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Published on: September 13, 2014
Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to
Daniel R Ganger1, Jody Rule1, Jorge Rakela1
1Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern university Feinberg School of Medicine, Chicago, IL, uSA. Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA. Department of Medicine, UCSF San Francisco, San Francisco, CA, USA. Medical University of South Carolina, Charleston, SC, USA. Section of Hepatology Virginia Commonwealth University, Richmond, VA, USA. Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA. Hepatology and Liver Transplantation, University of Washington, Seattle, WA, USA. Section of Pediatric Pharmacology and Toxicology, Arkansas Children's Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA. UCSF-Abbott Viral Diagnostics and Discovery Center, San Francisco, CA, USA. Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, USA. Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Objectives:
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.
Methods:
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.
Results:
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%.
Conclusions:
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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