药物性肝损伤的潜在机制、病理特点及生物标志物
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摘要
药物性肝损伤(DILI)是急性肝衰竭、黑盒子警告以及药物撤市的主要原因之一,也是公共卫生、医药研发以及制药行业关注的主要问题。但因缺乏特异性诊断标志物使DILI的诊断成为临床医生的一大挑战。总结了DILI研究的最新进展,包括潜在机制、病理特点、生物标志物以及体外研究方法等,希望为DILI的临床及病理诊断和判断预后等提供参考。
Drug-induced liver injury( DILI) is one of the main causes of acute liver failure,black box warnings,and drug withdrawal from the market,and it is also a major concern in public health,drug research and development,and the pharmaceutical industry. However,a lack of specific diagnostic markers for DILI makes the diagnosis of this disease a major challenge for clinicians. This article summarizes the recent advances in DILI research,including potential mechanisms,pathological features,biomarkers,and in vitro methods,in order to provide a reference for clinical and pathological diagnosis and prognostic evaluation of DILI.
Drug-induced liver injury( DILI) is one of the main causes of acute liver failure,black box warnings,and drug withdrawal from the market,and it is also a major concern in public health,drug research and development,and the pharmaceutical industry. However,a lack of specific diagnostic markers for DILI makes the diagnosis of this disease a major challenge for clinicians. This article summarizes the recent advances in DILI research,including potential mechanisms,pathological features,biomarkers,and in vitro methods,in order to provide a reference for clinical and pathological diagnosis and prognostic evaluation of DILI.
引文
[1]SGRO C,CLINARD F,OUAZIR K,et al.Incidence of druginduced hepatic injuries:A French populationbased study[J].Hepatology,2002,36(2):451-455.
[2]BJORNSSON ES,BERGMANN OM,BJORNSSON HK,et al.Incidence,presentation,and outcomes in patients with druginduced liver injury in the general population of Iceland[J].Gastroenterology,2013,144(7):1419-1425.
[3]KIM KA.Current status of liver diseases in Korea:Toxic and alcoholic liver diseases[J].Korean J Hepatol,2009,15(6):s29-s33.
[4]de ABAJO FJ,MONTERO D,MADURGA M,et al.Acute and clinically relevant drug-induced liver injury:A population based case-control study[J].Br J Clin Pharmacol,2004,58(1):71-80.
[5]RUIGO'MEZ A,BRAUER R,RODRI'GUEZ LA,et al.Ascertainment of acute liver injury in two European primary care databases[J].Eur J Clin Pharmacol,2014,70(10):1227-1235.
[6]ORTEGAALONSO A,ANDRADE RJ.Chronic liver injury induced by drugs and toxins[J].J Dig Dis,2018,19(9):514-521.
[7]HILLMAN L,GOTTFRIED M,WHITSETT M,et al.Clinical features and outcomes of complementary and alternative medicine induced acute liver failure and injury[J].Am J Gastroenterol,2016,111(7):958-965.
[8]SINGH D,CHO WC,UPADHYAY G.Drug-induced liver toxicity and prevention by herbal antioxidants:An overview[J].Front Physiol,2016,6:363.
[9]WATKINS PB,KAPLOWITZ N,SLATTERY JT,et al.Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily:A randomized controlled trial[J].JA-MA,2006,296(1):87-93.
[10]KULLAKUBLICK GA,ANDRADE RJ,MERZ M,et al.Druginduced liver injury:Recent advances in diagnosis and risk assessment[J].Gut,2017,66(6):1154-1164.
[11]KIM SH,NAISBITT DJ.Update on advances in research on idiosyncratic drug-induced liver injury[J].Allergy Asthma Immunol Res,2016,8(1):3-11.
[12]CORSINI A,BORTOLINI M.Drug-induced liver injury:The role of drug metabolism and transport[J].J Clin Pharmacol,2013,53(5):463-474.
[13]ROTH AD,LEE MY.Idiosyncratic drug-induced liver injury(IDILI):Potential mechanisms and predictive assays[J].Biomed Res Int,2017,2017(1):1-23.
[14]UTKARSH D,LORETZ C,LI AP.In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors:Identification of P450 activity as a potential risk factor for drug-induced liver injuries[J].Chem Biol Interact,2016,255:12-22.
