DILI (Hepatotoxicidad)

Transcription

1 DILI (Hepatotoxicidad) Raúl J Andrade Gastroenterology Service, University Hospital, Department of Medicine, University of Málaga, IBIMA and CIBERehd October 31, 2015

2 Drug-induced liver injury Relatively uncommon, potentially severe -Chief cause of ALF -Rank among main reasons for drug atrittion Diagnosis after exclusion of alternative causes -No diagnostic biomarkers -A wide range of phenotypes Many drugs involved

3 APAP Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeter Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,000) % ALF Study Group, Jan % 12%

4 Drug-induced liver Injury Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

5 Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

6 Drug-induced liver injury (DILI) Criteria for liver injury (Benichou, J Hepatol, 1990) > 2 xuln ALT > 2 xuln conjutated BL Combined increase in AST, ALP and total BL, with at least one being > 2 xuln Criteria for DILI qualification case (Aithal et al, Clin Pharmacol Ther, 2011) 5 xuln ALT 2 xuln ALP 3 xuln ALT + > 2 xuln TBL R= ALT/AP (ULN) Hepatocellular > 5 Mixed >= 2=< 5 Cholestatic < 2

7 DILI incidence rate Population based studies UK (de Abajo et al, 2004)** 2.4 per person-year France (Sgro et al, 2002)* 13.9 per person-year Iceland (Björnsson et al, 2013)* 19.1 per person-year *prospective study, **retrospective study

8 Epidemiology of Drug-induced Liver injury in Iceland n=251,860 Annual Incidence of DILI 19.1 per Case qualification: ALT > 3N 96 patients (27% jaundiced, 23% hospitalized) Prescription rate per person Björnsson et al Gastroenterology 2013; 144(7):

9 DILI demographics and clinical features Spain 1 Latin America 2 USA 3 DILI patients Male/female (%) 51/49 40/60 40/60 Age, mean (range) 54 (13-88) 52 (15-86) 48 (ND) Jaundice, % Hospitalization, % Type of injury Hepatocellular, % Cholestatic, % Mixed, % Liver related death or transplantation, % Lucena et al, Bessone et al, Chalasani et al, 2008

10 Causative agents ATC system group code *Fontana et al, Gastroenterology 2014

11 Drug Epidemiology of Drug-induced Liver injury in Iceland n=251,860 Patients treated, n Prescription, n Cases, n Proportion Per 100,000 95% CI 95% CI Amoxicillin /clavulanate 35,252 83, Diclofenac 54, , Azathioprine Infliximab 593 a Nitrofurantoin , Isotretinoin Atorvastatin , Doxycycline 32,677 54, 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; 144(7):

12 Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

13 Pathogenesis and progression of drug-induced liver injury Hepatocyte 1 Drug Metabolism CYP,GSH GSHT Toxicity (drug, T/B cell mediated) 3 DAMPs Drug HMGB1 HSPs DNA RNA Perforin Granzyme CTL Lymphocytes 2 Drug Toll-Like Receptors B IL-17 IL-21 IL-13 5 Drug TH TCR Neoantigen Costimulation 4 Drug MHC IL-6, TNFα Antigen Presenting cell De Lemos et al Semin Liver Dis 2014;34:

14 Genome-wide association (GWA) studies 201 amoxicillin-clavulanate DILI patients (96 English, 56 American and 49 Spanish cases) and 532 controles

15 Chromosome 6, HLA associations HLA-DRB1*1501-DQB1*0602 (classii) HLA A*0201 (class I) Lucena et al, Gastroenterology 2011

16 GWAS: chromosome 6 (HLA genes) OR= 80, low predictive positive value High predictive negative value 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

