Download Drug-induced Liver injury

Hepatitis aguda tóxica
Raúl J. Andrade
Hospital Universitario Virgen de la Victoria
Universidad de Málaga
Drug-induced Liver injury
• Idiosyncratic DILI is a rare yet potentially severe
cause of liver damage
•
Diagnosis is difficult and inaccurate in most
instances
•
•
Any drug may be responsible
Predictive value of preclinical and clinical studies
is limited
The Phases of Drug
Development
Number of subjects
25000
20000
Most type A
reactions detected
here
15000
10000
Most type B
reactions
detected here
Marketing
Authorisation
5000
0
PHASE 1
50 volunteers
PHASE 2
250 patients
PHASE 3
2,000 patients
PHASE 4
Many 1,000’s
Attrition of compounds during development: main
reasons for failure
ORGAN
Cardiovascular
Liver
Musculoskeletal
Immune system
Kidney
CNS
Testes
Gastrointestinal
Genetic toxicology
Reproductive toxicity
70% of drugs withdrawn from US market 1980-2005
were analgesics,cardiovascular, antiinfectives
225 drugs were analysed
Safety Biomarker
Working Group ABPI
No
64
42(19%)
15
13
12
10
10
8
7
7
Acute liver failure in US and transplant-free survival
600
475
80
400
60
300
40
200
151
119
100
20
75
31
55
43
50
17
9
0
8
0
Fontana Sem Liver Dis 2008
% Spontaneous survival
Number of patients
500
100
Drug-induced Liver injury:
what are the questions to be addressed
• Epidemiology and drugs most commonly
involved
•
•
•
•
•
Phenotypes
Risk factors: envirommental and genetic
Mechanisms: pathways of damage
Diagnosis
Therapy
Epidemiology of Drug-induced
Liver injury in Iceland n=251,860
15-24
Björnsson et al Gastroenterology 2013
Prescription rate per person
Annual Incidence of DILI 19.1 per 100.000
Epidemiology of Drug-induced
Liver injury in Iceland n=251,860
Drug
Patients Prescription, Cases, Proportion Per
95%
n
n
100,000 CI
treated,
n
Amoxicillin
/clavulanate
35,252
Diclofenac
54,889
Azathioprine
532
Infliximab
593
Nitrofurantoin
5476
Isotretinoin
2169
Atorvastatin
7385
Doxycycline
32,677
83,379
112,801
3054
a
12,034
7978
34,171
54,232
15
6
4
4
4
3
2
2
2350
9148
133
148
1369
732
3693
16,339
43
11
752
675
73
138
27
6
Only drugs associated with at least 2 cases of DILI are shown.
CI, confidence interval.
a Most patients on infliximab received continuous prescriptions
Björnsson et al Gastroenterology 2013
95%
CI
24
70
4
24
205 1914
184 1718
20 187
29 404
4
98
1
22
PHENOTYPES OF “IDIOSYNCRATIC” DILI
•
HEPATOCELLULAR:
Alanine aminotransferase
(ALT) predominantly raised
(ALT/AP>5)
•
CHOLESTATIC: Alkaline
phosphatase (AP)
predominantly raised
(ALT/AP <2)
•
MIXED ALT & ALP are
increased, and
2<ALT/ALP<5
Bénichou C. J Hepatol. 1990; 11: 272-6.
Fontana et al Hepatology 2010
Aithal et al Clin Pharmacol Ther 2011
Liver injury distribution in the Latin DILI
Network, Spanish DILI Registry and DrugInduced Liver Injury Network.
Hepatocellular R≥5, Cholestatic R≤2, Mixed R<2 y R>5
SLADILIN, 2013
Type of liver damage according to sex in patients
younger or older than 60 years of age (n=603)
Lucena et al. Hepatology 2009
Factors influencing clinical expression and early outcome
of DILI
• Hepatocellular pattern damage
– most common (58%)
– inversely correlated with age (P < .0001)
– & had worst outcome (Cox regression, P < 0.034)
Andrade RJ et al. Gastroenterology 2005; 129: 512-521
Development/Progression of
Drug Induced Liver Injury
Increased Susceptibility
Initiation of injury
Adaptation
Elevated aminotransferases
Resolves despite continuing therapy
Clinical
manifestation
Symptomatic (N/V, anorexia, fatigue)
Liver dysfunction
jaundice
Regeneration/repair
Cure
Severe Injury
Liver failure/Death
Need to improve prediction of severe DILI outcome
(better Hy’s Law ?)
Risk factors for acute liver failure in DILI
Variables
Coefficient
OR (95% CI)
P value
3.220
25.04 (4.14-151)
<.0001
Hepatocellular 2.064
damage
7.87 (1.68-36.9)
<.009
Total Bilirubin 0.143
1.15 (1.09-1.22)
<.0001
Female Sex
Constant = -8.7 Abbreviations: CI, confidence interval; OR, odds ratio.
