# Presentation: 505699

## 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**

## Slide 2

## 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

**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**

- Background/Rationale on ALF

## 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

**Case Report Form**

## Etiology of ALF in the USA:Adult Registry (n = 684)

- Etiology of ALF in the USA:Adult Registry (n = 684)

## Comparison of Different Etiology Groups:

|  | ACM
n=300 | Drug
n=86 | Indeterminate
n=97 | HepA/HepB
n=27/49 | All Others
n=125 |
| --- | --- | --- | --- | --- | --- |
| Age (median) | 36.5 | 40 | 37 | 47/40 | 41 |
| Sex (% F) | 74 | 71 | 55 | 48/47 | 78 |
| Jaundice (Days)
(median) | 0 | 9.5 | 9.5 | 3.0/5.5 | 8.0 |
| Coma 3⁄4 (%) | 51 | 41 | 48 | 48/60 | 42 |
| ALT (median) | 4091 | 580 | 904 | 2658/1601 | 677 |
| Bili (median) | 4.6 | 22.0 | 23.3 | 11.8/18.8 | 15.3 |
| Tx (%) | 8 | 45 | 42 | 26/53 | 33 |
| Spontaneous Survival (%) | 64 | 20 | 25 | 59/27 | 30 |
| Overall Survival (%) | 71 | 62 | 64 | 82/71 | 57 |

## Acetaminophen cases as % of all ALF per year

## Slide 9

## Suicidal vs. Accidental APAP cases

- 			      **Suicidal     Unintentional    p-value**
**	****	****	****        ****(n=101)****	****  (n=109)**
**Female (%)            75                 76                   NS**
**ACM dose****	****(g)****	****   28****	****	****     34   ****	****         NS**
**Dose per day        28                 10                0.001**
**Coma (%**_**>**_**3)          39                 55                0.026**
**ALT (IU/L)            6118             3975****	****       0.001**
**Spont surv (%)     67                 66                  NS**
**Antidepress’t****	****   35****	****	****     36 ****	****         NS**
**Narcotic cpd (%)   19****	****	****     ****62****	****                 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****	****   ACM        p-value**
**	****	****	****          ****(n=98)****	****  (n=120)**
**Female (%)****	****     85****	****	****     70****	****   ****	****    0.03**
**Suicidal OD (%)****	****     19****	****	****     63   ****	****  <0.001**
**Coma (% **_**>**_** 3)****	****     60****	****	****     38****	****	****    0.001**
**Platelets****	****	****   158****	****	****   121****	****	****    0.001**
**Spont surviv (%)     67****	****     65****	****	****      NS**
**Mean alcohol (g)     58              16              0.01**
**Alcohol abuse (%)  44              22              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!

- Cytochrome p450 2E1

- (phase I)

- OH

- HN

- C

- CH3

- O

- (phase II)

- Nontoxic Metabolites

- O

- GSH

- glutathione-S-transferase

- OH

**SG**

**Mercapturic Acid**
- (nontoxic)

**NAPQI**
**(highly reactive intermediate)**

**Hepatocyte Damage**

**Covalent binding to cell proteins, including enzyme itself**
**ADDUCTS**
**Derangement of apoptosis?**
**CAR?**

**Cytochromes P450 lead to unstable compounds!**

## 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**

## ALT and APAP adducts in 4 patients with acetaminophen OD

## 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: I**

## 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**

**Spectrum of Drug-Related Acute Liver Failure: II**

## 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

**	****	****	****	****	****      ****Peak**
_**Medication**__**	**__**	**__**     M/F**__**	**__**  Age(yr)     Enceph.         TX       Alive**_
- Valproic Acid (DPH/neurontin) M           5                III	     N           N
- Pravastatin		      F	      16	            IV	     N	     N
- DPH			      M            9               IV	     N           N
- Dantrium                              M           23             N/A	     N           N
- Isoflurane		      F           17               IV	     N           N
- INH			      M          14               III	     Y           Y
- Bactrim			      M          16               IV	     Y           Y
- Valproic Acid		      M	        4	            IV	     Y           Y
- Cytoxan/DPH		      M	      16	           N/A	     N           Y
- Valproic Acid		      F             2                I	     N           Y
- Minocycline		      M	      16	           N/A	     N	      Y

## Slide 22

## Overall survival:  n = 404 (66%)

- <date/time>

**610 Patients enrolled**

**Spontaneous**
** ****survivors **
**n= 270**
**(44%)**

**Died (Not**
**Transplanted) **
**n= 185**
**(30%)**

**Transplanted **
**n= 155**
**(25%)**

**Alive**
**n= 134**
**(86%)**

**Died **
**n= 21**
**(14%)**

## Prognosis in Acute Liver Failure

**Good prognosis:**
**Acetaminophen**
**Hepatitis A**
**Shock**

- Etiology an important outcome determinant

**Bad prognosis:**
**Drugs**
**Indeterminate**
**Hepatitis B**
**Wilson Disease**

## 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

**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**

## Slide 26

## 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**

## 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)

**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)**

**Future Research in DILI ALF**
**Goal: Improve outcomes for all while limiting use of transplantation**

## UCLA					Han

**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**
**Pennsylvania****	****	****	****	****Reddy**
**UCSD****	****	****	****	****	****Hassanein**
**Duke****	****	****	****	****	****Rockey**

## Slide 31