Pathogenesis of drug-induced liver injury: Current understanding and future needs

Yuecheng YU; Chengwei CHEN

doi:10.3969/j.issn.1001-5256.2021.11.003

Volume 37 Issue 11

Nov. 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(11): 2515-2524

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Pathogenesis of drug-induced liver injury: Current understanding and future needs

DOI: 10.3969/j.issn.1001-5256.2021.11.003

Yuecheng YU^{1
,
,},
Chengwei CHEN²

1.
Department of Infectious Diseases and Center of Liver Diseases, General Hospital of Eastern Theater Command, Nanjing 210002, China
2.
Liver Diseases Research Center, The 905 Hospital Affiliated to Navy Medical University, Shanghai 200235, China

Received Date: 2021-09-15
Accepted Date: 2021-09-15
Published Date: 2021-11-20

Abstract

Abstract

The risk factors for drug-induced liver injury (DILI) involve host factors (including general non-genetic factors and idiosyncratic genetic and immune factors), drug-related factors, and environmental factors. The pathogenesis of DILI can be classified as intrinsic (or direct) hepatotoxicity, idiosyncratic hepatotoxicity, and indirect hepatotoxicity, as well as tumorigenicity and carcinogenicity of some drugs to the liver. The pathogenesis of different types of hepatotoxicity not only has significant differences, but also has internal correlation at multiple links. The three-step model centered on mitochondrial permeability transition (MPT) and a two-stage model with liver cell regeneration and liver tissue repair capacity as the determinants of different outcomes display the mechanism progress of DILI from different perspectives. Clarification of the complex pathogenesis of DILI needs long-term collection of clinical cases and systematic studies, which is of great significance for the scientific prevention, diagnosis, and treatment of DILI.
- Chemical and Drug-Induced Liver Injury,
- Risk Factors,
- Pathogenesis

