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. 2020 Apr;72(4):688-701.
doi: 10.1016/j.jhep.2019.11.009. Epub 2019 Nov 25.

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF

Richard Moreau  1 , Joan Clària  2 , Ferran Aguilar  3 , François Fenaille  4 , Juan José Lozano  5 , Christophe Junot  4 , Benoit Colsch  4 , Paolo Caraceni  6 , Jonel Trebicka  7 , Marco Pavesi  3 , Carlo Alessandria  8 , Frederik Nevens  9 , Faouzi Saliba  10 , Tania M Welzel  11 , Agustin Albillos  12 , Thierry Gustot  13 , Javier Fernández  2 , Christophe Moreno  13 , Maurizio Baldassarre  6 , Giacomo Zaccherini  6 , Salvatore Piano  14 , Sara Montagnese  14 , Victor Vargas  15 , Joan Genescà  15 , Elsa Solà  16 , William Bernal  17 , Noémie Butin  4 , Thaïs Hautbergue  4 , Sophie Cholet  4 , Florence Castelli  4 , Christian Jansen  18 , Christian Steib  19 , Daniela Campion  8 , Raj Mookerjee  20 , Miguel Rodríguez-Gandía  12 , German Soriano  21 , François Durand  22 , Daniel Benten  23 , Rafael Bañares  24 , Rudolf E Stauber  25 , Henning Gronbaek  26 , Minneke J Coenraad  27 , Pere Ginès  16 , Alexander Gerbes  19 , Rajiv Jalan  28 , Mauro Bernardi  6 , Vicente Arroyo  3 , Paolo Angeli  29 ; CANONIC Study Investigators of the EASL Clif Consortium; Grifols Chair; European Foundation for the Study of Chronic Liver Failure (EF Clif)
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Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF

Richard Moreau et al. J Hepatol. 2020 Apr.

Erratum in

  • Correction to 'Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF' [J Hepatol 2020 (72) 688-701].
    Moreau R, Clària J, Aguilar F, Fenaille F, Lozano JJ, Junot C, Colsch B, Caraceni P, Trebicka J, Pavesi M, Alessandria C, Nevens F, Saliba F, Welzel TM, Albillos A, Gustot T, Fernández J, Moreno C, Baldassarre M, Zaccherini G, Piano S, Montagnese S, Vargas V, Genescà J, Solà E, Bernal W, Butin N, Hautbergue T, Cholet S, Castelli F, Jansen C, Steib C, Campion D, Mookerjee R, Rodríguez-Gandía M, Soriano G, Durand F, Benten D, Bañares R, Stauber RE, Gronbaek H, Coenraad MJ, Ginès P, Gerbes A, Jalan R, Bernardi M, Arroyo V, Angeli P; CANONIC Study Investigators of the EASL Clif Consortium; Grifols Chair and the European Foundation for the Study of Chronic Liver Failure (EF Clif). Moreau R, et al. J Hepatol. 2020 Jun;72(6):1218-1220. doi: 10.1016/j.jhep.2020.03.002. Epub 2020 Mar 17. J Hepatol. 2020. PMID: 32192825 No abstract available.

Abstract

Background & aims: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.

Methods: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.

Results: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.

Conclusions: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.

Lay summary: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.

Keywords: Biomarkers; CANONIC study; Multiorgan failure, Small-molecules.

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