The discovery of a strong association between hepatitis C virus(HCV) infection and mixed cryoglobulinemia(MC) has led to an increasingly rare diagnosis of idiopathic essential MC(EMC).The incidence of EMC is high in r...The discovery of a strong association between hepatitis C virus(HCV) infection and mixed cryoglobulinemia(MC) has led to an increasingly rare diagnosis of idiopathic essential MC(EMC).The incidence of EMC is high in regions where there is a comparatively low HCV infection burden and low in areas of high infection prevalence,including HCV.The diagnosis of EMC requires an extensive laboratory investigation to exclude all possible causes of cryoglobulin formation.In addition,although cryoglobulin testing is simple,improper testing conditions will result in false negative results.Here,we present a 46-year-old female patient with a case of EMC with dermatological and renal manifestations,highlighting the importance of extensive investigation to reacha proper diagnosis.We review the need for appropriate laboratory testing,which is often neglected in clinical practice and which can result in false negative results.This review also emphasizes the significance of an extended testing repertoire necessary for better patient management.Despite a strong association of MC with HCV infection and other causes that lead to cryoglobulin formation,EMC remains a separate entity.Correct diagnosis requires proper temperature regulation during sample handling,as well as characterization and quantification of the cryoprecipitate.Inclusion of rheumatoid factor activity and complement levels in the cryoglobulin test-panel promotes better patient management and monitoring.Consensus guidelines should be developed and implemented for cryoglobulin detection and the diagnosis of cryoglobulinemic syndrome,which will reduce variability in inter-laboratory reporting.展开更多
Mixed cryoglobulinemia(MC)is the extrahepatic manifestation most strictly correlated with hepatitis C virus(HCV)infection;it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in5%-10%of ...Mixed cryoglobulinemia(MC)is the extrahepatic manifestation most strictly correlated with hepatitis C virus(HCV)infection;it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in5%-10%of cases.MC is reputed to be a multistep and multifactorial process whose pathogenicity is still poorly understood.It is still unknown why only some chronically infected HCV patients develop MC and only some of these exhibit systemic symptoms(MC syndrome).Several studies have investigated the pathogenetic basis of MC and the most recent ones suggest that the virus is able to trigger such a disorder only in the presence of genetic factors that are still unknown.Here,we try to clarify the complex relationship between HCVrelated MC and the host’s genetic background.The data that we report are heterogeneous and sometimes even conflicting.Therefore,large,multicenter studies are clearly needed.The identification of a characteristic genetic signature of cryoglobulinemic patients would be an important step toward a personalized approach in their clinical care.The new wide-ranging genomics technologies will hopefully help to resolve these complex issues.展开更多
Hepatitis C virus(HCV) infection affects about 3% of the world's population and often leads to chronic liver disease.In some industrialized countries,HCV prevalence increases with age,but the optimal management of...Hepatitis C virus(HCV) infection affects about 3% of the world's population and often leads to chronic liver disease.In some industrialized countries,HCV prevalence increases with age,but the optimal management of older patients has not been accurately defined.HCV infection can also lead to lymphoproliferative disorders,the most common being mixed cryoglobulinemia(MC),and also for this condition that frequently affects elderly patients,the optimal therapeutic strategy is still debated.We report the case of a 77-year-old Caucasian woman with HCV-related chronic hepatitis and cutaneous manifestations consisting of urticaria and pruritus related to MC resistant to antihistamines.The patient underwent a treatment with interferon and ribavirin.Such a treatment led to early biochemical and virological response associated with the resolution of cryoglobulinemia and cutaneous symptoms.After the end of treatment,HCV replication relapsed,but cryoglobulinemia and cutaneous symptoms did not recur.In the absence of definite treatment guidelines in this particular context,our experience suggests that the presence of symptoms related to HCV-infection that deeply affect patient quality of life warrants antiviral therapy even beyond the age limits that currently exclude patients from treatment.展开更多
AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor α (TNF-α) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV)...AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor α (TNF-α) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).METHODS: Serum NTproBNP and TNF-α levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed signifi cantly higher mean NTproBNP and TNF-α levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (χ2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (χ2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as thepatients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (χ2, P = 0.08).CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-α in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction.展开更多
