Transcript Présentation PowerPoint

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
Reactive metabolite
(Low Amounts)
(High Amounts)
Extensive
covalent
Protein
binding
 GSH
Immune reactions
Direct toxicity
MITOCHONDRIAL DYSFUNCTION
Drugs
 Betaoxidation
 Respiration
Steatosis
Cell dysfunction
Cell death
Lactic acidosis
These
and other
mechanisms
Diverse liver diseases
ACUTE DILI
CHRONIC DILI
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
FOURTH CAUSE
C O KE
BO ZE
O
Burger
Obesity/
diabetes
B L OOD
HCV
HBV
D R UG
*Bagheri,
9%*
Br J Clin Pharmac
2000;50:479.
Abnormal
liver
tests
Yearly incidence rate
DILI:
6%
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)
Sgro, Hepatology 2002;36:451.
DISPROPORTIONATE ROLE
IN FULMINANT HEPATITIS
IN THE US AND UK
Drugs: first cause
FULMINANT HEPATITIS
in the USA
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
DILI:
IMPORTANT
LEGAL AND/OR FINANCIAL
IMPLICATIONS
FOR THE PHYSICIAN
Continued treatment
ALAT
3. Fulminant
hepatitis
2. Chronic
liver
disease
5 ULN
1 ULN
1. Adaptation
DRUG
FOR THE PHARMACEUTICAL INDUSTRY
DILI: Major cause for drug withdrawal
or prescribing restrictions
Recent cases:
Ximelagatran
Troglitazone
Bromofenac
Felbamate
Pemoline
Tolcapone
Trovafloxacin
NEW
HEPATOTOXIC DRUGS
ARE MARKETED
POOL OF
HEPATOTOXIC
DRUGS
DRUG RECALL
DIFFICULTY IN PREDICTING
THE HEPATOTOXIC
POTENTIAL OF DRUGS
BEFORE MARKETING
Drug candidates
Frequent
hepatotoxicity
Idiosyncratic
liver injury?
?
Toxicity
studies
&
Clinical
trials
Black, Gastroenterology , 1975;69:289
CLINICAL
INFRACLINICAL
0.1% Death
1% Jaundice
ALT > 10 ULN
Unfractionated
heparin
Isoniazid
30%  Transaminases 15%  Transaminases
Monreal, Eur J Clin Pharmacol
1989;37:415
Huang, Hepatology
2002;35:883-889
Hy’s rule
Mortality of drug-induced
hepatocellular jaundice: 10%
Example:
5 of 1 000 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
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
TRANSAMINASE
MONITORING:
USEFUL OR USELESS?
TRANSAMINASE MONITORING
2 Weeks
4 Weeks
Frequent
(e.g., tacrine)
ALAT > 5 ULN
Infrequent
Stop treatment
No jaundice
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”
CAN WE PREDICT
WHICH PATIENT
WILL DEVELOP DILI?
DILI and age
High drug
consumption
Old
 Susceptibility
(e.g., isoniazid)
>
Young
>
adults
Children
Exceptions: Reye’s
syndrome with
aspirin and Reye-like
syndrome with
valproate
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
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)
DILI and VIRAL INFECTIONS
Viral Hepatitis
 DILI
Paracetamol
Anti-tuberculous
drugs
HAART
Varicella, inflenza
 Reye
Aspirin
ADDITIVE IMPAIRMENT OF
MITOCHONDRIAL FUNCTION
DRUG(S) + OTHER
CONDITION(S)
Additively impair
mitochondrial function
Liver disease
NASH,
Alcohol abuse,
Viral Infections,
Pregnancy,
Inborn b-oxidation
defects,
Mitochondrial
cytopathies
CYP INDUCTION AND/OR MALNUTRITION
CAN INCREASE THE DIRECT TOXICITY
OF REACTIVE METABOLITES
Large doses of
paracetamol
CYP2E1 
Large amounts
of a reactive
metabolite
Susceptibility:
Alcohol abuse
Malnutrition
 GSH
Hepatitis due to
direct toxicity
THE N-ACETYL-TRANSFERASE POLYMORPHISM
CAN MODULATE AUTOIMMUNE HEPATITIS
Extensive acetylators
Poor acetylators
Dihydralazine
Dihydralazine
CYP1A2 NAT2
Reactive metabolite
CYP1A2
Reactive metabolite
CYP1A2-metabolite adducts
CYP1A2-metabolite adducts
Anti-CYP1A2 autoantibodies Anti-CYP1A2 autoantibodies
Uncommon hepatitis
More frequent 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 AcidInduced Hepatitis
HLA class II haplotype:
DRB1*1501-DRB5*01101-DQB1*0602
Patients: 57% Controls: 13%
Hautekeete, Gastroenterology 1999;117:1181
Acute cholangitis and
vanishing bile duct syndrome
A: O in clavulanic acid
S in flucloxacillin
Hepatocyte
R
A
N
O
Bile
duct
COOH
Opening of the b-lactam
ring
Covalent binding
*Lakehal,
Toxicity*
Chem Res Toxicol
14;6:694
T cell reactivity
and immune reactions*
*Mauri-Hellweg,
J Immunol
1996;157:1071
HOW CAN THE DIAGNOSIS
BE 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
10 ULN
1 ULN
DRUG
Few
weeks
Specific antibodies
Autoantibodies
Tienilic acid
anti-LKM2 (anti-CYP2C)
Dihydralazine anti-LM (anti-CYP1A2)
Halothane
anti-CYP2E1
Germander
anti-EH
Iproniazid
anti-M6 (anti-MAO B)
Beaune, PNAS 1987;84:551
Bourdi, JCI 1990;85:1967
Eliasson, Mol Pharmacol 1996;50:573
de Berardinis, Mol Pharmacol 2000;58:542
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.-protein
Aithal, Hepatology 2004;39:1430
Lymphocyte proliferation assay
With/without drug [3H]thymidine incorporation ratio
(
with indomethacin to prevent
32
inhibitory PGE2 formation)
16
8
56%
(26%
4
without
indomethacin)
Maria and Victorino,
Gut 1997;41:534-540
2
1
34%
100%
100%
95 pts
with DILI
106
controls
35 treated pts
without DILI
PREVENTION OF
RECURRENCE
- 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.
RECHALLENGE
1. Performing a rechallenge for the sake of
diagnosis 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.
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