Andrade et al, Gastroenterology 2005
Drug-induced acute liver failure in USA
(1998-2007)
•
•
•
•
•
Demographics (n=133)
– Overweight (BMI 28.7)
– Women (70.7%)
– Overrepresentation of minorities
Presentation
– Deep jaundice (mean bilirubin 20.8 mg/dL)
– Moderate ALT increases (median 580 U/L)
– Rash/eosinophilia (16%), autoantibodies (22%)
Type of damage
– HC 98(77,8%), Ch 16 (12, 6%), Mx 12(9,5%)
Causative drugs
– Antimicrobials (INH, sulfa-drugs, nitrofurantoin) 46%
– Alternative (illicit), antiepileptics, antimetabolites, statins
35%
Outcome predict
– SS (27%), LTs (42%), Non LT-Death (31%)
Reuben, Koch and Lee Hepatology 2010
Interplay of drug-related, environmental
and host factors in the susceptibility to develop DILI
Toxic potential of the drug
Reactive metabolites
Mitochondrial effects
BSEP effects
Genetic factors
bioactivation
detoxication
transport
Others: immune response
MHC, etc.
Envirommental factors
drugs
alcohol
Age, gender
HIV, HCV, HBV
Kaplowitz,AASLD 2002
Relative importance of Intrinsic Toxicty of Agent
Intrinsic vs Idiosyncrasyc liver damage
4+
2+
Agents toxic for
all exposed
individuals and
species e.g. white
phosphorus
Agents with
significant
interplay of
toxicity and
susceptility e.g.
tetracycline
Agents hardly ever
toxic produce injury
only in uniquely
susceptible
individuals e.g.
native penicillin
2+
4+
0
Relative importance of Susceptibility of Host
Zimmerman H, Textbook of hepatotoxicity 1976
Toxic potential of the drug in IDILI:
the effect of dose
• Doses ≥ 50 mg/daily associated with death, liver
failure and liver transplantation Lammert et al Hepatology
2008
•
Majority (77%) of the drugs incriminated in DILI in
the SADRAC and Spanish DILI Registry were
prescribed at doses ≥ 50 mg/daily Lammert et al
Hepatology 2008 and Lucena et al Hepatology 2009
•
Many false positives
Lipophilicity (octanol/water > 3) and High Daily Dose (> 100
mg/day) and Significant Risk for
Drug-Induced Liver Injury (the rule of two)
Chen et al. Hepatology 2013
Drug interference with BSEP function
Morgan et al Toxicol Sci 2010
GWAS: Chromosome 6 (HLA genes)
Flucoxacillin: HLA-B57*01
A-C and lumiracoxib: HLADRB1*1501-DQB1*0602
HLA –A*0201
Ximelagatran
Daly et al Nat Genet 2009
Lucena et al Gastroenterology 2011
Kaplowitz Hepatology 2013
Can genetic variants in DILI be used as biomarkers?
Gene
Diagnostic
Value
Predictive
Value
Drug
OR
HLA-B57*01
Flucoxacillin
80
HLA-DRB1*1501
-DQB1*0602
HLA –A*0201
Amoxicillin/clav 4.2
POLG( p.Q1236H)
Valproate
24
+
+
GST M1 T1
Several
(Antibacterials
/ NSAIDS)
2.7
-
-
+
-
±?
-
Lucena et al Hepatology 2008, Daly et al Nat Gen 2009
Stewart et al Hepatology 2010, Lucena et al Gastroenterology 2011
miRNA-122, HMGB1 and necrosis K18
as early biomarkers of paracetamol DILI
Antoine et al Hepatology 2013
Suspicion
Drug exposure data
and chronology
Not compatible
If compatible assess
Hepatotoxic potential
Search for an alternative diagnosis
Not found
Assess features suggesting drug-toxicity
● Allergic manifestations
● Course on de-challenge
● Look for possible unintentional re-challenge data
● Liver biopsy findings (if performed) and biochemical “signature”
Found
Specific therapy
Andrade RJ WJG 2007
• Case definition of drug-induced liver injury (Aithal GP. Clin Pharm
Ther 2011;89(6):806–815):
http://www.nature.com/clpt/journal/v89/n6/pdf/clpt201158a.pdf
• NIDDK Hepatotoxicity Website (>600 drugs):
•
http://livertox.nih.gov/
• 385 Drugs Associated with Hepatotoxicity (Suzuki A et al. Drug
Safety 2010; 33: 503-522):
http://www.ingentaconnect.com/content/adis/dsf/2010/00000033/00000006/art00007
• Spanish Drug-induced Liver Injury Registry website:
http://www.spanishdili.uma.es/index.php?option=com_content&view=frontpage&lang=en
• Herbal hepatotoxicity (Seeff LB. Clin Liver Dis 11 (2007) 577–596):
http://www.sciencedirect.com/science/article/pii/S1089326107000487
Causality assessment in DILI
•
•
Difficult and non-standardized
Expert Opinion may be more reliable
but is umpractical
•
Diagnostic scales may guide clinicians
searching the important points to be
addressed
CIOMS/RUCAM
•
•
•
•
•
•
•
Temporal relationship
Course
Risk factors
Concomitant drug
Non-drug causes
Prior reports/ information
Re-challenge
Score (-8 to 14)
Highly probable >8
Probable 6-8
(0 to 2)
(-2 to 3)
(0 to 2)
(0 to -3)
(-3 to 2)
(0 to 2)
(-2 to 3)
Possible 3-5 Excluded ≤0
Unlikely 1-2
J Clin Epidemiol 1993;46:1323-1330
RUCAM Strenghts
•
•
•
•
•
Provide an uniform approach. Adds consistency to the
diagnostic process
Excellent teaching tool, emphasizes the features that merit
attention
Help improve the quality of the information recorded (too
much important information is lacking in published cases)
Agarwal et al Clin Gastoenterol Hepatol 2010
Improvement in inter-intra rater agreement
Help standardize the reporting manner
Do not substitute common sense “clinical judgement”
Designed for finding support for and less for
excluding causality
RUCAM limitations
• Ambiguous instructions
• No clear criteria for alternative causes/drugs
(rule of two?)
