RT Journal Article
T1 Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.
A1 Mikus, Maria
A1 Drobin, Kimi
A1 Gry, Marcus
A1 Bachmann, Julie
A1 Lindberg, Johan
A1 Yimer, Getnet
A1 Aklillu, Eleni
A1 Makonnen, Eyasu
A1 Aderaye, Getachew
A1 Roach, James
A1 Fier, Ian
A1 Kampf, Caroline
A1 Göpfert, Jens
A1 Perazzo, Hugo
A1 Poynard, Thierry
A1 Stephens, Camilla
A1 Andrade, Raúl J
A1 Lucena, M Isabel
A1 Arber, Nadir
A1 Uhlén, Mathias
A1 Watkins, Paul B
A1 Schwenk, Jochen M
A1 Nilsson, Peter
A1 Schuppe-Koistinen, Ina
K1 affinity proteomics
K1 biomarker discovery
K1 drug-induced liver injury
K1 plasma profiling
K1 suspension bead arrays
AB The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
YR 2016
FD 2016-06-22
LK http://hdl.handle.net/10668/10122
UL http://hdl.handle.net/10668/10122
LA en
DS RISalud
RD Apr 4, 2025