传染病学传染病学 (8).pdf
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1、Downloaded from https:/ by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws=on 12/23/2021Downloaded from https:/ by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws=on 12/23/2021Non-
2、alcoholic steatohepatitis and risk of hepatocellular carcinomaRafael S.Rios1,Kenneth I.Zheng1,Ming-Hua Zheng1,2,31NAFLD Research Center,Department of Hepatology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325000,China;2Institute of Hepatology,Wenzhou Medical Universi
3、ty,Wenzhou,Zhejiang 325000,China;3Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province,Wenzhou,Zhejiang 325000,China.AbstractThe emergence of non-alcoholic fatty liver disease(NAFLD)as the leading chronic liver disease worldwide raises some conc
4、erns.Inparticular,NAFLD is closely tied to sedentary lifestyle habits and associated with other metabolic diseases,such as obesity anddiabetes.At the end of the disease spectrum,non-alcoholic steatohepatitis(NASH)may progress to cirrhosis and hepatocellularcarcinoma(HCC),representing a serious healt
5、h problem to modern society.Recently,an increasing number of HCC casesoriginating from this progressive disease spectrum have been identified,with different levels of severity and complications.Updatingthe current guidelines by placing a bigger focus on this emerging cause and highlighting some of i
6、ts unique features is necessary.Since,the drivers of the disease are complex and multifactorial,in order to improve future outcomes,having a better understandingofNASHprogressionintoHCCmaybehelpful.Therisksthatcanpromotediseaseprogressionandcurrentlyavailablemanagementstrategies employed to monitor
7、and treat NASH-related HCC make up the bulk of this review.Keywords:Non-alcoholic fatty liver disease;Non-alcoholic steatohepatitis;Liver disease;Hepatocellular carcinoma;Insulinresistance;Oxidative stress;Metabolic associated fatty liver diseaseIntroductionDespite non-alcoholic fatty liver disease(
8、NAFLD)affect-ing a great number of people(about one-quarter of theglobal population),only a small quantity of patientsprogressesbeyondtheinitialstagesofthediseaseintomoresevere conditions,with the onset of end-stage liver diseaseaffecting less than 13%of NAFLD patients.1These stagesare a reflection
9、of the disease spectrum,characterized byspecific histological signs,that range from non-alcoholicfattyliver(NAFL),tonon-alcoholicsteatohepatitis(NASH),to fibrosis and then cirrhosis.2Following thisexacerbation path,after cirrhosis,patients develophepatocellular carcinoma(HCC)and end-stage liverdisea
10、se.Despite affecting a large portion of the populationworldwide,we do not fully understand all factorscontributing to disease progression,as well as the impactthese factors have on clinical outcomes.NASH is defined by an accumulation of fat in hepatocytes(5%)together with measurable signs of cell in
11、jury(hepatocyte ballooning and lobular inflammation)that aredetected through histological examination.However,thefact that these histological changes to the normal liver cellscan also be observed in alcoholic hepatitis,and that a liverbiopsyisrequiredforadefinitediagnosis,indicatesthatthecurrent dia
12、gnostic methodology has some limitations.3-9Recently,there has been a push towards updating thedefinition of NAFLD to a more accurate reflection ofcurrently available knowledge.MAFLD,or metabolic-associatedfattyliverdisease,wasproposedtoaninternational panel of experts as an alternative nomencla-tur
13、eforNAFLD,where aconsensus was reachedregardingadopting this change,due to its many advantages such aspositive diagnostic criteria,capturing the full spectrum ofthe disease(instead of just NASH and simple steatosis),aswell as a concrete framework that includes other metaboliccauses of fatty liver di
14、sease.10,11The diagnostic criteria ofMAFLD are based on the presence of hepatic steatosis plusany of the next three criteria:elevated levels of body massindex(BMI),diabetes mellitus type 2,and evidence ofmetabolic dysregulation.11,12Obesity carries a negative impact in NASH patients,withelevated adi
15、posity levels,on average,being associated withincreased severity of fibrosis and inflammation.Likewise,diabetes(in particular type 2 diabetes),has been identifiedCorrespondence to:Dr.Ming-Hua Zheng,Non-alcoholic Fatty Liver DiseaseResearch Center,Department of Hepatology,the First Affiliated Hospita
16、l of WenzhouMedical University;No.2 Fuxue Lane,Wenzhou,Zhejiang 325000,ChinaE-Mail:Copyright 2021 The Chinese Medical Association,produced by Wolters Kluwer,Inc.under theCC-BY-NC-ND license.This is an open access article distributed under the terms of the CreativeCommons Attribution-Non Commercial-N
17、o Derivatives License 4.0(CCBY-NC-ND),where it ispermissible to download and share the work provided it is properly cited.The work cannot bechanged in any way or used commercially without permission from the journal.Chinese Medical Journal 2021;134(24)Received:09-08-2021 Edited by:Yuan-Yuan JiAccess
18、 this article onlineQuick Response Code:Website:www.cmj.orgDOI:10.1097/CM9.0000000000001888Review Article2911as a contributor to the development of NAFLD.Similarly,NAFLD being associated with an increased risk ofdiabetes has also been shown to be true.13As forHCC,it is more frequently associated wit
19、h risk factorssuch as age(65 years old),diabetes,and metabolicsyndrome.14-16This review aims to discuss the pathogenesis,diseaseprogression,and current management of NASH-relatedHCC,which is a pertinent topic,now that NAFLD hasbecome the most prevalent chronic liver disease in theworld.PathogenesisT
20、he path from NAFLD to HCC is underscored by multiplefactors.Fromthesimpleaccumulationoffatinhepatocytesto the more serious state of necroinflammation andfibrosis,it is currently understood that the foundation ofall complications lies in the metabolic disturbance ofNAFLD patients.17This section will
21、explore the role ofmultiple factors in NAFLD development,such as insulinresistance,lipotoxicity,oxidative stress,and DNA damageresponse.17Insulin resistanceInsulin resistance represents a growing problem that isexacerbated by the modern,western-influenced lifestyleand diet,and as the name states,imp
22、lies a decrease in theeffectiveness of the role that insulin molecules play in theregulation of glucose metabolism.Additionally,insulinresistance interferes in the metabolism of glucose,ketones,and lipids,generating an excess of free fatty acids(FFAs)thatinterfere withthenormal function ofthemitocho
23、ndriain hepatocytes,playing a key role in the progression fromNAFLD to HCC.18,19Initially,it was established thatreducedinsulinactivation,togetherwithlipidbuildup,wasassociated with interference to the tricarboxylic acid(TCA)cycle,as well as,with increased production ofreactive oxygen species(ROS).1
24、8In NASH patients,theproduction of ROS is almost doubled through a persistentincrease in activity by the TCA cycle,despite suboptimalb-oxidation,insufficient lipid esterification,and impairedketogenesis.18,20,21However,due to the adaptive capa-bilities of the hepatocytes to regulate their metabolism
25、 andto compensate for an initial disturbance(caused byincreased FFAs and insulin resistance),changes in theTCA cycle may not be easily detected.21The problemscaused by an increase in ROS,addressed in more detail inthe oxidative stress segment,include inflammation,fibro-genesis,and DNA damage.Therefo
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