Drug-Induced Liver Injury (DILI)

1. Drug-Induced Liver Injury (DILI) Dominique Pessayre, M.D. INSERM U 773, Faculté de Médecine Xavier Bichat, Paris et Hôpital Beaujon, Clichy, France

2. DIVERSITY > 1000 Hepatotoxic drugs Diverse mechanisms Variety of liver diseases

3. METABOLIC ACTIVATION Drug CYP Reactive metabolite (High Amounts) • (Low Amounts) Extensive covalent binding  GSH Protein Immune reactions Direct toxicity

4. MITOCHONDRIAL DYSFUNCTION Drugs  Beta- oxidation  Respi- ration Cell dysfunction Cell death Lactic acidosis Steatosis

5. These and other mechanisms Diverse liver diseases

6. ACUTE DILI CHRONIC DILI ACUTE HEPATITIS Cytolytic hepatitis Subacute or chronichepatitis Mixed hepatitis Cholestatic hepatitis + cholangi(oli)tis Vanishing bile duct syndrome Bland cholestasis Steatosis Steatohepatitis Sinusoidal dilation, Peliosis VOD (« SOS »), Budd-Chiari Hepatic adenoma, HCC

7. C E K O FOURTH CAUSE B E O Z O D B O L O Burger HCV HBV G D R U Obesity/ diabetes *Bagheri, Br J ClinPharmac 2000;50:479. 9%* Abnormal liver tests

8. Yearly incidence rate DILI: 14/100 000 inhabitants/year = 8000 cases/ year in France (16-times the number reported to the French Pharmacovigilance Agency) Fatal DILI (0.8/100 000 inhabitants/year) 6% Sgro, Hepatology 2002;36:451.

9. DISPROPORTIONATE ROLE IN FULMINANT HEPATITIS IN THE US AND UK

10. Drugs: first cause FULMINANT HEPATITIS in the USA

11. PARACETAMOL:40% Intentional overdoses Self medication with excessive doses in the USA DRUGS: 52% OTHER DRUGS: 12% OTHER CAUSES: 48% FULMINANT HEPATITIS IN THE USA Lee WM, Sem Liver Dis, 2003;23:217

12. DILI: IMPORTANT LEGAL AND/OR FINANCIAL IMPLICATIONS

13. FOR THE PHYSICIAN Continued treatment 3. Fulminant hepatitis ALAT 2. Chronic liver disease 5ULN 1. Adaptation 1 ULN DRUG

14. FOR THE PHARMACEUTICAL INDUSTRY DILI: Major cause for drug withdrawal or prescribing restrictions Recent cases: Ximelagatran Troglitazone Bromofenac Felbamate Pemoline Tolcapone Trovafloxacin

15. NEW HEPATOTOXIC DRUGS ARE MARKETED POOL OF HEPATOTOXIC DRUGS DRUG RECALL

16. DIFFICULTY IN PREDICTING THE HEPATOTOXIC POTENTIAL OF DRUGS BEFORE MARKETING

17. Drug candidates Toxicity studies & Clinical trials Frequent hepatotoxicity ? Idiosyncratic liver injury?

18. Black, Gastroenterology , 1975;69:289 0.1% Death CLINICAL 1% Jaundice INFRA- CLINICAL ALT > 10 ULN Unfractionated heparin Isoniazid 30%  Transaminases 15%  Transaminases Monreal, Eur J Clin Pharmacol 1989;37:415 Huang, Hepatology 2002;35:883-889

19. Hy’s rule Mortality of drug-induced hepatocellular jaundice: 10% Example: 5 of 1000 patients have ALAT > 10 ULN and bilirubin > 3 ULN in a clinical trial You can expect: 5 deaths with liver failure for 10 000 recipients after marketing

20. EVEN A MARKEDLY HEPATOTOXIC DRUG CAN SOMETIMES BE MARKETED • when the drug is required to treat a serious disease • - and no safer drug is available LFT MONITORING

21. TRANSAMINASE MONITORING: USEFUL OR USELESS?

22. 2 Weeks TRANSAMINASE MONITORING 4 Weeks Frequent (e.g., tacrine) ALAT > 5 ULNStop treatment No jaundice Infrequent

23. Rather than infrequent LFT monitoring, it’s best to WARN THE PATIENT “ Consult and have liver tests performed if you don’t feel well ” “Stop treatment immediately should you become jaundiced”

24. CAN WE PREDICT WHICH PATIENT WILL DEVELOP DILI?

25. DILI and age High drug consumption Young adults Old > > Children Exceptions: Reye’s syndrome with aspirin and Reye-like syndrome with valproate • Susceptibility (e.g., isoniazid)

26. DILI and gender Incidence of DILI: 2.6-fold higher in females than males in persons aged 50 years or more (Same in females and males before 50) Sgro, Hepatology 2002;36:451

27. DILI in cirrhosis CIRRHOSIS • - Does not change the incidence of DILI • but worsens it outcome • (The same degree of liver injury, which is well tolerated in a normal subject, can trigger liver failure, complications and death in patients with an already impaired liver function)

