Acute Liver Failure of Indeterminate Etiology

A Comprehensive Systematic Approach by An Expert Committee to Establish Causality

for the Acute Liver Failure Study Group

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1319-1328
Number of pages10
JournalAmerican Journal of Gastroenterology
Volume113
Issue number9
DOIs
StatePublished - Sep 1 2018

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Acute Liver Failure
Acetaminophen
Causality
Chemical and Drug Induced Liver Injury
Metagenomics
Autoimmune Hepatitis
Expert Testimony
Advisory Committees
Microarray Analysis
Registries
Ischemia
Research Personnel
Viruses
Biopsy
Liver
Serum
Proteins

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

@article{32e89851a53649a8907c453ab15ef130,
title = "Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to Establish Causality",
abstract = "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.",
author = "{for the Acute Liver Failure Study Group} and Ganger, {Daniel R} and Jody Rule and Jorge Rakela and Nathan Bass and A. Reuben and Rt Stravitz and Norman Sussman and Larson, {Anne M.} and Laura James and Charles Chiu and Lee, {William M.}",
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Acute Liver Failure of Indeterminate Etiology : A Comprehensive Systematic Approach by An Expert Committee to Establish Causality. / for the Acute Liver Failure Study Group.

In: American Journal of Gastroenterology, Vol. 113, No. 9, 01.09.2018, p. 1319-1328.

Research output: Contribution to journalArticle

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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.

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AU - Sussman, Norman

AU - Larson, Anne M.

AU - James, Laura

AU - Chiu, Charles

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