Drug Induced Liver Disease:2010
7/24/2012 10:17 AM
Drug-Induced Liver Disease:
2012
Paul J. Pockros,MD
Director of Clinical Research, Scripps Translational
Science Institute
Director of Liver Disease Center and Senior
Consultant, Division of Gastro/Hepatology
Scripps Clinic
With thanks to Willis Maddrey,MD for many of these slides
Drug-Induced Liver Injury
• Occurs in small fraction of individuals
• Difficult to predict
• Major clinical problem; often life-threatening
• Leading cause of acute liver failure
• Reason drugs removed from development and widespread
use
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Drug Induced Liver Disease:2010
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Importance of DILI in US Drug Market
 DILI is the most common cause of death from
acute liver failure and accounts for approximately
13% of cases of ALF in US.
 DILI is the most frequent adverse drug event
leading to abandonment of otherwise promising
new drug candidates during preclinical or clinical
development
 DILI is most common reason for withdrawal or
restriction of prescription drug use after initial
approval.
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;35:731–739
Examples of Drugs Withdrawn Due to
Liver Disease
Iproniazid
Ibufenac (in Europe only)
Ticrynafen
Benoxaprofen
Perhexiline (in France)
Dilevalol (in Portugal, Ireland)
Bromfenac
Troglitazone
Serzone
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1975
1979
1982
1985
1990
1998
2000
2004
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Drug Induced Liver Disease:2010
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Putative Mechanisms
• Mechanism often involves drug metabolites
– Affect critical biochemical functions
– Specific immune responses
• Only a few drugs demonstrate these
underlying causes
• Tissue susceptibility: imbalance between
protoxicants and protectants
– Environmental factors
– Genetic polymorphism
Cellular mechanisms of drug hepatotoxicity.
Kaplowitz N Clin Infect Dis. 2004;38:S44-S48
© 2004 by the Infectious Diseases Society of America
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Hepatotoxicants Potentiated by Exposure to Small
Doses of Lipopolysaccharide (LPS)
Xenobiotics
Source
CCl4
Galactosamine
Ethanol
T2-toxin
Cadmium
Halothane
Lead
Allyl Alcohol
Aflatoxin B1
Chlorpromazine
Ranitidine
Formal et al., 1960
Galanos et al., 1979
Nolan et al., 1980
Tai and Petska, 1988
Cook et al.., 1974
Lind et al., 1984
Honchel et al., 1991
Sneed et al., 1997
Barton et al., 2000
Buchweitz et al., 2002
Luyendyk et al., 2003
Cellular Level Events of LPS
LPS
TLR4
Macrophages
Neutrophils
Endothelial Cells
Epithelial Cells
Cytokines
Coagulation Factors
Platelet Activating Factor
Complement Activation
Leukotrienes
Arachidonic Acid Metabolites
Prostaglandins
Reactive Oxygen Species
Nitric Oxide
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Drug Induced Liver Disease:2010
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Drug
Liver
Reactive
Protein
Metabolites
Protective
Adducts
Factors
Response
Cellular
Homeostasis
Toxicity
IL-6, IL-10, COX-2
Protection
Stress Proteins
Altered
Extensive
(Inhibition)
Liver Injury
And Death
Does a loss in hepatoprotective
factors result in drug-induced
liver disease?
Idiosyncratic Drug-Induced Liver Disease
•
Complex “multihit” process
• Liver protoxicants and protectants have a role
in the overall pathogenesis
– Environmental Factors
– Genetic polymorphisms
• Underproduction of hepatoprotective and
overproduction of hepatoprotoxicant factors
(i.e., imbalance) influences susceptibility to
this liver disease
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Determination of Susceptibility Factors
• Identification of liver protoxicant and protectant factors
results in better understanding of
mechanism and in
facilitating prediction of
drug-induced liver disease
– Inflammatory mediators
– COX-2 products
– Heat shock proteins
• Application of new technologies
– Toxicogenomics
– Proteomics
– Metabonomics
Is Idiosyncratic Drug-Induced Liver Injury
Dose Related?
