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Drug-Induced Liver Injury (DILI). Dominique Pessayre, M.D . INSERM U 773, Faculté de Médecine Xavier Bichat, Paris et Hôpital Beaujon, Clichy, France . DIVERSITY. > 1000 Hepatotoxic drugs. Diverse mechanisms. Variety of liver diseases. METABOLIC ACTIVATION. Drug. CYP.

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slide1

Drug-Induced Liver Injury

(DILI)

Dominique Pessayre, M.D.

INSERM U 773,

Faculté de Médecine Xavier Bichat, Paris

et Hôpital Beaujon, Clichy,

France

slide2

DIVERSITY

> 1000 Hepatotoxic drugs

Diverse

mechanisms

Variety of liver diseases

slide3

METABOLIC ACTIVATION

Drug

CYP

Reactive metabolite

(High Amounts)

  • (Low Amounts)

Extensive

covalent

binding

 GSH

Protein

Immune reactions

Direct toxicity

slide4

MITOCHONDRIAL DYSFUNCTION

Drugs

 Beta-

oxidation

 Respi-

ration

Cell dysfunction

Cell death

Lactic acidosis

Steatosis

slide5

These

and other

mechanisms

Diverse liver diseases

slide6

ACUTE DILI

CHRONIC DILI

ACUTE HEPATITIS

Cytolytic hepatitis Subacute or chronichepatitis

Mixed hepatitis

Cholestatic hepatitis

+ cholangi(oli)tis Vanishing bile duct syndrome

Bland cholestasis

Steatosis Steatohepatitis

Sinusoidal dilation, Peliosis

VOD (« SOS »), Budd-Chiari

Hepatic adenoma, HCC

slide7

C

E

K

O

FOURTH CAUSE

B

E

O

Z

O

D

B

O

L

O

Burger

HCV

HBV

G

D

R U

Obesity/

diabetes

*Bagheri,

Br J ClinPharmac

2000;50:479.

9%*

Abnormal

liver

tests

slide8

Yearly incidence rate

DILI: 14/100 000 inhabitants/year

= 8000 cases/ year in France

(16-times the number reported to the French Pharmacovigilance Agency)

Fatal DILI (0.8/100 000 inhabitants/year)

6%

Sgro, Hepatology 2002;36:451.

slide9

DISPROPORTIONATE ROLE

IN FULMINANT HEPATITIS

IN THE US AND UK

slide10

Drugs: first cause

FULMINANT HEPATITIS

in the USA

slide11

PARACETAMOL:40%

Intentional overdoses

Self medication with

excessive doses in the USA

DRUGS: 52%

OTHER DRUGS: 12%

OTHER CAUSES: 48%

FULMINANT HEPATITIS IN THE USA

Lee WM, Sem Liver Dis, 2003;23:217

slide12

DILI:

IMPORTANT

LEGAL AND/OR FINANCIAL

IMPLICATIONS

slide13

FOR THE PHYSICIAN

Continued treatment

3. Fulminant

hepatitis

ALAT

2. Chronic

liver

disease

5ULN

1. Adaptation

1 ULN

DRUG

slide14

FOR THE PHARMACEUTICAL INDUSTRY

DILI: Major cause for drug withdrawal

or prescribing restrictions

Recent cases:

Ximelagatran

Troglitazone

Bromofenac

Felbamate

Pemoline

Tolcapone

Trovafloxacin

slide15

NEW

HEPATOTOXIC DRUGS

ARE MARKETED

POOL OF

HEPATOTOXIC

DRUGS

DRUG RECALL

slide16

DIFFICULTY IN PREDICTING

THE HEPATOTOXIC POTENTIAL OF DRUGS

BEFORE MARKETING

slide17

Drug candidates

Toxicity

studies

&

Clinical

trials

Frequent

hepatotoxicity

?

Idiosyncratic

liver injury?

slide18

Black, Gastroenterology , 1975;69:289

0.1% Death

CLINICAL

1% Jaundice

INFRA-

CLINICAL

ALT > 10 ULN

Unfractionated

heparin

Isoniazid

30%  Transaminases

15%  Transaminases

Monreal, Eur J Clin Pharmacol

1989;37:415

Huang, Hepatology

2002;35:883-889

slide19

Hy’s rule

Mortality of drug-induced

hepatocellular jaundice: 10%

Example:

5 of 1000 patients have

ALAT > 10 ULN and bilirubin > 3 ULN

in a clinical trial

You can expect:

5 deaths with liver failure for 10 000 recipients

after marketing

slide20

EVEN A MARKEDLY HEPATOTOXIC DRUG

CAN SOMETIMES BE MARKETED

  • when the drug is required to treat a serious disease
  • - and no safer drug is available

LFT MONITORING

slide21

TRANSAMINASE

MONITORING:

USEFUL OR USELESS?

slide22

2 Weeks

TRANSAMINASE MONITORING

4 Weeks

Frequent

(e.g., tacrine)

ALAT > 5 ULNStop treatment

No jaundice

Infrequent

slide23

Rather than infrequent LFT monitoring,

it’s best to

WARN THE PATIENT

“ Consult and have liver tests performed

if you don’t feel well ”

“Stop treatment immediately

should you become jaundiced”

slide24

CAN WE PREDICT

WHICH PATIENT

WILL DEVELOP DILI?

slide25

DILI and age

High drug

consumption

Young

adults

Old

>

>

Children

Exceptions: Reye’s syndrome with aspirin and Reye-like syndrome with valproate

  • Susceptibility

(e.g., isoniazid)

slide26

DILI and gender

Incidence of DILI:

2.6-fold higher in females than males

in persons aged 50 years or more

(Same in females and males before 50)

