Drug Induced Liver Injury - AASLD

Prospective studies of Drug
Induced Liver Injury
Robert J. Fontana, MD
University of Michigan Medical Center

• Spectrum of DILI
– Worldwide efforts
– Spanish DILI registry
DILI
• Drug Induced Liver Injury Network (DILIN)
– Enrollment and suspect agents
– Phenotyping
– Other initiatives

Spectrum of DILI
ALF
(Death, Txp)
0.0001 - 0.01%
Symptomatic
disease
0.01 - 1.0%
Mild liver injury
(ALT < 3X ULN)
0.1 - 10%

DILI Population based study
81,300 in France ’97-’00
• 95 suspected DILI cases
– 61 other causes/ inadequate data
– 34 probable DILI
• 25% antibiotics 23% psychotropic 13% hypolipidemic
• 80% outpatients
• 2 (7%) deaths
• Incidence: 14 to 24 per 100,000
– 16 X > than ADR surveillance
• US: 40,000 cases/yr & 3,000 deaths
(Hepatology 2002; 36)

DILI Registries Worldwide
Country Sweden Spain USA
DILIN
Korea
Japan
Years ‘75- ‘05 ‘94 – ‘08 ‘04-‘07 ’05-‘07 ’97-‘07
N 784 603 300 371 1,676
Structure
Govt
registry
Prospect
45 ctrs
Prospect,
5 ctrs
Prospect
17 ctrs
Retro,
29 ctrs
% Hepato
Mix/chol
52
21/29
55
21/25
56
20/ 24
-- 59
20/21
Age (yr) 58 54 48 49 55
% Female 57% 49% 60% 63% 57%
% Hospital NA 54% 54% 100% NA
% Died/
TXP
9.2% 5.4% 10.1% 1.3% 3.7%
% Chronic NA 16.9% 13.6% NA 8.4%
(International DILI Workshop Hepatology 2010)

Implicated Agents Vary
Country Sweden Spain USA
DILIN
Korea
Japan
% Antibiotics 27% 39% 45% -- 14%
% CNS -- 15% 15% -- 10%
% Hypolipidemic 1% 5% 3% -- --
% Other drugs 72% 41% 28% 27% 69%
% Herbals -- -- 9% 73% 9%
(International DILI Workshop Hepatology 2010)

Spanish Hepatotoxicity Network
603 cases ’94-’07
Dose/ d *
% < 10 mg
% 10-50 mg
Men
< 60 y > 60 y
(152) (158)
10
11
Women *
< 60 y > 60 y
(175) (115)
% > 50 mg
79 87 62 81
% Hepatocellular * 61 43 65 46
% Mix/ cholestasis 39 57 35 54
%ALF/Transplant * 1 1 6 7
5
9
20
19
6
13
* P < 0.01
(Lucena Hepatology 2009: 49)

DILIN 2010
CPMC
Davern
Mayo
Talwakar
U Michigan
Fontana
U Penn/ Jeff
Reddy/ Navarro
USC/ UCLA
Stoltz/ Durasgo
Indiana U
Chalasani
DCRI
Rochon
U N Carolina
Watkins
UTSW
Lee
UO1 Cooperative Agreement NIDDK
J Hoofnagle, J Serrano

Prospective study - AIMS
• #1 To identify bonafide cases of drug and
herbal & dietary supplement (HDS) induced
liver injury within 6 months of onset so that
clinical data and samples can be collected
for future mechanistic & genetic studies
• #2 To identify clinical, immunological, and
environmental risk factors for drug and HDS
liver injury by comparing cases to controls
(Fontana Drug Safety 2009; 32: 55)

Inclusion criteria
• Age > 2
• Within 6 months of DILI onset
• On 2 consecutive blood draws
– AST or ALT > 5 X ULN (baseline)
– Alk phos > 2 X ULN (baseline)
– T bilirubin > 2.5 mg/dl
• Chronic HBV, HCV, HIV allowed
(Fontana Drug Safety 2009; 32: 55)

Prospective Study Design
Case
< 6 6 6 mon
DRUG A
0 DILI
Onset
BL
Visit
6 mon
F/u
12 & 24
mon F/u
Control
DRUG A
0 BL
Visit
(Fontana Drug Safety 2009; 32: 55)

