DILI (Hepatotoxicidad)

Raúl J Andrade Gastroenterology Service,

University Hospital,

Department of Medicine, University of

Málaga, IBIMA and CIBERehd

October 31, 2015

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

Drug-induced liver injury

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220

142

36

137 112

25 15 18

134

245

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500

600

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Hep

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Hep

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ter

Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,000)

ALF Study Group, Jan 2013

46%

11% 12%

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

Proper case definition and reliable epidemiology Identification of susceptible subjects and

mechanisms

Clinical and histological phenotypic characterization

Prediction of severe outcomes Diagnosis

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

DILI incidence rate

Population based studies

UK (de Abajo et al, 2004)**

2.4 per 100 000 person-year France (Sgro et al, 2002)* 13.9 per 100 000 person-year

Iceland (Björnsson et al, 2013)*

19.1 per 100 000 person-year *prospective study, **retrospective study

Prescrip

tion

rate p

er perso

n

15-24

Epidemiology of Drug-induced Liver injury in Iceland n=251,860

Annual Incidence of DILI 19.1 per 100.000

Björnsson et al Gastroenterology 2013; 144(7):1419-1425

Case qualification: ALT > 3N

96 patients (27% jaundiced,

23% hospitalized)

DILI demographics and clinical features

Spain1 Latin

America2 USA3

DILI patients 603 73 300

Male/female (%) 51/49 40/60 40/60

Age, mean (range) 54 (13-88) 52 (15-86) 48 (ND)

Jaundice, % 69 71 69

Hospitalization, % 54 54 60

Type of injury

Hepatocellular, % 55 50 57

Cholestatic, % 25 32 23

Mixed, % 20 18 20

Liver related death or transplantation, %

3.8 5.1 6.0

1Lucena et al, 2009

2Bessone et al, 2013

3Chalasani et al, 2008

Causative agents

ATC system group code

*Fontana et al, Gastroenterology 2014

Drug Patients treated,

n

Prescription, n

Cases, n

Proportion Per 100,000

95% CI 95% CI

Amoxicillin /clavulanate 35,252 83,379 15 2350 43 24 70

Diclofenac 54,889 112,801 6 9148 11 4 24 Azathioprine 532 3054 4 133 752 205 1914 Infliximab 593 a 4 148 675 184 1718 Nitrofurantoin 5476 12,034 4 1369 73 20 187 Isotretinoin 2169 7978 3 732 138 29 404 Atorvastatin 7385 34,171 2 3693 27 4 98 Doxycycline 32,677 54,232 2 16339 6 1 22

Only drugs associated with at least 2 cases of DILI are shown.

CI, confidence interval.

a Most patients on infliximab received continuous prescriptions

Epidemiology of Drug-induced Liver injury in Iceland n=251,860

Björnsson et al Gastroenterology 2013; 144(7):1419-1425

Proper case definition and reliable epidemiology Identification of susceptible subjects and

mechanisms

Clinical and histological phenotypic characterization

Prediction of severe outcomes Diagnosis

Hepatocyte

Drug 3 DAMPs

HMGB1 RNA HSPs

DNA

Toxicity

(drug, T/B cell mediated)

Toll-Like Receptors

Antigen Presenting cell

Drug

Drug

Drug

Drug 1

5

2

4

TH B

CTL

IL-6, TNFα

Co- stimulation

Neo- antigen

MHC TCR

IL-13

IL-17 IL-21

Metabolism CYP,GSH

GSHT

Lymphocytes

Perforin Granzyme

Pathogenesis and progression of drug-induced liver injury

De Lemos et al Semin Liver Dis 2014;34:194–204.

Genome-wide association (GWA)

studies

201 amoxicillin-clavulanate DILI patients (96 English,

56 American and 49 Spanish cases) and 532 controles

Chromosome 6, HLA associations

HLA-DRB1*1501-DQB1*0602 (classII)

HLA –A*0201 (class I)

Lucena et al, Gastroenterology 2011

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

OR= 80 , low predictive positive value

High predictive negative value

GWAS: chromosome 6 (HLA genes)

Drug/Metabolite

Covalent Binding

Antigenic peptide

Adaptive Immunity Immune Tolerance

No injury Mild Liver Injury

Severe Liver Injury Immune Tolerance

IDILI

ALF (Hy´s Law)