28. DILI and VIRAL INFECTIONS Paracetamol Viral Hepatitis  DILI Anti-tuberculous drugs HAART  Reye Varicella, inflenza Aspirin

29. ADDITIVE IMPAIRMENT OF MITOCHONDRIAL FUNCTION NASH, Alcohol abuse, Viral Infections, Pregnancy, Inborn b-oxidation defects, Mitochondrial cytopathies DRUG(S) + OTHER CONDITION(S) Additively impair mitochondrial function Liver disease

30. CYP INDUCTION AND/OR MALNUTRITION CAN INCREASE THE DIRECT TOXICITY OF REACTIVE METABOLITES Large doses of paracetamol Susceptibility: CYP2E1  Alcohol abuse Malnutrition Large amounts of a reactive metabolite  GSH Hepatitis due to direct toxicity

31. THE N-ACETYL-TRANSFERASE POLYMORPHISM CAN MODULATE AUTOIMMUNE HEPATITIS Extensive acetylators Poor acetylators Dihydralazine Dihydralazine NAT2 CYP1A2 CYP1A2 Reactive metabolite Reactive metabolite CYP1A2-metabolite adducts CYP1A2-metabolite adducts Anti-CYP1A2 autoantibodies Anti-CYP1A2 autoantibodies Uncommon hepatitis Morefrequent hepatitis Bourdi, Mol Pharmacol 1994;45:1287

32. MHC POLYMORPHISMS CAN MODULATE IMMUNOALLERGIC HEPATITIS Metabolite Peptide MHC/HLA (Each MHC molecule presents different series of peptides)

33. Amoxicillin & Clavulanic Acid- Induced Hepatitis HLA class II haplotype: DRB1*1501-DRB5*01101-DQB1*0602 Patients: 57% Controls: 13% Hautekeete, Gastroenterology 1999;117:1181

34. Acute cholangitis and vanishing bile duct syndrome A: O in clavulanic acid S in flucloxacillin Hepatocyte R A N O COOH Opening of the b-lactam ring Bile duct Covalent binding Toxicity* T cell reactivity and immune reactions* *Lakehal, Chem Res Toxicol 14;6:694 *Mauri-Hellweg, J Immunol 1996;157:1071

35. HOW CAN THE DIAGNOSIS BE MADE?

36. DIAGNOSIS • Always consider a possible iatrogenic cause • Insistent questioning • (Analgesic drugs, illicit drugs, psychoactive drugs, NSAIDs, over-the-counter drugs, • herbal remedies) • Compatible chronology (DILI may sometimes appear 2 weeks after treatment is stopped) • Fever, rash, eosinophilia (immunoallergic mech.) • Similarity to previously reported cases • Exclusion of other causes • (obesity/diabetes, alcohol, …viral serologies, ultrasonography) • Deceleration after withdrawal

37. Drug withdrawal ALAT Few weeks 10ULN 1 ULN DRUG

38. Specific antibodies Autoantibodies Tienilic acid anti-LKM2 (anti-CYP2C)Beaune, PNAS 1987;84:551 Dihydralazine anti-LM (anti-CYP1A2)Bourdi, JCI 1990;85:1967 Halothane anti-CYP2E1 Eliasson, Mol Pharmacol 1996;50:573 Germander anti-EH de Berardinis, Mol Pharmacol 2000;58:542 Iproniazid anti-M6 (anti-MAO B)Pons, BBRC 1996;218:1118 Anti-metabolite-protein adduct antibodies Halothane anti-TFA-protein Kenna, JPET 1998;245:1103 Tienilic acid anti-TA-protein Robin, JCI 1996;98:1471 Diclofenac anti-Diclof.-proteinAithal, Hepatology 2004;39:1430

39. Lymphocyte proliferation assay With/without drug [3H]thymidine incorporation ratio (with indomethacin to prevent inhibitory PGE2 formation) 56% 32 16 Maria and Victorino, Gut 1997;41:534-540 8 (26% without indo- meth- acin) 4 2 100% 100% 34% 1 95 pts with DILI 106 controls 35 treated pts without DILI

40. PREVENTION OF RECURRENCE

41. Warn the patient and his/her doctors • against using the drug again. • Give the patient a list of all • pharmaceuticalspecialties containing • the drug,in order to avoidinadvertent • rechallenge.

42. RECHALLENGE • Performing a rechallenge for the sake of • diagnosis is unethical, and is particularly riskyif • immunoallergy is suspected(risk of rapid and • severe DILI). • 2. However, re-introduction may be attempted if: • - the drug is required to treat a serious disease; • - other drugs areless active; • - one suspects directtoxicity (ratherthan • immunoallergy); • - one use lower doses (or different • co-medications…); • -and transaminasesare monitored frequently.

43. CONCLUSION DILI: Difficult to avoid, predict and diagnose TWO GOLDEN RULES 1. Always consider the possibility of DILI 2. Immediately withdraw all suspected drugs in severe cases Avoid most mishaps