Cryoglobulinemia is a pathological condition usually associated with hepatitis C virus(HCV) chronic liver disease and less commonly with autoimmune or lymphoproliferative disorders.The possible association of cryoglob...Cryoglobulinemia is a pathological condition usually associated with hepatitis C virus(HCV) chronic liver disease and less commonly with autoimmune or lymphoproliferative disorders.The possible association of cryoglobulinemia with hepatitis B virus(HBV) infection is not widely accepted.In our patient,serum negativity for HCV markers initially led us to consider two other causes of cryoglobulinemia.Myelodysplastic disorders were excluded on the basis of hematological studies,while serum markers for active HBV infection were positive.Surprisingly,the detection of HCV RNA in the cryocrit,even in the absence of anti-HCV antibodies suggested a pathogenetic role of HCV in this case of cryoglobulinemia.Negative "first level" tests for HCV in the serum do not completely exclude HCV involvement in the pathogenesis of cryoglobulinemia.Analysis of the cryoprecipitate is always essential for diagnosis.展开更多
Background Mixed cryoglobulinemia （MC） is one of the most common and severe symptoms in chronic hepatitis C patients. The aim of this study was to investigate whether mixed cryoglobulinemia is a factor associated wi...Background Mixed cryoglobulinemia （MC） is one of the most common and severe symptoms in chronic hepatitis C patients. The aim of this study was to investigate whether mixed cryoglobulinemia is a factor associated with sustained virological response in chronic hepatitis C patients treated with combination therapy of pegylated interferon alpha-2a and ribavirin. Methods This is a single-center study including 57 chronic hepatitis C patients who received combination treatments of pegylated interferon alfa-2a and ribavirin. Serum cryoglobulin was detected by cryoprecipitation prior to treatment. Serum hepatitis C virus （HCV） RNA levels were checked before treatment, during the fourth and 12th week of treatment, and during the 24th week after cessation of treatment. The genotype of HCV was determined at baseline. Logistic regression analysis was used to assess the factors associated with sustained virological response. Results Twenty-five patients were with MC （43.9%）. Twenty-four weeks after cessation of antiviral treatment, sustained virological response achievement in MC~ patients was significantly lower than that in MC- patients （32.0% vs. 75.0%, P=-0.001）. Univariate Logistic regression analysis and multivariate Logistic regression analysis found that only MC （odds ratio： 6.375; 95% Ch 1.998-20.343, P=0.002） was negatively associated with sustained virological response achievement. Conclusion MC is an independent factor negatively associated with sustained virological response in chronic hepatitis C patients treated with pegylated interferon alpha-2a and ribavirin.展开更多
Background and aim:Mixed cryoglobulinemia(MC)has been associated with several viral infections,and chronic hepatitis C is recognized as a major cause.MC associated with hepatitis E virus(HEV)has been described and lit...Background and aim:Mixed cryoglobulinemia(MC)has been associated with several viral infections,and chronic hepatitis C is recognized as a major cause.MC associated with hepatitis E virus(HEV)has been described and little is known about this rare association.The aim of this study is to perform a systematic review of MC associated with HEV,and examine the presence of a causal relationship.Methods:An experienced librarian conducted a search of databases from each database’s inception to 12 December 2016 based on a priori criteria.The risk of bias was assessed,and Hill’s criteria were applied to determine causality.Results:Five publications met inclusion criteria,with a total of 15 cases.Three studies had low,one low to moderate and one moderate risk of bias.Median age was 43 years,and all patients came from Western Europe.Two patients were immunocompetent,while 13 were immunosuppressed,post solid organ transplant and had chronic hepatitis E.Renal involvement was observed in seven patients,mild to moderately severe cryoglobulinemic disease in one patient and severe cryoglobulinemic disease in three patients.One patient improved spontaneously,and another was treated with immunosuppressant reduction leading to viral clearance.Ten patients treated with peg-interferon or ribavirin for 3 months achieved loss of cryoglobulinemia and end-of-treatment response,but sustained virologic response was reported and achieved in two.Immunosuppressant achieved loss of cryoglobulinemia in three patients.One case of chronic renal failure,three cases of end-stage renal disease and one death were observed.Five of the nine Hill’s criteria were fulfilled.Conclusion:MC has been described with HEV infection.A causal relationship between HEV infection and cryoglobulinemia is highly probable.展开更多
