Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with antiinf...Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with antiinfectious agents, list on the top for causes of DrugInduced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the contro-versy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.展开更多
The proportion of hepatitis B virus(HBV) previously exposed patients who receive immunosuppressive treatment is usually very small. However, if these individuals are exposed to potent immunosuppressive compounds, the ...The proportion of hepatitis B virus(HBV) previously exposed patients who receive immunosuppressive treatment is usually very small. However, if these individuals are exposed to potent immunosuppressive compounds, the risk of HBV reactivation(HBVr) increases with the presence of hepatitis B surface antigen(HBsAg) in the serum. Chronic HBsAg carriers have a higher risk than those who have a total IgG anticore as the only marker of resolved/occult HBV disease. The loss of immune control in these patients may results in the reactivation of HBV replication within hepatocytes. Upon reconstitution of the immune system, infected hepatocytes are once again targeted and damaged by immune surveillance in an effort to clear the virus. There are different virological scenarios, and a wide spectrum of associated drugs with specific and stratified risk for the development of HBVr. Some of this agents can trigger a severe degree of hepatocellular damage, including hepatitis, acute liver failure, and even death despite employment of effective antiviral therapies. Currently, HBVr incidence seems to be increasing around the world; a fact mainly related to the incessant appearance of more powerful immunosuppressive drugs launched to the market. Moreover, there is no consensus on the length of prophylactic treatment before the patients are treated with immunosuppressive therapy, and for how long this therapy should be extended once treatment is completed. Therefore, this review article will focus on when to treat, when to monitor, what patients should receive HBV therapy, and what drugs should be selected for each scenario. Lastly, we will update the definition, risk factors, screening, and treatment recommendations based on both current and different HBV management guidelines.展开更多
AIM: To evaluate pre-treatment factors associated with sustained virological response(SVR) in patients with hepatitis C virus(HCV) genotype 3 treated with peginterferon and ribavirin(RBV). METHODS: We retrospectively ...AIM: To evaluate pre-treatment factors associated with sustained virological response(SVR) in patients with hepatitis C virus(HCV) genotype 3 treated with peginterferon and ribavirin(RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index,steatosis, INFL3 polymorphism, pre-treatment HCVRNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1(± 1.8) wk. Overall, 58%(62/107) of the patients achieved an SVR and 42%(45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/m L(OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis(OR = 0.278, 95%CI: 0.113-0.684,P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥600000 UI/m L and advanced fibrosis, the probability of achieving an SVR was 29%(95%CI: 13.1-45.2).In patients with pre-treatment HCV-RNA < 600000UI/m L and mild to moderate fibrosis, the probability of achieving an SVR was 81%(95%CI: 68.8-93.4).CONCLUSION: In patients with HCV genotype 3infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agentsbased regimes.展开更多
Immunological checkpoint inhibitors(ICIs)have revolutionized therapy of many different malignanices.Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin,lungs,gastrointest...Immunological checkpoint inhibitors(ICIs)have revolutionized therapy of many different malignanices.Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin,lungs,gastrointestinal and endocrine organs as well as the liver.Liver injury has been reported in 3%-8%of patients with grade III-IV hepatitis in retrospective studies.The liver injury is characterized by hepatocellular injury resembling autoimmune hepatitis biochemically but not immunologically as patients with ICI induced hepatoxicity rarely have auto-antibodies or IgG elevation.The role for liver biopsy(LB)in patients with suspected liver injury due to ICIs is controversial and it is not clear whether results of a LB will change clinical management.LB can be helpful when there is diagnostic uncertainty and pre-existing liver disease is suspected.Although there are no distinctive histological features,the finding of granulomas and endothelitis may suggest a specific type of hepatitis induced by ICIs.The natural history of hepatotoxicity of ICI therapy is not well known.Recent studies have demonstrated that 33%-50%of patients improve spontaneously with discontinuation of ICIs.In patients with jaundice and/or coagulopathy corticosteroids are used.The high doses of corticosteroids with 1-2 mg/kg/d of methylprednisolone recommended by the oncological societies are controversial.Recently it has shown that initial treatment with 1 mg/kg/d provided similar liver tests improvement which was also associated with a reduced risk of steroid-induced adverse effects in comparison with higher-dose regimens.Secondary immunosuppression mostly with mycophenolate mofetil has been reported to be helpful.展开更多