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References

[1]	YU YC, MAO YM, CHEN CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury[J]. Hepatol Int, 2017, 11(3): 221-241. DOI: 10.1007/s12072-017-9793-2.
[2]	European Association for the Study of the Liver. EASL clinical practice guidelines: Drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261. DOI: 10.1016/j.jhep.2019.02.014.
[3]	CHALASANI NP, MADDUR H, RUSSO MW, et al. ACG Clinical Guideline: Diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2021, 116(5): 878-898. DOI: 10.14309/ajg.0000000000001259.
[4]	DEVARBHAVI H, AITHAL G, TREEPRASERTSUK S, et al. Drug-induced liver injury: Asia Pacific Association of study of liver consensus guidelines[J]. Hepatol Int, 2021, 15(2): 258-282. DOI: 10.1007/s12072-021-10144-3.
[5]	BJÖRNSSON ES, BERGMANN OM, BJÖRNSSON HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland[J]. Gastroenterology, 2013, 144(7): 1419-1425, e1-e3; quiz e19-e20. DOI: 10.1053/j.gastro.2013.02.006.
[6]	TREEM WR, PALMER M, LONJON-DOMANEC I, et al. Consensus guidelines: Best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in adults with chronic viral hepatitis and adults with cirrhosis secondary to hepatitis B, C and nonalcoholic steatohepatitis[J]. Drug Saf, 2021, 44(2): 133-165. DOI: 10.1007/s40264-020-01014-2.
[7]	LIU M, YANG XZ, YU YC. Current status of the pathogenesis, diagnosis and treatment of drug-induced cholestasis[J]. J Clin Hepatol, 2019, 35(2): 115-120. DOI: 10.3969/j.issn.1001-5256.2019.02.003. 刘梦, 杨玄子, 于乐成. 药物性胆汁淤积的发病机制及诊疗现状[J]. 临床肝胆病杂志, 2019, 35(2): 252-257. DOI: 10.3969/j.issn.1001-5256.2019.02.003.
[8]	CHEN K, GUO R, WEI C. Synonymous mutation rs2515641 affects CYP2E1 mRNA and protein expression and susceptibility to drug-induced liver injury[J]. Pharmacogenomics, 2020, 21(7): 459-470. DOI: 10.2217/pgs-2019-0151.
[9]	CHEN R, WANG J, TANG SW, et al. CYP7A1, BAAT and UGT1A1 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity[J]. Int J Tuberc Lung Dis, 2016, 20(6): 812-818. DOI: 10.5588/ijtld.15.0450.
[10]	ZHANG M, WANG S, WILFFERT B, et al. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: A systematic review and meta-analysis[J]. Br J Clin Pharmacol, 2018, 84(12): 2747-2760. DOI: 10.1111/bcp.13722.
[11]	CHANHOM N, UDOMSINPRASERT W, CHAIKLEDKAEW U, et al. GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug-induced liver injury[J]. Biomed Rep, 2020, 12(4): 153-162. DOI: 10.3892/br.2020.1275.
[12]	DALY AK, DAY CP. Genetic factors in the pathogenesis of drug-induced liver injury[M]// KAPLOWITZ N, DELEVE LD. Drug-induced liver disease, 3rd ed. San Diego: Academic Press, 2013: 215-225.
[13]	WATKINS PB, SELIGMAN PJ, PEARS JS, et al. Using controlled clinical trials to learn more about acute drug-induced liver injury[J]. Hepatology, 2008, 48(5): 1680-1689. DOI: 10.1002/hep.22633.
[14]	YANG WN, PANG LL, ZHOU JY, et al. Single-nucleotide polymorphisms of HLA and polygonum multiflorum-induced liver injury in the Han Chinese population[J]. World J Gastroenterol, 2020, 26(12): 1329-1339. DOI: 10.3748/wjg.v26.i12.1329.
[15]	YU YC, HE CL. Outcome of liver injury and liver tissue repair[J]. Chin Hepatol, 2010, 15(6): 460-464. DOI: 10.3969/j.issn.1008-1704.2010.06.023. 于乐成, 何长伦. 肝损伤转归与肝组织修复[J]. 肝脏, 2010, 15(6): 460-464. DOI: 10.3969/j.issn.1008-1704.2010.06.023.
[16]	HUI CL, LEE ZJ. Hepatic disorders associated with exogenous sex steroids: MR imaging findings[J]. Abdom Radiol (NY), 2019, 44(7): 2436-2447. DOI: 10.1007/s00261-019-01941-4.
[17]	LU ZN, LUO Q, ZHAO LN, et al. The mutational features of aristolochic acid-induced mouse and human liver cancers[J]. Hepatology, 2020, 71(3): 929-942. DOI: 10.1002/hep.30863.
[18]	HOOFNAGLE JH, BJÖRNSSON ES. Drug-induced liver injury-types and phenotypes[J]. N Engl J Med, 2019, 381(3): 264-273. DOI: 10.1056/NEJMra1816149.
[19]	ZHUGE Y, LIU Y, XIE W, et al. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome[J]. J Gastroenterol Hepatol, 2019, 34(4): 634-642. DOI: 10.1111/jgh.14612.
[20]	CHEN M, BORLAK J, TONG W. A Model to predict severity of drug-induced liver injury in humans[J]. Hepatology, 2016, 64(3): 931-940. DOI: 10.1002/hep.28678.
[21]	MEHENDALE HM. Tissue repair: An important determinant of final outcome of toxicant-induced injury[J]. Toxicol Pathol, 2005, 33(1): 41-51. DOI: 10.1080/01926230590881808.
[22]	ANAND SS, MURTHY SN, VAIDYA VS, et al. Tissue repair plays pivotal role in final outcome of liver injury following chloroform and allyl alcohol binary mixture[J]. Food Chem Toxicol, 2003, 41(8): 1123-1132. DOI: 10.1016/s0278-6915(03)00066-8.
[23]	ANAND SS, SONI MG, VAIDYA VS, et al. Extent and timeliness of tissue repair determines the dose-related hepatotoxicity of chloroform[J]. Int J Toxicol, 2003, 22(1): 25-33. DOI: 10.1080/10915810305074.
[24]	FONTANA RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives[J]. Gastroenterology, 2014, 146(4): 914-928. DOI: 10.1053/j.gastro.2013.12.032.
[25]	HOU JX, YAN FQ, YU YC. The pathogenesis, diagnosis and treatment of drug-induced liver injury with extrahepatic adverse drug reactions[J]. J Clin Hepatol, 2020, 36(3): 497-500. DOI: 10.3969/j.issn.1001-5256.2020.03.003. 侯俊兴, 严粉琴, 于乐成. 药物性肝损伤合并肝外药物不良反应的发生机制及诊疗问题[J]. 临床肝胆病杂志, 2020, 36(3): 497-500. DOI: 10.3969/j.issn.1001-5256.2020.03.003.