Idiosyncratic Reactions
• Unpredictable
• Poorly Understood
• Likely Multifactorial
Drugs given at a dose
of < 10 mg/d rarely
associated with injury
598 Cases of DILI
Patients Taking:
77%
>50 mg/d
14%
11 - 49 mg/d
9%
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<10 mg/d
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Drug-Induced Liver Injury
Consider the Possibility
Often a Diagnosis of Exclusion
The Weight of Evidence Approach
Recognize That Underlying Liver
Injury Can Divert Attention From
the Role of a Drug
Importance of Deceleration After Withdrawal
Response Question #1
Which of the following are true statements about
drug-induced liver disease in the US:
1. DILI is caused by a single prescription
medication in most of the cases
2. DILI is caused by dietary supplements in most
of the cases
3. Antimicrobials account for > half of cases
4. CNS agents account for > half of cases
5. 1 and 2
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Causes of DILI in a Large Cohort NIH Trial
 DILI was caused by a single prescription
medication in 73% of the cases
 dietary supplements in 9%
 multiple agents in 18%
 antimicrobials (45.5%)
 central nervous system agents (15%)
 Causality was considered to be definite in 32%,
highly likely in 41%, probable in 14%.
Chalasani N,et al. Gastroenterology 2008;135:1924-34.
Risk factors for susceptibility to drug-induced hepatotoxicity.
Kaplowitz N Clin Infect Dis. 2004;38:S44-S48
© 2004 by the Infectious Diseases Society of America
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Inadequate
Disposition
Intermediates
Overproduction
Intermediates
Contributions of
the Innate
Immune System
Mechanisms
Intracellular
Accumulation
Site/Extent
Mitochondrial
Damage
P450 levels
Genetics
Immune
Response
Failure to Adapt
Disruption of
Oxidative
Phosphorylation
Aminotransferase Elevations in Healthy Adults
Receiving 4 Grams of Acetaminophen Daily
Watkins, 2006
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Response Question #2
Which prescription drug is the most common cause
of DILI in the US?
1. Acetaminophen
2. Amoxicillin/clavulanate
3. Nitrofurantoin
4. Isoniazid
5. Valproate
Most Common Drugs causing DILI
(out of 217 single Rx cases)
 Amoxicillin/clavulanate (n = 23)
 Nitrofurantoin (n = 13)
 Isoniazid (n = 13)
 TMP/SMX (n = 9)
 Duloxetine (n = 6)
 Valproate (n = 6)
 Interferon beta (n = 6)
 Ciprofloxacin (n = 5)
 Lamotrigine (n = 5)
 Methyldopa (n = 5)
 Telithromycin (5)
 Phenytoin (n = 5)
 Diclofenac (n = 4)
Chalasani N,et al. Gastroenterology 2008;135:1924-34.
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Most Common Drugs causing DILI
(out of 217 single Rx cases)
 Amoxicillin/clavulanate (n = 23)
 Nitrofurantoin (n = 13)
 Isoniazid (n = 13)
 TMP/SMX (n = 9)
 Duloxetine (n = 6)
 Valproate (n = 6)
 Interferon beta (n = 6)
 Ciprofloxacin (n = 5)
 Lamotrigine (n = 5)
 Methyldopa (n = 5)
 Telithromycin (5)
 Phenytoin (n = 5)
 Diclofenac (n = 4)
Chalasani N,et al. Gastroenterology 2008;135:1924-34.
Metabolism of Isoniazid in the Liver
Isoniazid
acetylation
Acetylisoniazid
N-acetyltransferase
(NAT2)
hydrolysis
Acetylhydrazine
oxidation
CYP 2EI
N-acetyltransferase
(NAT2)
Hepatotoxins
acetylation
Diacetylhydrazine
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NAT2 Slow Acetylator
Genotype and Susceptibility
NAT2 slow acetylator
(lacking wild type NAT2*4 allele)
26% vs. 11.1%
Cytochrome P450 2E1 Genotype And
Susceptibility to Isoniazid-Induced Hepatitis
Genotype
Risk of
Hepatotoxicity
CYP 2E1 c1/c1
20%
Odds Ratio
2.52
CYP 2E1 c1/c2
9%
Or
c2/c2
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Drug Induced Liver Disease:2010
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Most Common Drugs causing DILI
(out of 217 single Rx cases)
 Amoxicillin/clavulanate (n = 23)
 Nitrofurantoin (n = 13)
 Isoniazid (n = 13)
 TMP/SMX (n = 9)
 Duloxetine (n = 6)
 Valproate (n = 6)
 Interferon beta (n = 6)
 Ciprofloxacin (n = 5)
 Lamotrigine (n = 5)
 Methyldopa (n = 5)
 Telithromycin (5)
 Phenytoin (n = 5)
 Diclofenac (n = 4)
Chalasani N,et al. Gastroenterology 2008;135:1924-34.
