It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form ...It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver.In this review,we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin,transferrin,and ferritin in iron homeostasis.The regulation of ferroptosis by endogenous and exogenous modulators will be examined.Furthermore,the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease,chronic hepatitis B and C,liver fibrosis,and hepatocellular carcinoma(HCC)will be analyzed.Finally,experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented.Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC,where induction of ferroptosis is the desired effect.Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.展开更多
AIM: To investigate the transforming growth factor-β (TGF-β) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients. METHODS: We examined TGF-β1, TGF-β2 and TGF-β3 (enzyme...AIM: To investigate the transforming growth factor-β (TGF-β) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients. METHODS: We examined TGF-β1, TGF-β2 and TGF-β3 (enzyme-linked immunosorbent assay), in 27 stage Ⅳ PBC patients (27 peripheral and 15 hepatic vein sera), 35 early (Ⅰ-Ⅱ) PBC and 60 healthy controls. As disease controls 28 hepatitis C virus (HCV) cirrhosis (28 peripheral and 17 hepatic vein serum), 44 chronic HCV hepatitis and 38 HCV-related hepatocellular carcinomas were included. We also tested liver tissue by immunohistochemistry to identify localization of TGF isoforms. RESULTS: TGF-β1 was significantly decreased in all cirrhotics (PBC Ⅲ-Ⅳ: median 13.4 ng/mL; range, 7.4-26.2, HCV cirrhosis: 11.6 ng/mL; range, 5.0-33.8), compared to controls (30.9 ng/mL; range, 20.9-37.8). TGF-β2 was increased in viral cirrhosis but not in PBC and chronic hepatitis. TGF-β3 (47.2 pg/mL; range, 27.0-79.7 in healthy controls) was increased in early and late PBC (Ⅰ-Ⅱ: 94.3 pg/mL; range, 41.5-358.6; Ⅲ-Ⅳ: 152.8 pg/mL; range, 60.4-361.2; P < 0.001) and decreased in viral cirrhosis (37.4 pg/mL; range, 13.3-84.0; P < 0.05). Hepatic vein TGF-β levels were analogous to those in peripheral blood. Immunohistochemistry identified all isoforms in portal tract lymphocytes, sinusoidal cells and cholangiocytes. TGF-β3 was additionally overexpressed in hepatocytes in PBC patients. CONCLUSION: The serum profile of TGF-β isoforms is different in cirrhotics. Increased TGF-β3 is characteristic of PBC. These findings may be related to the immunological abnormalities of PBC.展开更多
AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis(PBC).METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsie...AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis(PBC).METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B(HBV) virus,3 patients with hepatitis C virus(HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis(AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targetedby autoantibodies present in the patients sera was performed by indirect immunofluorescence(IIF) analysis using paraffin-embedded liver sections as a substrate.Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.RESULTS: In total, 18/21(85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21(47.6%) in lymphocytes, 8/21(38%) in cholangiocytes and 7/21(33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G(IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining(20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody,positive staining was observed in 75% of lymphocytes,62.5% of cholangiocytes, 37.5% of hepatocytes and50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections,weak positive staining of cholangiocytes was observed in 3/21(14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.展开更多
Introduction of effective drugs in the treatment of hepatitis C virus(HCV)infection has prompted the World Health Organization to declare a global eradication target by 2030.Propositions have been made to screen the g...Introduction of effective drugs in the treatment of hepatitis C virus(HCV)infection has prompted the World Health Organization to declare a global eradication target by 2030.Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status.A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease.Huge financial resources were redirected,and the pandemic became the first priority in every country.In this review,we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection.We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination.Alcohol consumption,HIV coinfection and the presence of components of metabolic syndrome including obesity,hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liverrelated morbidity and mortality of HCV.We also examined the significance of special subpopulations like people who inject drugs and males having sex with males.Finally,we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income.We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.展开更多
文摘It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease.The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver.In this review,we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin,transferrin,and ferritin in iron homeostasis.The regulation of ferroptosis by endogenous and exogenous modulators will be examined.Furthermore,the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease,chronic hepatitis B and C,liver fibrosis,and hepatocellular carcinoma(HCC)will be analyzed.Finally,experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented.Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC,where induction of ferroptosis is the desired effect.Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
基金Supported by Research funds of the University of Crete
文摘AIM: To investigate the transforming growth factor-β (TGF-β) isoforms in the peripheral and hepatic venous blood of primary biliary cirrhosis (PBC) patients. METHODS: We examined TGF-β1, TGF-β2 and TGF-β3 (enzyme-linked immunosorbent assay), in 27 stage Ⅳ PBC patients (27 peripheral and 15 hepatic vein sera), 35 early (Ⅰ-Ⅱ) PBC and 60 healthy controls. As disease controls 28 hepatitis C virus (HCV) cirrhosis (28 peripheral and 17 hepatic vein serum), 44 chronic HCV hepatitis and 38 HCV-related hepatocellular carcinomas were included. We also tested liver tissue by immunohistochemistry to identify localization of TGF isoforms. RESULTS: TGF-β1 was significantly decreased in all cirrhotics (PBC Ⅲ-Ⅳ: median 13.4 ng/mL; range, 7.4-26.2, HCV cirrhosis: 11.6 ng/mL; range, 5.0-33.8), compared to controls (30.9 ng/mL; range, 20.9-37.8). TGF-β2 was increased in viral cirrhosis but not in PBC and chronic hepatitis. TGF-β3 (47.2 pg/mL; range, 27.0-79.7 in healthy controls) was increased in early and late PBC (Ⅰ-Ⅱ: 94.3 pg/mL; range, 41.5-358.6; Ⅲ-Ⅳ: 152.8 pg/mL; range, 60.4-361.2; P < 0.001) and decreased in viral cirrhosis (37.4 pg/mL; range, 13.3-84.0; P < 0.05). Hepatic vein TGF-β levels were analogous to those in peripheral blood. Immunohistochemistry identified all isoforms in portal tract lymphocytes, sinusoidal cells and cholangiocytes. TGF-β3 was additionally overexpressed in hepatocytes in PBC patients. CONCLUSION: The serum profile of TGF-β isoforms is different in cirrhotics. Increased TGF-β3 is characteristic of PBC. These findings may be related to the immunological abnormalities of PBC.
文摘AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis(PBC).METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B(HBV) virus,3 patients with hepatitis C virus(HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis(AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targetedby autoantibodies present in the patients sera was performed by indirect immunofluorescence(IIF) analysis using paraffin-embedded liver sections as a substrate.Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.RESULTS: In total, 18/21(85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21(47.6%) in lymphocytes, 8/21(38%) in cholangiocytes and 7/21(33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G(IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining(20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody,positive staining was observed in 75% of lymphocytes,62.5% of cholangiocytes, 37.5% of hepatocytes and50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections,weak positive staining of cholangiocytes was observed in 3/21(14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.
基金Corresponding author:Elias Kouroumalis,MD,PhD,Emeritus Professor,Department of Gastroenterology,University of Crete Medical School,Voutes,Heraklion 71500,Crete,Greece.kouroumi@uoc.gr。
文摘Introduction of effective drugs in the treatment of hepatitis C virus(HCV)infection has prompted the World Health Organization to declare a global eradication target by 2030.Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status.A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease.Huge financial resources were redirected,and the pandemic became the first priority in every country.In this review,we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection.We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination.Alcohol consumption,HIV coinfection and the presence of components of metabolic syndrome including obesity,hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liverrelated morbidity and mortality of HCV.We also examined the significance of special subpopulations like people who inject drugs and males having sex with males.Finally,we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income.We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
