Liver Injury From Tumor Necrosis Factor-α Antagonists

Analysis of Thirty-four Cases

Marwan Ghabril, Herbert L. Bonkovsky, Clarissa Kum, Tim Davern, Paul H. Hayashi, David E. Kleiner, Jose Serrano, Jim Rochon, Robert J. Fontana, Maurizio Bonacini

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Background & Aims: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. Methods: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. Results: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. Conclusions: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

Original languageEnglish
JournalClinical Gastroenterology and Hepatology
Volume11
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

Chemical and Drug Induced Liver Injury
Tumor Necrosis Factor-alpha
Liver
Wounds and Injuries
Cholestasis
Adrenal Cortex Hormones
Pharmaceutical Preparations
Alanine Transaminase
Autoimmunity
PubMed
Causality
Liver Transplantation
Smooth Muscle
Fibrosis
Databases
Phenotype
Biopsy
Antibodies

Keywords

  • Autoimmunity
  • Drug-Induced Liver Injury
  • Hepatotoxicity
  • TNF-α Antagonists
  • Tumor Necrosis Factor

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Liver Injury From Tumor Necrosis Factor-α Antagonists : Analysis of Thirty-four Cases. / Ghabril, Marwan; Bonkovsky, Herbert L.; Kum, Clarissa; Davern, Tim; Hayashi, Paul H.; Kleiner, David E.; Serrano, Jose; Rochon, Jim; Fontana, Robert J.; Bonacini, Maurizio.

In: Clinical Gastroenterology and Hepatology, Vol. 11, No. 5, 05.2013.

Research output: Contribution to journalArticle

Ghabril, M, Bonkovsky, HL, Kum, C, Davern, T, Hayashi, PH, Kleiner, DE, Serrano, J, Rochon, J, Fontana, RJ & Bonacini, M 2013, 'Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases', Clinical Gastroenterology and Hepatology, vol. 11, no. 5. https://doi.org/10.1016/j.cgh.2012.12.025
Ghabril, Marwan ; Bonkovsky, Herbert L. ; Kum, Clarissa ; Davern, Tim ; Hayashi, Paul H. ; Kleiner, David E. ; Serrano, Jose ; Rochon, Jim ; Fontana, Robert J. ; Bonacini, Maurizio. / Liver Injury From Tumor Necrosis Factor-α Antagonists : Analysis of Thirty-four Cases. In: Clinical Gastroenterology and Hepatology. 2013 ; Vol. 11, No. 5.
@article{b9f2aa2d0408409a8a8a4fa0e98182b6,
title = "Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases",
abstract = "Background & Aims: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. Methods: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. Results: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35{\%}), a very likely cause for 21 (62{\%}), and a definite cause for 1 (3{\%}). Median latency was 13 weeks (range, 2-104); however, 7 cases (20{\%}) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67{\%}) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. Conclusions: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.",
keywords = "Autoimmunity, Drug-Induced Liver Injury, Hepatotoxicity, TNF-α Antagonists, Tumor Necrosis Factor",
author = "Marwan Ghabril and Bonkovsky, {Herbert L.} and Clarissa Kum and Tim Davern and Hayashi, {Paul H.} and Kleiner, {David E.} and Jose Serrano and Jim Rochon and Fontana, {Robert J.} and Maurizio Bonacini",
year = "2013",
month = "5",
doi = "10.1016/j.cgh.2012.12.025",
language = "English",
volume = "11",
journal = "Clinical Gastroenterology and Hepatology",
issn = "1542-3565",
publisher = "W.B. Saunders Ltd",
number = "5",

}

TY - JOUR

T1 - Liver Injury From Tumor Necrosis Factor-α Antagonists

T2 - Analysis of Thirty-four Cases

AU - Ghabril, Marwan

AU - Bonkovsky, Herbert L.

AU - Kum, Clarissa

AU - Davern, Tim

AU - Hayashi, Paul H.

AU - Kleiner, David E.

AU - Serrano, Jose

AU - Rochon, Jim

AU - Fontana, Robert J.

AU - Bonacini, Maurizio

PY - 2013/5

Y1 - 2013/5

N2 - Background & Aims: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. Methods: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. Results: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. Conclusions: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

AB - Background & Aims: Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. Methods: We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. Results: The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. Conclusions: Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

KW - Autoimmunity

KW - Drug-Induced Liver Injury

KW - Hepatotoxicity

KW - TNF-α Antagonists

KW - Tumor Necrosis Factor

UR - http://www.scopus.com/inward/record.url?scp=84876732000&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876732000&partnerID=8YFLogxK

U2 - 10.1016/j.cgh.2012.12.025

DO - 10.1016/j.cgh.2012.12.025

M3 - Article

VL - 11

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

SN - 1542-3565

IS - 5

ER -