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December 16th 2016 NEWS FROM THE GRIFOLS CHAIR #1 Richard Moreau, Joan Clària, Vicente Arroyo

The Grifols Chair for Translational Research has been recently created because of the results of the CANONIC study showing that acute-on-chronic liver failure (ACLF) was associated with systemic inflammation, assessed with routinely available markers such as white-cell count and plasma C-reactive protein levels (1). The nature of relationships underlying this association were unknown, indicating the need for developing translational research in patients with ACLF and more largely in acutely decompensated patients.In this context, the first achievement of the Grifols Chair was to promote a study that was aimed to elucidate the respective role of systemic inflammation (and is correlate, systemic oxidative stress) and systemic circulatory dysfunction in the development of acutely decompensated cirrhosis with or without ACLF. This study used plasma samples from 522 acutely decompensated patients (237 with ACLF) of the CANONIC cohort. Systemic inflammation was assessed by measuring 29 cytokines and systemic oxidative stress by measuring the form of circulating albumin (called, human nonmercaptalbumin 2), which is irreversibly oxidized at cysteine 34. Systemic circulatory dysfunction was estimated by plasma renin and copeptin concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. Plasma from healthy subjects served for control measurements. The results have now been published as a full article (2), that can be considered as a landmark paper. First, it was the description of the inflammatory and circulatory landscape according to absence or presence of ACLF: patients with acute decompensation without ACLF exhibited systemic alterations including marked inflammation, oxidative stress, and circulatory dysfunction; and these systemic features were even more marked in patients with ACLF. Next, it was found that the intensity of systemic inflammation correlated closely with the severity of ACLF at enrollment. Systemic inflammation and ACLF were strongly associated regarding their course (improvement, no change, or worsening). Last but not least, the association of ACLF was closer with systemic inflammation than with circulatory dysfunction. Together these results support systemic inflammation as the primary driver of ACLF in cirrhosis.

This first study by the Grifols Chair described the landscape of systemic inflammation and oxidative stress and systemic circulatory dysfunction in acutely decompensated cirrhosis. Studies promoted by the Grifols Chair are ongoing or will be performed in a very next future, taking opportunity of studies that will be performed under the umbrella of the EASL-CLIF Consortium. These studies, using high throughput techniques, being "agnostic" in nature, will enlarge our vision of the landscape of acutely decompensated cirrhosis. For example, using untargeted metabolomics and lipidomics with ultra-high performance liquid chromatographic system followed by high-resolution mass-spectrometry analysis at positive and negative electrospray ionization modes, there will be the largest description of the metabolome and lipidome profiles at enrollment of patients in the CANONIC cohort. Another example is the involvement of the Grifols Chair in the ALADDIN study that will be embedded in the plasma exchange RCT called APACHE. Among other goals, the ALADDIN study will characterize systemic inflammation using whole-blood transcriptome analysis. In addition, it will perform a genome-wide association study to further increase our understanding of genes that influence transcriptome and inflammatory cues in the blood circuit.

In the future, the Grifols Chair will have to develop tools to address the core question of the heterogeneity of acutely decompensated patients with ACLF. We learnt from the CANONIC cohort that ACLF is a dynamic syndrome; among patients admitted for ACLF, 49% improved within the first days, 31% remained stable, and 20% rapidly worsened (and died) (3). However, we do not know whether differences in disease progression are related to differences in the intensity of systemic inflammation (which is potentially driven by gene variation or gene-by-environment interactions) or the effects of therapies on systemic inflammation. Indeed, patients with ACLF are candidates to receive a broad variety of treatments, including non-selective beta-blockers, terlipressin, antibiotics (curative or for prophylaxis), diuretics, and corticosteroids (in patients with severe alcoholic hepatitis). Together these findings indicate that ACLF is a complex and heterogeneous syndrome that deserves to be investigated with appropriate tools for deciphering the influence of different factors on the outcome. A major limitation of research in the field of ACLF is the lack of reliable animal models of this syndrome. This is why great efforts should be made to perform high-quality translational studies in large cohort of patients who have been rigorously "phenotyped" in expert centers. The Grifols Chair has both a skilled Data Management Center (DMC) and large facilities for storing biological samples from participating centers. Bioinformaticians at the DMC are fully competent to develop and compute models addressing the question of heterogeneity (and inter-individual variations) in acutely decompensated cirrhosis with ACLF and beyond, those without ACLF.

References

1. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V; CANONIC Study Investigators of the EASL-CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-37, 1437.e1-9.

2. Stauber RE, Coenraad MJ, Moreau R, Jalan R, Pavesi M, Amorós À, Titos E, Alcaraz-Quiles J, Oettl K, Morales-Ruiz M, Angeli P, Domenicali M, Alessandria C, Gerbes A, Wendon J, Nevens F, Trebicka J, Laleman W, Saliba F, Welzel TM, Albillos A, Gustot T, Benten D, Durand F, Ginès P, Bernardi M, Arroyo V; CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology 2016;64:1249-64.

3. Gustot T, Fernandez J, Garcia E, Morando F, Caraceni P, Alessandria C, Laleman W, Trebicka J, Elkrief L, Hopf C, Solís-Munoz P, Saliba F, Zeuzem S, Albillos A, Benten D, Montero-Alvarez JL, Chivas MT, Concepción M, Córdoba J, McCormick A, Stauber R, Vogel W, de Gottardi A, Welzel TM, Domenicali M, Risso A, Wendon J, Deulofeu C, Angeli P, Durand F, Pavesi M, Gerbes A, Jalan R, Moreau R, Ginés P, Bernardi M, Arroyo V; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015;62:243-52.

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