Hepatitis aguda tóxica Hepatitis aguda tóxica

Raúl J. Andrade

Hospital Universitario Virgen de la Victoria

Universidad de MálagaUniversidad de Málaga

• 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

Drug-induced Liver injuryDrug-induced Liver injury

Most type B reactions

detected here

0

5000

10000

15000

20000

25000

PHASE 1 PHASE 2 PHASE 3 PHASE 4

50 volunteers 250 patients

Nu

mb

er

of

su

bje

cts

Most type A reactions detected

here

Marketing Authorisation

2,000 patients Many 1,000’s

The Phases of Drug Development

ORGANORGAN NoNo

CardiovascularCardiovascular 6464

LiverLiver42(19%)42(19%)

MusculoskeletalMusculoskeletal 1515

Immune systemImmune system 1313

KidneyKidney 1212

CNSCNS 1010

TestesTestes 1010

GastrointestinalGastrointestinal 88

Genetic toxicologyGenetic toxicology 77

Reproductive toxicityReproductive toxicity 77

Attrition of compounds during development: main reasons for failure

225 drugs were analysedSafety Biomarker Working Group ABPI

70% of drugs withdrawn from US market 1980-2005 were analgesics,cardiovascular, antiinfectives

Acute liver failure in US and transplant-free survival

Fontana Sem Liver Dis 2008

• Epidemiology and drugs most commonly

involved

• Phenotypes

• Risk factors: envirommental and genetic

• Mechanisms: pathways of damage

• Diagnosis

• Therapy

Drug-induced Liver injury: what are the questions to be addressed

Drug-induced Liver injury: what are the questions to be addressed

Prescrip

tion rate p

er person

15-24

Björnsson et al Gastroenterology 2013

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

Liver injury in Iceland n=251,860

Annual Incidence of DILI 19.1 per 100.000

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 70Diclofenac 54,889 112,801 6 9148 11 4 24Azathioprine 532 3054 4 133 752 205 1914Infliximab 593 a 4 148 675 184 1718Nitrofurantoin 5476 12,034 4 1369 73 20 187Isotretinoin 2169 7978 3 732 138 29 404Atorvastatin 7385 34,171 2 3693 27 4 98Doxycycline 32,677 54,232 2 16,339 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

Björnsson et al Gastroenterology 2013

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

Liver injury in Iceland n=251,860

PHENOTYPES OF PHENOTYPES OF ““IDIOSYNCRATIC” DILIIDIOSYNCRATIC” DILI

• HEPATOCELLULAR: HEPATOCELLULAR: Alanine aminotransferase Alanine aminotransferase (ALT) predominantly raised (ALT) predominantly raised (ALT/AP>5)(ALT/AP>5)

• CHOLESTATIC: Alkaline CHOLESTATIC: Alkaline phosphatase (AP) phosphatase (AP) predominantly raised predominantly raised (ALT/AP <2)(ALT/AP <2)

• MIXED ALT & ALP are MIXED ALT & ALP are increased, and increased, and 2<ALT/ALP<52<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 Drug-

Induced Liver Injury Network.

SLADILIN, 2013

Hepatocellular R≥5, Cholestatic R≤2, Mixed R<2 y R>5

Lucena et al. Hepatology 2009Lucena et al. Hepatology 2009

Type of liver damage according to sex in patients younger or older than 60 years of age (n=603)

Factors influencing clinical expression and early outcome of DILI

Andrade RJ et al. Gastroenterology 2005; 129: 512-521

• Hepatocellular pattern damage

– most common (58%)– inversely correlated with age (P < .0001)

– & had worst outcome (Cox regression, P < 0.034)

Development/Progression of Drug Induced Liver Injury

Initiation of injury Adaptation

Regeneration/repairClinical manifestation

Severe Injury

Increased Susceptibility

Elevated aminotransferases Resolves despite continuing therapy

Symptomatic (N/V, anorexia, fatigue)

Liver dysfunctionjaundice

Liver failure/Death

Cure

Variables Coefficient OR (95% CI)

Female Sex 3.220

Hepatocellular 2.064damage

Total Bilirubin 0.143

25.04 (4.14-151)

7.87 (1.68-36.9)

1.15 (1.09-1.22)

<.0001

<.009

<.0001

Andrade et al, Gastroenterology 2005

P value

Constant = -8.7 Abbreviations: CI, confidence interval; OR, odds ratio.