Hepatitis C virus(HCV) infection in patients with end-stage renal disease(ESRD) is associated with more rapid liver disease progression and reduced renal graft and patients' survival following kidney transplantati...Hepatitis C virus(HCV) infection in patients with end-stage renal disease(ESRD) is associated with more rapid liver disease progression and reduced renal graft and patients' survival following kidney transplantation. Evaluations and management of HCV in patients with renal disease are challenging. The pharmacokinetics of interferons(IFN), ribavirin(RBV) and some direct acting antiviral(DAA), such as sofosbuvir, are altered in patients with ESRD. With dose adjustment and careful monitoring, treatment of HCV in patients with ESRD can be associated with sustained virological response(SVR) rates nearly comparable to that of patients with normal renal function. DAA-based regimens, especially the IFNfree and RBV-free regimens, are theoretically preferred for patients with ESRD and KT in order to increase SVR rates and to reduce treatment side effects. However, based on the data for pharmacokinetics, dosing safety and efficacy of DAA for patients with severe renal impairment are lacking. This review will be focused on the evaluations, available pharmacologic data, and management of HCV in patients with severe renal impairment, patients who underwent KT, and those who suffered from HCV-related renal disease, according to the available treatment options, including DAA.展开更多
BACKGROUND Direct-acting antiviral agents(DAAs)are extremely effective in eradicating hepatitis C virus(HCV)in chronically infected patients.However,the protective role of the sustained virologic response(SVR)achieved...BACKGROUND Direct-acting antiviral agents(DAAs)are extremely effective in eradicating hepatitis C virus(HCV)in chronically infected patients.However,the protective role of the sustained virologic response(SVR)achieved by second-and thirdgeneration DAAs against the onset of hepatocellular carcinoma(HCC)and mortality is less well established.AIM To examine the occurrence of HCC or death from any cause in a retrospectiveprospective study of patients treated with DAAs.METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy.The study was conducted in 380 patients(age:60±13 years,224 males,32%with cirrhosis)treated with DAAs with or without SVR(95/5%),with a median follow up of 58 wk(interquartile range:38-117).The baseline anthropometric features,HCV viral load,severity of liver disease,presence of extra-hepatic complications,coinfection with HIV and/or HBV,alcohol consumption,previous interferon use,alphafetoprotein levels,and renal function were considered to be confounders.RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years,respectively(incidence rate ratio:44,95%CI:15-136,P<0.001).Considering the combined endpoint of HCC or death from any cause,the hazard ratio(HR)for the SVR patients was 0.070(95%CI:0.025-0.194,P<0.001).Other independent predictors of HCC or death were low HCV viremia(HR:0.808,P=0.030),low platelet count(HR:0.910,P=0.041),and presence of mixed cryoglobulinemia(HR:3.460,P=0.044).Considering SVR in a multi-state model,the independent predictors of SVR achievement were absence of cirrhosis(HR:0.521,P<0.001)and high platelet count(HR:1.019,P=0.026).Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR(HR:5.982,P=0.028 and HR:5.633,P=0.047,respectively).CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death.A residual risk of HCC persists in patients with advanced liver disease or with complications,such as mixed cryoglobulinemia or renal failure.展开更多
The clinical course of chronic hepatitis C virus(HCV)infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several i...The clinical course of chronic hepatitis C virus(HCV)infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinicoepidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells nonHodgkin's lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCVrelated thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients' populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.展开更多
文摘The discovery of a strong association between hepatitis C virus(HCV) infection and mixed cryoglobulinemia(MC) has led to an increasingly rare diagnosis of idiopathic essential MC(EMC).The incidence of EMC is high in regions where there is a comparatively low HCV infection burden and low in areas of high infection prevalence,including HCV.The diagnosis of EMC requires an extensive laboratory investigation to exclude all possible causes of cryoglobulin formation.In addition,although cryoglobulin testing is simple,improper testing conditions will result in false negative results.Here,we present a 46-year-old female patient with a case of EMC with dermatological and renal manifestations,highlighting the importance of extensive investigation to reacha proper diagnosis.We review the need for appropriate laboratory testing,which is often neglected in clinical practice and which can result in false negative results.This review also emphasizes the significance of an extended testing repertoire necessary for better patient management.Despite a strong association of MC with HCV infection and other causes that lead to cryoglobulin formation,EMC remains a separate entity.Correct diagnosis requires proper temperature regulation during sample handling,as well as characterization and quantification of the cryoprecipitate.Inclusion of rheumatoid factor activity and complement levels in the cryoglobulin test-panel promotes better patient management and monitoring.Consensus guidelines should be developed and implemented for cryoglobulin detection and the diagnosis of cryoglobulinemic syndrome,which will reduce variability in inter-laboratory reporting.
