Drug Induced Liver Injury

1
Drug Induced Liver Injury

• Robert J. Fontana, MD
• University of Michigan Medical Center

2
DILI

• Idiosyncratic DILI
• Epidemiology
• Clinical manifestations
• Causality assessment
• Prognosis
• Genetics in DILI
• Drug Induced Liver Injury Network
• Acetaminophen hepatotoxicity
• Epidemiology prevention

3
Drug Induced Liver Injury

• DILI is the most common reason for regulatory
  actions concerning drugs
• Denial Exanta
• Withdrawal Nefazadone
• Warnings Ketek
• Significant morbidity mortality
• Leading cause of ALF in the US
• Acetaminophen 40 Idiosyncratic 13
• Hepatocellular jaundice ? 10 mortality
• No reliable means to predict/ prevent

4
Hepatic Adverse Event Nomenclature

• Liver injury
• ALT 3X ULN or
• Alk phos 2X ULN or
• T Bili 2X ULN elevated ALT or alk
• Abnormality of liver tests all others
• DILI categories
• Hepatocellular R 5
• Cholestatic R
• Mixed 2

R (ALT/(ULN)) (Alk/ (ULN))
(HAEN Working Group 2005)
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Liver Injury Classification

• Acute liver injury
• Chronic liver injury 6 mon /- symptoms
• Severe liver injury
• Jaundice (Bili 2 xULN)
• INR 1.5 xULN
• Encephalopathy
• Fulminant liver injury
• Coagulopathy and encephalopathy within 4 weeks

(HAEN Working Group 2005)
6
DILI is uncommon
(1 J Clin Pharm 1986 26 633) (2 Pharmacoepi
Drug Safety 1999 8 275) (3 Eur J Clin Pharm
2005 61 135) (4 Hepatology 2002 36 451)
7
DILI Population based study81,300 in France
97-00

• 95 suspected DILI cases
• 34 probable DILI
• 25 antibiotics 23 psychotropic 13 hypolipid
• 80 outpatients
• 2 (7) deaths
• 61 other causes/ inadequate data
• Incidence 14 to 24 per 100,000
• 8,000 annual cases, 500 deaths
• 16 X than ADR surveillance

(Hepatology 2002 36)
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DILI Diagnosis

• DILI is a diagnosis of exclusion based on
  circumstantial evidence due to lack of
  confirmatory lab test, rechallenge, or GOLD
  standard
• DILI diagnosis is invariably retrospective
• Exclude other causes
• Dechallenge requires follow-up
• Requires a high index of suspicion

9
Clinicopathologic forms of DILI

• Acute hepatitis
• Acute cholestasis
• Chronic hepatitis
• Fatty liver/ NASH
• Granulomatous hepatitis
• Fibrosis/ cirrhosis
• Vanishing bile duct
• VOD, peliosis
• Benign malignant neoplasia

10
DILI A Diagnosis of exclusion

• Temporal relationship
• Latency usually
• Not dose related
• ? Clinical risk factors
• Biochemical injury pattern
• Signature vs protean
• Prior reports/ cases
• Exclude other likely causes
• Improve with discontinuation

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Acute Hepatocellular Differential Dx
Ultrasound/ CT

Viral(A, B, C, CMV, EBV HEV, HSV)
Biliary (ERCP)
Mass (AFP, MRI)
Autoimmune(SPEP, ANA, SmAb)
NAFLD
Ischemia(History, 2D-Echo)
Observe/ biopsy
Metabolic(Iron, TIBC, ferritin, ceruloplasmin,
SPEP)
DILI ( (Gordon J Clin Gastro 2005 39 64)
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ADR Causality Assessment
? Definite ? Highly probable ? Probable ?
Possible ? Unlikely ? Excluded / other
100 50 0
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DILI Causality Assessment

• Generic instruments
• WHO
• Bayesian
• Liver specific
• Expert opinion
• Roussel Uclaf Causality Assessment Method (RUCAM)
  89
• Clinical Diagnostic Scale (CDS) 97

