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

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. Acute Liver Failure (ALF): Definition. Altered mentation

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

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  1. 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

  2. Acute Liver Failure (ALF): Definition • Altered mentation • Coagulopathy (INR >1.5) • Acute illness (< 26 wks) • No cirrhosis • Variety of etiologies

  3. 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?

  4. 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)

  5. Case Report Form

  6. ALF etiologies: prior US studies (%) * ‘Infectious and serum hepatitis’ Medicine 1969;48:151-72, Dig Dis Sci 1991;36:1223-8, Mayo Clin Proc 1985;60:289-92, Liver Transpl Surg 1999;5:29-34, and Liver Transpl 2000;6:163-9.

  7. Etiology of ALF in the USA(n = 395)

  8. Comparison Between Retrospective Study (1994-96; n = 295) and Current Study (1998-2001; n = 308) + NS

  9. 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 <0.001 Coma III/IV (%) 50 43 47 47 NS ALT 4310 574 947 1060 <0.001 Bilirubin 4.3 20.2 24.5 12.6 <0.001 Tx (%) 6 53 51 36<0.001 Spont surv (%) 68 25 17 33 <0.001 Overall surv (%) 73 70 64 61 NS

  10. ALF etiologies outside the US (%)

  11. Presentations of acetaminophen poisoningAccidental vs. suicidal cases • Suicidal: single time point ingestion with suicidal intent • Accidental: multiple time points, cause for pain, suicidal intent denied

  12. Acetaminophen Toxicity in an Urban County Hospital The Parkland Study: Schiødt et al., NEJM 1997;337:1112-7 All patients admitted with potential ACM injury Accidental Suicidal p-value (n=21) (n=50) Present >24h 64% 14% 0.001 EtOH abuse 63% 25% 0.009 ACM level mg/L 7 126 <0.001 ALT (IU/L) 7430 1501 0.001 ALT ≥1000 IU/L 62% 20% <0.002 Rec’d NAC 76% 80% 0.76 Hepatic coma 33% 6% <0.001 Death 19% 2% 0.04

  13. 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%; > 50 mg/L: 42% • ALT > 7,000 IU/L: 51%; ALT > 3,500 IU/L: 92% • Cr ≥ 2.0 52%; pH ≤ 7.3 17%

  14. Suicidal vs. Accidental ACM ALF Cases Accidental Suicidal p-value (n=59) (n=44) Age 39 33 0.011 Tot ACM (g) 20 29 NS Antidepress’t 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 <0.001 Creatinine 2.5 1.3 0.008 Survival 71% 75% NS

  15. 308 Patients enrolled Transplanted n= 89 (29%) Died before transplantation n= 87 (28%) Spontaneous survivors n= 132 (43%) Alive (n= 75) Died (n= 14) 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

  16. 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%)

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