• Late onset > 30 after stopping therapy (e.g.
Augmentine)
• Negative dechallenge substracts points (FHF,
AIH-DILI)
• Derived from expert opinion and not from
prospectively captured information
• Limited risk factors
• Excessive weight for rechallenge
Therapy
• ¡Stop immediatly any non essential drug!
• If impending liver failure (encephalopathy, INR >
1.5) referral for liver Tx
• Empirically
– Steroids if prominent hypersensitivity features
– UDCA if prolonged cholestasis
• NAC has proved useful in early stages
(encephalopathy I-II) of fulminant hepatic failure
due to drugs (non acetaminophen)
Summary
• Idiosyncratic DILI is partially dose dependent
• Age and sex influence DILI phenotype and severity
• Genetic variants accounting for DILI susceptibility
are being identified
• Causality assessment is complex and uncertain and
current diagnostic scales are imperfect
• Specific biomarkers is an unmet necessity
• Therapy is largely supportive. NAC increases free
transplant survival in early phases of acute liver
failure related to drugs
Acknowledgements
Maribel Lucena
Camilla Stephens
Inma Moreno
Inma Medina
Eugenia Ulzurrun
Mercedes Robles
Miren GarcíaCortés
Esperanza Crespo
Ramón Hidalgo
Mª Rosario Cabello
InInt e Consortium, Ltd.
SAE
r
Ayako Suzuky (Duke)
Guru Aithal
(Nottingham)
Einar Björnsson
(Reikijavik, Iceland)
Ann Daly (Newcastle
Upon Tyne)
Paul Watkins (North
Carolina)
Robert Fontana
(Michigan)
Dominique Larrey
(Montpellier)
SAEC members
Scores for individual axes of the diagnostic scales
CIOMS/RUCAM and Maria & Victorino
CIOMS/RUCAM (1990)
AXIS
SCORE
CHRONOLOGICAL CRITERIA
Maria & Victorino/CDS (1997)
AXIS
CHRONOLOGICAL CRITERIA
From drug intake until onset event
From drug withdrawal until onset
event
Course of the reaction
+2 to +1 From drug intake until onset event
+1 to 0 From drug withdrawal until onset
event
-2 to +3 Course of the reaction
Probability of DILI
EXCLUSION ALTERNATIVE
CIOMS:
+1 to 0
RISK FACTORS
Age
Highly probable>8;
Alcohol
Probable
Possible 3-5;
Unlikely 1-2;
+1 to6-8;
0 EXTRAHEPATIC
MANIFESTATION
Excluded ≤ 0
CONCOMITANT THERAPY
-3 to 0
EXCLUSION NON-DRUG RELATED
-3 to +2
BIBLIOGRAPHICAL DATA
M&V:RECHALLENGE
Definite: > 17; Probable: 14-17; Possible: 10-13; Unlikely: 6-9;
0 to +2
BIBLIOGRAPHICAL DATA
Excluded
<6
RECHALLENGE
SCORE
-2 to +3
+1 to +3
-3 to +3
0 to +3
-3 to +3
0 to +3
-3 to +2
0 to +3
•
•
Diagnostic scales
General scales for the assessment of ADR
Karch y Lasagna 1977
Kramer 1979
Naranjo 1981
Jones 1982
The French Method, Begaud 1984
Arimone 2006
Specific scales for DILI
Striker decision tree
1992
Council International Organizations Medical Sciences /
Roussel Uclaf Causality Assessment Method 1990
M & V/CDS
1997
DDW-J [modifies CIOMS scale]
2003