To evaluate hepatic injury induced by antituberculosis drugs(ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis(bee hive product) against ATDs induced hepatic injury. Meth...To evaluate hepatic injury induced by antituberculosis drugs(ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis(bee hive product) against ATDs induced hepatic injury. Methods: The ATDs were administered for 8 weeks as well as propolis extract at three different doses(100, 200, 400 mg/kg) conjointly for 8 weeks in rats. Silymarin(50 mg/kg) was given as positive control. Animals were euthanized after 8 weeks; blood and liver samples were collected to perform various biochemicals, serological and histopathological and ultramorphological studies. Results: Significant increase(P < 0.05) in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglyceride and cholesterol along with reduction in glucose and albumin level were noted after ATDs induced hepatic injury. Significant increase(P < 0.05) in lipid peroxidation, triglyceride, cholesterol and CYP2E1 activity; decline in reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glucose-6-phosphatase dehydrogenase activity were observed after ATDs intoxication. Due to presence of a wide range of flavonoids and polyphenols in propolis extract, its administration reduced hepatic injury and maintained biochemical indices towards control. Histopathological and electron microscopic observations indicated hepatoprotective potential of propolis at cellular level whereas, TNF-α, IL-6 and IGF-1 confirmed therapeutic potential of propolis at molecular level. Conclusions: It can be concluded that propolis possess hepatoprotective potential against ATDs induced hepatic injury that may prove itself as a clinically useful natural product in management of drug induced liver injury.展开更多
The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-gr...The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-ground mainly consisting of some risk alleles of the major histocompatibility complex(HLA).Many drugs have been linked to AIH phenotypes,which sometimes persist after drug discontinuation,suggesting that they awaken latent autoimmunity.At least three clini-cal scenarios have been proposed that refers to drug- induced autoimmune liver disease(DIAILD):AIH with drug-induced liver injury(DILI); drug induced-AIH(DI-AIH); and immune mediated DILI(IM-DILI).In addi-tion,there are instances showing mixed features of DI-AIH and IM-DILI,as well as DILI cases with positive autoantibodies.Histologically distinguishing DILI from AIH remains a challenge.Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however,a detailed standard-ised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diag-nosis between both entities.Growing information on the relationship of drugs and AIH is being available,being drugs like statins and biologic agents more fre-quently involved in cases of DIAILD.In addition,there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepa-totoxicity.Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of展开更多
Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases(IBD),both in Crohn’s disease and ulcerative colitis(UC),and therefore represent a diagnostic challenge.I...Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases(IBD),both in Crohn’s disease and ulcerative colitis(UC),and therefore represent a diagnostic challenge.Immunemediated conditions include primary sclerosing cholangitis(PSC)as the main form,variant forms of PSC(namely small-duct PSC,PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis)and granulomatous hepatitis.PSC is by far the most common,presenting in up to 8%of IBD patients,more frequently in UC.Several genetic foci have been identified,but environmental factors are preponderant on disease pathogenesis.The course of the two diseases is typically independent.PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies.Risk of cholangiocarcinoma is significantly increased in PSC,as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis.No disease-modifying drugs are approved to date.Thus,PSC management is directed against symptoms and complications and includes medical therapies for pruritus,endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease.Other nonimmune-mediated hepatobiliary disorders are gallstone disease,whose incidence is higher in IBD and reported in up to one third of IBD patients,non-alcoholic fatty liver disease,pyogenic liver abscess and portal vein thrombosis.Druginduced liver injury(DILI)is an important issue in IBD,since most IBD therapies may cause liver toxicity;however,the incidence of serious adverse events is low.Thiopurines and methotrexate are the most associated with DILI,while the risk related to anti-tumor necrosis factor-αand anti-integrins is low.Data on hepatotoxicity of newer drugs approved for IBD,like anti-interleukin 12/23 and tofacitinib,are still scarce,but the evidence from other rheumatic diseases is reassuring.Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD,and adequate screening and vaccination is warranted.On the other hand,hepatitis C reactivation does not seem to be a real risk,and hepatitis C antiviral treatment does not influence IBD natural history.The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis,but it is of paramount importance to make a quick and accurate diagnosis,as it may influence the therapeutic management.展开更多
Objective:To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia(P.daemia) against anti-tuberculosis drugs(ATDs) induced liver injury.Methods:Wistar albino rats were divided into seven groups...Objective:To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia(P.daemia) against anti-tuberculosis drugs(ATDs) induced liver injury.Methods:Wistar albino rats were divided into seven groups of six animal in each.The ATDs and P.daemia extract(100,200 and 400 mg/kg,p.o.) were conjointly administered for 8 weeks and various biochemical,histoarchitectural,ultrastructural studies were performed.Results:Administration of ATDs significantly increased aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,triglycerides,cholesterol,bilirubin and decreased glucose and albumin level.Increased lipid peroxidation and reduction in glutathione,superoxide dismutase,catalase,glutathione peroxidase,glutathione reductase and glucose-6-phosphate dehydrogenase were found after ATDs exposure.Administration of P.daemia extract maintained serum biochemical indices as well as antioxidant status similar to control and diminished oxidative stress in dose dependent manner.Histological and ultra-structural observations substantiated biochemical findings.Conclusions:P.daemia has therapeutic potential against ATDs induced liver injury and may be of clinical significance after extensive studies.展开更多
The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,dise...The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.展开更多
Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI...Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to months.Recent knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic targets.Hepatic macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental cues.In this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.展开更多
基金financially supported by UGC Major Research Project [(F42-520/2013(SR)]
文摘To evaluate hepatic injury induced by antituberculosis drugs(ATDs) when administered orally for 2, 4, 6 and 8 weeks and the therapeutic potential of propolis(bee hive product) against ATDs induced hepatic injury. Methods: The ATDs were administered for 8 weeks as well as propolis extract at three different doses(100, 200, 400 mg/kg) conjointly for 8 weeks in rats. Silymarin(50 mg/kg) was given as positive control. Animals were euthanized after 8 weeks; blood and liver samples were collected to perform various biochemicals, serological and histopathological and ultramorphological studies. Results: Significant increase(P < 0.05) in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triglyceride and cholesterol along with reduction in glucose and albumin level were noted after ATDs induced hepatic injury. Significant increase(P < 0.05) in lipid peroxidation, triglyceride, cholesterol and CYP2E1 activity; decline in reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glucose-6-phosphatase dehydrogenase activity were observed after ATDs intoxication. Due to presence of a wide range of flavonoids and polyphenols in propolis extract, its administration reduced hepatic injury and maintained biochemical indices towards control. Histopathological and electron microscopic observations indicated hepatoprotective potential of propolis at cellular level whereas, TNF-α, IL-6 and IGF-1 confirmed therapeutic potential of propolis at molecular level. Conclusions: It can be concluded that propolis possess hepatoprotective potential against ATDs induced hepatic injury that may prove itself as a clinically useful natural product in management of drug induced liver injury.