基金Supported by Grants from the"Associazione Italiana per la Ricerca sul Cancro"Investigator Grant,No.1461‘‘Istituto Toscano Tumori’’+1 种基金"Fondazione Istituto di Ricerche Virologiche Oretta Bartolomei Corsi""Ente Cassa di Risparmio di Firenze"
文摘Mixed cryoglobulinemia(MC)is the extrahepatic manifestation most strictly correlated with hepatitis C virus(HCV)infection;it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in5%-10%of cases.MC is reputed to be a multistep and multifactorial process whose pathogenicity is still poorly understood.It is still unknown why only some chronically infected HCV patients develop MC and only some of these exhibit systemic symptoms(MC syndrome).Several studies have investigated the pathogenetic basis of MC and the most recent ones suggest that the virus is able to trigger such a disorder only in the presence of genetic factors that are still unknown.Here,we try to clarify the complex relationship between HCVrelated MC and the host’s genetic background.The data that we report are heterogeneous and sometimes even conflicting.Therefore,large,multicenter studies are clearly needed.The identification of a characteristic genetic signature of cryoglobulinemic patients would be an important step toward a personalized approach in their clinical care.The new wide-ranging genomics technologies will hopefully help to resolve these complex issues.
文摘Hepatitis C virus(HCV) infection affects about 3% of the world's population and often leads to chronic liver disease.In some industrialized countries,HCV prevalence increases with age,but the optimal management of older patients has not been accurately defined.HCV infection can also lead to lymphoproliferative disorders,the most common being mixed cryoglobulinemia(MC),and also for this condition that frequently affects elderly patients,the optimal therapeutic strategy is still debated.We report the case of a 77-year-old Caucasian woman with HCV-related chronic hepatitis and cutaneous manifestations consisting of urticaria and pruritus related to MC resistant to antihistamines.The patient underwent a treatment with interferon and ribavirin.Such a treatment led to early biochemical and virological response associated with the resolution of cryoglobulinemia and cutaneous symptoms.After the end of treatment,HCV replication relapsed,but cryoglobulinemia and cutaneous symptoms did not recur.In the absence of definite treatment guidelines in this particular context,our experience suggests that the presence of symptoms related to HCV-infection that deeply affect patient quality of life warrants antiviral therapy even beyond the age limits that currently exclude patients from treatment.
文摘AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor α (TNF-α) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).METHODS: Serum NTproBNP and TNF-α levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed signifi cantly higher mean NTproBNP and TNF-α levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (χ2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (χ2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as thepatients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (χ2, P = 0.08).CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-α in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction.
文摘Cryoglobulinemia is a pathological condition usually associated with hepatitis C virus(HCV) chronic liver disease and less commonly with autoimmune or lymphoproliferative disorders.The possible association of cryoglobulinemia with hepatitis B virus(HBV) infection is not widely accepted.In our patient,serum negativity for HCV markers initially led us to consider two other causes of cryoglobulinemia.Myelodysplastic disorders were excluded on the basis of hematological studies,while serum markers for active HBV infection were positive.Surprisingly,the detection of HCV RNA in the cryocrit,even in the absence of anti-HCV antibodies suggested a pathogenetic role of HCV in this case of cryoglobulinemia.Negative "first level" tests for HCV in the serum do not completely exclude HCV involvement in the pathogenesis of cryoglobulinemia.Analysis of the cryoprecipitate is always essential for diagnosis.
基金This study was supported by the grants from the National Major Project for Infectious Diseases Control，the National Natural Science Foundation of China，the Ph.D.Programs Foundation of Ministry of Education of China
文摘Background Mixed cryoglobulinemia （MC） is one of the most common and severe symptoms in chronic hepatitis C patients. The aim of this study was to investigate whether mixed cryoglobulinemia is a factor associated with sustained virological response in chronic hepatitis C patients treated with combination therapy of pegylated interferon alpha-2a and ribavirin. Methods This is a single-center study including 57 chronic hepatitis C patients who received combination treatments of pegylated interferon alfa-2a and ribavirin. Serum cryoglobulin was detected by cryoprecipitation prior to treatment. Serum hepatitis C virus （HCV） RNA levels were checked before treatment, during the fourth and 12th week of treatment, and during the 24th week after cessation of treatment. The genotype of HCV was determined at baseline. Logistic regression analysis was used to assess the factors associated with sustained virological response. Results Twenty-five patients were with MC （43.9%）. Twenty-four weeks after cessation of antiviral treatment, sustained virological response achievement in MC~ patients was significantly lower than that in MC- patients （32.0% vs. 75.0%, P=-0.001）. Univariate Logistic regression analysis and multivariate Logistic regression analysis found that only MC （odds ratio： 6.375; 95% Ch 1.998-20.343, P=0.002） was negatively associated with sustained virological response achievement. Conclusion MC is an independent factor negatively associated with sustained virological response in chronic hepatitis C patients treated with pegylated interferon alpha-2a and ribavirin.