[26]	WANG DY, SALEM JE, COHEN JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis[J]. JAMA Oncol, 2018, 4(12): 1721-1728. DOI: 10.1001/jamaoncol.2018.3923.
[27]	POSTOW MA, SIDLOW R, HELLMANN MD. Immune-related adverse events associated with immune checkpoint blockade[J]. N Engl J Med, 2018, 378(2): 158-168. DOI: 10.1056/NEJMra1703481.
[28]	VADDEPALLY RK, KHAREL P, PANDEY R, et al. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence[J]. Cancers (Basel), 2020, 12(3): 738. DOI: 10.3390/cancers12030738.
[29]	PEERAPHATDIT TB, WANG J, ODENWALD MA, et al. Hepatotoxicity from immune checkpoint inhibitors: A systematic review and management recommendation[J]. Hepatology, 2020, 72(1): 315-329. DOI: 10.1002/hep.31227.
[30]	KOK B, LESTER E, LEE WM, et al. Acute liver failure from tumor necrosis factor-α antagonists: Report of four cases and literature review[J]. Dig Dis Sci, 2018, 63(6): 1654-1666. DOI: 10.1007/s10620-018-5023-6.
[31]	LOPETUSO LR, MOCCI G, MARZO M, et al. Harmful effects and potential benefits of anti-tumor necrosis factor (TNF)-α on the liver[J]. Int J Mol Sci, 2018, 19(8): 2199. DOI: 10.3390/ijms19082199.
[32]	ZOUBEK ME, PINAZO-BANDERA J, ORTEGA-ALONSO A, et al. Liver injury after methylprednisolone pulses: A disputable cause of hepatotoxicity. A case series and literature review[J]. United European Gastroenterol J, 2019, 7(6): 825-837. DOI: 10.1177/2050640619840147.
[33]	LOOMBA R, LIANG TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: Current concepts, management strategies, and future directions[J]. Gastroenterology, 2017, 152(6): 1297-1309. DOI: 10.1053/j.gastro.2017.02.009.
[34]	KAPILA N, AL-KHALLOUFI K, BEJARANO PA, et al. Fibrosing cholestatic hepatitis after kidney transplantation from HCV-viremic donors to HCV-negative recipients: A unique complication in the DAA era[J]. Am J Transplant, 2020, 20(2): 600-605. DOI: 10.1111/ajt.15583.
[35]	YU YC, HE CL, WANG YM. Recent progress of fibrosing cholestatic hepatitis or immunosuppression-induced liver failure[J]. Infect Dis Info, 2011, 24(3): 185-188. DOI: 10.3969/j.issn.1007-8134.2011.03.018. 于乐成, 何长伦, 王宇明. 纤维淤胆性肝炎/免疫抑制诱导性肝衰竭新进展[J]. 传染病信息, 2011, 24(3): 185-188. DOI: 10.3969/j.issn.1007-8134.2011.03.018.
[36]	RUSSMANN S, KULLAK-UBLICK GA, GRATTAGLIANO I. Current concepts of mechanisms in drug-induced hepatotoxicity[J]. Curr Med Chem, 2009, 16(23): 3041-3053. DOI: 10.2174/092986709788803097.
[37]	KRÄHENBUHL S, BRAUCHLI Y, KUMMER O, et al. Acute liver failure in two patients with regular alcohol consumption ingesting paracetamol at therapeutic dosage[J]. Digestion, 2007, 75(4): 232-237. DOI: 10.1159/000111032.
[38]	GALLUZZI L, VITALE I, AARONSON SA, et al. Molecular mechanisms of cell death: Recommendations of the nomenclature committee on cell death 2018[J]. Cell Death Differ, 2018, 25(3): 486-541. DOI: 10.1038/s41418-017-0012-4.
[39]	TANG D, KANG R, BERGHE TV, et al. The molecular machinery of regulated cell death[J]. Cell Res, 2019, 29(5): 347-364. DOI: 10.1038/s41422-019-0164-5.
[40]	COPPLE IM, GOLDRING CE, JENKINS RE, et al. The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system[J]. Hepatology, 2008, 48(4): 1292-1301. DOI: 10.1002/hep.22472.
[41]	KALGUTKAR AS, GARDNER I, OBACH RS, et al. A comprehensive listing of bioactivation pathways of organic functional groups[J]. Curr Drug Metab, 2005, 6(3): 161-225. DOI: 10.2174/1389200054021799.
[42]	SÉGUIN B, UETRECHT J. The danger hypothesis applied to idiosyncratic drug reactions[J]. Curr Opin Allergy Clin Immunol, 2003, 3(4): 235-242. DOI: 10.1097/00130832-200308000-00001.
[43]	WANG X, TOMSO DJ, CHORLEY BN, et al. Identification of polymorphic antioxidant response elements in the human genome[J]. Hum Mol Genet, 2007, 16(10): 1188-1200. DOI: 10.1093/hmg/ddm066.
[44]	GRATTAGLIANO I, LAUTERBURG BH, PORTINCASA P, et al. Mitochondrial glutathione content determines the rate of liver regeneration after partial hepatectomy in eu- and hypothyroid rats[J]. J Hepatol, 2003, 39(4): 571-579. DOI: 10.1016/s0168-8278(03)00317-9.
[45]	FAUSTO N, CAMPBELL JS, RIEHLE KJ. Liver regeneration[J]. J Hepatol, 2012, 57(3): 692-694. DOI: 10.1016/j.jhep.2012.04.016.
[46]	MALATO Y, NAQVI S, SCHVRMANN N, et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration[J]. J Clin Invest, 2011, 121(12): 4850-4860. DOI: 10.1172/JCI59261.
[47]	LIU L, YANNAM GR, NISHIKAWA T, et al. The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis[J]. Hepatology, 2012, 55(5): 1529-1539. DOI: 10.1002/hep.24815.
[48]	YU YC, HE CL, HOU JL. Biomarkers in drug-induced liver injuries[J]. J Prac Hepatol, 2014, 17(6): 564-568. DOI: 10.3969/j.issn.1672-5069.2014.06.03. 于乐成, 何长伦, 侯金林. 药物诱导性肝损伤生物标志物研究进展[J]. 实用肝脏病杂志, 2014, 17(6): 564-568. DOI: 10.3969/j.issn.1672-5069.2014.06.03.

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Pathogenesis of drug-induced liver injury: Current understanding and future needs

DOI: 10.3969/j.issn.1001-5256.2021.11.003

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