Drug-Induced Liver Injury(DILI)

Dominique Pessayre, M.D.

INSERM U 773, Faculté de Médecine Xavier Bichat, Paris

et Hôpital Beaujon, Clichy,France

> 1000 Hepatotoxic drugs

Diversemechanisms

Variety of liver diseases

DIVERSITY

METABOLIC ACTIVATION

Protein

(Low Amounts)

Immune reactions

Extensive covalent binding GSH

(High Amounts)

Direct toxicity

Reactive metabolite

Drug

CYP

Drugs

Beta-oxidation

Respi-ration

Steatosis Cell dysfunctionCell death

Lactic acidosis

MITOCHONDRIAL DYSFUNCTION

Theseand other

mechanisms

Diverse liver diseases

ACUTE HEPATITIS Cytolytic hepatitis Subacute or chronic hepatitis 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

ACUTE DILI CHRONIC DILI

BOO EZ

DR UG

COKE

Burger BLOOD

Obesity/diabetes

Abnormallivertests

HCVHBV

FOURTH CAUSE

9%**Bagheri,Br J Clin Pharmac2000;50:479.

Yearly incidence rate

DILI: 14/100 000 inhabitants/year = 8 000 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.

DISPROPORTIONATE ROLEIN FULMINANT HEPATITIS

IN THE US AND UK

Drugs: first cause

FULMINANT HEPATITIS

in the USA

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

FULMINANT HEPATITIS IN THE USA

OTHER CAUSES: 48%

OTHER DRUGS: 12%

PARACETAMOL: 40%

DRUGS: 52% Intentional overdoses Self medication withexcessive doses in the USA

DILI:IMPORTANT

LEGAL AND/OR FINANCIAL IMPLICATIONS

Continued treatment

ALAT

1 ULN

5 ULN

DRUG

3. Fulminant hepatitis

1. Adaptation

2. Chronic liver

disease

FOR THE PHYSICIAN

DILI: Major cause for drug withdrawalor prescribing restrictions

Recent cases:

XimelagatranTroglitazoneBromofenac

FelbamatePemolineTolcaponeTrovafloxacin

FOR THE PHARMACEUTICAL INDUSTRY

POOL OFHEPATOTOXIC

DRUGS

NEWHEPATOTOXIC DRUGS

ARE MARKETED

DRUG RECALL

DIFFICULTY IN PREDICTINGTHE HEPATOTOXIC

POTENTIAL OF DRUGSBEFORE MARKETING

Toxicitystudies

&Clinical

trials

Frequenthepatotoxicity

Idiosyncraticliver injury?

Drug candidates

?

CLINICAL

INFRA-CLINICAL

15% Transaminases

1% Jaundice0.1% Death

30% Transaminases

Monreal, Eur J Clin Pharmacol1989;37:415

Unfractionatedheparin Isoniazid

Black, Gastroenterology , 1975;69:289

Huang, Hepatology2002;35:883-889

ALT > 10 ULN

Hy’s rule

Mortality of drug-inducedhepatocellular jaundice: 10%

Example: 5 of 1 000 patients have

ALAT > 10 ULN and bilirubin > 3 ULNin a clinical trial

You can expect: 5 deaths with liver failure for 10 000 recipients

after marketing

EVEN A MARKEDLY HEPATOTOXIC DRUGCAN SOMETIMES BE MARKETED

- when the drug is required to treat a serious disease

- and no safer drug is available

LFT MONITORING

TRANSAMINASEMONITORING:

USEFUL OR USELESS?

TRANSAMINASE MONITORING

Infrequent

ALAT > 5 ULN Stop treatment

Frequent

(e.g., tacrine)

No jaundice

2 Weeks 4 Weeks

WARN THE PATIENT

“ Consult and have liver tests performed if you don’t feel well ”

“Stop treatment immediatelyshould you become jaundiced”

Rather than infrequent LFT monitoring,it’s best to

CAN WE PREDICTWHICH PATIENT

WILL DEVELOP DILI?

