TY - JOUR
T1 - Acute Liver Failure of Indeterminate Etiology
T2 - A Comprehensive Systematic Approach by An Expert Committee to Establish Causality
AU - for the Acute Liver Failure Study Group
AU - Ganger, Daniel R.
AU - Rule, Jody
AU - Rakela, Jorge
AU - Bass, Nathan
AU - Reuben, A.
AU - Stravitz, R. T.
AU - Sussman, Norman
AU - Larson, Anne M.
AU - James, Laura
AU - Chiu, Charles
AU - Lee, William M.
N1 - Funding Information:
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: None.
Publisher Copyright:
© 2018, American College of Gastroenterology.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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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U2 - 10.1038/s41395-018-0160-2
DO - 10.1038/s41395-018-0160-2
M3 - Article
C2 - 29946176
AN - SCOPUS:85049068542
SN - 0002-9270
VL - 113
SP - 1319
EP - 1328
JO - American Journal of Gastroenterology
JF - American Journal of Gastroenterology
IS - 9
ER -