Intrahepatic cholestasis due to drug-induced liver injury (DILI)

1、Proprietary and confidential do not distribute INTERNAL USE ONLY Intrahepatic cholestasis due to drug-induced liver injury (DILI)TRAININGProprietary and confidential do not distribute- INTERNAL USE ONLY December 22, 20212ABBREVIATIONSTermDefinitionGT-glutamyl transpeptidaseA1ATAlpha1-antitrypsinALDA

2、lcoholic liver diseaseALFAcute liver failure ALPAlkaline phosphatase ALTAlanine aminotransferase ASTAspartate aminotransferase CANMATCanadian Network for Mood and Anxiety TreatmentCHCChronic hepatitis CCLDChronic liver diseaseCNSCentral nervous systemCRCColorectal cancerCTComputed tomography CTLA-4c

3、ytotoxic T-lymphocyte-associated antigen 4DILIDrug-induced liver injuryDNADeoxyribonucleic acidEASLEuropean Association for the Study of the LiverEREndoplasmic reticulumFISFatigue impact scoreGGTGamma-glutamyltransferaseGSHGlutathioneHADSHospital Anxiety and Depression ScaleHDSHerbals and dietary su

4、pplementsHLAHuman leukocyte antigenHRQoLHealth-related quality of lifeHRSD21-item Hamilton Rating Scale for DepressionIBDInflammatory bowel disease TermDefinitionIHCIntrahepatic cholestasisiDILIIdiosyncratic drug-induced liver injuryIRAEsImmune-related adverse events LDHLactate dehydrogenasemCRCMeta

5、static colorectal cancerMRCPMagnetic resonance cholangiopancreatographyMDDMajor depressive disorderMRIMagnetic resonance imagingMTAMethylthioadenosineNACN-AcetylcysteineNCI-CTCAENational Cancer Institute Common Terminology Criteria for Adverse EventsNSAIDNonsteroidal anti-inflammatory drug(s)PBCPrim

6、ary biliary cholangitisPGI-S7-point Patient Global Impression Severity ScalePD-1Programmed cell death proteinPD-L1Programmed cell death protein ligandRRatioRARheumatoid arthritisRCTRandomized controlled trialROSReactive oxygen speciesTIBCTotal iron-binding capacityTKITyrosine kinase inhibitorTNFTumo

7、r necrosis factorUDCAUrsodeoxycholic acidUKUnited KingdomULNUpper limit of normalUSUnited StatesProprietary and confidential do not distribute -INTERNAL USE ONLYCONTENTSDecember 22, 20213SlideA. IntroductionDefinitionsEpidemiologyB. PathophysiologyC. Diagnosis & managementD. AdemetionineMechanis

8、m of actionClinical efficacyE. ConclusionsProprietary and confidential do not distribute INTERNAL USE ONLY A: IntroductionDecember 22, 20214Proprietary and confidential do not distribute INTERNAL USE ONLY Definitions & epidemiologyDILIDecember 22, 20215Proprietary and confidential do not distrib

9、ute -INTERNAL USE ONLYCHOLESTASISDefinition:1,2An arrest or impedance in the flow of bileNot a disease or disorder in itselfNot due to a single disease or conditionCommon sign seen in many liver and biliary disordersAcute or chronic (6 months)December 22, 202161. Elias E. Chapter 11 Jaundice and Cho

10、lestasis. In Sherlocks Diseases of the Liver and Biliary System. 12th Edition. Willey-Blackwell. 2011. 2. EASL Clinical Practice Guidelines. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51(2):237267.Proprietary and confidential do not distribute -INTER

11、NAL USE ONLYINTRAHEPATIC VS EXTRAHEPATIC CHOLESTASISCholestasis classification:1,2Intrahepatic or extrahepatic depending at which level the bile flow is impededDecember 22, 202171. Elias E. Chapter 11 Jaundice and Cholestasis. In Sherlocks Diseases of the Liver and Biliary System. 12th Edition. Will

