Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disea...Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.展开更多
Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hep...Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.展开更多
Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 20...Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.展开更多
The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morpho...The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morphologically,NAFLD is characterized by excess fatty infiltration of the liver in the absence of known causes of liver disease(eg,alcohol,autoimmune liver disease,viral hepatitis,etc).The clinical manifestations of NAFLD(both hepatic and extrahepatic)depend on the outcome of complex interactions between its primary drivers including poor lifestyle habits and diet,a dysfunctional microbiota,genetic predisposition,and environmental cues that result in metabolic dysfunction and liver disease.However,bringing all patients with their markedly different clinical courses under the NAFLD umbrella belies its complexity and implies a homogeneous disease state that then negatively impacts clinical management and a deeper understanding of pathogenesis.With advances in current knowledge on the spectrum of fatty liver diseases,it is apparent that the fourdecade-old outdated term NAFLD can no longer serve to usefully describe a highly heterogeneous disease.The disease as we understand it today not only impacts patients who consume alcohol and those who do not,but also potentially impacts all patients with any form of liver disease,by acting as a disease modifier.[2]展开更多
The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepato...The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepatocellular carcinoma,and liver transplants.In addition,it has also been linked to extrahepatic consequences,such as cardiovascular disease,diabetes,and various types of cancers.However,only a small proportion of patients with MAFLD develop these complications.Therefore,the identification of high-risk patients is paramount.Liver fibrosis is the major determinant in developing these complications.Although,liver biopsy is still considered the gold standard for the assessment of patients with MAFLD.Because of its invasive nature,among many other limitations,the search for noninvasive biomarkers for MAFLD remains an area of intensive research.In this review,we provide an update on the current and future biomarkers of MAFLD,including a discussion of the associated genetics,epigenetics,microbiota,and metabolomics.We also touch on the next wave of multiomic-based biomarkers.展开更多
Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic C...Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.展开更多
With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty ...With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty liver disease(NAFLD)]has risen in prevalence and present a significant challenge to global health causing considerable morbidity and mortality,particularly when fibrosis is present(1).展开更多
The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident canc...The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident cancer cases worldwide in 2018,43.8 million are living with cancer and 9.6 million deaths from cancer.One in 6 deaths is due to cancer and these numbers are projected to rise to 13 million by 2030,more than that from tuberculosis,malaria and HIV/AIDS combined.In addition,the total annual global cost of cancer was estimated at around US$1.16 trillion,representing a significant burden on health care systems and families(1).展开更多
As of today, March 30, 2020, when this Editorial is being written, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causal agent of the coronavirus disease (COVID-19) has been confirmed in more than 7...As of today, March 30, 2020, when this Editorial is being written, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causal agent of the coronavirus disease (COVID-19) has been confirmed in more than 745,000 cases worldwide and has claimed the lives of more than 35,000 people.1 In addition to the morbidity and mortality associated with COVID-19, this betacoronavirus has placed several of the world's major economies in strife, mainly in Western Europe and North America, paralyzing travel and regular social interactions, making COVID-19 undoubtedly one of the most important pandemics in human history.展开更多
Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a he...Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a heterogeneous disease with a spectrum of liver pathologies that spans from hepatic lipid accumulation(steatosis)to chronic inflammation(steatohepatitis),which can progress to cirrhosis and hepatocellular carcinoma.It is impacted by a myriad of factors,including metabolic health,biological and chronological age,genetics and epigenetics(2-4).However,only a proportion(5-40%)of patients develop liver inflammation or steatohepatitis(5).This transition is a cardinal feature of progressive liver disease,which is the precursor to the development of the hepatic and extra-hepatic outcomes.展开更多
Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approxi...Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approximately one in four people have the disease(3).As a consequence,MAFLD-related cirrhosis is expected to become the leading cause for liver failure and liver cancer,and the major indication for liver transplantation this century(3).展开更多
文摘Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries.The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney disease.The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development.This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of MAFLD.We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose tissue.We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.
基金Supported by A National Health and Medical Research Council Project grant, APP1006759the Robert W. Storr bequest to the Sydney Medical Foundation of the University of Sydney, to Ahlenstiel G and George J+1 种基金an International Postgraduate Research Scholarshipsan Australian Postgraduate Award of the University of Sydney, to Eslam M
文摘Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)infection.Further,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in CHC.The emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin resistance.This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.
