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Diagnosis and innovative treatment
A European study involving CEA-Joliot researchers provides the first overview of the amino acids circulating in the blood of patients with decompensated cirrhosis and concludes that there is a strong redistribution of their metabolism in order to provide the fuel necessary for the intense inflammatory response observed in these patients.
Several European research and clinical teams, including the LEMM (DMTS/CEA-Joliot), are pooling their efforts within two consortiums,
DECISION4LIVER, to better manage people suffering from decompensated cirrhosis (people are no longer able to compensate for the dysfunction of their liver), or ACLF (Acute-on-Chronic Liver Failure), a severe form of cirrhosis. ACLF affects about 30% of patients hospitalized for decompensated cirrhosis and is associated with high mortality (>20% at 28 days). It is characterized by intense systemic inflammation and failure of one or more organs or systems (liver but also kidneys, brain, circulatory and respiratory systems). The two consortia, coordinated by the European Foundation for the Study of Chronic Liver Failure (EF-CLIF), arose from the observation of a very high degree of heterogeneity in the development and evolution of the disease and from the hypothesis that genetic predispositions and/or infections may increase the risk of decompensated cirrhosis and worsen the prognosis.
Among the avenues being explored to better understand the pathophysiological mechanisms and ultimately discover specific markers and identify future therapeutic targets, some consortia teams are working to determine the metabolic changes associated with systemic inflammation in ACLF. In a study published in 2019, these teams, including that of the LEMM, had already demonstrated, using metabolomic data, an activation of the tryptophan pathway in patients with decompensated cirrhosis (cf. news 2019). In a study published in 2020 (Moreau et al, J Hepatol 2020), analysis of the metabolome of 831 people with decompensated cirrhosis with or without acute complications (ACLF) showed that there was a metabolic signature consisting of 38 compounds that specifically accumulate in the serum of ACLF patients. The very nature of these compounds suggests that the mechanisms responsible for organ failure in ACLF would be close to those responsible for sepsis, including a strong inhibition of energy production in the mitochondria.
In a new study also published in the Journal of Hepatology, the researchers are focusing on the amino acids circulating in the blood of patients with acute decompensated cirrhosis, particularly those with ACLF. The analysis was done on data from the above-mentioned study. The results show that both populations of cirrhotic patients exhibit characteristics of intense skeletal muscle catabolism leading to the mobilization of amino acids for anabolic and catabolic purposes. In patients with ACLF, the amino acids would be used together with glucose for increased de novo synthesis of nucleotides and proteins, presumably in the activated innate immune system. Eventually, as if the entire system were reprogrammed to provide the fuel for the intense systemic inflammatory response. Another observation in ACLF patients is that ketogenesis - the metabolic pathway of liver cells to produce "ketone bodies" used by muscles as an energy source - appears to be defective or inhibited. The catabolism of the ketogenic amino acid substrates of ketogenesis appears to be very pronounced. Finally, the researchers found that blood levels of spermidine are significantly decreased. This polyamine is thought to play a role in inducing autophagy, an essential cellular recycling mechanism in the immune response. The decrease in blood spermidine levels could thus contribute to the pro-inflammatory phenotype of ACLF patients.
The study concludes on the interest of evaluating in the future the potential benefit of certain nutritional supplements (ketone bodies, polyamine...) to reduce systemic inflammation and restore the functionality of several organs in ACLF patients.
Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF. J of Hepatology, 2020G. Zaccherini, F. Aguilar, P. Caraceni, J. Clària, J.J. Lozano, F. Fenaille, F. Castelli, C. Junot, A. Curto, C. Formentin, E. Weiss, M. Bernardi, R. Jalan, P. Angeli, R. Moreau.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.