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RUCAM

• Temporal relationship (0 to 2)
• Course (-2 to 3)
• Risk factors (0 to 2)
• Concomitant drug (0 to -3)
• Non-drug causes (-3 to 2)
• Prior reports/ information (0 to 2)
• Re-challenge (-2 to 3)
• Score (- 8 to 14)
• Highly probable 8 Possible 3-5 Excluded 0
• Probable 6-8 Unlikely 1-2

J Clin Epidemiol 1993461323-1330
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RUCAM limitations

• Ambiguous instructions
• Criteria for competing cause/drug not clear
• Onset 30 days after d/c (e.g. Augmentin)
• Derived from expert opinion rather than
  prospectively collected data set
• Limited risk factors
• Overweighting of rechallenge
• Low inter-observer reproducibility

16
228 Spanish cases 94-00Gold standard Expert
panel
CDS RUCAM Exclude Unlike
Poss Prob Def Exclude 21
2 Unlike 4 3 Poss
8 1 Prob 1 30
43 16 Definite 5
40 53 1
30 non-drug cases
K 0.28
Poor performance in ALF/ Death (6) CDS 6
possible 7 unlikely/ excluded RUCAM 6 definite
6 probable 1 possible
(Hepatology 2001 33 123)
17
Prognosis in DILI with jaundice836 Swedish cases
(70-04)
P Age, AST, bilirubin predict death/txp
However, suspect drug also important - 0
erythromycin 40 halothane
(Bjornson Hepatology 2005)
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Spectrum of DILI
19
ALT monitoring and DILI

• INH causes ? ALT 1-3X ULN in 20
• ? Adaptation with continued treatment
• INH hepatitis ALT 3X ULN jaundice 1-2
• 50 in first 2 months, non-specific symptoms
• Most resolve with INH discontinuation
• Fulminant hepatitis
• 177 deaths due to INH 19921
• Leading cause of DILI-ALF leading to LT 2
• Age 40 ? Female ? Alcohol/ liver disease
• Monitor serum ALT levels on INH?
• In who? Frequency ? Criteria to discontinue ?
• Alternate regimen ? Rif PZA contraindicated

(1 Am Rev Respir Dis 1992 145 494) (2 Liver
Transplantation 2004 10 1018)
20
ALT monitoring with INH

• CDC recommends baseline and regular LFT
  monitoring in
• HIV , pregnancy
• Liver disease, selected elderly
• Monthly clinical assessment and labs if
  symptoms
• Individualize monitoring for active TB

(JAMA 1999 281 1014)
21

• Idiosyncracy
• Hippocrates, 400 B.C.
• (idios) - ones own, self
• (syn) together
• (crasis) - a mixing, mixture
• A persons own mixture of characteristics,
  factors, nature and nurture, uniquely

John Senior - FDA
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DILI pathogenesis
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Drug Induced Liver Injury Network
A cooperative Agreement funded by the Division
of Digestive Diseases and Nutrition National
Institute of Diabetes and Digestive and Kidney
Diseases
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DILIN Sphere of Influence
U Michigan R. Fontana
Indiana U N. Chalasani
U Conn H. Bonkovsky
UCSF T. Davern
U N Carolina P. Watkins
12.8 million lives
25
 
     
Prospective study Multicenter, longitudinal study
of Drug- and CAM- induced liver injury
Retrospective study Idiosyncratic Liver Injury
Associated with Drugs (ILIAD)
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Prospective study - AIMS

• 1 To identify bona fide cases of drug and CAM
  induced liver injury within 6 months of
  presentation so that clinical data and samples
  can be collected for future mechanistic and
  genetic studies
• 2 To identify clinical, immunological, and
  environmental risk factors for drug and CAM liver
  injury by comparing cases to controls

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Prospective Study

• Liver injury within 6 months
• Medications and CAM
• Children and adults
• Pre-defined eligibility criteria for cases and
  controls
• Distinct entry criteria for patients with
  underlying liver disease (HCV, HBV)
• Minimum of 6 months follow-up
• Maximum of 24 months follow-up
• Detailed data collection