文摘Background and aim:Mixed cryoglobulinemia(MC)has been associated with several viral infections,and chronic hepatitis C is recognized as a major cause.MC associated with hepatitis E virus(HEV)has been described and little is known about this rare association.The aim of this study is to perform a systematic review of MC associated with HEV,and examine the presence of a causal relationship.Methods:An experienced librarian conducted a search of databases from each database’s inception to 12 December 2016 based on a priori criteria.The risk of bias was assessed,and Hill’s criteria were applied to determine causality.Results:Five publications met inclusion criteria,with a total of 15 cases.Three studies had low,one low to moderate and one moderate risk of bias.Median age was 43 years,and all patients came from Western Europe.Two patients were immunocompetent,while 13 were immunosuppressed,post solid organ transplant and had chronic hepatitis E.Renal involvement was observed in seven patients,mild to moderately severe cryoglobulinemic disease in one patient and severe cryoglobulinemic disease in three patients.One patient improved spontaneously,and another was treated with immunosuppressant reduction leading to viral clearance.Ten patients treated with peg-interferon or ribavirin for 3 months achieved loss of cryoglobulinemia and end-of-treatment response,but sustained virologic response was reported and achieved in two.Immunosuppressant achieved loss of cryoglobulinemia in three patients.One case of chronic renal failure,three cases of end-stage renal disease and one death were observed.Five of the nine Hill’s criteria were fulfilled.Conclusion:MC has been described with HEV infection.A causal relationship between HEV infection and cryoglobulinemia is highly probable.
文摘Hepatitis C virus(HCV) infection in patients with end-stage renal disease(ESRD) is associated with more rapid liver disease progression and reduced renal graft and patients' survival following kidney transplantation. Evaluations and management of HCV in patients with renal disease are challenging. The pharmacokinetics of interferons(IFN), ribavirin(RBV) and some direct acting antiviral(DAA), such as sofosbuvir, are altered in patients with ESRD. With dose adjustment and careful monitoring, treatment of HCV in patients with ESRD can be associated with sustained virological response(SVR) rates nearly comparable to that of patients with normal renal function. DAA-based regimens, especially the IFNfree and RBV-free regimens, are theoretically preferred for patients with ESRD and KT in order to increase SVR rates and to reduce treatment side effects. However, based on the data for pharmacokinetics, dosing safety and efficacy of DAA for patients with severe renal impairment are lacking. This review will be focused on the evaluations, available pharmacologic data, and management of HCV in patients with severe renal impairment, patients who underwent KT, and those who suffered from HCV-related renal disease, according to the available treatment options, including DAA.
文摘BACKGROUND Direct-acting antiviral agents(DAAs)are extremely effective in eradicating hepatitis C virus(HCV)in chronically infected patients.However,the protective role of the sustained virologic response(SVR)achieved by second-and thirdgeneration DAAs against the onset of hepatocellular carcinoma(HCC)and mortality is less well established.AIM To examine the occurrence of HCC or death from any cause in a retrospectiveprospective study of patients treated with DAAs.METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy.The study was conducted in 380 patients(age:60±13 years,224 males,32%with cirrhosis)treated with DAAs with or without SVR(95/5%),with a median follow up of 58 wk(interquartile range:38-117).The baseline anthropometric features,HCV viral load,severity of liver disease,presence of extra-hepatic complications,coinfection with HIV and/or HBV,alcohol consumption,previous interferon use,alphafetoprotein levels,and renal function were considered to be confounders.RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years,respectively(incidence rate ratio:44,95%CI:15-136,P<0.001).Considering the combined endpoint of HCC or death from any cause,the hazard ratio(HR)for the SVR patients was 0.070(95%CI:0.025-0.194,P<0.001).Other independent predictors of HCC or death were low HCV viremia(HR:0.808,P=0.030),low platelet count(HR:0.910,P=0.041),and presence of mixed cryoglobulinemia(HR:3.460,P=0.044).Considering SVR in a multi-state model,the independent predictors of SVR achievement were absence of cirrhosis(HR:0.521,P<0.001)and high platelet count(HR:1.019,P=0.026).Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR(HR:5.982,P=0.028 and HR:5.633,P=0.047,respectively).CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death.A residual risk of HCC persists in patients with advanced liver disease or with complications,such as mixed cryoglobulinemia or renal failure.
文摘The clinical course of chronic hepatitis C virus(HCV)infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinicoepidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells nonHodgkin's lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCVrelated thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients' populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.
