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Hepatitis aguda tóxica

Hepatitis aguda tóxica. Raúl J. Andrade Hospital Universitario Virgen de la Victoria Universidad de Málaga. Drug-induced Liver injury. Idiosyncratic DILI is a rare yet potentially severe cause of liver damage Diagnosis is difficult and inaccurate in most instances

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Hepatitis aguda tóxica

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  1. Hepatitis aguda tóxica Raúl J. Andrade Hospital Universitario Virgen de la Victoria Universidad de Málaga

  2. Drug-inducedLiverinjury • Idiosyncratic DILI is a rareyetpotentiallysevere cause of liverdamage • Diagnosis isdifficult and inaccurate in mostinstances • Anydrugmay be responsible • Predictivevalue of preclinical and clinicalstudiesislimited

  3. Marketing Authorisation The Phases of Drug Development Most type A reactions detected here Most type B reactions detected here 25000 20000 15000 Number of subjects 10000 5000 0 PHASE 1 PHASE 2 PHASE 3 PHASE 4 50 volunteers 250 patients 2,000 patients Many 1,000’s

  4. Attrition of compounds during development: main reasons for failure ORGAN No Cardiovascular 64 Liver 42(19%) Musculoskeletal 15 Immune system 13 Kidney 12 CNS 10 Testes 10 Gastrointestinal 8 Genetic toxicology 7 Reproductive toxicity 7 70% of drugs withdrawn from US market 1980-2005 were analgesics,cardiovascular, antiinfectives 225 drugs were analysed Safety Biomarker Working Group ABPI

  5. Fontana Sem Liver Dis 2008 Acute liver failure in US and transplant-free survival

  6. Drug-inducedLiverinjury: what are thequestionstobeaddressed • Epidemiology and drugsmostcommonlyinvolved • Phenotypes • Riskfactors: envirommental and genetic • Mechanisms: pathways of damage • Diagnosis • Therapy

  7. Epidemiology of Drug-induced Liverinjury in Iceland n=251,860 Prescriptionrate per person 15-24 Björnsson et al Gastroenterology 2013

  8. Epidemiology of Drug-induced Liverinjury in Iceland n=251,860 Onlydrugsassociatedwith at least 2 cases of DILI are shown. CI, confidenceinterval. a Mostpatientsoninfliximabreceivedcontinuousprescriptions Björnsson et al Gastroenterology 2013

  9. HEPATOCELLULAR: Alanine aminotransferase (ALT) predominantly raised (ALT/AP>5) CHOLESTATIC: Alkaline phosphatase (AP) predominantly raised (ALT/AP <2) MIXED ALT & ALP are increased, and 2<ALT/ALP<5 PHENOTYPES OF “IDIOSYNCRATIC” DILI Bénichou C. J Hepatol. 1990; 11: 272-6. Fontana et al Hepatology 2010 Aithal et al Clin Pharmacol Ther 2011

  10. Liver injury distribution in the Latin DILI Network, Spanish DILI Registry and Drug-Induced Liver Injury Network. Hepatocellular R≥5, Cholestatic R≤2, Mixed R<2 y R>5 SLADILIN, 2013

  11. Type of liver damage according to sex in patients younger or older than 60 years of age (n=603) Lucena et al. Hepatology 2009

  12. Factors influencing clinical expression and early outcome of DILI Hepatocellular pattern damage most common (58%) inversely correlated with age (P < .0001) & had worst outcome (Cox regression, P < 0.034) Andrade RJ et al. Gastroenterology 2005; 129: 512-521

  13. Development/Progression of Drug Induced Liver Injury Increased Susceptibility Initiation of injury Adaptation Elevated aminotransferases Resolves despite continuing therapy Clinical manifestation Regeneration/repair Cure Symptomatic (N/V, anorexia, fatigue) Liver dysfunctionjaundice Severe Injury Liver failure/Death

  14. Needtoimproveprediction of severe DILI outcome (betterHy’sLaw ?)

  15. Risk factors for acute liver failure in DILI Variables Coefficient OR (95% CI) P value Female Sex 3.220 Hepatocellular 2.064 damage Total Bilirubin 0.143 25.04 (4.14-151) 7.87 (1.68-36.9) 1.15 (1.09-1.22) <.0001 <.009 <.0001 Constant = -8.7 Abbreviations: CI, confidence interval; OR, odds ratio. Andrade et al, Gastroenterology 2005