Diclofenac
Serious
Hepatotoxicity
Presentation
Within 6 Months
6.3/100,000
85%
Elevated
Aminotransferases
15%
ALT > 3X
Presentation
After 1 Year
3%
If Jaundice Develops,
8-20% Fatalities
5%
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Diclofenac: Metabolic Pathways
Biliary excretion
UGT2B7
Diclofenac
acylglucuronide
4'-OH-diclofenac
acylglucuronide
?
Diclofenac
?UGT2B7
4'-OH-diclofenac
Covalent adducts
5'-OH-diclofenac
Diclofenac-2,5quinoneimine
?
Diclofenac: Metabolic Pathways
Biliary excretion
MRP2 (ABCC2)
UGT2B7
Diclofenac
acylglucuronide
4'-OH-diclofenac
acylglucuronide
?
Diclofenac
?UGT2B7
4'-OH-diclofenac
Covalent adducts
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5'-OH-diclofenac
Diclofenac-2,5quinoneimine
?
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Diclofenac: Genetic Polymorphisms of Interest
Specific Allele Promotes:
UGT2B7*2
MRP2 (ABCC2)
Reactive Metabolites
Extracellular Transport
Most Common Drugs causing DILI
(out of 217 single Rx cases)
 Amoxicillin/clavulanate (n = 23)
 Nitrofurantoin (n = 13)
 Isoniazid (n = 13)
 TMP/SMX (n = 9)
 Duloxetine (n = 6)
 Valproate (n = 6)
 Interferon beta (n = 6)
 Ciprofloxacin (n = 5)
 Lamotrigine (n = 5)
 Methyldopa (n = 5)
 Telithromycin (5)
 Phenytoin (n = 5)
 Diclofenac (n = 4)
Chalasani N,et al. Gastroenterology 2008;135:1924-34.
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Amoxicillin-Clavulanic Acid
Clavulanic Acid
Hepatotoxicity
Cholestatic Injury
1:100,000
Onset 1- 6 weeks: Mean 18 days
Onset up to 6 weeks after therapy
Recovery 1- 4 months
Drug-Induced Liver Injury: Flucloxacillin
Cholestatic
Hepatic Reactions
Risk Factors
Female
Elderly
Prolonged Therapy
Occurs in 8.5 / 100,000 New Users
1-45 day onset
Considerable Differences Based on Ancestry
Higher:
Northern Europeans
Lower:
Asians and Africans
Daly, 2009
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Minocycline
Semisynthetic
Derivative of
Tetracycline
Widely Used
Treatment
For Acne
Mimicks
or Unmasks
Autoimmune
Hepatitis
+ ANA
+ Anti-Smooth
Muscle Antibody
Iminoquinone
Metabolite
Causes A
Lupus-like
Syndrome
Activates T-cells
Immunomodulatory
Anti-Inflammatory
Response Question #3
The following statements regarding HMG-CoA
Reductase Inhibitors (statins) are true:
1. Risk of drug-induced hepatotoxicity is extremely high
2. Patients should be monitored regularly
3. Patients with liver disease should avoid them
4. All of the Above
5. None of the Above
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HMG-CoA Reductase Inhibitors
All cause
 ALT
ALT  may be
related to
lipid dose
Risk of drug-induced
hepatotoxicity
extremely low
Increases
often
transient
adaptation
No evidence
monitoring of value
Common Herbals and Dietary Supplements
Associated with DILI
 Right approach
 Herbalife Formula
 Green tea (mega tea, Arizona
green tea)
 Herbalife Cell Activator,
Herbalife shake, Herbalife Total
Control, Herbalife Xtra
 Lavender oil, Frankincense oil
 Nixia redMelatonexDHEA
 VPX Redline Fat Burner
 M one T (17 α methyl 1testesterone)
 Testron-Sx
 Hydroxycut
 Slim QuickLipozene
 Niacin
 Airborne
 Cimicifuga racemosa
 G3 (Gac fruit juice with other
Chinese fruit juices
 Airborne