[15]TAN XQ,YANG GQ,ZHANG L,et al.Research progress on CYP2E1 mediating toxicity by exogenous chemicals[J].China Occup Med,2016,43(2):234-236.(in Chinese)谭孝琼,杨光谦,张林,等.细胞色素P450 2E1介导外源性化合物毒性损伤研究进展[J].中国职业医学,2016,43(2):234-236.
[16]MACKAY RJ,MCENTYRE CJ,HENDERSON C,et al.Trimethylaminuria:Causes and diagnosis of a socially distressing condition[J].Clin Biochem Rev,2011,32(1):33-34.
[17]MARQUES SC,IKEDIOBI ON.The clinical application of UGT1A1pharmacogenetic testing:Gene-environment interactions[J].Hum Genomics,2010,4(4):238-249.
[18]CRETTOL S,PETROVIC N,MURRAY M.Pharmacogenetics of phase I and phase II drug metabolism[J].Curr Pharm Des,2010,16(2):204-219.
[19]KALIYAPERUMAL K,GROVE JI,DELAHAY RM,et al.Pharmacogenomics of drug-induced liver injury(DILI):Molecular biology to clinical applications[J].J Hepatol,2018,69(4):948-957.
[20]GMEZLECHN MJ,TOLOSA L,DONATO MT.Metabolic activation and drug-induced liver injury:In vitro approaches for the safety risk assessment of new drugs[J].J Appl Toxicol,2016,36(6):752-768.
[21]BHARATHI V,RENGARAJAN RL,RADHAKRISHNAN R,et al.Effects of a medicinal plant Macrotyloma uniflorum,(Lam.)Verdc.formulation(MUF)on obesity-associated oxidative stress-induced liver injury[J].Saudi J Biol Sci,2018,25(6):1115-1121.
[22]AYALA A,MUOZ MF,ARGELLES S.Lipid peroxidation:Production,metabolism,and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J].Oxid Med Cell Longev,2014,2014(6):1-31.
[23]SHEHU AI,MA X,VENKATARAMANAN R.Mechanisms of drug-induced hepatotoxicity[J].Clin Liver Dis,2017,21(1):35-54.
[24]MASUBUCHI Y,SUDA C,HORIE T.Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice[J].J Hepatol,2005,42(1):110-116.
[25]ALEO MD,LUO Y,SWISS R,et al.Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump[J].Hepatology,2014,60(3):1015-1022.
[26]MOSEDALE M,WATKINS PB.Drug-induced liver injury:Advances in mechanistic understanding that will inform risk management[J].Clin Pharmacol Ther,2017,101(4):469-480.
[27]DARA L,LIU ZX,KAPLOWITZ N.Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury,clinical implications[J].Liver Int,2016,36(2):158-165.
[28]KLEINER DE,CHALASANI NP,LEE WM,et al.Hepatic histological findings in suspected drug-induced liver injury:Systematic evaluation and clinical associations[J].Hepatology,2014,59(2):661-670.
[29]KLEINER DE.The histopathological evaluation of drug-induced liver injury[J].Histopathology,2017,70(1):81-93.
[30]YANG RY,ZHAO XY.Significance of liver histopathological examination in diagnosis and treatment of drug-induced liver injury[J].J Clin Hepatol,2018,34(6):1172-1175.(in Chinese)杨瑞园,赵新颜.肝组织病理学检查在药物性肝损伤诊治中的意义[J].临床肝胆病杂志,2018,34(6):1172-1175.
[31]KHOURY T,RMEILEH AA,YOSHA L,et al.Drug induced liver injury:Review with a focus on genetic factors,tissue diagnosis,and treatment options[J].J Clin Transl Hepatol,2015,3(2):99-108.
[32]LAWAL A,ZHANG M,DITTMAR M,et al.Heme oxygenase-1protects endothelial cells from the toxicity of air pollutant chemicals[J].Toxicol Appl Pharmacol,2015,284(3):281-291.
[33]BAKHAUTDIN B,DAS D,MANDAL P,et al.Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice[J].J Hepatol,2014,61(5):1029-1037.
[34]GAO Y,CAO Z,YANG X,et al.Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury[J].Proteomics Clin Appl,2017,11(1-2).
[35]CHURCH RJ,KULLAK-UBLICK GA,AUBRECHT J,et al.Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury:An international collaborative effort[J].Hepatology,2019,69(2):760-773.
[36]ROBLES-DAZ M,MEDINA-CALIZ I,STEPHENS C,et al.Biomarkers in DILI:One more step forward[J].Front Pharmacol,2016,7:267.
