# Presentation: 816657

## Drug-Induced Hepatotoxicity 2004: Current Issues

**William M. Lee, MD**
**Meredith Mosle Distinguished Professor in Liver Disease**
**UT Southwestern Medical Center**
**Dallas, TX**
**www8.utsouthwestern.edu/liver**

## Acute Liver Failure (ALF) Background/Rationale

**Orphan disease: ca. 2,000 cases/yr**
**No one center can study the condition**
**No viable treatment for all patients**
**High mortality/morbidity**
**Transplantation has helped--how much?**

## Acute Liver Failure Study Group Funded by NIH R03, FDA Orphan Grant, Now R01 (‘00-’05)

**14 sites initially 1998, now 24**
**Also 24 pediatric sites, since 2000**
**Collect prospective data, sera and DNA**
**N-acetylcysteine trial for non-ACM ALF**
**Numerous ancillary studies in progress**
**660 Adult and 220 pediatric cases enrolled**

## Case Report Form

**Case Report Form**

## Altered mentation
Coagulopathy (INR  1.5)
Acute illness (< 8 or < 26 wks)
No cirrhosis
Variety of etiologies

**Coagulopathy (INR ******** 1.5)**
**Acute illness (< 8 or < 26 wks)**
**No cirrhosis**
**Variety of etiologies**

**D****efining Acute Liver Failure (ALF)**

**All sites but one are transplant referral centers: 85% of patients are referred from other hospitals**

## Etiology of ALF in the USA:Adult Registry (n = 610)

**Etiology of ALF in the USA:****Adult Registry**** ****(n = 610)**

## Etiology of ALF in the USA:

**Etiology of ALF in the USA:**

- 1998-2000
- 2001-2003

## Acute Liver Failure Study Group Mechanics

**Sites enroll patients when meet criteria: enceph/INR**
**Collect data (Admit and Outcome) on CRF’s**
**Daily serum samples X 7days**
**DNA samples one time**
**Histology if available**
**Long term follow-up at one and two years**
**Focus is not exclusively DILI**

## Acute Liver Failure Study GroupEnrollment Hurdles

**No obligate funding for sites, only per case**
**$400 for patient enrolled in registry**
**Additional $1,800 if enrolled in NAC**
**Next of kin approval needed for enrollment **
**NAC trial applies to only < 50% of enrollees**
**Cases scarce to begin with**
**Needed marketing!**

## Acute Liver Failure Study GroupMarketing Strategies

**Annual meeting since 1997 in Dallas**
***Target***** newsletter published 3-4x/year**
**Names on papers **
**Study info cards and phone nos. given to sites**
**Lunches at AASLD and DDW since ‘97**
**Annual site visits/talks**
**Giveaways: T-shirts, mouse pads, etc.**
**Teleconferences starting this year**

## Only represent 12% of all cases of a rare disease
Severe disease only: coagulopathy/encephalopathy
Informed consent required
All inpatients at transplant ctrs: no community hosp
No or few bone marrow transplants, HIV or substance abusers, elderly
‘Hidden’ cases: no one available to admit patient, colleagues forget about study (rare disease)

**Severe disease only: coagulopathy/encephalopathy**
**Informed consent required**
**All inpatients at transplant ctrs: no community hosp**
**No or few bone marrow transplants, HIV or substance abusers, elderly**
**‘****Hidden’ cases: no one available to admit patient, colleagues forget about study (rare disease)**

**Challenges in tracking DILI via ALFSG**

**Centers represent 40% of US transplant capacity**

## No informed consent
Doesn’t make criteria: no encephalopathy
Disease category not likely to be transplanted:
BMT/Other cancer
Elderly
Substance abuse
HIV

**Doesn’t make criteria: no encephalopathy**
**Disease category not likely to be transplanted:**
**BMT/Other cancer**
**Elderly**
**Substance abuse**
**HIV**

**Reasons for missing cases**

**An additional 50% are probably missed at sites**

## Comparison of Different Etiology Groups of ALF

|  | ACM
n=262 | Drug
n=76 | Indeterminate
n=90 | Hep A/Hep B
n=22/47 | All Others
n=113 |
| --- | --- | --- | --- | --- | --- |
| Age | 36 | 42 | 37 | 48/40 | 42 |
| Sex (% F) | 74 | 72 | 57 | 55/47 | 79 |
| Jaundice (Days) | 1 | 12 | 10 | 4/5.5 | 8 |
| Coma 3/4 | 52 | 43 | 48 | 50/60 | 43 |
| ALT | 4055 | 491 | 1015 | 2658/1707 | 709 |
| Bili | 4.6 | 21.3 | 23.5 | 11.7/18.8 | 14.7 |
| Tx (%) | 8 | 44 | 40 | 18/51 | 34 |
| Spont. Survival (%) | 65 | 20 | 26 | 64/28 | 31 |
| Overall Survival (%) | 71 | 60 | 62 | 82/70 | 58 |

## Drug-Induced Acute Liver Failure:ALFSG 1998-2002 (n=65)

- <date/time>

**Drug-Induced Acute Liver Failure:****ALFSG 1998-2002 (n=65)**

- Median age:   41
- Female:  49 (75%)
- Spont Survival:  13 (20%)
- Transplanted:  32 (49%)
- Overall Survival:  41 (63%)

## Drug-Induced ALF: Cases from the ALFSG

|  | Anti-TB drugs
(n=12) | Other anti-biot’s            incl anti-fngl
(n=11) | ‘Statins’

