Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 • • Any drug may be responsible Predictive value of preclinical and clinical studies is limited The Phases of Drug Development Number of subjects 25000 20000 Most type A reactions detected here 15000 10000 Most type B reactions detected here Marketing Authorisation 5000 0 PHASE 1 50 volunteers PHASE 2 250 patients PHASE 3 2,000 patients PHASE 4 Many 1,000’s Attrition of compounds during development: main reasons for failure ORGAN Cardiovascular Liver Musculoskeletal Immune system Kidney CNS Testes Gastrointestinal Genetic toxicology Reproductive toxicity 70% of drugs withdrawn from US market 1980-2005 were analgesics,cardiovascular, antiinfectives 225 drugs were analysed Safety Biomarker Working Group ABPI No 64 42(19%) 15 13 12 10 10 8 7 7 Acute liver failure in US and transplant-free survival 600 475 80 400 60 300 40 200 151 119 100 20 75 31 55 43 50 17 9 0 8 0 Fontana Sem Liver Dis 2008 % Spontaneous survival Number of patients 500 100 Drug-induced Liver injury: what are the questions to be addressed • Epidemiology and drugs most commonly involved • • • • • Phenotypes Risk factors: envirommental and genetic Mechanisms: pathways of damage Diagnosis Therapy Epidemiology of Drug-induced Liver injury in Iceland n=251,860 15-24 Björnsson et al Gastroenterology 2013 Prescription rate per person Annual Incidence of DILI 19.1 per 100.000 Epidemiology of Drug-induced Liver injury in Iceland n=251,860 Drug Patients Prescription, Cases, Proportion Per 95% n n 100,000 CI treated, n Amoxicillin /clavulanate 35,252 Diclofenac 54,889 Azathioprine 532 Infliximab 593 Nitrofurantoin 5476 Isotretinoin 2169 Atorvastatin 7385 Doxycycline 32,677 83,379 112,801 3054 a 12,034 7978 34,171 54,232 15 6 4 4 4 3 2 2 2350 9148 133 148 1369 732 3693 16,339 43 11 752 675 73 138 27 6 Only drugs associated with at least 2 cases of DILI are shown. CI, confidence interval. a Most patients on infliximab received continuous prescriptions Björnsson et al Gastroenterology 2013 95% CI 24 70 4 24 205 1914 184 1718 20 187 29 404 4 98 1 22 PHENOTYPES OF “IDIOSYNCRATIC” DILI • 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 Bénichou C. J Hepatol. 1990; 11: 272-6. Fontana et al Hepatology 2010 Aithal et al Clin Pharmacol Ther 2011 Liver injury distribution in the Latin DILI Network, Spanish DILI Registry and DrugInduced Liver Injury Network. Hepatocellular R≥5, Cholestatic R≤2, Mixed R<2 y R>5 SLADILIN, 2013 Type of liver damage according to sex in patients younger or older than 60 years of age (n=603) Lucena et al. Hepatology 2009 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 Development/Progression of Drug Induced Liver Injury Increased Susceptibility Initiation of injury Adaptation Elevated aminotransferases Resolves despite continuing therapy Clinical manifestation Symptomatic (N/V, anorexia, fatigue) Liver dysfunction jaundice Regeneration/repair Cure Severe Injury Liver failure/Death Need to improve prediction of severe DILI outcome (better Hy’s Law ?) Risk factors for acute liver failure in DILI Variables Coefficient OR (95% CI) P value 3.220 25.04 (4.14-151) <.0001 Hepatocellular 2.064 damage 7.87 (1.68-36.9) <.009 Total Bilirubin 0.143 1.15 (1.09-1.22) <.0001 Female Sex Constant = -8.7 Abbreviations: CI, confidence interval; OR, odds ratio. Andrade et al, Gastroenterology 2005 Drug-induced acute liver failure in USA (1998-2007) • • • • • 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%) Reuben, Koch and Lee Hepatology 2010 Interplay of drug-related, environmental and host factors in the susceptibility to develop DILI Toxic potential of the drug Reactive metabolites Mitochondrial effects BSEP effects Genetic factors bioactivation detoxication transport Others: immune response MHC, etc. Envirommental factors drugs alcohol Age, gender HIV, HCV, HBV Kaplowitz,AASLD 2002 Relative importance of Intrinsic Toxicty of Agent Intrinsic vs Idiosyncrasyc liver damage 4+ 2+ Agents toxic for all exposed individuals and species e.g. white phosphorus Agents with significant interplay of toxicity and susceptility e.g. tetracycline Agents hardly