12、ey-Blackwell. 2011. 2. EASL Clinical Practice Guidelines. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51(2):237267.CholestasisExtrahepatic cholestasis(EHC)Intrahepatic cholestasis(IHC)Obstruction is outside the liver, i.e. stone, cancer or benign bile

13、 duct stricturesDilated intrahepatic bile ductsObstruction is inside the liver, usually at the hepatocellular levelAbsence of dilated ducts in jaundiced patients with serum bilirubin 10 mg/dLProprietary and confidential do not distribute -INTERNAL USE ONLYINTRAHEPATIC VS EXTRAHEPATIC CHOLESTASISIntr

14、ahepatic cholestasis:1,2December 22, 202181. Elias E. Chapter 11 Jaundice and Cholestasis. In Sherlocks Diseases of the Liver and Biliary System. 12th Edition. Willey-Blackwell. 2011. 2. EASL Clinical Practice Guidelines. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J

15、 Hepatol 2009; 51(2):237267.Intrahepatic cholestasis (IHC)Hepatocellular IHCCholangiocellular IHC Alcoholic fatty liver disease (ALD) Non-alcoholic fatty liver disease (NAFLD) Viral hepatitis (VH) Drug-induced cholestasis (DILI) Progressive familial IHC Critical illness-associated (ischemic) IHC IHC

16、 with total parenteral nutrition Drug-induced cholestasis (DILI) Intrahepatic cholestasis of pregnancy Primary biliary cirrhosis Primary sclerosing cholangitis Secondary sclerosing cholangitis IgG4-associated cholangitis Cystic fibrosis-associated liver diseaseProprietary and confidential do not dis

17、tribute -INTERNAL USE ONLYDILI: DRUG-INDUCED LIVER INJURYDILI is defined as a liver injury or disease due to medications, herbs, or other toxic substances1Two main types of DILI are observed:1About 1000 drugs compounds are estimated to be associated with iDILI, with central nervous system (CNS) agen

18、ts and antibiotics being the most common medications that cause DILI2Diagnosis can be a clinical challenge as DILI may imitate any form of liver disease1DILI has significant negative impact on medical prescribing attitudes3Hepatotoxicity is the most commonly reported adverse drug reaction leading to

19、 drug withdrawal worldwide (81 cases; 18%)December 22, 202191. Gayam V, Khalid M, Shrestha B et al. Drug-Induced Liver Injury: An Institutional Case Series and Review of Literature. J Investig Med High Impact Case Rep. 2018;6:2324709618761754. 2. Kuna L, Bozic I, Kizivat T, et al. Models of Drug Ind

20、uced Liver Injury (DILI) - Current Issues and Future Perspectives. Curr Drug Metab. 2018 May 22. doi: 10.2174/1389200219666180523095355. Epub ahead of print. 3. Raschi E, De Ponti F. Drug-induced liver injury: Towards early prediction and risk stratification. World J Hepatol. 2017;9(1):30-37.Intrins

21、ic DILIIdiosyncratic DILI (iDILI)Potentially affect all individualsAffect rare susceptible individualsPredictable, stereotypical, dose-dependentUnpredictable, varied, not dose-dependentProprietary and confidential do not distribute -INTERNAL USE ONLYEPIDEMIOLOGY OF DILILimited data on DILI epidemiol

22、ogy are available:1The real incidence and prevalence of DILI are underestimated and the pharmacovigilance chain may be unsuccessful as cases are largely underreported1Population studies show an annual (%) incidence of:1,2DILI is the most common cause of acute liver failure in the US3Approximately 2,

23、000 cases of acute liver failure annually with drugs accounting for 50% of them4Identification of at-risk patients for a potential DILI may be beneficial, as early intervention may improve patient outcomes3December 22, 2021101. Licata A, Minissale MG, Calvaruso V, et al. A focus on epidemiology of d

