Drug-Induced Acute Liver Failure in the US 2005: Results from the US Acute Liver Failure Study Group
William M. Lee, MD Meredith Mosle Chair in Liver Disease UT Southwestern Medical Center Dallas, TX www8.utsouthwestern.edu/liver
Background/Rationale on ALF
• Altered mentation, coagulopathy, no cirrhosis • Relatively rare disease: ca. 2,000 cases/yr • No one center can study the condition • High mortality/morbidity • Transplantation has helped – but ALF remains largely untreatable or uses large amt resources • DILI ALF is the top of a larger iceberg
Acute Liver Failure Study Group
Funded by NIH R03, FDA Orphan Grant, Now R01 (‘00-’05) • 14 sites initially 1998, now 25 • Also 25 pediatric sites, since 2000 • 820 cases in adult, 320 in pediatric registry • N-acetylcysteine trial for non-APAP ALF
• Numerous (38) ancillary studies in progress
• Provides a surveillance network for DILI cases
Case Report Form
Etiology of ALF in the USA:
Adult Registry (n = 684)
n 320
300 280 260 240 220 200 180 160 140 120 100 80 60 40 20 0
300
97 86 49 27 40 30 15 8 5 27
Drug
Bu dd-Chia ri
W ils on's
He p B
He p A
Othe r
AC M
Au to imm
Is che mic
P re gna ncy
Inde ter
Comparison of Different Etiology Groups:
ACM n=300 Age (median) Sex (% F) Jaundice (Days) (median) Coma ¾ (%) ALT (median) Bili (median) Tx (%) Spontaneous Survival (%) Overall Survival (%) 36.5 74 0 Drug n=86 40 71 9.5 Indeterminate n=97 37 55 9.5 HepA/HepB n=27/49 47/40 48/47 3.0/5.5 All Others n=125 41 78 8.0
51 4091 4.6 8 64 71
41 580 22.0 45 20 62
48 904 23.3 42 25 64
48/60 2658/1601 11.8/18.8 26/53 59/27 82/71
42 677 15.3 33 30 57
Acetaminophen cases as % of all ALF per year
Total ALF cases:
85
94
99
123
133
128
60%
P er ce nt of A LF C as es
50% 40% 30% 20% 10% 0% 1998 1999 28% 38%
44% 38%
47%
51%
2000 YEAR
2001
2002
2003
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) 76 34 10 55 3975 66 36 62 p-value
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
ACM/Narcotic vs. ACM alone
ACM/Narc (n=98) Female (%) 85 Suicidal OD (%) 19 Coma (% > 3) 60 Platelets 158 Spont surviv (%) 67 Mean alcohol (g) 58 Alcohol abuse (%) 44 ACM (n=120) 70 63 38 121 65 16 22 p-value
0.03 <0.001 0.001 0.001 NS 0.01 0.01
Narcotic:APAP Combinations Is there a rationale for them?
• Is there really synergy between pain relievers? • Isn’t it just easier to prescribe: no triplicate?
• How many abuse these combinations?
• Do we need triplicates any longer? Electronic tracking used widely to prevent multiple Rx
• Would separation of combinations work?
Cytochromes P450 lead to unstable compounds!
O C HN CH3 N O C CH3
O C HN CH3
SG
OH
Cytochrome p450 2E1 (phase I)
Mercapturic Acid
(nontoxic)
OH
O
NAPQI
(highly reactive intermediate) (phase II)
Hepatocyte Damage
•Covalent binding to cell proteins, including enzyme itself •ADDUCTS •Derangement of apoptosis? •CAR?
Nontoxic Metabolites
Acetaminophen (APAP) adducts assay
• HPLC-EC detects APAP-cysteine residues • Highly sensitive and specific
• Remains positive up to 9 days after ingestion
• Present in 20% of indeterminate cases, peds and
adults
16
P a tie n t 1 ; A d m issio n A P A P = 9 0 m g /d L
40
7000
P a tie n t 2 ; A d m issio n A P A P = 1 0 5 m g /d L
10000
14
6000
8000 30
12
A d d u c ts (u M )
A d d u c ts (u M )
5000
4000 8 3000 6 2000 4 1000
A L T (IU /L )
10
6000 20
4000
10 2000
2
0
0 1 2 3 4 5 6 7 0
0 1 2 3 4 5 6 7
H o s p ita l D a y
H o s p ita l D a y
24 22
P a tie n t 3 ; A d m issio n A P A P = 9 0 m g /d L
12000
3 .0
P a tie n t 4 ; A d m issio n A P A P = 0 m g /d L
1600
1400
11000 20 18 16 9000 14 12 10 7000 8 6 1 .0 1 .5 2 .0 2 .5 3 .0 6000 8000 10000
2 .5 1200
A d d u c ts (u M )
A d d u c ts (u M )
2 .0
A L T (IU /L )
1 .5
800
600 1 .0 400 0 .5 200
0 .0 1 2 3 4 5 6 7
0
H o s p ita l D a y
H o s p ita l D a y
ALT and APAP adducts in 4 patients with acetaminophen OD
A L T (IU /L )
1000
A L T (IU /)
Spectrum of Drug-Related Acute Liver Failure: I Anti-TB drugs: 16
8 INH without other anti-TB drugs
2 with other non-TB drugs
5 INH + rifampin + pyrazinamide 1 INH + ethambutol 2 rifampin + pyrazinamide
Sulfa-related drugs : 6 Septra, sulfadiazine, sulfasalazine Other antibiotics: 8
1 Augmentin, 4 nitrofurantoin, 1 ciprofloxacin, 1 doxycycline, 1 itraconazole
Spectrum of Drug-Related Acute Liver Failure: II
Miscellaneous: Phenytoin 6; Valproate 1; PTU 4; Disulfiram 4 Statins : 6, including 2 Baychol® Bromfenac (Duract®): 4 Troglitazone (Rezulin®): 4 Herbals and/or dietary supplements: 10 –includes 2 Kava-Kava HAART: 2 Halothane/Isoflurane: 2
Statins: Do They Lead to ALF?
