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Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis
Author(s) -
Clària Joan,
Moreau Richard,
Fenaille François,
Amorós Alex,
Junot Christophe,
Gronbaek Henning,
Coenraad Minneke J.,
Pruvost Alain,
Ghettas Aurélie,
ChuVan Emeline,
LópezVicario Cristina,
Oettl Karl,
Caraceni Paolo,
Alessandria Carlo,
Trebicka Jonel,
Pavesi Marco,
Deulofeu Carme,
Albillos Agustin,
Gustot Thierry,
Welzel Tania M.,
Fernández Javier,
Stauber Rudolf E.,
Saliba Faouzi,
Butin Noémie,
Colsch Benoit,
Moreno Christophe,
Durand François,
Nevens Frederik,
Bañares Rafael,
Benten Daniel,
Ginès Pere,
Gerbes Alexander,
Jalan Rajiv,
Angeli Paolo,
Bernardi Mauro,
Arroyo Vicente
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30363
Subject(s) - decompensation , kynurenine , cirrhosis , medicine , kynurenine pathway , quinolinic acid , indoleamine 2,3 dioxygenase , gastroenterology , immunosuppression , immune system , endocrinology , immunology , tryptophan , biology , biochemistry , amino acid
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.