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Inclusion criteria

• Age 2
• DILI within 6 months of presentation
• On 2 consecutive blood draws
• AST/ ALT 5 X ULN or baseline
• Alk phos 2 X ULN or baseline
• T bilirubin 2.5 mg/dl
• Chronic HBV, HCV, HIV allowed

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DILIN Causality Committee5 site PIs, 1 DCC, 1
NIH

• 3 independent reviewers
• Review clinical narrative, subset CRF
• Score causality (25 1 drug)
• RUCAM
• Data completeness checklist
• Conference call to finalize

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DILIN Causality assessment

• Likelihood Category
• 95 Definite
• 75 -95 Likely
• 50 -75 Probable
• 25 -50 Possible

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(No Transcript)
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Implicated drugs (N141)
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143 Prospective cases
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New agent signals

• Arava (leflunomide) (2)
• Enbrel (etanercept) (2)
• Stratera (atomoxetine) (2)
• Telethromycin (ketek) (3)
• Rebif (IFNB-1a) (2)
• Research agents (2)

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Demographics (n141)
36
Drug
Stable metabolites, excretion
reactive metabolite
immune mechanisms
Non-immune mechanisms
Hepatocyte damage
37
DILIN Scientific AIMS

• HYPOTHESES Variation in host drug metabolizing,
  detoxification, or regeneration/ adaptation
  pathways may explain (in part) susceptibility to
  DILI
• METHODS Collect DNA and compare DILI cases vs
  controls

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Human genome

• Human genome 30,000 unique genes
• 10 x 10 6 single nucleotide polymorphisms
• May influence susceptibility or outcome with
  disease and/ or drugs
• 50 of interindividual variation
• Multiple SNPs likely required
• Whole genome scanning
• High throughput technology available
• 500,000 SNPs across entire genome
• Studies require well phenotyped cases

39
DILI susceptibility High risk Homozygous for
red/ dysfunctional SNPs on 50 of genes Low
risk
40
DILIN Genotyping Initiative

• Collaboration with GlaxoSmithKline
• Affymetrix Gene chip for 500k SNPs
• Analyze DILI cases vs 500 population controls
  matched by age, race, ethnicity
• 50k non-synonomous SNP chip
• 1,300 Absorption, Distribution, Metabolism and
  elimination genes
• 5,000 markers in candidate genes
• Replicate genetic associations in other
  populations, investigate pathways, etc

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Acetaminophen Friend or foe ?

• Safe effective
• 1 billion tabs / yr
• Preferred to ASA in liver dz, children
• 200 OTC products 20 Rx drugs
• Hepatotoxicity
• Dose dependent ( 4 grams)
• 60,000 overdose/ yr
• Impulsive suicide gestures
• 500 deaths/yr

42
Glucuronyl transferases sulfotransferases
stable metabolites, excretion
Acetaminophen
CYP2E1, CYP3A4, CYP1A2
Glutathione transferases
NAPQI
Hepatocyte damage
43
Acetaminophen ALF in the US
(W Lee ALFSG 2005)
44
ACM related ALF in the US
P (Larson et al Hepatology 2005)
45
ACM-cysteine adducts
Intentional
Non-intentional ACM overdose ACM
overdose
Biomarker for ACM hepatotoxicity - Sensitive
specific for ACM liver damage - 19 of
indeterminate ALF
(Davern US ALFSG 2005)
46
Implications of ACM related ALF

• ALF due to ACM is increasing over time
• 50 non-intentional misadventures
• Late presentation/ low serum ACM levels
• High index of suspicion for early NAC
• ? Adduct assay ? Prognostic criteria
• Regulatory actions
• Dispensing, packaging, label of OTC
• ? Composition of narcotic-ACM

47
Acetaminophen (4 g/d) x 14 days in healthy
volunteers
56 Hispanic Mean age 33
? Adducts ? Adaptation ? Generalizability
(Watkins JAMA 2006 296 87-93)
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Acetaminophen advice

• ACM is a safe and effective analgesic
• American Liver Foundation July 18 2006
• Do not exceed 3 g/d for prolonged time
• Liver dz patients should check with their
  doctor
• To avoid inadvertent toxicity
• Read labels monitor total dose
• ? Change narcotic-ACM congeners

