Abstract
Introduction: A proportion of patients with drug-induced liver injury (DILI) present with autoantibodies, which has led to the current concept of autoimmune-like DILI. However, no standardized definition exists and the clinical relevance has not been studied in detail yet. Methods: 143 patients with DILI enrolled in a prospective study were analyzed. DILI diagnosis was based on the monocyte-derived hepatocyte-like cell test and supported by Roussel Uclaf Causality Assessment Method (RUCAM) and expert adjudication. Testing for antinuclear antibodies (ANA) and antimitochondrial antibodies (AMA) was performed using immunofluorescence. ANA titers ≥1:100 were considered positive and ≥1:400 clinically relevant; AMA positivity was considered at titers ≥1:100. Results: 67% exhibited ANA ≥1:100 and 29% ANA ≥1:400; 10% were AMA positive. There was no significant correlation between the ANA titers and the causative drug, while AMA positive patients had taken nonsteroidal anti-inflammatory drugs more frequently. No difference was seen regarding clinical characteristics or laboratory parameters in patients with ANA ≥1:400, while patients with positive AMA presented with higher aminotransferases, bilirubin, and international normalized ratio. Significantly higher proportions of patients with ANA ≥1:400 or AMA positivity exhibited elevated immunoglobulin G levels. AMA positivity but not elevated ANA titers correlated with a higher proportion of Hy’s law positivity. Conclusion: A closer look in a causality proven DILI cohort provided no evidence that presence of ANA titers is specific for DILI by a certain medication. AMA rather than ANA positivity was related to a more pronounced liver injury.
References
1.
Bjornsson
ES
, Bergmann
OM
, Bjornsson
HK
, Kvaran
RB
, Olafsson
S
. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland
. Gastroenterology
. 2013
;144
(7
):1419
–25
. 25 e1–3; quiz e19–20
.2.
Goldberg
DS
, Forde
KA
, Carbonari
DM
, Lewis
JD
, Leidl
KB
, Reddy
KR
, et al. Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system
. Gastroenterology
. 2015
;148
(7
):1353
–e3
. .3.
Ostapowicz
G
, Fontana
RJ
, Schiødt
FV
, Larson
A
, Davern
TJ
, Han
SH
, 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
(12
):947
. .4.
Sgro
C
, Clinard
F
, Ouazir
K
, Chanay
H
, Allard
C
, Guilleminet
C
, et al. Incidence of drug-induced hepatic injuries: a French population-based study
. Hepatology
. 2002
;36
(2
):451
–5
. .5.
Castiella
A
, Zapata
E
, Lucena
MI
, Andrade
RJ
. Drug-induced autoimmune liver disease: a diagnostic dilemma of an increasingly reported disease
. World J Hepatol
. 2014
;6
(4
):160
–8
. .6.
Sebode
M
, Schulz
L
, Lohse
AW
. “Autoimmune(-like)” drug and herb induced liver injury: new insights into molecular pathogenesis
. Int J Mol Sci
. 2017
;18
(9
):1954
.7.
Weiler-Normann
C
, Schramm
C
. Drug induced liver injury and its relationship to autoimmune hepatitis
. J Hepatol
. 2011
;55
(4
):747
–9
. .8.
Kullak-Ublick
GA
, Andrade
RJ
, Merz
M
, End
P
, Benesic
A
, Gerbes
AL
, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment
. Gut
. 2017
;66
(6
):1154
–64
. .9.
Bjornsson
E
, Talwalkar
J
, Treeprasertsuk
S
, Kamath
PS
, Takahashi
N
, Sanderson
S
, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis
. Hepatology
. 2010
;51
(6
):2040
–8
.10.
deLemos
AS
, Foureau
DM
, Jacobs
C
, Ahrens
W
, Russo
MW
, Bonkovsky
HL
. Drug-induced liver injury with autoimmune features
. Semin Liver Dis
. 2014
;34
(2
):194
–204
. .11.
Ghabril
M
, Bonkovsky
HL
, Kum
C
, Davern
T
, Hayashi
PH
, Kleiner
DE
, et al. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases
. Clin Gastroenterol Hepatol
. 2013
;11
(5
):558
–64.e3
.12.
Raschi
E
, De Ponti
F
. Strategies for early prediction and timely recognition of drug-induced liver injury: the case of cyclin-dependent kinase 4/6 inhibitors
. Front Pharmacol
. 2019
;10
:1235
. .13.
Russo
MW
, Hoofnagle
JH
, Gu
J
, Fontana
RJ
, Barnhart
H
, Kleiner
DE
, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network
. Hepatology
. 2014
;60
(2
):679
–86
. .14.
Sakaan
SA
, Twilla
JD
, Usery
JB
, Winton
JC
, Self
TH
. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication
. South Med J
. 2014
;107
(2
):107
–13
. .15.
Sherigar
JM
, Fazio
R
, Zuang
M
, Arsura
E
. Autoimmune hepatitis induced by nitrofurantoin. The importance of the autoantibodies for an early diagnosis of immune disease
. Clin Pract
. 2012
;2
(4
):e83
. .16.
Lucena
MI
, Kaplowitz
N
, Hallal
H
, Castiella
A
, García-Bengoechea
M
, Otazua
P
, et al. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis
. J Hepatol
. 2011
;55
(4
):820
–7
. .17.
Li
J
, Zhu
X
, Liu
F
, Cai
P
, Sanders
C
, Lee
WM
, et al. Cytokine and autoantibody patterns in acute liver failure
. J Immunotoxicol
. 2010
;7
(3
):157
–64
. .18.