  16. Demographics (n=133) Overweight (BMI 28.7) Women (70.7%) Overrepresentation of minorities Presentation Deep jaundice (mean bilirubin 20.8 mg/dL) Moderate ALT increases (median 580 U/L) Rash/eosinophilia (16%), autoantibodies (22%) Type of damage HC 98(77,8%), Ch 16 (12, 6%), Mx 12(9,5%) Causative drugs Antimicrobials (INH, sulfa-drugs, nitrofurantoin) 46% Alternative (illicit), antiepileptics, antimetabolites, statins 35% Outcome predict SS (27%), LTs (42%), Non LT-Death (31%) Drug-induced acute liver failure in USA(1998-2007) Reuben, Koch and Lee Hepatology 2010

  17. Interplay of drug-related, environmentaland host factors in thesusceptibilitytodevelop DILI Toxic potential of the drug Genetic factors Reactive metabolites Mitochondrial effects BSEP effects bioactivation detoxication transport Others: immune response MHC, etc. Envirommental factors drugs alcohol Age, gender HIV, HCV, HBV Kaplowitz,AASLD 2002

  18. Intrinsic vsIdiosyncrasyc liver damage Agentstoxicforallexposedindividuals and speciese.g. whitephosphorus 4 + Agentswithsignificantinterplay of toxicity and susceptilitye.g. tetracycline Relativeimportance of IntrinsicToxicty of Agent 2 + Agentshardlyevertoxic produce injuryonly in uniquely susceptible individualse.g. nativepenicillin 2 + 4 + 0 Relativeimportance of Susceptibility of Host Zimmerman H, Textbook of hepatotoxicity 1976

  19. Toxicpotential of thedrug in IDILI: theeffect of dose • Doses ≥ 50 mg/dailyassociatedwithdeath, liverfailure and livertransplantationLammert et al Hepatology 2008 • Majority (77%) of thedrugsincriminated in DILI in the SADRAC and Spanish DILI Registrywereprescribed at doses ≥ 50 mg/dailyLammert et al Hepatology 2008 and Lucena et al Hepatology 2009 • Many false positives

  20. Lipophilicity (octanol/water > 3) and High Daily Dose (> 100 mg/day) and Significant Risk for Drug-Induced Liver Injury (the rule of two) Chen et al. Hepatology 2013

  21. Druginterferencewith BSEP function Morgan et al ToxicolSci 2010

  22. GWAS: Chromosome 6 (HLA genes) Flucoxacillin: HLA-B57*01 A-C and lumiracoxib:HLA-DRB1*1501-DQB1*0602 HLA –A*0201 Ximelagatran Daly et al Nat Genet 2009 Lucena et al Gastroenterology 2011

  23. Kaplowitz Hepatology 2013

  24. Can genetic variants in DILI be used as biomarkers? Diagnostic Predictive Value Value Gene Drug OR HLA-B57*01 HLA-DRB1*1501 -DQB1*0602 HLA –A*0201 POLG( p.Q1236H) GST M1 T1 Flucoxacillin 80 Amoxicillin/clav 4.2 Valproate 24 Several 2.7 (Antibacterials / NSAIDS) + - ±? - ++ -- Lucena et al Hepatology 2008, Daly et al Nat Gen 2009 Stewart et al Hepatology 2010, Lucena et al Gastroenterology 2011

  25. miRNA-122, HMGB1 and necrosis K18 as early biomarkers of paracetamol DILI Antoine et al Hepatology 2013

  26. Suspicion LIVER DISEASE Drug exposure data and chronology Not compatible If compatible assess Hepatotoxic potential Search for an alternative diagnosis Not found Found Assess features suggesting drug-toxicity ● Allergic manifestations ●Course on de-challenge ●Look for possible unintentional re-challenge data ●Liver biopsy findings (if performed) and biochemical “signature” Specific therapy Andrade RJ WJG 2007

  27. Resources Case definition of drug-induced liver injury (Aithal GP. ClinPharmTher 2011;89(6):806–815): http://www.nature.com/clpt/journal/v89/n6/pdf/clpt201158a.pdf NIDDK Hepatotoxicity Website (>600 drugs): http://livertox.nih.gov/ 385 Drugs Associated with Hepatotoxicity (Suzuki A et al. Drug Safety 2010; 33: 503-522): http://www.ingentaconnect.com/content/adis/dsf/2010/00000033/00000006/art00007 Spanish Drug-induced Liver Injury Registry website: http://www.spanishdili.uma.es/index.php?option=com_content&view=frontpage&lang=en Herbal hepatotoxicity (Seeff LB. Clin Liver Dis 11 (2007) 577–596): http://www.sciencedirect.com/science/article/pii/S1089326107000487