文摘Background:With the rising global prevalence of fatty liver disease related to metabolic dysfunction,the association of this common liver condition with chronic kidney disease(CKD)has become increasingly evident.In 2020,the more inclusive term metabolic dysfunction-associated fatty liver disease(MAFLD)was proposed to replace the term non-alcoholic fatty liver disease(NAFLD).The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD.However,to date,there is no appropriate guidance on CKD in individuals with MAFLD.Furthermore,there has been little attention paid to the link between MAFLD and CKD in the Nephrology community.Methods and Results:Using a Delphi-based approach,a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD.Conclusions:This Delphi-based consensus statement provided guidance on the epidemiology,mechanisms,management and treatment of MAFLD and CKD,as well as the relationship between the severity of MAFLD and risk of CKD,which establish a framework for the early prevention and management of these two common and interconnected diseases.
基金the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(No.APP1053206 and APP1149976)+2 种基金Project grants(No.APP1107178 and APP1108422)Ming-Hua Zheng is supported by grants from the National Natural Science Foundation of China(No.81500665)High Level Creative Talents from Department of Public Health in Zhejiang Province and Project of New Century 551 Talent Nurturing in Wenzhou.
文摘The term non-alcoholic fatty liver disease(NAFLD)was coined in 1980 to characterize a disease similar to alcoholic fatty liver disease that developed in patients without a history of excessive alcohol intake.[1]Morphologically,NAFLD is characterized by excess fatty infiltration of the liver in the absence of known causes of liver disease(eg,alcohol,autoimmune liver disease,viral hepatitis,etc).The clinical manifestations of NAFLD(both hepatic and extrahepatic)depend on the outcome of complex interactions between its primary drivers including poor lifestyle habits and diet,a dysfunctional microbiota,genetic predisposition,and environmental cues that result in metabolic dysfunction and liver disease.However,bringing all patients with their markedly different clinical courses under the NAFLD umbrella belies its complexity and implies a homogeneous disease state that then negatively impacts clinical management and a deeper understanding of pathogenesis.With advances in current knowledge on the spectrum of fatty liver diseases,it is apparent that the fourdecade-old outdated term NAFLD can no longer serve to usefully describe a highly heterogeneous disease.The disease as we understand it today not only impacts patients who consume alcohol and those who do not,but also potentially impacts all patients with any form of liver disease,by acting as a disease modifier.[2]
基金ME is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney,the National Health and Medical Research Council of Australia(NHMRC)program grants(1053206 and 1149976)various project grants(1107178,1108422,and 2001692).
文摘The prevalence of metabolic(dysfunction)-associated fatty liver disease(MAFLD)is rapidly increasing and affects up to two billion individuals globally,and this has also resulted in increased risks for cirrhosis,hepatocellular carcinoma,and liver transplants.In addition,it has also been linked to extrahepatic consequences,such as cardiovascular disease,diabetes,and various types of cancers.However,only a small proportion of patients with MAFLD develop these complications.Therefore,the identification of high-risk patients is paramount.Liver fibrosis is the major determinant in developing these complications.Although,liver biopsy is still considered the gold standard for the assessment of patients with MAFLD.Because of its invasive nature,among many other limitations,the search for noninvasive biomarkers for MAFLD remains an area of intensive research.In this review,we provide an update on the current and future biomarkers of MAFLD,including a discussion of the associated genetics,epigenetics,microbiota,and metabolomics.We also touch on the next wave of multiomic-based biomarkers.
基金This work was supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)+3 种基金Project of New Century 551 Talent Nurturing in Wenzhou.GT was supported in part by grants from the University School of Medicine of Verona(Verona,Italy)CDB was supported in part by the Southampton NIHR Biomedical Research Centre(ISBRC-20004)UK.ME and JG were supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydney(Sydney,Australia)and the National Health and Medical Research Council of Australia(NHMRC)Program(APP1053206,APP1149976)Project(APP1107178 and APP1108422)grants.