Bernal
W
, Ma
Y
, Smith
HM
, Portmann
B
, Wendon
J
, Vergani
D
. The significance of autoantibodies and immunoglobulins in acute liver failure: a cohort study
. J Hepatol
. 2007
;47
(5
):664
–70
. .19.
Aithal
GP
, Watkins
PB
, Andrade
RJ
, Larrey
D
, Molokhia
M
, Takikawa
H
, et al. Case definition and phenotype standardization in drug-induced liver injury
. Clin Pharmacol Ther
. 2011
;89
(6
):806
–15
. .20.
Benesic
A
, Leitl
A
, Gerbes
AL
. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury
. Gut
. 2016
;65
(9
):1555
–63
. .21.
Benesic
A
, Rahm
NL
, Ernst
S
, Gerbes
AL
. Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies
. Lab Invest
. 2012
;92
(6
):926
–36
. .22.
Benesic
A
, Rotter
I
, Dragoi
D
, Weber
S
, Leitl
ML
, Buchholtz
ML
, et al. Development and validation of a test to identify drugs that cause idiosyncratic drug-induced liver injury
. Clin Gastroenterol Hepatol
. 2018
;16
(9
):1488
–e5
. .23.
Tillmann
HL
, Suzuki
A
, Barnhart
HX
, Serrano
J
, Rockey
DC
. Tools for causality assessment in drug-induced liver disease
. Curr Opin Gastroenterol
. 2019
;35
(3
):183
–90
. .24.
Danan
G
, Benichou
C
. Causality assessment of adverse reactions to drugs: I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries
. J Clin Epidemiol
. 1993
;46
(11
):1323
–30
.25.
Hayashi
PH
. Drug-induced liver injury network causality assessment: criteria and experience in the United States
. Int J Mol Sci
. 2016
;17
(2
):201
. .26.
Bénichou
C
. Criteria of drug-induced liver disorders
. J Hepatol
. 1990
;11
(2
):272
–6
.27.
Polson
J
, Lee
WM
. AASLD position paper: the management of acute liver failure
. Hepatology
. 2005
;41
(5
):1179
–97
. .28.
Regev
A
, Bjornsson
ES
. Drug-induced liver injury: morbidity, mortality, and Hy’s law
. Gastroenterology
. 2014
;147
(1
):20
–4
.29.
Alvarez
F
, Berg
PA
, Bianchi
FB
, Bianchi
L
, Burroughs
AK
, Cancado
EL
, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis
. J Hepatol
. 1999
;31
(5
):929
–38
. .30.
de Boer
YS
, Kosinski
AS
, Urban
TJ
, Zhao
Z
, Long
N
, Chalasani
N
, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury
. Clin Gastroenterol Hepatol
. 2017
;15
(1
):103
–e2
. .31.
Stephens
C
, Castiella
A
, Gomez-Moreno
EM
, Otazua
P
, López-Nevot
MÁ
, Zapata
E
, et al. Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: the influence of human leucocyte antigen alleles
. Pharmacogenet Genomics
. 2016
;26
(9
):414
–22
. .32.
Kavanaugh
A
, Tomar
R
, Reveille
J
, Solomon
DH
, Homburger
HA
. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists
. Arch Pathol Lab Med
. 2000
;124
(1
):71
–81
. .33.
Tan
EM
, Feltkamp
TE
, Smolen
JS
, Butcher
B
, Dawkins
R
, Fritzler
MJ
, et al. Range of antinuclear antibodies in “healthy” individuals
. Arthritis Rheum
. 1997
;40
(9
):1601
–11
. .34.
Mariz
HA
, Sato
EI
, Barbosa
SH
, Rodrigues
SH
, Dellavance
A
, Andrade
LE
. Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases
. Arthritis Rheum
. 2011
;63
(1
):191
–200
. .35.
Kakisaka
K
, Kataoka
K
, Suzuki
Y
, Okada
Y
, Yoshida
Y
, Kuroda
H
, et al. Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury
. Cytokine
. 2016
;86
:21
–8
. .36.
Karkhanis
J
, Verna
EC
, Chang
MS
, Stravitz
RT
, Schilsky
M
, Lee
WM
, et al. Steroid use in acute liver failure
. Hepatology
. 2014
;59
(2
):612
–21
. .37.
Jones
DEJ
. Pathogenesis of primary biliary cirrhosis
. Gut
. 2007
;56
(11
):1615
–24
. .38.
Yang
J
, Yu
YL
, Jin
Y
, Zhang
Y
, Zheng
CQ
. Clinical characteristics of drug-induced liver injury and primary biliary cirrhosis
. World J Gastroenterol
. 2016
;22
(33
):7579
–86
. .39.
Narciso-Schiavon
JL
, Freire
FC
, Suarez
MM
, Ferrari
MV
, Scanhola
GQ
, Schiavon
LL
, et al. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon?
Eur J Gastroenterol Hepatol
. 2009
;21
(4
):440
–6
. .40.
Narkewicz
MR
, Horslen
S
, Belle
SH
, Rudnick
DA
, Ng
VL
, Rosenthal
P
, et al. Prevalence and significance of autoantibodies in children with acute liver failure
. J Pediatr Gastroenterol Nutr
. 2017
;64
(2
):210
–7
. .© 2020 S. Karger AG, Basel
2020
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