AIM:To estimate the progression of the hepatitis C virus(HCV)epidemic and measure the burden of HCVrelated morbidity and mortality.METHODS:Age-and gender-defined cohorts were used to follow the viremic population in A...AIM:To estimate the progression of the hepatitis C virus(HCV)epidemic and measure the burden of HCVrelated morbidity and mortality.METHODS:Age-and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence,prevalence,hepatic complications,and mortality.The relative impact of two scenarios on HCV-related outcomes was assessed:(1)increased sustained virologic response(SVR);and(2)increased SVR and treatment.RESULTS:Under scenario 1,SVR raised to 85%-95%in 2016.Compared to the base case scenario,there was a 0.3%reduction in prevalent cases and liverrelated deaths by 2030.Given low treatment rates,cases of hepatocellular carcinoma and decompensated cirrhosis decreased<1%,in contrast to the base case in 2030.Under scenario 2,the same increases in SVR were modeled,with gradual increases in the annual diagnosed and treated populations.This scenario decreased prevalent infections 45%,liver-related deaths 55%,liver cancer cases 60%,and decompensated cirrhosis 55%,as compared to the base case by 2030.CONCLUSION:In Argentina,cases of end stage liver disease and liver-related deaths due to HCV are still growing,while its prevalence is decreasing.Increasing in SVR rates is not enough,and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden.Based on this scenario,strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.展开更多
Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain e...Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.展开更多
Drug-induced liver injury(DILI)is a harmful reaction to medications,herbs,and dietary supplements that results in liver dysfunction.Based on the distinct clinical patterns of liver damage,DILI can be categorized into ...Drug-induced liver injury(DILI)is a harmful reaction to medications,herbs,and dietary supplements that results in liver dysfunction.Based on the distinct clinical patterns of liver damage,DILI can be categorized into hepatocellular,cholestatic,and mixed types.Hepatocellular DILI is linked to inflammation,apoptosis,and necrosis,while cholestatic DILI is commonly associated with bile plugs and,in rare cases,ductopenia.Ursodeoxycholic acid(UDCA)is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies of diverse etiologies and has been mainly used as a supportive treatment in cholestatic DILI.In this review,we presented a more structured and systematic framework for the potential application of this hepatoprotective agent across a broader range of DILI scenarios.A MEDLINE search of the literature from 1995 to the present retrieved 41 preliminary clinical studies suggesting that UDCA may offer curative and preventive benefits for hepatocellular DILI as well.This aligns with preclinical studies in rodents,showing beneficial effects of UDCA in experimental DILI irrespective of the clinical patterns of injury involved.This could be due to the broad range of potentially beneficial effects of UDCA,which may address the various types of liver damage with different causes and mechanisms seen in all forms of DILI.UDCA’s beneficial properties include anticholestatic,antioxidant,anti-inflammatory,anti-apoptotic,anti-necrotic,mitochondrial protective,endoplasmic reticulum stress-relieving,and immunomodulatory effects.Controlled studies with systematic use of standardized causality assessments are eagerly awaited to properly validate the use of UDCA in DILI.Meanwhile,we hope this article helps clarify and systematize the use of this versatile and safe hepatoprotective medication for different types of liver toxicity.展开更多
Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer,rheumatologic,autoimmune,and inflammatory diseases,and are currently being evaluated in hepatocellular...Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer,rheumatologic,autoimmune,and inflammatory diseases,and are currently being evaluated in hepatocellular carcinoma(HCC).They are classified by their mechanism of action and include tumor necrosis factor-alpha(TNF-α)antagonists,T cell mediated antitumor inhibitors,interleukin receptor antagonists,and immune checkpoint inhibitors(ICIs).Some ICIs cause frequent hepatotoxicity with a variable clinical,biochemical,and serological presentation,especially in patients receiving another immunomodulatory agent.Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal,but the others require steroid therapy.Unfortunately,there are no widely accepted recommendation for the use of corticosteroids in these patients,even though international cancer societies have their own guidelines.Differentiating drug-induced autoimmune hepatitis(DIAIH)from classic AIH is challenging for pathologists,but liver biopsy is valuable,particularly in cases with unclear clinical presentation.Interesting,novel histological patterns have been described in liver damage induced by these agents(i.e.,endothelitis,ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells).Here,we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-αantagonists and ICIs.Controversial issues involved in the administration of corticosteroid therapy,and hepatitis B virus(HBV)reactivation induced by immunosuppressive therapy are also discussed.展开更多
文摘Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with antiinfectious agents, list on the top for causes of DrugInduced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the contro-versy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.