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 MT-80 (methyl testosterone)
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Drug-Induced Liver Disease
Patterns of Histologic Injury
 Acute
 Chronic
Hepatocellular
Hepatocellular
Cholestatic
Cholestatic
Mixed
Granulomas
Vascular
Fibrosis/cirrhosis
Vascular
Neoplasms
Drug-Induced Liver Disease
Patterns of Injury - Examples
 Tetracycline
Microvesicular fat
Chronic cholestasis (rare)
Chronic hepatitis (minocycline)
 Amoxicillin-Clavulanate
Cholestasis  cholangitis, hepatocellular
injury, granulomas
 Nitrofurantoin - incidence approx. 1/3000
Acute hepatitis - 30%
Chronic hepatitis - 50%
Cholestasis - 10%
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Drug Induced Liver Disease:2010
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Drug-Induced Liver Disease
Suspect
 Always
 Atypical Patterns
Cholestatic hepatitis
Granulomatous hepatitis
Hepatitis + eosinophils
Zonal necrosis
Severe acute hepatitis
CLINICAL AND PATHOLOGICAL SYMPTOMS OF DRUG-INDUCED LIVER DISEASES.
Kaplowitz N Clin Infect Dis. 2004;38:S44-S48
© 2004 by the Infectious Diseases Society of America
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Model Compound
•
Many of the protective factors discovered through
acetaminophen (APAP) toxicity
research on
• Acetaminophen
– Clinically relevant; analgesic, antipyretic
– Over 50,000 ER visits per year
– 450 death per year
• Suicide
• Accidental ingestion
• “Therapeutic misadventures”
– Unlike with drug idiosyncrasy, it is well characterized
and reproducible in animals
•
Bioactivation to N-acetyl-p-benzoquinone imine (NAPQI)
APAP-Induced Liver Injury
O
HN
Sulfation
CH 3
Glucuronidation
Detox
Detox
P450 2E1
P450 1A2
P450 3A4
OH
ACETAMINOPHEN
O
N
Cysteinyl
Conjugate
CH 3
GSH
Detox
Depleted
O
NAPQI
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Protein Adducts
Mitochondria Dysfunction
Reactive Oxygen Species
LIVER
INJURY
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Acetaminophen cases as % of all ALF per year
Percent of ALF Cases
Total ALF cases:
60%
85
94
50%
123
133
128
47%
44%
38%
40%
30%
99
51%
38%
28%
20%
10%
0%
1998
1999
2000
2001
2002
2003
YEAR
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Suicidal vs. Accidental APAP cases
Suicidal
(n=101)
Female (%)
75
ACM dose(g)
28
Dose per day
28
Coma (%>3)
39
ALT (IU/L)
6118
Spont surv (%) 67
Antidepress’t
35
Narcotic cpd (%) 19
Unintentional
(n=109)
p-value
76
34
10
55
3975
66
36
62
NS
NS
0.001
0.026
0.001
NS
NS
0.001
ACM/Narcotic compounds (n=98; 43%)
Brands most commonly reported
Vicodin
72
Percocet
8
Lortab
8
Tylenol #3
7
Darvocet
5
Lorcet, Norco: 3 each
Compound users were more likely to receive NAC, had higher coma
grades but similar survival to others
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Prognosis in Acute Liver Failure
Etiology an important outcome determinant
Bad prognosis:
Good prognosis:
 Drugs
 Acetaminophen
 Indeterminate
 Hepatitis A
 Hepatitis B
 Shock
 Wilson Disease
SUMMARY
• Occurs in small fraction of individuals
• Difficult to predict
• Major clinical problem; often life-threatening
• Leading cause of acute liver failure
• Reason drugs removed from development and
widespread use
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