文摘The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-ground mainly consisting of some risk alleles of the major histocompatibility complex(HLA).Many drugs have been linked to AIH phenotypes,which sometimes persist after drug discontinuation,suggesting that they awaken latent autoimmunity.At least three clini-cal scenarios have been proposed that refers to drug- induced autoimmune liver disease(DIAILD):AIH with drug-induced liver injury(DILI); drug induced-AIH(DI-AIH); and immune mediated DILI(IM-DILI).In addi-tion,there are instances showing mixed features of DI-AIH and IM-DILI,as well as DILI cases with positive autoantibodies.Histologically distinguishing DILI from AIH remains a challenge.Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however,a detailed standard-ised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diag-nosis between both entities.Growing information on the relationship of drugs and AIH is being available,being drugs like statins and biologic agents more fre-quently involved in cases of DIAILD.In addition,there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepa-totoxicity.Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of
文摘Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases(IBD),both in Crohn’s disease and ulcerative colitis(UC),and therefore represent a diagnostic challenge.Immunemediated conditions include primary sclerosing cholangitis(PSC)as the main form,variant forms of PSC(namely small-duct PSC,PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis)and granulomatous hepatitis.PSC is by far the most common,presenting in up to 8%of IBD patients,more frequently in UC.Several genetic foci have been identified,but environmental factors are preponderant on disease pathogenesis.The course of the two diseases is typically independent.PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies.Risk of cholangiocarcinoma is significantly increased in PSC,as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis.No disease-modifying drugs are approved to date.Thus,PSC management is directed against symptoms and complications and includes medical therapies for pruritus,endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease.Other nonimmune-mediated hepatobiliary disorders are gallstone disease,whose incidence is higher in IBD and reported in up to one third of IBD patients,non-alcoholic fatty liver disease,pyogenic liver abscess and portal vein thrombosis.Druginduced liver injury(DILI)is an important issue in IBD,since most IBD therapies may cause liver toxicity;however,the incidence of serious adverse events is low.Thiopurines and methotrexate are the most associated with DILI,while the risk related to anti-tumor necrosis factor-αand anti-integrins is low.Data on hepatotoxicity of newer drugs approved for IBD,like anti-interleukin 12/23 and tofacitinib,are still scarce,but the evidence from other rheumatic diseases is reassuring.Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD,and adequate screening and vaccination is warranted.On the other hand,hepatitis C reactivation does not seem to be a real risk,and hepatitis C antiviral treatment does not influence IBD natural history.The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis,but it is of paramount importance to make a quick and accurate diagnosis,as it may influence the therapeutic management.
基金Financial assistance from University Grants Commission,New Delhi(UGC-MRP,F.42-520/2013 SR)Guru Ghasidas University,Bilaspur for providing laboratory facility
文摘Objective:To evaluate therapeutic potential of hydroethanolic extract of Pergularia daemia(P.daemia) against anti-tuberculosis drugs(ATDs) induced liver injury.Methods:Wistar albino rats were divided into seven groups of six animal in each.The ATDs and P.daemia extract(100,200 and 400 mg/kg,p.o.) were conjointly administered for 8 weeks and various biochemical,histoarchitectural,ultrastructural studies were performed.Results:Administration of ATDs significantly increased aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,triglycerides,cholesterol,bilirubin and decreased glucose and albumin level.Increased lipid peroxidation and reduction in glutathione,superoxide dismutase,catalase,glutathione peroxidase,glutathione reductase and glucose-6-phosphate dehydrogenase were found after ATDs exposure.Administration of P.daemia extract maintained serum biochemical indices as well as antioxidant status similar to control and diminished oxidative stress in dose dependent manner.Histological and ultra-structural observations substantiated biochemical findings.Conclusions:P.daemia has therapeutic potential against ATDs induced liver injury and may be of clinical significance after extensive studies.
文摘The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.
基金supported by USA National Institutes of Health(NIH)funds R01DK109574 and R01DK122708(C.Ju).
文摘Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to months.Recent knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic targets.Hepatic macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental cues.In this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.