Sgro, Hepatology 2002;36:451

slide27

DILI in cirrhosis

CIRRHOSIS

  • - Does not change the incidence of DILI
  • but worsens it outcome
  • (The same degree of liver injury, which is well tolerated in a normal subject, can trigger liver failure, complications and death in patients with an already impaired liver function)
slide28

DILI and VIRAL INFECTIONS

Paracetamol

Viral Hepatitis

 DILI

Anti-tuberculous

drugs

HAART

 Reye

Varicella, inflenza

Aspirin

slide29

ADDITIVE IMPAIRMENT OF

MITOCHONDRIAL FUNCTION

NASH,

Alcohol abuse,

Viral Infections,

Pregnancy,

Inborn b-oxidation

defects,

Mitochondrial

cytopathies

DRUG(S) +

OTHER

CONDITION(S)

Additively impair

mitochondrial function

Liver disease

slide30

CYP INDUCTION AND/OR MALNUTRITION

CAN INCREASE THE DIRECT TOXICITY

OF REACTIVE METABOLITES

Large doses of

paracetamol

Susceptibility:

CYP2E1 

Alcohol abuse

Malnutrition

Large amounts

of a reactive

metabolite

 GSH

Hepatitis due to

direct toxicity

slide31

THE N-ACETYL-TRANSFERASE POLYMORPHISM

CAN MODULATE AUTOIMMUNE HEPATITIS

Extensive acetylators

Poor acetylators

Dihydralazine

Dihydralazine

NAT2

CYP1A2

CYP1A2

Reactive metabolite

Reactive metabolite

CYP1A2-metabolite adducts

CYP1A2-metabolite adducts

Anti-CYP1A2 autoantibodies

Anti-CYP1A2 autoantibodies

Uncommon hepatitis

Morefrequent hepatitis

Bourdi, Mol Pharmacol 1994;45:1287

m hc polymorphisms can modulate immunoallergic hepatitis
MHC POLYMORPHISMS CAN MODULATE IMMUNOALLERGIC HEPATITIS

Metabolite

Peptide

MHC/HLA

(Each MHC molecule presents different series of peptides)

slide33

Amoxicillin & Clavulanic Acid-

Induced Hepatitis

HLA class II haplotype:

DRB1*1501-DRB5*01101-DQB1*0602

Patients: 57% Controls: 13%

Hautekeete, Gastroenterology 1999;117:1181

slide34

Acute cholangitis and

vanishing bile duct syndrome

A: O in clavulanic acid

S in flucloxacillin

Hepatocyte

R

A

N

O

COOH

Opening of the b-lactam

ring

Bile

duct

Covalent binding

Toxicity*

T cell reactivity

and immune reactions*

*Lakehal,

Chem Res Toxicol

14;6:694

*Mauri-Hellweg,

J Immunol

1996;157:1071

slide36

DIAGNOSIS

  • Always consider a possible iatrogenic cause
  • Insistent questioning
  • (Analgesic drugs, illicit drugs, psychoactive drugs, NSAIDs, over-the-counter drugs,
  • herbal remedies)
  • Compatible chronology (DILI may sometimes appear 2 weeks after treatment is stopped)
  • Fever, rash, eosinophilia (immunoallergic mech.)
  • Similarity to previously reported cases
  • Exclusion of other causes
  • (obesity/diabetes, alcohol, …viral serologies, ultrasonography)
  • Deceleration after withdrawal
slide37

Drug withdrawal

ALAT

Few

weeks

10ULN

1 ULN

DRUG

specific antibodies
Specific antibodies

Autoantibodies

Tienilic acid anti-LKM2 (anti-CYP2C)Beaune, PNAS 1987;84:551

Dihydralazine anti-LM (anti-CYP1A2)Bourdi, JCI 1990;85:1967

Halothane anti-CYP2E1 Eliasson, Mol Pharmacol 1996;50:573

Germander anti-EH de Berardinis, Mol Pharmacol 2000;58:542

Iproniazid anti-M6 (anti-MAO B)Pons, BBRC 1996;218:1118

Anti-metabolite-protein adduct antibodies

Halothane anti-TFA-protein Kenna, JPET 1998;245:1103

Tienilic acid anti-TA-protein Robin, JCI 1996;98:1471

Diclofenac anti-Diclof.-proteinAithal, Hepatology 2004;39:1430

slide39

Lymphocyte proliferation assay

With/without drug [3H]thymidine incorporation ratio

(with indomethacin to prevent inhibitory PGE2 formation)

56%

32

16

Maria and Victorino,

Gut 1997;41:534-540

8

(26% without

indo-

meth-

acin)

4

2

100%

100%

34%

1

95 pts

with DILI

106

controls

35 treated pts

without DILI

slide40

PREVENTION OF

RECURRENCE

slide41

Warn the patient and his/her doctors

  • against using the drug again.
  • Give the patient a list of all
  • pharmaceuticalspecialties containing
  • the drug,in order to avoidinadvertent
  • rechallenge.
slide42

RECHALLENGE

  • Performing a rechallenge for the sake of
  • diagnosis is unethical, and is particularly riskyif
  • immunoallergy is suspected(risk of rapid and
  • severe DILI).
  • 2. However, re-introduction may be attempted if:
  • - the drug is required to treat a serious disease;
  • - other drugs areless active;
  • - one suspects directtoxicity (ratherthan
  • immunoallergy);
  • - one use lower doses (or different
  • co-medications…);
  • -and transaminasesare monitored frequently.
slide43

CONCLUSION

DILI: Difficult to avoid, predict and diagnose

TWO GOLDEN RULES

1. Always consider

the possibility of DILI

2. Immediately withdraw

all suspected drugs

in severe cases

Avoid most mishaps