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Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to Establish Causality

The American Journal of Gastroenterologyvolume 113pages13191328 (2018) | Download Citation




In the United States, the Acute Liver Failure Study Group (ALFSG) registry lists approximately 11% of cases as of indeterminate etiology (IND-ALF) as determined by the respective local site principal investigator (PI). Traditionally, IND-ALF has prompted concern that other viruses or toxins might be implicated. We hypothesized that many IND- ALF cases would have an identifiable etiology upon further investigation. Improving the identification process should reduce the number of truly indeterminate cases.


Specific definitions for each etiology (“etiology-specific algorithms”) were developed by a Causality Adjudication Committee that included six reviewers (each with 20 or more years of experience). Of 2718 patients with ALF, 303 initially deemed IND-ALF by site PIs underwent committee review guided by the algorithms. Acetaminophen (APAP) protein adducts were measured in sera when available, additional HEV testing was performed, and viral sequences sought by microarray analysis and metagenomic next-generation sequencing (mNGS). Study sites were asked to provide liver biopsy and/or explant reports and to update serological findings not reported previously.


Nearly half (142, 46.9%) of the 303 IND-ALF cases could be reassigned to a single, defined etiology and rated as highly likely or probable; 11 additional cases, upon review, did not meet ALF criteria. Amongst reassigned etiologies, 45 were previously unrecognized APAP, 34 autoimmune hepatitis (AIH), 24 drug-induced liver injury (DILI), 13 various viral causes, 12 ischemia, and 14 miscellaneous other etiologies. The remaining 150, deemed true IND-ALF, represented just 5.5%.


The indeterminate etiology in ALF includes patients with a diagnosis that is discernible after closer examination. Revision of etiologic diagnoses of indeterminate cases using added testing and expert opinion is useful in understanding all aspects of ALF.

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  1. 1.

    Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525–34.

  2. 2.

    Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol. 2013;59:74–80.

  3. 3.

    Reuben A, Tillman H, Fontana RJ, et al. Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med. 2016;164:724–32.

  4. 4.

    Squires RH Jr. Acute liver failure in children. Semin Liver Dis. 2008;28:153–66.

  5. 5.

    Mendizabal M, Marciano S, Videla MG, et al. Changing etiologies and outcomes of acute liver failure: perspectives from 6 transplant centers in Argentina. Liver Transpl. 2014;20:483–9.

  6. 6.

    Nakao M, Nakayama N, Uchida Y, et al. Nationwide survey for acute liver failure and late-onset hepatic failure in Japan. J Gastroenterol. 2018;53:752-769.

  7. 7.

    Donnelly MC, Davidson JS, Martin K, et al. Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study). Aliment Pharmacol Ther. 2017;45:833–43.

  8. 8.

    Shalimar, Kedia S, Gunjan D, et al. Acute liver failure due to hepatitis E virus infection is associated with better survival than other etiologies in Indian patients. Dig Dis Sci. 2017;62:1058–66.

  9. 9.

    Koch DG, Speiser JL, Durkalski V, et al. The natural history of acute liver injury. Am J Gastroenterol. 2017;112:1389–96.

  10. 10.

    James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009;37:1779–84.

  11. 11.

    Somasekar S, Lee D, Rule J, et al. Viral surveillance in serum samples from patients with acute liver failure by metagenomic Next-Generation sequencing. Clin Infect Dis. 2017;65:1477–85.

  12. 12.

    NIH policy on reporting race and ethnicity data: subjects—NIH OER. Racial and Ethnic Categories and Definitions for NIH Diversity Programs and for Other Reporting Purposes, Notice Number: NOT-OD-15-089, released on 8 April 2015.

  13. 13.

    Schiødt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther. 2002;71:221–5.

  14. 14.

    Khandelwal N, James LP, Sanders C, Larson AM, Lee WM; Acute Liver Failure Study Group. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology. 2011;53:567–76;

  15. 15.

    Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364–72.

  16. 16.

    Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–38.

  17. 17.

    Hennes EM, Zeniya M, Czaja AJ, et al. International Autoimmune Hepatitis Group simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76.

  18. 18.

    Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology. 2011;53:517–26.

