Orchestration of tryptophan-kynurenine pathway, Acute decompensation, and acute-on-chronic liver failure in cirrhosis
Joan Clària
(1, 2)
,
Richard Moreau
(1, 3)
,
François Fenaille
(4, 5, 6, 7, 8)
,
Alex Amoros
(1, 2)
,
Christophe Junot
(4, 5)
,
Henning Gronbaek
(9)
,
Minneke J. Coenraad
(10)
,
Alain Pruvost
(11)
,
Aurelie Ghettas
(11)
,
Emeline Chu-Van
(11)
,
Cristina López-Vicario
(2)
,
Karl Oettl
(12)
,
Paolo Caraceni
(13)
,
Carlo Alessandria
(14)
,
Jonel Trebicka
(1, 15)
,
Marco Pavesi
(1)
,
Carme Deulofeu
(1)
,
Agustin Albillos
(16)
,
Thierry Gustot
(17)
,
Tania M. Welzel
(18)
,
Javier Fernández
(1, 2)
,
Rudolf E. Stauber
(12)
,
Faouzi Saliba
(19)
,
Noemie Buttin
(4, 5)
,
Benoit Colsch
(4, 5)
,
Christophe Moreno
(17)
,
François Durand
(3)
,
Frederik Nevens
(20)
,
Rafael Banares
(21)
,
Daniel Benten
(22)
,
Pere Gines
(2)
,
Alexander Gerbes
(23)
,
Rajiv Jalan
(24)
,
Paolo Angeli
(25, 1)
,
Mauro Bernardi
(13)
,
Vicente Arroyo
(1)
1
Grifols Chair
2 Institut d'Investigacions Biomèdiques August Pi i Sunyer
3 UPD7 - Université Paris Diderot - Paris 7
4 SPI - Service de Pharmacologie et Immunoanalyse
5 Université Paris Saclay (COmUE)
6 MetaboHUB-IDF
7 LI-MS - Laboratoire Innovations en Spectrométrie de Masse pour la santé
8 MTS - Médicaments et Technologies pour la Santé
9 Aarhus University Hospital
10 Department of Gastroenterology and Hepatology
11 INRA - Institut National de la Recherche Agronomique
12 Medical University of Graz = Medizinische Universität Graz
13 Department of Medical and Surgical Sciences
14 San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy
15 Rheinische Friedrich-Wilhelms-Universität Bonn
16 Hospital Universitario
17 ULB - Université libre de Bruxelles
18 Goethe-Universität Frankfurt am Main
19 Hôpital Paul Brousse
20 UCL - Université Catholique de Louvain = Catholic University of Louvain
21 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
22 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
23 Univ Hosp LMU Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany
24 UCL - University College of London [London]
25 Unipd - Università degli Studi di Padova = University of Padua
2 Institut d'Investigacions Biomèdiques August Pi i Sunyer
3 UPD7 - Université Paris Diderot - Paris 7
4 SPI - Service de Pharmacologie et Immunoanalyse
5 Université Paris Saclay (COmUE)
6 MetaboHUB-IDF
7 LI-MS - Laboratoire Innovations en Spectrométrie de Masse pour la santé
8 MTS - Médicaments et Technologies pour la Santé
9 Aarhus University Hospital
10 Department of Gastroenterology and Hepatology
11 INRA - Institut National de la Recherche Agronomique
12 Medical University of Graz = Medizinische Universität Graz
13 Department of Medical and Surgical Sciences
14 San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy
15 Rheinische Friedrich-Wilhelms-Universität Bonn
16 Hospital Universitario
17 ULB - Université libre de Bruxelles
18 Goethe-Universität Frankfurt am Main
19 Hôpital Paul Brousse
20 UCL - Université Catholique de Louvain = Catholic University of Louvain
21 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
22 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
23 Univ Hosp LMU Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany
24 UCL - University College of London [London]
25 Unipd - Università degli Studi di Padova = University of Padua
Joan Clària
- Fonction : Auteur correspondant
François Fenaille
- Fonction : Auteur
- PersonId : 1136732
- IdHAL : francois-fenaille
- ORCID : 0000-0001-6787-4149
- IdRef : 089320964
Alex Amoros
- Fonction : Auteur
Alain Pruvost
- Fonction : Auteur
- PersonId : 758519
- ORCID : 0000-0002-7781-7735
Emeline Chu-Van
- Fonction : Auteur
- PersonId : 1341876
- IdHAL : emeline-chu-van
- ORCID : 0000-0003-1827-2138
Jonel Trebicka
- Fonction : Auteur
- PersonId : 785930
- ORCID : 0000-0002-7028-3881
Benoit Colsch
- Fonction : Auteur
- PersonId : 761794
- IdHAL : benoit-colsch
- ORCID : 0000-0002-8023-504X
- IdRef : 123757002
Résumé
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 through 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 the 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.