24、rug-induced liver injury: analysis of a prospective cohort. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):112-121. 2. Ye H, Nelson LJ, Gmez Del Moral M, et al. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol. 2018;24(13):1373-1385. 3. Gayam V, Khalid M, Shr

25、estha B et al. Drug-Induced Liver Injury: An Institutional Case Series and Review of Literature. J Investig Med High Impact Case Rep. 2018;6:2324709618761754. 4. Mehta N. Drug-Induced Hepatotoxicity. Medscape ONLINE; cited 2016. URL: https:/ Accessed June 2018.FranceIcelandItalySouth KoreaSpainUKUSS

26、weden0.1390.1910.0410.120.030.007 0.0130.10 1.500.023Proprietary and confidential do not distribute INTERNAL USE ONLY B: PathophysiologyDecember 22, 202111Proprietary and confidential do not distribute -INTERNAL USE ONLYCOMPLEX PATHOLOGY IN DILIDILI etiopathogenesis is complex and involves genetic,

27、metabolic, immune and environmental factors1The main event in the pathogenesis of DILI is death of hepatocytes, although cholangiocytes or endothelial cells could also be potential targets1DILI can be divided into three steps: An initial insulting stimulation causes mitochondrial dysfunction leading

28、 to cell death2DILI can be further characterized as immune-mediated versus nonimmune-mediated or non-allergic:3Immune-mediated (allergic) DILI is likely generated by antigen recognition-mediated by helper T cells, suggesting the influence of the adaptive immune response1In non-allergic DILI, drugs i

29、nduce hepatotoxicity by reactive metabolites gradually accumulate in hepatocytes, which could cause mitochondrial impairment1December 22, 2021121. Kuna L, Bozic I, Kizivat T, et al. Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives. Curr Drug Metab. 2018 May 22. doi

30、: 10.2174/1389200219666180523095355. Epub ahead of print. 2. Ye H, Nelson LJ, Gmez Del Moral M, et al. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol. 2018;24(13):1373-1385. 3. Gonzalez HC, Jafri SM, Gordon SC. Management of acute hepatotoxicity includin

31、g medical agents and liver support.Systems. Clin Liver Dis. 2017;21(1):163-180.Proprietary and confidential do not distribute -INTERNAL USE ONLYMODELS OF DILI PATHOLOGYAlgorithm of liver damage in allergic and non-allergic DILI models1December 22, 2021131. Kuna L, Bozic I, Kizivat T, et al. Models o

32、f Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives. Curr Drug Metab. 2018 May 22. doi: 10.2174/1389200219666180523095355. Epub ahead of print.Immune mediated DILI (allergic)Non-allergic DILIHelper T cellsAntigen recognitionAccumulation of drugs/reactive metabolites in hepato

33、cytesKey cytokinesInvolvement of adaptive immune systemCause of mitochondrial damage Endoplasmic reticulum stress Generation of reactive oxygen speciesProprietary and confidential do not distribute -INTERNAL USE ONLYDRUGS MOST COMMONLY INVOLVED AS CAUSES OF DILI IN A PROSPECTIVE COHORTNonsteroidal a

34、nti-inflammatory drugs (NSAIDs) are typically most commonly implicated in DILI1December 22, 2021141. Licata A, Minissale MG, Calvaruso V, et al. A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):112-121. 2. Vincenzi B,

35、 Armento G, Spalato Ceruso M, et al. Drug-induced hepatotoxicity in cancer patients - implication for treatment. Expert Opin Drug Saf. 2016;15(9):1219-38.DILI chronic evolution:1Antibiotics, NSAIDs, immunosuppressant frequently responsible for chronicityStatins, anti-psychiatric and anti-platelets d

36、rugs not responsible for chronicityMost antitumor drugs can cause idiosyncratic liver injury2Proprietary and confidential do not distribute -INTERNAL USE ONLYDILI CLINICAL CONSORTIA: A GLOBAL RESEARCH RESPONSE FOR A WORLDWIDE HEALTH CHALLENGETherapeutic group of drugs implicated in DILI across prosp

