, several proteins that are exclusively or predominantly secreted from the liver are now known to directly affect glucose and lipid metabolism. In analogy to the functional proteins released from adipose tissue and skeletal muscle-adipokines and myokines-these liver-derived proteins are known as hepatokines. The first hepatokine that has been proven to have a major pathogenetic role in metabolic diseases is α2-HS-glycoprotein (fetuin-A). Production of this glycoprotein is increased in steatotic and inflamed liver, but not in expanded and dysregulated adipose tissue. Thus, research into this molecule and other hepatokines is expected to aid in differentiating between the contribution of liver and those of skeletal muscle and adipose tissue, to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease.
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              Adipose tissue: the new endocrine organ? A review article.

              Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity's comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses.
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                Author and article information

                Journal
                HRP
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2014
                November 2014
                15 October 2014
                : 82
                : 5
                : 283-289
                Affiliations
                Hepato-Metabolic Disease Unit and Liver Research Unit, ‘Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
                Author notes
                *Prof. Valerio Nobili, Hepato-Metabolic Disease Unit, ‘Bambino Gesù' Children's Hospital, IRCCS, P. le S. Onofrio, 4, IT-00165 Rome (Italy), E-Mail valerio.nobili@opbg.net
                Article
                365192 Horm Res Paediatr 2014;82:283-289
                10.1159/000365192
                25324136
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Pages: 7
                Categories
                Mini Review

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