Acute Liver Failure in the USA: Results of the US ALF Study Group

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Acute Liver Failure in the USA Results of the
US ALF Study Group

• William M. Lee, MD
• Meredith Mosle Distinguished Professor in Liver
  Disease
• University of Texas Southwestern Medical Center
  Dallas, TX
• www3.utsouthwestern.edu/liver

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Acute Liver Failure (ALF) Definition

• Altered mentation
• Coagulopathy (INR gt1.5)
• Acute illness (lt 26 wks)
• No cirrhosis
• Variety of etiologies

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Acute Liver Failure (ALF) Background

• 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?

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Acute Liver Failure Study GroupA consortium to
study a rare disease

• 14 academic med centers initially in 1998, now 25
• Also 23 pediatric sites, since 2000
• Detailed prospective data and serum samples
• N-acetylcysteine trial for non-ACM ALF
• Numerous ancillary studies in progress

Funded by NIH R03, FDA Orphan Grant, NIH R01
(00-05)
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Case Report Form
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ALF etiologies prior US studies ()
Infectious and serum hepatitis
Medicine 196948151-72, Dig Dis Sci
1991361223-8, Mayo Clin Proc 198560289-92,
Liver Transpl Surg 1999529-34, and Liver
Transpl 20006163-9.
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Comparison Between Retrospective Study (1994-96
n 295) and Current Study (1998-2001 n 308)

NS
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Comparison of Different ALF Etiology
Groups Variable Acetaminophen Drug
Induced Indeterminate All Others p
(n 120) (n 40)
(n 53) (n 95) value Sex (F)
79 73
60 72 NS Age (yrs) 36
41 38
43 0.02 Jaundice (days)
1 12 12 4
lt0.001 Coma III/IV () 50
43 47
47 NS ALT 4310
574 947
1060 lt0.001 Bilirubin 4.3
20.2 24.5
12.6 lt0.001 Tx ()
6 53 51
36 lt0.001 Spont surv ()
68 25
17 33
lt0.001 Overall surv () 73
70 64
61 NS
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ALF etiologies outside the US ()
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Presentations of acetaminophen poisoningAccidenta
l vs. suicidal cases

• Suicidal single time point ingestion with
  suicidal intent
• Accidental multiple time points, cause for pain,
  suicidal intent denied

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Acetaminophen Toxicity in an Urban County Hospital
The Parkland Study Schiødt et al., NEJM
19973371112-7 All patients admitted with
potential ACM injury
Accidental Suicidal p-value
(n21) (n50) Present gt24h 64
14 0.001 EtOH abuse 63 25
0.009 ACM level mg/L 7 126 lt0.001 ALT
(IU/L) 7430 1501
0.001 ALT 1000 IU/L 62 20 lt0.002 Recd
NAC 76 80 0.76 Hepatic coma
33 6 lt0.001 Death 19
2 0.04
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Acetaminophen Toxicity Leading to ALF
Results in 108 patients, 12 deleted

• Female 79, median age 36 (19-63)
• Alcohol use 57 alcohol abuse 19
• Narcotic combinations 38
• Dose 4 gm/day 69 10 gm/day 32
• ACM level detectable 82 gt 50 mg/L 42
• ALT gt 7,000 IU/L 51 ALT gt 3,500 IU/L 92
• Cr 2.0 52 pH 7.3 17

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Suicidal vs. Accidental ACM ALF Cases
Accidental Suicidal p-value
(n59) (n44) Age 39 33
0.011 Tot ACM (g) 20 29
NS Antidepresst 36 34
NS EtOH 55 61 NS Double use 24
5 0.02 Narcotic/acet 54 14
0.001 ALT (IU/L) 3,616
5,929 lt0.001 Creatinine 2.5 1.3
0.008 Survival 71 75 NS
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Outcomes for Acute Liver Failure patients
Acetamin. 30 Indetermin 20 Drug-induced
9 Shock liver 7 Hepatitis B 4 Malignancy
4 Pregnancy 3 Autoimm. hep. 3 Wilson
2 Hepatitis A 2 Budd-Chiari 1 Others 2
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Summary Acetaminophen-related ALFConstitutes
1/3 of all US ALF deaths

• The most common cause for ALF and a (?growing)
  problem in US (150-800/year in US)
• Alcohol relationship less apparent
• Accidental and suicidal cases similar clinically
• Relatively low mortality cf. other ALF causes
• Role of anti-depressants 35, narcotics 38 and
  repeated daily dosing needs further attention
• Pediatric cases also of concern (20)