文摘The proportion of hepatitis B virus(HBV) previously exposed patients who receive immunosuppressive treatment is usually very small. However, if these individuals are exposed to potent immunosuppressive compounds, the risk of HBV reactivation(HBVr) increases with the presence of hepatitis B surface antigen(HBsAg) in the serum. Chronic HBsAg carriers have a higher risk than those who have a total IgG anticore as the only marker of resolved/occult HBV disease. The loss of immune control in these patients may results in the reactivation of HBV replication within hepatocytes. Upon reconstitution of the immune system, infected hepatocytes are once again targeted and damaged by immune surveillance in an effort to clear the virus. There are different virological scenarios, and a wide spectrum of associated drugs with specific and stratified risk for the development of HBVr. Some of this agents can trigger a severe degree of hepatocellular damage, including hepatitis, acute liver failure, and even death despite employment of effective antiviral therapies. Currently, HBVr incidence seems to be increasing around the world; a fact mainly related to the incessant appearance of more powerful immunosuppressive drugs launched to the market. Moreover, there is no consensus on the length of prophylactic treatment before the patients are treated with immunosuppressive therapy, and for how long this therapy should be extended once treatment is completed. Therefore, this review article will focus on when to treat, when to monitor, what patients should receive HBV therapy, and what drugs should be selected for each scenario. Lastly, we will update the definition, risk factors, screening, and treatment recommendations based on both current and different HBV management guidelines.
文摘AIM: To evaluate pre-treatment factors associated with sustained virological response(SVR) in patients with hepatitis C virus(HCV) genotype 3 treated with peginterferon and ribavirin(RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index,steatosis, INFL3 polymorphism, pre-treatment HCVRNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1(± 1.8) wk. Overall, 58%(62/107) of the patients achieved an SVR and 42%(45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/m L(OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis(OR = 0.278, 95%CI: 0.113-0.684,P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥600000 UI/m L and advanced fibrosis, the probability of achieving an SVR was 29%(95%CI: 13.1-45.2).In patients with pre-treatment HCV-RNA < 600000UI/m L and mild to moderate fibrosis, the probability of achieving an SVR was 81%(95%CI: 68.8-93.4).CONCLUSION: In patients with HCV genotype 3infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agentsbased regimes.
文摘Immunological checkpoint inhibitors(ICIs)have revolutionized therapy of many different malignanices.Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin,lungs,gastrointestinal and endocrine organs as well as the liver.Liver injury has been reported in 3%-8%of patients with grade III-IV hepatitis in retrospective studies.The liver injury is characterized by hepatocellular injury resembling autoimmune hepatitis biochemically but not immunologically as patients with ICI induced hepatoxicity rarely have auto-antibodies or IgG elevation.The role for liver biopsy(LB)in patients with suspected liver injury due to ICIs is controversial and it is not clear whether results of a LB will change clinical management.LB can be helpful when there is diagnostic uncertainty and pre-existing liver disease is suspected.Although there are no distinctive histological features,the finding of granulomas and endothelitis may suggest a specific type of hepatitis induced by ICIs.The natural history of hepatotoxicity of ICI therapy is not well known.Recent studies have demonstrated that 33%-50%of patients improve spontaneously with discontinuation of ICIs.In patients with jaundice and/or coagulopathy corticosteroids are used.The high doses of corticosteroids with 1-2 mg/kg/d of methylprednisolone recommended by the oncological societies are controversial.Recently it has shown that initial treatment with 1 mg/kg/d provided similar liver tests improvement which was also associated with a reduced risk of steroid-induced adverse effects in comparison with higher-dose regimens.Secondary immunosuppression mostly with mycophenolate mofetil has been reported to be helpful.