ever toxic produce injury only in uniquely susceptible individuals e.g. native penicillin 2+ 4+ 0 Relative importance of Susceptibility of Host Zimmerman H, Textbook of hepatotoxicity 1976 Toxic potential of the drug in IDILI: the effect of dose • Doses ≥ 50 mg/daily associated with death, liver failure and liver transplantation Lammert et al Hepatology 2008 • Majority (77%) of the drugs incriminated in DILI in the SADRAC and Spanish DILI Registry were prescribed at doses ≥ 50 mg/daily Lammert et al Hepatology 2008 and Lucena et al Hepatology 2009 • Many false positives 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 Drug interference with BSEP function Morgan et al Toxicol Sci 2010 GWAS: Chromosome 6 (HLA genes) Flucoxacillin: HLA-B57*01 A-C and lumiracoxib: HLADRB1*1501-DQB1*0602 HLA –A*0201 Ximelagatran Daly et al Nat Genet 2009 Lucena et al Gastroenterology 2011 Kaplowitz Hepatology 2013 Can genetic variants in DILI be used as biomarkers? Gene Diagnostic Value Predictive Value Drug OR HLA-B57*01 Flucoxacillin 80 HLA-DRB1*1501 -DQB1*0602 HLA –A*0201 Amoxicillin/clav 4.2 POLG( p.Q1236H) Valproate 24 + + GST M1 T1 Several (Antibacterials / NSAIDS) 2.7 - - + - ±? - Lucena et al Hepatology 2008, Daly et al Nat Gen 2009 Stewart et al Hepatology 2010, Lucena et al Gastroenterology 2011 miRNA-122, HMGB1 and necrosis K18 as early biomarkers of paracetamol DILI Antoine et al Hepatology 2013 Suspicion Drug exposure data and chronology Not compatible If compatible assess Hepatotoxic potential Search for an alternative diagnosis Not 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” Found Specific therapy Andrade RJ WJG 2007 • Case definition of drug-induced liver injury (Aithal GP. Clin Pharm Ther 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 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 CIOMS/RUCAM • • • • • • • Temporal relationship Course Risk factors Concomitant drug Non-drug causes Prior reports/ information Re-challenge Score (-8 to 14) Highly probable >8 Probable 6-8 (0 to 2) (-2 to 3) (0 to 2) (0 to -3) (-3 to 2) (0 to 2) (-2 to 3) Possible 3-5 Excluded ≤0 Unlikely 1-2 J Clin Epidemiol 1993;46:1323-1330 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 Do not substitute common sense “clinical judgement” Designed for finding support for and less for excluding causality RUCAM limitations • Ambiguous instructions • No clear criteria for alternative causes/drugs (rule of two?) • Late onset > 30 after stopping therapy (e.g. Augmentine) • Negative dechallenge substracts points (FHF, AIH-DILI) • Derived from expert opinion and not from prospectively captured information • Limited risk factors • Excessive weight for rechallenge 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) 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 Acknowledgements Maribel Lucena Camilla Stephens Inma Moreno Inma Medina Eugenia Ulzurrun Mercedes Robles Miren GarcíaCortés Esperanza Crespo Ramón Hidalgo Mª Rosario Cabello InInt e Consortium, Ltd. SAE r 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 Scores for individual axes of the diagnostic scales CIOMS/RUCAM and Maria & Victorino CIOMS/RUCAM (1990) AXIS SCORE CHRONOLOGICAL CRITERIA Maria & Victorino/CDS (1997) AXIS CHRONOLOGICAL CRITERIA From drug intake until onset event From drug withdrawal until onset event Course of the reaction +2 to +1 From drug intake until onset event +1 to 0 From drug withdrawal until onset event -2 to +3 Course of the reaction Probability of DILI EXCLUSION ALTERNATIVE CIOMS: +1 to 0 RISK FACTORS Age Highly probable>8; Alcohol Probable Possible 3-5; Unlikely 1-2; +1 to6-8; 0 EXTRAHEPATIC MANIFESTATION Excluded ≤ 0 CONCOMITANT THERAPY -3 to 0 EXCLUSION NON-DRUG RELATED -3 to +2 BIBLIOGRAPHICAL DATA M&V:RECHALLENGE Definite: > 17; Probable: 14-17; Possible: 10-13; Unlikely: 6-9; 0 to +2 BIBLIOGRAPHICAL DATA Excluded <6 RECHALLENGE SCORE -2 to +3 +1 to +3 -3 to +3 0 to +3 -3 to +3 0 to +3 -3 to +2 0 to +3 • • 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 Medical Sciences / Roussel Uclaf Causality Assessment Method 1990 M & V/CDS 1997 DDW-J [modifies CIOMS scale] 2003