  19. 19.

    Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48:1167–74.

  20. 20.

    Parekh J, Matei VM, Canas-Coto A, Friedman D, Lee WM, the Acute Liver Failure Study Group. Budd-Chiari syndrome causing acute liver failure: a multicenter case series. Liver Transpl. 2017;23:135–42.

  21. 21.

    Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method. Hepatology. 2010;51:2117–26.

  22. 22.

    Chalasani N, Fontana RJ, Watkins PB, et al. Drug Induced Liver Injury Network, (DILIN). Causes, clinical features and outcomes from a prospective study, of drug induced liver injury in The United States. Gastroenterology. 2008;135:1924–34.

  23. 23.

    Ostapowicz G, 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;137:947–54.

  24. 24.

    Schiødt FV, Davern TJ, Shakil AO, et al. Viral hepatitis- related acute liver failure. Am J Gastroenterol. 2003;98:448–53.

  25. 25.

    Fontana RJ, Engle RE, Scaglione S, et al. The role of hepatitis E virus infection in Adult Americans with acute liver failure. Hepatology. 2016;64:1870–80.

  26. 26.

    Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to Hydroxycut: a case series. Am J Gastroenterol. 2010;105:1561–6.

  27. 27.

    O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342:273–5.

  28. 28.

    Roberts DW, Lee WM, Hinson JA, et al. An immunoassay to rapidly measure acetaminophen protein adducts accurately identifies patients with acute liver injury or failure. Clin Gastroenterol Hepatol. 2017;15:555–62.

  29. 29.

    Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137:856–64.

  30. 30.

    Fix O, Liou I, Karvellas CJ, et al. Acute Liver Failure Study Group. Development and pilot of a checklist for management of acute liver failure in the intensive care unit. PLoS ONE. 2016;11:1–11.

  31. 31.

    Donaldson BW, Gopinath R, Wanless IR, et al. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators. Hepatology. 1993;18:1370–6.

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We greatly appreciate and thank our NIDDK Project Officers, Edward Doo MD, and Averell H. Sherker MD for their scientific and administrative advice and support.

Author information


  1. Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    • Daniel R. Ganger MD
  2. Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Jody Rule PhD
  3. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA

    • Jorge Rakela MD
  4. Department of Medicine, UCSF San Francisco, San Francisco, CA, USA

    • Nathan Bass MD, PhD
  5. Medical University of South Carolina, Charleston, SC, USA

    • A Reuben MD
  6. Section of Hepatology Virginia Commonwealth University, Richmond, VA, USA

    • RT Stravitz MD
  7. Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA

    • Norman Sussman MD
  8. Hepatology and Liver Transplantation, University of Washington, Seattle, WA, USA

    • Anne M. Larson MD
  9. Section of Pediatric Pharmacology and Toxicology, Arkansas Children’s Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    • Laura James MD
  10. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

    • Charles Chiu MD, PhD
  11. UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA

    • Charles Chiu MD, PhD
  12. Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA

    • Charles Chiu MD, PhD
  13. Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • William M. Lee MD


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  1. for the Acute Liver Failure Study Group

    Guarantor of the article

    Daniel R. Ganger, MD.

    Specific author contributions

    DRG: drafting of manuscript and final approval of submission and concept design of study. JAR: drafting of manuscript and final approval of submission; and data collection, analysis, and interpretation of data. JR: critical revision of manuscript; drafting of manuscript and final approval of submission; and adjudication committee member. NB: critical revision of manuscript; drafting of manuscript and final approval of submission; and adjudication committee member. AR, RTS, NS, and AML: drafting of manuscript and final approval of submission; and adjudication committee member. LJ: drafting of manuscript and final approval of submission; and Investigator of adduct testing. CC: drafting of manuscript and final approval of submission; and Investigator of the viral sequencing tests. WML: study supervision, critical revision of manuscript, drafting of manuscript, and final approval of submission; and adjudication committee member.

    Financial support

    The ALFSG receives funding from the National Institutes of Health (National Institute of Diabetes, Digestive and Kidney Disease). Grant U-01-5836.

    Potential competing interests


    Corresponding author

    Correspondence to Daniel R. Ganger MD.

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