  28. Causality assessment in DILI • Difficult and non-standardized • Expert Opinion may be more reliable but is umpractical • Diagnostic scales may guide clinicians searching the important points to be addressed

  29. CIOMS/RUCAM • Temporal relationship (0 to 2) • Course (-2 to 3) • Risk factors (0 to 2) • Concomitant drug (0 to -3) • Non-drug causes (-3 to 2) • Prior reports/ information (0 to 2) • Re-challenge (-2 to 3) Score (-8 to 14) Highly probable >8 Possible 3-5 Excluded ≤0 Probable 6-8 Unlikely 1-2 J Clin Epidemiol 1993;46:1323-1330

  30. Do not substitute common sense “clinical judgement” Designed for finding support for and less for excluding causality RUCAM Strenghts • Provide an uniform approach. Adds consistency to the diagnostic process • Excellent teaching tool, emphasizes the features that merit attention • Help improve the quality of the information recorded (too much important information is lacking in published cases) Agarwal et al Clin Gastoenterol Hepatol 2010 • Improvement in inter-intra rater agreement • Help standardize the reporting manner

  31. RUCAM limitations • Ambiguous instructions • No clear criteria for alternative causes/drugs (rule of two?) • Late onset > 30 after stopping therapy (e.g. Augmentine) • Negative dechallengesubstracts points (FHF, AIH-DILI) • Derived from expert opinion and not from prospectively captured information • Limited risk factors • Excessive weight for rechallenge

  32. Therapy ¡Stop immediatly any non essential drug! If impending liver failure (encephalopathy, INR > 1.5) referral for liver Tx Empirically Steroids if prominent hypersensitivity features UDCA if prolonged cholestasis NAC has proved useful in early stages (encephalopathy I-II) of fulminant hepatic failure due to drugs (non acetaminophen)

  33. Summary • Idiosyncratic DILI is partially dose dependent • Age and sex influence DILI phenotype and severity • Genetic variants accounting for DILI susceptibility are being identified • Causality assessment is complex and uncertain and current diagnostic scales are imperfect • Specific biomarkers is an unmet necessity • Therapy is largely supportive. NAC increases free transplant survival in early phases of acute liver failure related to drugs

  34. Acknowledgements Maribel Lucena Camilla Stephens Inma Moreno Inma Medina Eugenia Ulzurrun Mercedes Robles Miren García-Cortés Esperanza Crespo Ramón Hidalgo Mª Rosario Cabello Ayako Suzuky (Duke) Guru Aithal (Nottingham) Einar Björnsson (Reikijavik, Iceland) Ann Daly (Newcastle Upon Tyne) Paul Watkins (North Carolina) Robert Fontana (Michigan) Dominique Larrey (Montpellier) SAEC members

  35. Scores for individual axes of thediagnosticscales CIOMS/RUCAM and Maria & Victorino CIOMS/RUCAM (1990) Maria & Victorino/CDS (1997) AXIS CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction RISK FACTORS Age Alcohol CONCOMITANT THERAPY EXCLUSION NON-DRUG RELATED BIBLIOGRAPHICAL DATA RECHALLENGE SCORE +2 to +1 +1 to 0 -2 to +3 +1 to 0 +1 to 0 -3 to 0 -3 to +2 0 to +2 -2 to +3 AXIS CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction EXCLUSION ALTERNATIVE EXTRAHEPATIC MANIFESTATION BIBLIOGRAPHICAL DATA RECHALLENGE SCORE +1 to +3 -3 to +3 0 to +3 -3 to +3 0 to +3 -3 to +2 0 to +3 Probability of DILI CIOMS: Highly probable>8; Probable 6-8; Possible 3-5; Unlikely 1-2; Excluded ≤ 0 M&V: Definite: > 17; Probable: 14-17; Possible: 10-13; Unlikely: 6-9; Excluded < 6

  36. Diagnostic scales • General scales for the assessment of ADR Karch y Lasagna 1977 Kramer 1979 Naranjo 1981 Jones 1982 The French Method, Begaud 1984 Arimone 2006 • Specific scales for DILI Striker decision tree 1992 Council International Organizations MedicalSciences/ Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003

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