Gastroenterology
Volume 137, Issue 3 , Pages 856-864.e1 , September 2009

Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure

  • William M. Lee

      Affiliations

    • Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
    • Corresponding Author InformationReprint requests William M. Lee, MD, Division of Digestive and Liver Diseases, The University of Texas Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, HP.4.420, Dallas, Texas 75390-8887. fax: (214) 645-6114
    • ,
  • Linda S. Hynan

      Affiliations

    • Department of Clinical Sciences (Biostatistics) and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
    • ,
  • Lorenzo Rossaro

      Affiliations

    • University of California Davis, Sacramento, California
    • ,
  • Robert J. Fontana

      Affiliations

    • Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
    • ,
  • R. Todd Stravitz

      Affiliations

    • Section of Hepatology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
    • ,
  • Anne M. Larson

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Washington, Seattle, Washington
    • ,
  • Timothy J. Davern II

      Affiliations

    • Division of Gastroenterology, Department of Internal Medicine, University of California, San Francisco, California
    • ,
  • Natalie G. Murray

      Affiliations

    • Division of Gastroenterology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas
    • ,
  • Timothy McCashland

      Affiliations

    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska, Omaha, Nebraska
    • ,
  • Joan S. Reisch

      Affiliations

    • Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
    • ,
  • Patricia R. Robuck

      Affiliations

    • National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and the Acute Liver Failure Study Group Investigators (see Appendix for list of participating members and institutions)
    • ,
  • Acute Liver Failure Study Group

Received 15 October 2008 ,Accepted 2 June 2009.

References 

  1. Lee WM. Medical progress: acute liver failure. N Engl J Med. 1993;329:1862–1872
  2. Polson J, Lee WM. American Association for the Study of Liver Disease position paper: the management of acute liver failure. Hepatology. 2005;41:1179–1197
  3. Rakela J, Mosley JW, Edwards VM, et al. A double-blinded, randomized trial of hydrocortisone in acute hepatic failure (The Acute Hepatic Failure Study Group). Dig Dis Sci. 1991;36:1223–1228
  4. Rake MO, Flute PT, Shilkin KB, et al. Early and intensive therapy of intravascular coagulation in acute liver failure. Lancet. 1971;ii:1215–1218
  5. Harrison PM, Hughes RD, Forbes A, et al. Failure of insulin and glucagon infusions to stimulate liver regeneration in fulminant hepatic failure. J Hepatol. 1990;10:332–336
  6. Sinclair SB, Levy GA. Treatment of fulminant viral hepatic failure with prostaglandin E (A preliminary report). Dig Dis Sci. 1991;36:791–800
  7. Ostapowicz GA, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:945–954
  8. Prescott LF, Critchley JA. The treatment of acetaminophen poisoning. Annu Rev Pharmacol Toxicol. 1983;23:87–101
  9. Hamlyn AN, Douglas AP, James O. The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad Med J. 1978;54:400–404
  10. Rumack BH. Acetaminophen overdose in young children. Am J Dis Child. 1984;138:428–433
  11. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993). Gastroenterology. 1995;109:1907–1916
  12. Harrison PM, Wendon JA, Gimson AE, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991;324:1852–1857
  13. Walsh TS, Hopton P, Philips BJ, et al. The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology. 1998;27:1332–1340
  14. Rank N, Michel C, Haertel C, et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Crit Care Med. 2000;28:3799–3807
  15. Schneider J, Lutun P, Boudjema K, et al. In vivo evidence of enhanced guanylyl cyclase activation during the hyperdynamic circulation of acute liver failure. Hepatology. 1994;19:38–44
  16. Alonso A, Lau J, Jaber BL, et al. Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis. 2004;43:1–9
  17. Zwingmann C, Bilodeau M. Metabolic insights into the hepatoprotective effect of N-acetylcysteine in mouse liver. Hepatology. 2006;443:454–463
  18. Hein OV, Ohring R, Schilling A, et al. N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report. Crit Care. 2004;8:R66–R71
  19. Sklar GE, Subramaniam M. Acetylcysteine treatment for non-acetaminophen-induced acute liver failure. Ann Pharmacother. 2004;38:498–500
  20. Trey C, Davidson CS. The management of fulminant hepatic failure. In:  Popper H,  Schaffner F editor. Progress in liver diseases. New York: Grune & Stratton; 1970;p. 282–298
  21. Davern TJ, James LP, Hinson JA, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006;130:687–694
  22. James LP, Alonso EM, Hynan LS, et al. Detection of acetaminophen-protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006;118:676–681
  23. O'Grady J, Alexander GJM, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:439–445
  24. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91–96
  25. Kremers WK, van IJperen M, Kim WR, et al. MELD score as a predictor of pre-transplant and posttransplant survival in OPTN/UNOS status 1 patients. Hepatology. 2004;39:764–769
  26. Zaman MB, Hoti E, Qasim A, et al. MELD score as a prognostic model for listing acute liver failure patients for liver transplantation. Transplant Proc. 2006;38:2097–2098
  27. Katoonizadeh A, Decaestecker J, Wilmer A, et al. MELD score to predict outcome in adult patients with non-acetaminophen induced acute liver failure. Liver Int. 2007;27:329–334
  28. Kortsalioudaki C, Taylor RM, Cheeseman P, et al. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008;14:25–30

 Conflict of interest The authors disclose no conflicts. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician who is not employed by the corporate entity. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. This was a randomized clinical trial (ClinicalTrials.gov number NCT00004467).

 Funding The study was supported by the following grants: R-03 DK52827, R-01 DK58369, and U-01 DK58369 from the National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and FD-R-001661 from the Orphan Products Division, United States Food and Drug Administration. Additional funding was provided by the Stephen Tips Fund of the Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation. This study was performed under IND #56925, filed with the Food and Drug Administration. The N-acetylcysteine used in the trial was supplied initially by Apothecon/Geneva Pharmaceuticals (Princeton, NJ), a division of Bristol Myers Squibb, and after April 2003 was supplied by Cumberland Pharmaceuticals (Nashville, TN). No additional support, data analysis, or input of any kind was provided by these companies.

 To view this article’s video abstract, go to the AGA's YouTube Channel.

PII: S0016-5085(09)00915-9

doi: 10.1053/j.gastro.2009.06.006

Gastroenterology
Volume 137, Issue 3 , Pages 856-864.e1 , September 2009

Article Tools

* Image Usage & Resolution