17 Drug/Metabolite Covalent Binding Antigenic peptide Susceptible HLA 10-30% WT HLA 70-90% Adaptive Immunity ~2-10% Mild Liver Injury ~20% Immune Tolerance No injury DEFECTIVE ADAPTATION < 1% Severe Liver Injury < 0.1% IDILI ALF (Hy s Law) ADAPTATION > 90% of susceptibles Immune Tolerance Resolution Clinical adaptation Dara, Liu and Kaplowitz Liver Intern 2015; in press

18 Drug Drug properties Physiochemical Pharmacological Toxicological Bio-physiological effects Cellular injury initiation Pharmacological responses Reactive metabolites, drug elimination Toxicological responses Covalent binding, haptenization, oxidative stress, mitochondrial injury, ER stress Cell death Apoptosis, necrosis, DAMP release Host response to injury insult Immune/ inflammation Host factors Genetic variants Race/ethnicity Age Gender Reproductive state nutrition, alcohol, smoking Lifestyles Disease conditions Medications Gut flora Repair Tissue injury Clinical manifestation and outcome Chen et al J Hepatol 2015 Apr 22. pii: S (15) doi: /j.jhep

19 Toxic potential of the drug in IDILI: the effect of dose -Doses 50 mg/daily associated with death, liver failure and liver transplantation 1 -Majority (77%) of the drugs incriminated in DILI in the SADRAC and Spanish DILI Registry were prescribed at doses 50 mg/daily 1,2 -Many false positives 1 Lammert et al Hepatology 2008; 47: , 2 Lucena et al Hepatology 2009; 49:

20 Lipophilicity (octanol/water > 3) and High Daily Dose (> 100 mg/day) (the rule of two) Many false negatives! Chen, Borlak and Tong et al. Hepatology 2013

21 Drug interference with BSEP function Many false negatives! Morgan et al Toxicol Sci 2010

22 Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

23 Type of liver injury and gender

24 100 Kleiner et al., Hepatology, 2014 ;59: Liver biopsies from 249 cases of suspected DILI blindly reviewed 18 DILI patterns identified R Acute Hepatitic Chronic Hepatitic Acute Cholestatic Chronic Cholestatic Cholestastic Hepatitic Zonal Necrosis

25 Number of cases Age and gender as DILI risks DILI according to age and gender Peak age of DILI occurs earlier in women (40-49 vs years) Lucena et al, Hepatology 2009 Age (years) Type of liver injury according to age and gender Women <60 years are more prone to develop hepatocellular DILI, while men >60 years cholestatic DILI

26 DAÑO HEPATOCELULAR DAÑO COLESTÁSICO *p<0.001 **p=0.012 p=0.01 p<0.001 Test de Kruskal-Wallis: *p<0.001 AAS vs resto de clases terapéuticas, **p=0.012 AAS vs CNS y HDS, p<0.001 AAS vs resto de clases terapéuticas, p=0.01 AAS vs amoxicilina clavulánico, antineoplásicos y cardiovasculares.

27 Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

28 Risk of drug-induced acute liver failure (ALF) Logistic regression analysis of demographic, clinical and laboratory parameters in DILI cases with (31) and without (774) ALF resulting in death or OLT Predictive risk factors of ALF TBL (at recogntion, peak ALT and peak TBL AST/ALT (recognition, peak ALT, peak TBL) Hepatocellular damage (recognition, peak TBL) Female gender Gastroenterology 2014; 147: ALF incidence rate: 32 of 771 DILI patients (4.2%)

29 Prognostic algorithm for ALF in DILI Chi-squared automatic interaction detection (CHAID) Specificity 82% Sensitivity 80% Robles-Díaz M et al Gastroenterology 2014; 147(1):

30 Algorithm for prediction of ALF outcome in DILI Spanish DILI Registry 804 DILI episodes (30 ALF) Specificity: 82% Sensitivity: 80% SLATINDILI 97 DILI episodes (5 ALF) Specificity: 82% Sensitivity: 80% Robles-Díaz M et al Gastroenterology 2014; 147(1):

31 (better Hy s Law?) Need to improve prediction of severe DILI outcome?