Resolution

Clinical adaptation

Susceptible HLA

10-30%

WT HLA

70-90%

~20%

~2-10%

DEFECTIVE

ADAPTATION

< 1%

ADAPTATION

> 90% of

susceptibles

< 0.1% Dara, Liu and Kaplowitz Liver Intern 2015; in press

Clinical manifestation and outcome

Immune/ inflammation

RepairTissue injury

Drug

Host factors

Genetic variantsRace/ethnicity

AgeGender

Reproductive statenutrition, alcohol, smoking

Lifestyles Disease conditions

MedicationsGut flora

Drug properties

PhysiochemicalPharmacological

ToxicologicalBio-physiological effects

Host response to injury insult

Cellular injury initiation

Pharmacological responsesReactive metabolites, drug elimination

Toxicological responsesCovalent binding, haptenization,

oxidative stress, mitochondrial injury, ER stress

Cell deathApoptosis, necrosis, DAMP release

Chen et al J Hepatol 2015 Apr 22. pii: S0168-8278(15)00299-8. doi: 10.1016/j.jhep.2015.04.016

-Doses ≥ 50 mg/daily associated with death, liver failure

and liver transplantation1

•-Majority (77%) of the drugs incriminated in DILI in the

SADRAC and Spanish DILI Registry were prescribed at

doses ≥ 50 mg/daily1,2

•-Many false positives

Toxic potential of the drug in IDILI: the effect of dose

1 Lammert et al Hepatology 2008; 47: 2003-2009,

2 Lucena et al Hepatology 2009; 49: 2001-2009.

Chen, Borlak and Tong et al. Hepatology 2013

Lipophilicity (octanol/water > 3) and High Daily Dose (> 100 mg/day) (the rule of two)

¡Many false negatives!

Morgan et al Toxicol Sci 2010

Drug interference with BSEP function

¡Many false negatives!

Proper case definition and reliable epidemiology Identification of susceptible subjects and

mechanisms

Clinical and histological phenotypic characterization

Prediction of severe outcomes Diagnosis

Type of liver injury and gender

• Liver biopsies from 249 cases of suspected DILI blindly reviewed – 18 DILI patterns identified

Kleiner et al., Hepatology, 2014 ;59:661-70

.1

1

10

100

1 2 3 4 5 10

Acute

Hepatitic

Chronic

Hepatitic

Acute

Cholestatic

Chronic

Cholestatic

Cholestastic

Hepatitic

Zonal

Necrosis

R

8 74 25 23 35 51

Age and gender as DILI risks

N

umbe

r of

cas

es

DILI according to age and gender

Age (years) Type of liver injury according to age and gender

Peak age of DILI

occurs earlier in

women (40-49 vs

60-69 years)

Women <60 years are

more prone to develop

hepatocellular DILI,

while men >60 years

cholestatic DILI

Lucena et al, Hepatology 2009

DAÑO HEPATOCELULAR DAÑO COLESTÁSICO

*p<0.001 †p<0.001 **p=0.012

††p=0.01

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.

Proper case definition and reliable epidemiology Identification of susceptible subjects and

mechanisms

Clinical and histological phenotypic characterization

Prediction of severe outcomes Diagnosis

Risk of drug-induced acute liver failure (ALF)

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

Logistic regression analysis of demographic, clinical and laboratory parameters in

DILI cases with (31) and without (774) ALF resulting in death or OLT

Gastroenterology 2014; 147: 109-118

ALF incidence rate: 32 of 771 DILI patients (4.2%)

Robles-Díaz M et al Gastroenterology 2014; 147(1):109-118.

Prognostic algorithm for ALF in DILI Chi-squared automatic interaction detection (CHAID)

Specificity 82%

Sensitivity 80%

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):109-118.

(better Hy’s Law ?)

Need to improve prediction of severe DILI outcome?

Days to resolution

0-60 61-90 91-180 181-365 366-730 731-1095 1096-2000 2001-3020

Hepatocellular cases (N=193)

71 30 57 27 4 3 1 -

Cholestatic cases (N=46)

9 8 17 10 - - 2 -

Mixed cases (N=46)

15 13 12 4 1 - - 1

The inset shows the same data on an enlarged y axis

p=0.4 by long-rank

test

Chol, p= 0.95

HC, p= 0.9

Mix , p= 0.97

348 d

Abbreviations: Chol: cholestatic, HC: hepatocellular, Mix: mixed

Chronicity definition

Robles-Díaz et al unpublished data 2015

Proper case definition and reliable epidemiology Identification of susceptible subjects and

mechanisms

Clinical and histological phenotypic characterization

Prediction of severe outcomes Diagnosis

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: 683-691

¡There is an urgent need of

Specific biomarkers!

•Bacterial Hepatitis •Wilson´s Disease

•Deficit of α- 1antitrypsin

•Haemocromatosis

A, B, C, E

Viral

hepatitis Biliary

obstruction

Autoinmune

Hepatitis.

PBC

Alcoholic

Hepatitis

Isquemic

Hepatitis

Diseases

Dalton et al Aliment Pharmacol Ther 2007 Davern et al Gastroenterology 2011

• 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;46:1323-1330

CIOMS/RUCAM

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: 683-691

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

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

Collaborating hosptial units in the Spanish DILI Registry