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DILI in 2006

• DILI is uncommon and difficult to diagnose
• Annual incidence of 1 in 10,000 person years
• Diagnosis of exclusion
• However, DILI is important
• Most common reason for FDA actions
• 10 mortality if hepatocellular jaundice
• Prospective surveillance networks (DILIN) may
  improve understanding of host, environmental, and
  genetic risk factors of well-phenotyped cases

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DILIN Initiatives

• AASLD STC on DILI (Sept 2005)
• Hepatology 2006 43 618-631
• FDA/PHARMA/ AASLD Steering committee
• Jan 24, 2006- RFA for industry collaboration
• National Library of Medicine (J Snyder)
• LIVERTOX database on the web
• Annotated references re causality
• ? Post DILIN cases
• Genetic polymorphism analysis

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Acetaminophen toxicity in severe acute HAV/ HBV

• Sera from 72 HAV/ HBV ALFSG patients assayed for
  ACM-protein adducts
• Adduct 5/49 (10) HBV (0.4 nmol/l)
• Adduct 4/23 (17) HAV
• Adduct 10/10 (100) ACM OD (5.6 nmol/l)
• 8 of 9 patients reported some ACM use
• All
• 67 of adduct died vs 27 adduct (-)

(S1002 Polson DDW 2006)
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(No Transcript)
53
Indeterminate with adducts N7
Known APAP
Acetaminophen-CYS (umol/L)/mg protein
Other ALF
APAP No tox
Indeterminate N29
Patient Group
Davern TJ, et al. Gastroenterology 2006130687-94
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Dispensing, packaging, label changes of ACM
products in UK 98
(BMJ 2001 3221)
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287 Japanese DILI cases 78-0255
hepatocellular 24 mixed 22 cholestatic

• Latency 15 or 30 d changed, other drugs
  omitted,
• DLST 2 Eosinophils 6 1

(Hep Research 2003 27 191)
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Prognosis in Hepatocellular DILI

• Fulminant DILI has poor prognosis 1
• Acetaminophen (39) 70 survival
• Idiosyncratic DILI (13) 25 survival
• Hys rule Hepatocellular DILI leading to
  jaundice has 10 mortality 2

(1 Annals Int Med 2002 137 947) (2 Zimmerman
Hepatotoxicity 1975)
57
Prospective Study Design
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DILI Causality Instrument

• Sensitive
• Specific- Low probability in non-drug cases
• Reproducible
• Content validity- weighting is evidence based
• Criterion validity- Gold Standard expert panel
• Discrimination- a semi-quantitative estimate
• Validated in independent groups
• Generalizability- Young vs old, mild vs severe,
  hepatocellular vs cholestatic, normal vs abnormal
  baseline LFTs
• Ease of use

59
Baseline features (n141)
60
US ALFSG 98-05 n838 adults
45
Spontaneous survival
12
61
ACM related ALF in the US
(Larson Hepatology 2005)
P 62
(No Transcript)
63
DILI Clinical features
(1 Hepatology 2002 36 451) (2 Hepatology 2005
42 481) (3 Hepatology Research 2003 27 192) (4
Gastroenterology 2005 129 512)
64
Prognosis in DILI with jaundice

• 836 presumed DILI cases with jaundice from Sweden
  (70-04)
• 454 hepatocellular (54)
• 213 cholestatic (25)
• 169 mixed (21)
• AIM Verify if Hys rule applies to consecutive
  cases of severe hepatocellular injury and
  identify predictors of death/ transplant

(Bjornsson Hepatology 2005)
65
Regulatory actions due to DILI (1995-2005)

• Second Line
• felbamate
• pemoline
• tolcapone
• trovafloxacin

Withdrawals bromfenac troglitazone
Warnings acetaminophen leflunomide nefazodone
nevirapine pyrazinamide/rifampin terbin
afine valproic acid zifirlukast atomoxetine saquin
avir/rifampin Interferon 1a infliximab (kava,
lipokinetix)
http//www.fda.gov/medwatch/safety.htm