[37]LIU XQ,WU WX,GENG XC,et al.Research progress of biomarkers of druginduced liver injury[J].Chin J New Drugs,2018,27(1):47-52.(in Chinese)刘小茜,吴文晓,耿兴超,等.药物性肝损伤生物标志物研究进展[J].中国新药杂志,2018,27(1):47-52.
[38]CHO YE,SONG BJ,AKBAR M,et al.Extracellular vesicles as potential biomarkers for alcohol-and drug-induced liver injury and their therapeutic applications[J].Pharmacol Ther,2018,187:180-194.
[39]BENESIC A,ROTTER I,DRAGOI D,et al.Development and validation of a test to identify drugs that cause idiosyncratic drug-induced liver injury[J].Clin Gastroenterol Hepatol,2018,16(9):1488-1494.e5.
[2]BJORNSSON ES,BERGMANN OM,BJORNSSON HK,et al.Incidence,presentation,and outcomes in patients with druginduced liver injury in the general population of Iceland[J].Gastroenterology,2013,144(7):1419-1425.
[3]KIM KA.Current status of liver diseases in Korea:Toxic and alcoholic liver diseases[J].Korean J Hepatol,2009,15(6):s29-s33.
[4]de ABAJO FJ,MONTERO D,MADURGA M,et al.Acute and clinically relevant drug-induced liver injury:A population based case-control study[J].Br J Clin Pharmacol,2004,58(1):71-80.
[5]RUIGO'MEZ A,BRAUER R,RODRI'GUEZ LA,et al.Ascertainment of acute liver injury in two European primary care databases[J].Eur J Clin Pharmacol,2014,70(10):1227-1235.
[6]ORTEGAALONSO A,ANDRADE RJ.Chronic liver injury induced by drugs and toxins[J].J Dig Dis,2018,19(9):514-521.
[7]HILLMAN L,GOTTFRIED M,WHITSETT M,et al.Clinical features and outcomes of complementary and alternative medicine induced acute liver failure and injury[J].Am J Gastroenterol,2016,111(7):958-965.
[8]SINGH D,CHO WC,UPADHYAY G.Drug-induced liver toxicity and prevention by herbal antioxidants:An overview[J].Front Physiol,2016,6:363.
[9]WATKINS PB,KAPLOWITZ N,SLATTERY JT,et al.Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily:A randomized controlled trial[J].JA-MA,2006,296(1):87-93.
[10]KULLAKUBLICK GA,ANDRADE RJ,MERZ M,et al.Druginduced liver injury:Recent advances in diagnosis and risk assessment[J].Gut,2017,66(6):1154-1164.
[11]KIM SH,NAISBITT DJ.Update on advances in research on idiosyncratic drug-induced liver injury[J].Allergy Asthma Immunol Res,2016,8(1):3-11.
[12]CORSINI A,BORTOLINI M.Drug-induced liver injury:The role of drug metabolism and transport[J].J Clin Pharmacol,2013,53(5):463-474.
[13]ROTH AD,LEE MY.Idiosyncratic drug-induced liver injury(IDILI):Potential mechanisms and predictive assays[J].Biomed Res Int,2017,2017(1):1-23.
[14]UTKARSH D,LORETZ C,LI AP.In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors:Identification of P450 activity as a potential risk factor for drug-induced liver injuries[J].Chem Biol Interact,2016,255:12-22.
[15]TAN XQ,YANG GQ,ZHANG L,et al.Research progress on CYP2E1 mediating toxicity by exogenous chemicals[J].China Occup Med,2016,43(2):234-236.(in Chinese)谭孝琼,杨光谦,张林,等.细胞色素P450 2E1介导外源性化合物毒性损伤研究进展[J].中国职业医学,2016,43(2):234-236.
[16]MACKAY RJ,MCENTYRE CJ,HENDERSON C,et al.Trimethylaminuria:Causes and diagnosis of a socially distressing condition[J].Clin Biochem Rev,2011,32(1):33-34.
[17]MARQUES SC,IKEDIOBI ON.The clinical application of UGT1A1pharmacogenetic testing:Gene-environment interactions[J].Hum Genomics,2010,4(4):238-249.
[18]CRETTOL S,PETROVIC N,MURRAY M.Pharmacogenetics of phase I and phase II drug metabolism[J].Curr Pharm Des,2010,16(2):204-219.