(n=6) | Dilantin

(n=5) | Other*

(n=31) |
| --- | --- | --- | --- | --- | --- |
| Female (%) |   58% |    73% |  100% |  80% |  77% |
| Age (median) |   32.5 |    53 |    60 |   27 |   41 |
| Spont survival |     3 (25%) |     3 (27%) |     2 (33%) |    2 (40%) |    3 (10%) |
| Transplant |     6 |     6 |     2 |    2 |   16 |
| Overall surv’l |     8 (67%) |     8 (73%) |     4 (67%) |    4 (80%) |   17 (55%) |

*	**	*** **See next slide*

## Drug-Induced ALF in the ALFSG

***Other miscellaneous cases: 31***
**Herbals : 3 cases,  all female,  all died**
**Propylthiouracil:  3 cases,  all female,  all survived**
**Drugs already withdrawn: ****4 bromfenac, 4 troglitazone**
**Others: 2 disulfiram**
**One each:**** ****didanosine,  metformin,  ecstasy, efavirenz,   methyldopa, allopurinol, isoflurane, halothane,  nefazodone, zafirlukast, quetiapine,  “thermaslim”, gemtuzumab**

## An alternative: the Severe Liver Injury (SLI) Study Setting the threshold lower: a pilot study

**What is the burden of severe liver injury?**
** ****Definition: Bili > 10, or Bili > 4 with INR > 1.5**
**Six centers screened 964 cases retrospectively --> 307**
**Case report forms included investigator’s diagnosis**
**Multivariate analysis and study of RUCAM underway**
**Funded by BMS**

## Severe Liver Injury Cases

**n = 307**

## Severe Liver Injury Study  Preliminary results on 307 pts.

**63% women**
**66% had ALF (encephalopathy)**
**9% transplanted (vs. 27% in ALF series)**
**71% spontaneous survival (vs. 42% in ALF)**
**CAM could be scored in 85%**
**Overlap in CAM scores between indeterminate and drug-induced cases**

## SLI Overall Results

**Feature  ACM 110; Drugs 65; Viral 57; Ind 24; Other 51 p value**

**Age****	****	****35****	****      49****	****	****33****	****   37****	****    48****	****        .001**
**%Female****	****73****	****      67****	****	****49****	****   50****	****    58****	****        .018**
**%ALF****	****	****69****	****      71****	****	****36****	****   79****	****    80****	****        .001**
**Bili****	****	****3.5****	****      12****	****	****14****	****   14****	****     6 ****	****        .001**
**ALT****	****         3182****	****     501        2169       1121    237****	****        .001**
**INR****	****	****2.3****	****      1.9****	****1.4****	****   2.2****	****    1.8****	****        .001**
**Alive %****	****78****	****      73****	****	****90****	****   63****	****    35****	****        .001**
**Transplt%****	****1****	****      20****	****	**** 7****	****   30****	****    11****	****        .001**

## Severe Liver Injury Study

**Idiosyncratic drugs = 20% of overall SLI **
**Idiosyncratic patients ingest more drugs!**
**Idiosyncratic cases are slow to evolve**
**Acetaminophen cases still predominate**
**More viral hepatitis than in ALF study**

**Lessons Learned i: DILI still relatively rare**

## Severe Liver Injury Study

**Detailed drug info often lacking in pt record. **
**Causality assessment is difficult/subjective.**
**Physicians need to gather data carefully.**
**And need to be encouraged to report SAE’s.**
**Need for a new surveillance system in US.**

**Lessons Learned ii: Retrospective studies are difficult**

## SLI

- DILIN

- ALFSG

- Not all drug tox

## ALFSG compared to DILINDifferences/Similarities

**Only hospitalized pts.****	****	****Community/outpt.**
**Short term study****	****	****	****Short term study **
**High morbidity****	****	****	****Less morbidity, “all comers”**
**All ALF****	****	****	****	****Only DILI cases**
**Readily available sera/data****	****	****Data gathering challenge**
**Treatment trial****	****	****	****No treatment trial**
**Many sites****	****	****	****	**** Few sites, but putative network**
**Serum and DNA****	****	****	****Serum and DNA**

## Possibilities for New DILI Network

- <date/time>

**Possibilities for New DILI Network**

- Expand the scope of work of ALFSG
- Expand the scope and site number of DILIN
- Start something totally new
- Challenges: Community participation difficult, university hospitals not real world but the best you have, patients not overwhelmingly enthusiastic to participate, should we look to HMO’s?

## On Using New Drugs

- <date/time>

**On Using New Drugs**

**“****Be not the first by whom the new are tried,****Nor yet the last to lay the old aside..”****	****	****-- Alexander Pope, 1601**

## Michigan				Fontana

**UT Southwestern****	****	****	****	****Lee**
**U Washington****	****	****	****	****Larson**
**Wash Univ St Louis****	****	****	****Crippin**
**UCSF****	****	****	****	****	****Davern**
**Mt. Sinai NYC****	****	****	****	****Emre**
**Univ Nebraska Omaha****	****	****	****McCashland**
**Baylor Dallas****	****	****	****	****Murray**
**Univ Pittsburgh****	****	****	****	****Shakil**
**Northwestern Univ****	****	****	****Blei**
**OHSU, Portland****	****	****	****	****Zaman**
**UCLA****	****	****	****	****	****Han**
**Michigan****	****	****	****	****Fontana**
**Univ Alabama Birmingham****	****	****	****McGuire**
**Mass General ****	****	****	****	****Chung**
**Columbia/Cornell****	**** NYC****	****	****	****Brown/Schilsky**
**VCU****	****	****	****	****	****Stravitz**
**Mayo Clinic: Rochester, Jax, Scottsdale****	****Hay, Raj, Harrison**
**UC Davis****	****	****	****	****Rossaro**
**Einstein Philadelphia****	****	****	****Munoz**
**MUSC Charleston****	****	****	****Reuben**
**UMDNJ****	****	****	****	****Samanta**
**Pennsylvania****	****	****	****	****Reddy**