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Orchestration of Tryptophan-Kynurenine pathway, acute decompensation and acute-on-chronic liver failure in cirrhosis

Clària, J; Moreau, R; Fenaille, F; Amorós, A; Junot, C; Gronbaek, H; Coenraad, MJ; ... CANONIC Study Investigators of the EASL Clif Consortium Grifols, .; + view all (2019) Orchestration of Tryptophan-Kynurenine pathway, acute decompensation and acute-on-chronic liver failure in cirrhosis. Hepatology , 69 (4) pp. 1686-1701. 10.1002/hep.30363. Green open access

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Abstract

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation via the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers), were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. CONCLUSION: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course and mortality. This article is protected by copyright. All rights reserved.

Type: Article
Title: Orchestration of Tryptophan-Kynurenine pathway, acute decompensation and acute-on-chronic liver failure in cirrhosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/hep.30363
Publisher version: https://doi.org/10.1002/hep.30363
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Decompensated cirrhosis; systemic inflammation; kynurenine; metabolomics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10065131
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