Case #1: 61 yo African American woman, survived pravastatin x 6 months Other drugs: losartan, HCTZ, metformin, ASA – 6 months paroxetine, trazodone – 12 months; TMP/SMX – 14 Days Case #2: 59 yo Caucasian woman, transplanted simvastatin x 6 months 20 mg qd, x 3 wks 40 mg qd Other drugs: Prempro, synthroid – 6 months; vitamin A ?high dose, vitamin E– 6 wks Labs: Bili 23.2, AST 649, ALT 471, Alk Phos 201, INR 4.4, ANA 1:160, ASMA 1:40 Case #3: 40 yr Caucasian woman, transplanted simvastatin x 2 months; atorvastatin x 1 month Other drugs: fexofenadine, Lo-Ovral – 24-36 months, nitrofurantoin – 12 months
Case #4 62 yr Caucasian woman, died atorvastatin x 36 months Other drugs: atenolol, HCTZ, chlothalidone x 60 months’ use Labs: Bili 28.1, AST 267, ALT 477, Alk Phos 176, INR 1.6, creat 3.6
Causality Assessment in DILI ALF
Remains a major issue/need
• All reports rely on the site investigator’s judgment • Medication lists are often inaccurate • RUCAM requires specifics that often cannot be met • Guilt by association at best • DNA assays would fill a need here • Adduct assays might be useful for other drugs
Pediatric ALF Due to Drugs: 6% of first 189 cases
Medication M/F Age(yr) 5 16 9 23 17 14 16 4 16 2 16 Peak Enceph. III IV IV N/A IV III IV IV N/A I N/A TX N N N N N Y Y Y N N N Alive N N N N N Y Y Y Y Y Y
Valproic Acid (DPH/neurontin) M Pravastatin F DPH M Dantrium M Isoflurane F INH M Bactrim M Valproic Acid M Cytoxan/DPH M Valproic Acid F Minocycline M
610 Patients enrolled
Spontaneous survivors n= 270 (44%)
Transplanted n= 155 (25%)
Died (Not Transplanted) n= 185 (30%)
Alive n= 134 (86%)
Died n= 21 (14%)
Overall survival: n = 404 (66%)
Prognosis in Acute Liver Failure
Etiology an important outcome determinant
Good prognosis: • Acetaminophen Bad prognosis: • Drugs • Indeterminate • Hepatitis B • Wilson Disease
• Hepatitis A
• Shock
International Study: Retrospective Data
• 6 sites contributed: Kings, London; Rigshospitalet, Copenhagen; Hannover, Germany; Aga Khan, Karachi; Royal Prince Alfred, Sydney; Queen Mary Hospital, Hong Kong
284 patients over a 2 yr period: 7/02-6/04 54% female Overall etiologies similar but striking regional differences
• • •
Etiologies by Site: International Study
120
100
80 OTHER IND 60 DILI HEV HBV ACM 40
20
0 KCH RHC UHH AKU QMH RPAH
Summary: ALF in the US
An Ongoing Problem
• More than 60% related to drugs: APAP ~ 50%
• A disease of developed countries • Viral hepatitis may be on the decline • Indeterminate cases still not elucidated • Transplantation not an option for many • Much work to be done
Current ancillary studies on DILI
• Overview of the idiosyncratic group still in process
• False positive APAP assays • APAP adducts assays
• DNA studies: cytokine polymorphisms USC
• APAP DNA polymorphism studies:
– Cyp 2E1: University of Louisville – Glucuronidation: Boston University
Future Research in DILI ALF
Goal: Improve outcomes for all while limiting use of transplantation
• Limit the number of drug-induced cases, particularly acetaminophen-related • Finish testing N-acetylcysteine for non-ACM ALF • Test hypothermia as treatment for ALF • Internationalize the multi-center data study • Broaden surveillance (different definitions)
Study Sites (Adult) in the ALFSG 98-2005
• • • • • • • • • • UT Southwestern U Washington Wash Univ St Louis UCSF Mt. Sinai NYC Univ Nebraska Omaha Baylor Dallas Univ Pittsburgh Northwestern Univ OHSU, Portland Lee Larson Crippin Davern Emre McCashland Murray Shakil Blei Zaman
• •
• • • • • • • • • • •
UCLA Michigan
Univ Alabama Birmingham Mass General Columbia/Cornell NYC VCU Mayo Clinic: Rochester, Jax, Scottsdale UC Davis Einstein Philadelphia MUSC Charleston Pennsylvania UCSD Duke
Han Fontana
McGuire Chung Brown/Schilsky Stravitz Hay, Raj, Harrison Rossaro Munoz Reuben Reddy Hassanein Rockey