37、ective registries1December 22, 2021151. Andrade RJ, Ortega-Alonso A, Lucena MI. Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge. Expert Opin Drug Metab Toxicol. 2016;12(6):589-93.DILI Consortia:Spanish DILISpanish Latin American DILIIcelandDI

38、LI NetworkYears19942015201220152010201120042013Type of registryNational (43 centers)Multinational (10 countries)Population-based studyNational (5 centers)DILI casesMost frequent drug classes n (%)906aAnti-infectives 333 (37)Nervous system 131 (14)Cardiovascular system 98 (11)Musculo-skeletal system

39、97 (11)Anti-neoplastic drugs 69 (8)200Anti-infectives 48 (24)Musculo-skeletal system 36 (18)Genito urinary system and sex hormones 18 (9)Nervous system 18 (9)96Antibiotics 36 (37)Dietary supplements 15 (16)Immunosuppressant drugs 10 (10)Psychotropic 7 (7)NSAIDs 6 (6)899Antimicrobials 408 (45)Cardiov

40、ascular drugs 88 (10)CNS agents 82 (9)Anti-neoplastic drugs 49 (5)HDS, n (%)51 (6)19 (10)15 (16)145 (16)aThe actual number of patients was 867 but in 39 patients there were 2 DILI incidents.Antiinfectives refers to antibiotics, antituberculosis drugs, antifungals and antivirals.HDS: herbals and diet

41、ary supplements.Proprietary and confidential do not distribute -INTERNAL USE ONLYPATTERN OF INJURYDecember 22, 202116Many drugs create a pattern of injury that has characteristic biochemical, clinical, histologic, and chronologic features, or a combination1Three categories of DILI based on biochemic

42、al injury patterns:1Several patterns of drug-related hepatotoxicity are recognized each with a different mechanism of injury11. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-739.Hepatocellular or cytolytic injuryCholestatic injury Marked elevations of serum aminot

43、ransferase levels, usually preceding increases in total bilirubin levelsModest increases in ALP levelsIncreases in ALP levels that precede or are relatively more prominent than increases in the alanine aminotransferase or aspartate aminotransferase levelsExamples include isoniazid or troglitazoneExa

44、mples include amoxicillin-clavulanic acid or chlorpromazineHepatocellularMixedCholestaticElevated ALTElevated ALP + Elevated ALTElevated ALP + TBLProprietary and confidential do not distribute -INTERNAL USE ONLYTWO MAIN PATTERNS OF DILIDecember 22, 2021171. Navarro VJ, Senior JR. Drug-related hepato

45、toxicity. N Engl J Med. 2006;354(7):731-739.Hepatocellular patternMicro-vesicular steatosisCholestatic patternBile-stained hepatocytes, cellular swelling and minimal inflammationLiver-biopsy specimens showing common histologic features of drug-related hepatotoxicity1Proprietary and confidential do n

46、ot distribute -INTERNAL USE ONLYDIAGNOSIS OF DILI PATTERNDecember 22, 2021181. Chalasani P, Hayashi P, Bonkovsky H, et al. ACG Clinical Guideline: the diagnosis and management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol 2014;109:950-966. 2. Licata A, Minissale MG, Calvaruso V, et

47、al. A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):112-121.American College of Gastroenterology Guidelines 20141Diagnosis is made by evaluating the alteration of liver enzymes, clinical history and physical examinat

48、ion of the patient1,2The pattern of liver injury assessed by the ratio1,2R = (ALT/ULN)/(ALP/ULN)Allows us to define if the DILI has a:1,2Hepatocellular pattern (R 5)Cholestatic pattern (R 2)Mixed pattern (2 R 60% of DILI; antihypertensive and diabetic medications are less common1 Certain drugs can h