Youngadults

DILI and age

High drugconsumption

Old Children

Exceptions: Reye’s syndrome with

aspirin and Reye-like syndrome with

valproate

> >

Susceptibility(e.g., isoniazid)

(Same in females and males before 50)

DILI and gender

Sgro, Hepatology 2002;36:451

Incidence of DILI: 2.6-fold higher in females than males

in persons aged 50 years or more

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)

DILI in cirrhosis

DILI and VIRAL INFECTIONS

Viral Hepatitis DILI

HAART

Anti-tuberculousdrugs

Paracetamol

Varicella, inflenza Reye Aspirin

NASH,Alcohol abuse, Viral Infections,Pregnancy,Inborn -oxidation

defects, Mitochondrial

cytopathies

DRUG(S) + OTHERCONDITION(S)

Additively impairmitochondrial function

Liver disease

ADDITIVE IMPAIRMENT OFMITOCHONDRIAL FUNCTION

Large doses ofparacetamol

Hepatitis due to direct toxicity

CYP2E1

CYP INDUCTION AND/OR MALNUTRITIONCAN INCREASE THE DIRECT TOXICITY

OF REACTIVE METABOLITES

Large amountsof a reactivemetabolite

GSH

Susceptibility:

Alcohol abuse Malnutrition

THE N-ACETYL-TRANSFERASE POLYMORPHISMCAN MODULATE AUTOIMMUNE HEPATITIS

More frequent hepatitis

Dihydralazine

Reactive metabolite

CYP1A2-metabolite adducts

Anti-CYP1A2 autoantibodies

CYP1A2

Extensive acetylators

NAT2Dihydralazine

Reactive metabolite

CYP1A2-metabolite adducts

Anti-CYP1A2 autoantibodies

CYP1A2

Poor acetylators

Uncommon hepatitis

Bourdi, Mol Pharmacol 1994;45:1287

MHC POLYMORPHISMS CAN MODULATE IMMUNOALLERGIC HEPATITIS

Metabolite

Peptide

MHC/HLA(Each MHC molecule presents

different series of peptides)

Amoxicillin & Clavulanic Acid-Induced Hepatitis

Hautekeete, Gastroenterology 1999;117:1181

HLA class II haplotype:DRB1*1501-DRB5*01101-DQB1*0602

Patients: 57% Controls: 13%

Acute cholangitis and vanishing bile duct syndrome

Hepatocyte

Bileduct *Lakehal,

Chem Res Toxicol 14;6:694

NO

A

COOH

R

A: O in clavulanic acid S in flucloxacillin

Covalent binding

Toxicity*

T cell reactivity

and immune reactions*

Opening of the -lactam ring

*Mauri-Hellweg, J Immunol

1996;157:1071

HOW CAN THE DIAGNOSISBE MADE?

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

Drug withdrawal

ALAT

1 ULN

10 ULN

DRUG

Fewweeks

Specific antibodies

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

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

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

Lymphocyte proliferation assay

1

2

4

8

16

32

34%

56%

100% 100%

95 ptswith DILI

106 controls

35 treated ptswithout DILI

(26% without

indo-meth-acin)

With/without drug [3H]thymidine incorporation ratio(with indomethacin to prevent inhibitory PGE2 formation)

Maria and Victorino,Gut 1997;41:534-540

PREVENTION OFRECURRENCE

- Warn the patient and his/her doctors against using the drug again.

- Give the patient a list of all pharmaceutical specialties containing the drug, in order to avoid inadvertent rechallenge.

1. Performing a rechallenge for the sake ofdiagnosis is unethical, and is particularly risky if

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 are less active;- one suspects direct toxicity (rather than

immunoallergy);- one use lower doses (or different

co-medications…); - and transaminases are monitored frequently.

RECHALLENGE

CONCLUSION

TWO GOLDEN RULES1. Always consider

the possibility of DILI

2. Immediately withdrawall suspected drugs

in severe cases

DILI: Difficult to avoid, predict and diagnose

Avoid most mishaps