文摘Background and Aims:In Europeans,variants in the hydroxysteroid 17-beta dehydrogenase 13(HSD17B13)gene impact liver histology in metabolic-associated fatty liver disease(MAFLD).The impact of these variants in ethnic Chinese is unknown.The aim of this study was to investigate the potential associations in Chinese patients.Methods:In total,427 Han Chinese with biopsy-confirmed MAFLD were enrolled.Two single nucleotide polymorphisms in HSD17B13 were genotyped:rs72613567 and rs6531975.Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.Results:In our cohort,the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis[odds ratio(OR):2.93(1.20–7.17),p=0.019 for the additive model;OR:3.32(1.39–7.91),p=0.007 for the recessive model],representing an inverse association as compared to the results from European cohorts.In contrast,we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant[OR:0.48(0.24–0.98),p=0.043 for the additive model;OR:0.62(0.40–0.94),p=0.025 for the dominant model].HSD17B13 variants were only associated with fibrosis but no other histological features.Furthermore,HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis.Conclusions:HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans.These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
基金ME is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of SydneyNational Health and Medical Research Council of Australia(NHMRC)Program Grants(1053206 and 1149976)Project grants(1107178 and 1108422,2001692).
文摘With the widespread increase in energy intake and physical inactivity,the prevalence of metabolic health is declining.Consequently,metabolic associated fatty liver disease(MAFLD)[formerly known as non-alcoholic fatty liver disease(NAFLD)]has risen in prevalence and present a significant challenge to global health causing considerable morbidity and mortality,particularly when fibrosis is present(1).
文摘The majority of global deaths are attributed to one of the noncommunicable diseases(NCDs),and cancer is projected to be the leading cause of death worldwide in the 21st century(1).There were 18.1 million incident cancer cases worldwide in 2018,43.8 million are living with cancer and 9.6 million deaths from cancer.One in 6 deaths is due to cancer and these numbers are projected to rise to 13 million by 2030,more than that from tuberculosis,malaria and HIV/AIDS combined.In addition,the total annual global cost of cancer was estimated at around US$1.16 trillion,representing a significant burden on health care systems and families(1).
文摘As of today, March 30, 2020, when this Editorial is being written, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causal agent of the coronavirus disease (COVID-19) has been confirmed in more than 745,000 cases worldwide and has claimed the lives of more than 35,000 people.1 In addition to the morbidity and mortality associated with COVID-19, this betacoronavirus has placed several of the world's major economies in strife, mainly in Western Europe and North America, paralyzing travel and regular social interactions, making COVID-19 undoubtedly one of the most important pandemics in human history.
基金Mohammed Eslam is supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of SydneyNational Health and Medical Research Council of Australia(NHMRC)Program Grants(1053206 and 1149976)Project grants(1107178 and 1108422,2001692).
文摘Metabolic(dysfunction)-associated fatty liver disease(MAFLD;formerly known as non-alcoholic fatty liver disease)is the most common liver disorder,affecting around one-third of the population worldwide(1).MAFLD is a heterogeneous disease with a spectrum of liver pathologies that spans from hepatic lipid accumulation(steatosis)to chronic inflammation(steatohepatitis),which can progress to cirrhosis and hepatocellular carcinoma.It is impacted by a myriad of factors,including metabolic health,biological and chronological age,genetics and epigenetics(2-4).However,only a proportion(5-40%)of patients develop liver inflammation or steatohepatitis(5).This transition is a cardinal feature of progressive liver disease,which is the precursor to the development of the hepatic and extra-hepatic outcomes.
基金ME and JG are supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program Grant(APP1053206,APP1149976)+3 种基金Project grants(APP1107178 and APP1108422)MHZ is supported by grants from the National Natural Science Foundation of China(82070588)High Level Creative Talents from Department of Public Health in Zhejiang Province(S2032102600032)Project of New Century 551 Talent Nurturing in Wenzhou.
文摘Metabolic-associated fatty liver disease(MAFLD)(1),formerly known as non-alcoholic fatty liver disease,is a major causes of liver cirrhosis(2).MAFLD represents a growing global health and economic burden since approximately one in four people have the disease(3).As a consequence,MAFLD-related cirrhosis is expected to become the leading cause for liver failure and liver cancer,and the major indication for liver transplantation this century(3).