32 Chronicity definition Chol, p= 0.95 HC, p= 0.9 Mix, p= d p=0.4 by long-rank test Days to resolution The inset shows the same data on an enlarged y axis Robles-Díaz et al unpublished data Hepatocellular cases (N=193) Cholestatic cases (N=46) Mixed cases (N=46) Abbreviations: Chol: cholestatic, HC: hepatocellular, Mix: mixed

33 Proper case definition and reliable epidemiology Identification of susceptible subjects and mechanisms Clinical and histological phenotypic characterization Prediction of severe outcomes Diagnosis

34 There is an urgent need of Specific biomarkers! Step-by-step approach for suspected DILI cases *García-Cortés M, Stephens C, Lucena MI, Fernández-Castañer A, Andrade RJ.. Causality Assessment Methods in Drug Induced Liver Injury: Strengths and Weaknesses. Journal of Hepatology, 2011; 55:

35 Isquemic Hepatitis Bacterial Hepatitis Wilson s Disease Deficit of α- 1antitrypsin Haemocromatosis Viral hepatitis A, B, C, E Diseases Alcoholic Hepatitis Autoinmune Hepatitis. PBC Biliary obstruction Dalton et al Aliment Pharmacol Ther 2007 Davern et al Gastroenterology 2011

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37 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 Danan et al J Clin Epidemiol 1993;46:

38 Causality scales: Weaknesses Often complex and time consuming Lack of clear user instructions Lack of case information or follow-up data can lead to reduced probability Do not discriminate among concomitant drugs Evaluation of atypical cases remains challenging Restrictive criteria and arbitrary weighting of factors may lead to incorrect evaluations Do not substitute clinical judgement García-Cortés M et al J Hepatol, 2011; 55:

39 Summary DILI is not so rare as formerly thought Idiosyncratic DILI results from complex drug-host interactions and the failure to adapt to minor degree of injury DILI phenotype is influenced by age and sex Demographics and routine liver biochemistry can be of help in predicting fulminant course Causality assessment is complex and uncertain and current diagnostic scales are imperfect

40 Collaborating hosptial units in the Spanish DILI Registry H. Torrecárdenas, Almería: MC Fernández, G Peláez, M Casado H. Virgen Macarena, Sevilla: JA Durán, M Villar H. Universitario Virgen de Valme, Sevilla: M Romero, H. Central de Asturias, Oviedo: L Rodrigo-Saez, R Perez-Alvarez H. de Puerto Real, Cádiz: JM Pérez-Moreno, M Puertas H. Universitario San Cecilio, Granada: J Salmerón, A Gila H. Germans Trias i Puyol, Barcelona: I Barriocanal, Eva Montané, J Costa H. Costa del Sol, Málaga: JM Navarro, JF Rodríguez H. 12 de Octubre, Madrid: T. Muñoz-Yagüe, JA Solis-Herruzo H. Marqués de Valdecilla, Santander: F Pons, J Crespo H. Sant Pau, Barcelona: C Guarner, G Soriano H. Carlos Haya, Málaga: M Jiménez, R González-Grande H. Xeral-Calde, Lugo: S Avila-Nasi H. Puerta de Hierro, Madrid: JL Calleja, J de la Revilla H. Nuestra Sra. de Aranzazu, San Sebastián: M García-Bengoechea, J Arenas H. de Mendaro, Guipuzcuoa: A Castiella, E Zapata H. Alto Deba, Mondragón, Guipuzcuoa: P Otazua H. de Basurto, Bilbao: S Blanco, P Martinez Odriozola H. Clínico Provincial: M Bruguera, P Ginés H. Morales Messeguer: H Hallal H. de Albacete, Albacete: JM Moreno H. Puerta del Mar, Cádiz: P Rendón H. de Salamanca: F González H. De Alcorcón: C Fernández H. De Sagunto: J Primo H. La Fe: M Prieto

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