[19]KALIYAPERUMAL K,GROVE JI,DELAHAY RM,et al.Pharmacogenomics of drug-induced liver injury(DILI):Molecular biology to clinical applications[J].J Hepatol,2018,69(4):948-957.
[20]GMEZLECHN MJ,TOLOSA L,DONATO MT.Metabolic activation and drug-induced liver injury:In vitro approaches for the safety risk assessment of new drugs[J].J Appl Toxicol,2016,36(6):752-768.
[21]BHARATHI V,RENGARAJAN RL,RADHAKRISHNAN R,et al.Effects of a medicinal plant Macrotyloma uniflorum,(Lam.)Verdc.formulation(MUF)on obesity-associated oxidative stress-induced liver injury[J].Saudi J Biol Sci,2018,25(6):1115-1121.
[22]AYALA A,MUOZ MF,ARGELLES S.Lipid peroxidation:Production,metabolism,and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J].Oxid Med Cell Longev,2014,2014(6):1-31.
[23]SHEHU AI,MA X,VENKATARAMANAN R.Mechanisms of drug-induced hepatotoxicity[J].Clin Liver Dis,2017,21(1):35-54.
[24]MASUBUCHI Y,SUDA C,HORIE T.Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice[J].J Hepatol,2005,42(1):110-116.
[25]ALEO MD,LUO Y,SWISS R,et al.Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump[J].Hepatology,2014,60(3):1015-1022.
[26]MOSEDALE M,WATKINS PB.Drug-induced liver injury:Advances in mechanistic understanding that will inform risk management[J].Clin Pharmacol Ther,2017,101(4):469-480.
[27]DARA L,LIU ZX,KAPLOWITZ N.Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury,clinical implications[J].Liver Int,2016,36(2):158-165.
[28]KLEINER DE,CHALASANI NP,LEE WM,et al.Hepatic histological findings in suspected drug-induced liver injury:Systematic evaluation and clinical associations[J].Hepatology,2014,59(2):661-670.
[29]KLEINER DE.The histopathological evaluation of drug-induced liver injury[J].Histopathology,2017,70(1):81-93.
[30]YANG RY,ZHAO XY.Significance of liver histopathological examination in diagnosis and treatment of drug-induced liver injury[J].J Clin Hepatol,2018,34(6):1172-1175.(in Chinese)杨瑞园,赵新颜.肝组织病理学检查在药物性肝损伤诊治中的意义[J].临床肝胆病杂志,2018,34(6):1172-1175.
[31]KHOURY T,RMEILEH AA,YOSHA L,et al.Drug induced liver injury:Review with a focus on genetic factors,tissue diagnosis,and treatment options[J].J Clin Transl Hepatol,2015,3(2):99-108.
[32]LAWAL A,ZHANG M,DITTMAR M,et al.Heme oxygenase-1protects endothelial cells from the toxicity of air pollutant chemicals[J].Toxicol Appl Pharmacol,2015,284(3):281-291.
[33]BAKHAUTDIN B,DAS D,MANDAL P,et al.Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice[J].J Hepatol,2014,61(5):1029-1037.
[34]GAO Y,CAO Z,YANG X,et al.Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury[J].Proteomics Clin Appl,2017,11(1-2).
[35]CHURCH RJ,KULLAK-UBLICK GA,AUBRECHT J,et al.Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury:An international collaborative effort[J].Hepatology,2019,69(2):760-773.
[36]ROBLES-DAZ M,MEDINA-CALIZ I,STEPHENS C,et al.Biomarkers in DILI:One more step forward[J].Front Pharmacol,2016,7:267.
[37]LIU XQ,WU WX,GENG XC,et al.Research progress of biomarkers of druginduced liver injury[J].Chin J New Drugs,2018,27(1):47-52.(in Chinese)刘小茜,吴文晓,耿兴超,等.药物性肝损伤生物标志物研究进展[J].中国新药杂志,2018,27(1):47-52.
[38]CHO YE,SONG BJ,AKBAR M,et al.Extracellular vesicles as potential biomarkers for alcohol-and drug-induced liver injury and their therapeutic applications[J].Pharmacol Ther,2018,187:180-194.
[39]BENESIC A,ROTTER I,DRAGOI D,et al.Development and validation of a test to identify drugs that cause idiosyncratic drug-induced liver injury[J].Clin Gastroenterol Hepatol,2018,16(9):1488-1494.e5.