Risk factors for acute liver failure in DILI

• 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 2010Reuben, Koch and Lee Hepatology 2010

Drug-induced acute liver failure in USA(1998-2007)

Toxic potential of the drug

Reactive metabolites Mitochondrial effectsBSEP effects

Genetic factors

bioactivation detoxication transport Others: immune response MHC, etc.

Envirommental factors

drugs alcohol Age, gender HIV, HCV, HBV

Kaplowitz,AASLD 2002

Interplay of drug-related, environmental and host factors in the susceptibility to develop DILI

Agents toxic for all exposed

individuals and species e.g. white

phosphorus

0 2 + 4 +

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

4 +

2 +

Relative importance of Susceptibility of HostRel

ativ

e im

port

ance

of

Intr

insi

c T

oxic

ty o

f A

gent Intrinsic vs Idiosyncrasyc liver damage

Zimmerman H, Textbook of hepatotoxicity 1976

• 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

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

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

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 Chen et al. Hepatology 2013

Morgan et al Toxicol Sci 2010

Drug interference with BSEP function

GWAS: Chromosome 6 (HLA genes)

Flucoxacillin: HLA-B57*01A-C and lumiracoxib: HLA-DRB1*1501-DQB1*0602HLA –A*0201Ximelagatran

Daly et al Nat Genet 2009Lucena et al Gastroenterology 2011

Kaplowitz Hepatology 2013

Gene Drug OR

HLA-B57*01

HLA-DRB1*1501-DQB1*0602HLA –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 2009Stewart et al Hepatology 2010, Lucena et al Gastroenterology 2011

Diagnostic Predictive Value Value

Can genetic variants in DILI be used as biomarkers?

Antoine et al Hepatology 2013

miRNA-122, HMGB1 and necrosis K18 as early biomarkers of paracetamol DILI

Suspicion

Drug exposure dataand chronology Not compatible

If compatible assess

Hepatotoxic potential

Search for an alternative diagnosis

Found

Specific therapy

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”

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” 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

• 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 ≤0Probable 6-8 Unlikely 1-2

J Clin Epidemiol 1993;46:1323-1330

CIOMS/RUCAM

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”Do not substitute common sense “clinical judgement”Designed for finding support for and less for Designed for finding support for and less for

excluding causalityexcluding causality

• 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

RUCAM limitations

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)

• 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

Summary

Maribel LucenaCamilla Stephens

Inma MorenoInma Medina

Eugenia Ulzurrun Mercedes Robles

Miren García-Cortés

Esperanza Crespo Ramón Hidalgo

Mª Rosario Cabello

Acknowledgements

InInter SAE Consortium, Ltd.

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

AXIS

CHRONOLOGICAL CRITERIA

From drug intake until onset eventFrom drug withdrawal until onset eventCourse of the reaction

RISK FACTORSAgeAlcohol

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

CIOMS/RUCAM (1990)

SCORE   

+1 to +3-3 to +3

0 to +3 

-3 to +3

0 to +3

-3 to +2

0 to +3

AXIS

CHRONOLOGICAL CRITERIA

From drug intake until onset eventFrom drug withdrawal until onset eventCourse of the reaction

EXCLUSION ALTERNATIVE

EXTRAHEPATIC MANIFESTATION

BIBLIOGRAPHICAL DATA

RECHALLENGE

Maria & Victorino/CDS (1997)

Probability of DILICIOMS:

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

Probability of DILICIOMS:

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

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