drug-induced liver injury (dili) dominique pessayre, m.d. inserm u 773, faculté de médecine xavier...
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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
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> 1000 Hepatotoxic drugs
Diversemechanisms
Variety of liver diseases
DIVERSITY
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METABOLIC ACTIVATION
Protein
(Low Amounts)
Immune reactions
Extensive covalent binding GSH
(High Amounts)
Direct toxicity
Reactive metabolite
Drug
CYP
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Drugs
Beta-oxidation
Respi-ration
Steatosis Cell dysfunctionCell death
Lactic acidosis
MITOCHONDRIAL DYSFUNCTION
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Theseand other
mechanisms
Diverse liver diseases
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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
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BOO EZ
DR UG
COKE
Burger BLOOD
Obesity/diabetes
Abnormallivertests
HCVHBV
FOURTH CAUSE
9%**Bagheri,Br J Clin Pharmac2000;50:479.
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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.
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DISPROPORTIONATE ROLEIN FULMINANT HEPATITIS
IN THE US AND UK
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Drugs: first cause
FULMINANT HEPATITIS
in the USA
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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
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DILI:IMPORTANT
LEGAL AND/OR FINANCIAL IMPLICATIONS
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Continued treatment
ALAT
1 ULN
5 ULN
DRUG
3. Fulminant hepatitis
1. Adaptation
2. Chronic liver
disease
FOR THE PHYSICIAN
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DILI: Major cause for drug withdrawalor prescribing restrictions
Recent cases:
XimelagatranTroglitazoneBromofenac
FelbamatePemolineTolcaponeTrovafloxacin
FOR THE PHARMACEUTICAL INDUSTRY
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POOL OFHEPATOTOXIC
DRUGS
NEWHEPATOTOXIC DRUGS
ARE MARKETED
DRUG RECALL
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DIFFICULTY IN PREDICTINGTHE HEPATOTOXIC
POTENTIAL OF DRUGSBEFORE MARKETING
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Toxicitystudies
&Clinical
trials
Frequenthepatotoxicity
Idiosyncraticliver injury?
Drug candidates
?
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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
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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
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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
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TRANSAMINASEMONITORING:
USEFUL OR USELESS?
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TRANSAMINASE MONITORING
Infrequent
ALAT > 5 ULN Stop treatment
Frequent
(e.g., tacrine)
No jaundice
2 Weeks 4 Weeks
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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
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CAN WE PREDICTWHICH PATIENT
WILL DEVELOP DILI?
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Youngadults
DILI and age
High drugconsumption
Old Children
Exceptions: Reye’s syndrome with
aspirin and Reye-like syndrome with
valproate
> >
Susceptibility(e.g., isoniazid)
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(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
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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
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DILI and VIRAL INFECTIONS
Viral Hepatitis DILI
HAART
Anti-tuberculousdrugs
Paracetamol
Varicella, inflenza Reye Aspirin
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NASH,Alcohol abuse, Viral Infections,Pregnancy,Inborn -oxidation
defects, Mitochondrial
cytopathies
DRUG(S) + OTHERCONDITION(S)
Additively impairmitochondrial function
Liver disease
ADDITIVE IMPAIRMENT OFMITOCHONDRIAL FUNCTION
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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
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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
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MHC POLYMORPHISMS CAN MODULATE IMMUNOALLERGIC HEPATITIS
Metabolite
Peptide
MHC/HLA(Each MHC molecule presents
different series of peptides)
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Amoxicillin & Clavulanic Acid-Induced Hepatitis
Hautekeete, Gastroenterology 1999;117:1181
HLA class II haplotype:DRB1*1501-DRB5*01101-DQB1*0602
Patients: 57% Controls: 13%
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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
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HOW CAN THE DIAGNOSISBE MADE?
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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
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Drug withdrawal
ALAT
1 ULN
10 ULN
DRUG
Fewweeks
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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
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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
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PREVENTION OFRECURRENCE
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- 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.
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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
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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