49、ave a “signature” presentation in terms of latency, biochemical pattern and other characteristics1 All chemotherapeutic agents can cause cytolytic, cholestatic or mixed liver damage2December 22, 2021201. Chalasani NP, Hayashi PH, Bonkovsky HL, et al; Practice Parameters Committee of the American Col

50、lege of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966. 2. Vincenzi B, Armento G, Spalato Ceruso M, et al. Drug-induced hepatotoxicity in cancer patients - implication for treatment. Expert Op

51、in Drug Saf. 2016;15(9):1219-38.DrugLatencyPrimary pattern of injuryAmoxicillin + clavulanateShort to moderateCholestaticFluoroquinolonesShortMixedMacrolidesShortHepatocellularNSAIDsModerate to longHepatocellularPhenytoinShort to moderateVariable, w/ immune-allergic featuresGreen tea extractShort to

52、 moderateHepatocellularAnabolic steroidsModerate to longCholestaticAmiodaroneModerate to longVariable w/ steatotic featuresAnti-TNF agentsModerate to longHepatocellularProprietary and confidential do not distribute -INTERNAL USE ONLYMOST COMMON OR WELL-DESCRIBED DILI AGENTS AND PATTERNS OF LIVER INJ

53、URYThe implicated agents that cause DILI vary substantially around the world1Etiologies and outcomes of DILI in studies from around the world1December 22, 2021211. Hasan A, Fontana RJ. Diagnosis and management of idiosyncratic drug-induced liver injury. Liver Int. 2018. doi: 10.1111/liv.13931.USSpai

54、nIcelandKoreaJapanIndiaPatients (n)899461963711,676313Mean age (years)495340-59495539% Female59%49%56%63%57%42%Agents implicatedAntimicrobials (45%)HDS (16%)CVS Agents (10%)Antimicrobials (32%)CNS Drugs(17%)Musculoskeletal (17%)Antimicrobials (37%)HDS (16%)NSAIDS (6%)HDS (28%)Non HDS (17%)Pills, pow

55、der (6%)Antimicrobials (14%)CNS Drugs (10%)HDS (10%)Antimicrobials (31%)CNS Drugs (11%)% Hepatocellular / Cholestatic / Mixed54% / 23% / 23%58% / 20% /22%42% / 32% /26%76% / 9% / 15%59% / 21% / 20%58% / 23% /19% Transplant or death9%7%1%2%2%3% Chronic17%6%7%NANANAProprietary and confidential do not

56、distribute -INTERNAL USE ONLYCANCER THERAPY-INDUCED DILIChemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI1Patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate

57、 and which drug doses should be modified1The liver is responsible for the metabolism and elimination of many anticancer agents, so hepatotoxicity can result in altered hepatic clearance and increased non-hepatic toxicityCancer therapy-induced hepatotoxicity represents the principle cause of dose red

58、uction or chemotherapy delaysThe incidence of chemotherapy-induced hepatotoxicity is rare, unrelated to drug dose, unpredictable, typically observed between 1 and 4 weeks after drug dosingThree main types of cancer therapy can be associated with DILI:Severe hepatotoxicity is more frequent when combi

59、ning immunotherapy with chemotherapy or targeted therapyDecember 22, 2021221. Vincenzi B, Russo A, Terenzio A, et al. The use of SAMe in chemotherapy-induced liver injury. Crit Rev Oncol / Hematol. 2018;130:70-77.ChemotherapyTargeted therapy (mainly tyrosine kinase inhibitors; TKI)ImmunotherapyPropr

60、ietary and confidential do not distribute -INTERNAL USE ONLYCANCER THERAPY-INDUCED DILIIncidence of cancer therapy-induced liver toxicity1December 22, 2021231. Vincenzi B, Russo A, Terenzio A, et al. The use of SAMe in chemotherapy-induced liver injury. Crit Rev Oncol / Hematol. 2018;130:70-77.LIVER TOXIC E