文摘AIM:To estimate the progression of the hepatitis C virus(HCV)epidemic and measure the burden of HCVrelated morbidity and mortality.METHODS:Age-and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence,prevalence,hepatic complications,and mortality.The relative impact of two scenarios on HCV-related outcomes was assessed:(1)increased sustained virologic response(SVR);and(2)increased SVR and treatment.RESULTS:Under scenario 1,SVR raised to 85%-95%in 2016.Compared to the base case scenario,there was a 0.3%reduction in prevalent cases and liverrelated deaths by 2030.Given low treatment rates,cases of hepatocellular carcinoma and decompensated cirrhosis decreased<1%,in contrast to the base case in 2030.Under scenario 2,the same increases in SVR were modeled,with gradual increases in the annual diagnosed and treated populations.This scenario decreased prevalent infections 45%,liver-related deaths 55%,liver cancer cases 60%,and decompensated cirrhosis 55%,as compared to the base case by 2030.CONCLUSION:In Argentina,cases of end stage liver disease and liver-related deaths due to HCV are still growing,while its prevalence is decreasing.Increasing in SVR rates is not enough,and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden.Based on this scenario,strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.
文摘Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.
文摘Drug-induced liver injury(DILI)is a harmful reaction to medications,herbs,and dietary supplements that results in liver dysfunction.Based on the distinct clinical patterns of liver damage,DILI can be categorized into hepatocellular,cholestatic,and mixed types.Hepatocellular DILI is linked to inflammation,apoptosis,and necrosis,while cholestatic DILI is commonly associated with bile plugs and,in rare cases,ductopenia.Ursodeoxycholic acid(UDCA)is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies of diverse etiologies and has been mainly used as a supportive treatment in cholestatic DILI.In this review,we presented a more structured and systematic framework for the potential application of this hepatoprotective agent across a broader range of DILI scenarios.A MEDLINE search of the literature from 1995 to the present retrieved 41 preliminary clinical studies suggesting that UDCA may offer curative and preventive benefits for hepatocellular DILI as well.This aligns with preclinical studies in rodents,showing beneficial effects of UDCA in experimental DILI irrespective of the clinical patterns of injury involved.This could be due to the broad range of potentially beneficial effects of UDCA,which may address the various types of liver damage with different causes and mechanisms seen in all forms of DILI.UDCA’s beneficial properties include anticholestatic,antioxidant,anti-inflammatory,anti-apoptotic,anti-necrotic,mitochondrial protective,endoplasmic reticulum stress-relieving,and immunomodulatory effects.Controlled studies with systematic use of standardized causality assessments are eagerly awaited to properly validate the use of UDCA in DILI.Meanwhile,we hope this article helps clarify and systematize the use of this versatile and safe hepatoprotective medication for different types of liver toxicity.
文摘Novel biological agents including cytokines and recombinant fusion proteins are increasingly prescribed for cancer,rheumatologic,autoimmune,and inflammatory diseases,and are currently being evaluated in hepatocellular carcinoma(HCC).They are classified by their mechanism of action and include tumor necrosis factor-alpha(TNF-α)antagonists,T cell mediated antitumor inhibitors,interleukin receptor antagonists,and immune checkpoint inhibitors(ICIs).Some ICIs cause frequent hepatotoxicity with a variable clinical,biochemical,and serological presentation,especially in patients receiving another immunomodulatory agent.Half of the cases of liver damage induced by biological agents spontaneously regress after drug withdrawal,but the others require steroid therapy.Unfortunately,there are no widely accepted recommendation for the use of corticosteroids in these patients,even though international cancer societies have their own guidelines.Differentiating drug-induced autoimmune hepatitis(DIAIH)from classic AIH is challenging for pathologists,but liver biopsy is valuable,particularly in cases with unclear clinical presentation.Interesting,novel histological patterns have been described in liver damage induced by these agents(i.e.,endothelitis,ring granuloma and secundary sclerosing cholangitis associated with lymphocytic infiltration of cytotoxic CD8+T cells).Here,we describe the clinical and biochemical characteristics of patients with hepatotoxicity induced by TNF-αantagonists and ICIs.Controversial issues involved in the administration of corticosteroid therapy,and hepatitis B virus(HBV)reactivation induced by immunosuppressive therapy are also discussed.