DILIN Prospective Study
8 clinical sites: 2 pts/ site/ month

Implicated drugs (N=300)
9/04-12/07
Single prescription drug 73% *
Herbal & dietary supp (HDS) 9% **
Multiple drugs 18%
*Antimicrobials 45% CNS drugs 15%
Augmentin (23) Nitrofurantoin (13) Isoniazid (13)
** Muscle building (11) wt loss (8) well being (6)
(Green tea, slimquick, hydroxycut, Airborne)
(Chalasani Gastroenterology 2008)

DILIN Prospective Study
’04-’07 ’04- ’09
(n=300) (n=588)
Mean age 48 + 18 49 + 18
% Female 60% 59%
% Cau/ AA 79%/ 11% 77%/ 11%
Mean BMI (kg/m 2 ) 27 + 6 27 + 8
% Diabetes 27% 27%
% Known liver dz 6% 12%
Median drug use (d) 42 (20- 117) 38 (19- 98)
(Chalasani Gastroenterology 2008)

DILIN Prospective study
’04-’07
(n=300)
’04-’09
(n=588)
% Hep /mix/ cholestatic 56%/ 20/ 24 54%/20/26
Peak ALT (Iu/ml) 985 + 1168 852 + 1018
Peak Alk phos (IU/ml) 390 + 382 390 + 399
Peak bilirubin (mg/dl) 11.4 + 10.2 11.9 + 11.5
% Hospitalized 60% 56%
% Liver biopsy 52% 53%
(Chalasani Gastroenterology 2008)

DILIN Outcomes
Overall
N=300
Single
drug
n=217
HDS
N=28
p
% Chronic DILI 13.6 12.7 7.7 0.6
% 6 mon mortality 8.0 * 9.5 0 0.2
% Transplant 2.1 3.0 0 0.5
* 56% of deaths non-liver related
Outcomes independent of age, gender, and injury pattern
but worse in diabetics
(Chalasani Gastroenterology 2008)

DILI: A Diagnosis of exclusion
• Circumstantial evidence
– Latency: usually < 12 months
– Hypersensitivity features < 10%
– Dechallenge: Requires follow-up
– Exclude more common causes
• Biochemical injury pattern
– “Signature” vs protean
– Prior reports/ cases
• No objective/ confirmatory lab test

DILIN Causality Scores
Likelihood ’04-’07
N=210
’04-’09
N=317
Definite (1) > 95% 32% 28%
Highly likely (2) 75-95% 41% 42%
Probable (3) 50-75% 13% 14%
Possible (4) 25-50% 10% 11%
Unlikely (5) < 25% 4% 5%
3 reviewers: Clinical narratives and lab/ diagnostic data
(Rockey et al Hepatology 2010)

Causality & Drug Type
Single drug
(225)
Def Very Prob Poss Unlik
(1) lik (2) (3) (4) (5)
31% 41% 14% 11% 4%
Multi-drugs (57) 19% 49% 14% 10% 7%
Single HDS (20) 25% 30% 15% 25% 5%
Multi-HDS (8) 12% 50% 37% 0 0
Drug-HDS (7) 29% 43% 0 0 29%

Causality & Single Agents
Def
(1)
Very
lik (2)
Prob
(3)
Poss
(4)
Unlik
(5)
Amox-clavunate (18) 67% 22% 11% 0 0
Isoniazid (13) 77% 15% 0 8% 0
Nitrofurantoin (12) 17% 67% 17% 0 0
TMP-SMX (11) 54% 18% 9% 9% 9%

Ongoing DILIN Initiatives
• GWAS – 1k Illumina SNP chip
– Candidate gene approach
• Phenotyping
– Autoimmune working group
– New causality instrument
– Clinical-pathological correlation
– Herbal & dietary supplements
– HEV
• LiverTox – NIDDK, NLM
– Standard definitions/ terminology

Studies of DILI in 2010
• DILI is uncommon with most drugs
– Variable severity & phenotype at presentation
– No confirmatory diagnostic test
• Worldwide multi-center registry studies
– Prospectively collecting cases & samples
– Suspect drugs vary
• DILIN
– Antibiotics and CNS agents leading cause
– Natural history/ risk factors being studied

Thank YOU !!!