New study published in Hepatology elucidates the role of systemic inflammation, systemic oxidative stress and systemic circulatory dysfunction in the development of acutely decompensated cirrhosis with or without ACLF. The study used plasma samples from 522 acutely decompensated patients of which 237 patients presented ACLF in the CANONIC cohort. Systemic inflammation was assessed by measuring 29 cytokines and human nonmercaptalbumin 2 – a form of circulating albumin which is irreversibly oxidized. Systemic circulatory dysfunction was estimated by measuring the concentration of plasma renin and copeptin.

One of the key findings of this study is the description of the inflammatory and circulatory landscape according to the absence or presence of ACLF: patients with acute decompensation of cirrhosis without ACLF exhibited systemic alterations including marked inflammation, oxidative stress, and circulatory dysfunction; and these systemic features were even more pronounced in patients with ACLF. Moreover, 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). Also, the association of ACLF was closer with systemic inflammation than with circulatory dysfunction. Together, these findings support systemic inflammation as the primary driver of ACLF in cirrhosis.

Other studies promoted by the Grifols Chair are ongoing or will be carried out in the very next future, taking the opportunity of studies that will be conducted 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. 

In the future, the Grifols Chair will develop tools to address the core question of the heterogeneity of acutely decompensated patients with ACLF. We learned from the CANONIC cohort that ACLF is a dynamic syndrome; among patients admitted to hospital for ACLF, 49% improved within the first days, 31% remained stable, and 20% rapidly worsened (and died). 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-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, (curative or preventive) antibiotics, diuretics, and corticosteroids (in patients with severe alcohol-related hepatitis). Together these findings indicate that ACLF is a complex and heterogeneous syndrome that deserves to be investigated with appropriate tools to understand the influence of different factors on patient’s 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” according to the highest standards. The Grifols Chair counts with a skilled team of statisticians, bioinformaticians and data managers and large facilities for storing biological samples from centers participating in large observational studies.