Prognostic Impact of 3-HM Concentration in Patients with Alcoholic or Viral Cirrhosis

The role of endotoxemia related to intestinal bacterial translocation in worsening liver disease is the subject of many studies, but its impact on cirrhosis mortality has not been well evaluated. In this study, 3-hydroxymyristate (3-HM) (specific lipid of lipopolysaccharides) was directly quantified by an innovative patented assay with the aim of assessing the impact on cirrhosis mortality. The 3-HM concentration was measured in 593 patients with alcoholic or viral cirrhosis in stable clinical condition. A Cox hazards regression model was used to evaluate association between 3-HM and its fractions bound or nor bound to lipoprotein and the mortality. The 3-HM concentration was increased in patients with more severe cirrhosis (p<0.001). After 5 years of follow-up, 271 (45.7%) patients had died. In multivariate analysis, high level of 3HM was strongly associated with high risk of death in patients with Child-Pugh A cirrhosis (Hazard ratio (HR)Tertile3vsTertile1(T3vsT1)=3.86, confidence interval to 95% (CI 95%) 1.66-6.04, p-trend<0.001), as well as the 3-HM fraction bound to lipoprotein (HR T3vsT1=2.32, CI 95% 1.31-4.13, p-trend=0.005), and not bound to lipoprotein (HR T3vsT1=2.86, CI 95% 1.61-5.08, p-trend<0.001). Such association did not exist in Child-Pugh B or C patients. In patients without liver complication before inclusion, 3-HM concentration was associated with the occurrence of at least one complication of cirrhosis (p<0.001) as occurrence of ascites (p=0.001) and encephalopathy (p=0.008) but not with gastrointestinal bleeding (p=0.56). Conclusion: This study revealed that a high concentration of 3-HM was strongly associated with 5-year mortality in patients with alcoholic or viral cirrhosis. Our results suggest that a high 3-HM concentration in cirrhosis patients leads to an irreversible chronic process of disease worsening independently of cirrhosis severity. Funding Statement: This work was supported by a French Government grant managed by the French National Research Agency under the program “Investissements d’Avenir” [reference ANR-11-LABX-0021], French National Cancer Institute, Canceropole Grand-Est, Ligue Nationale contre le Cancer, Fondation de France, Conseil Regional de Bourgogne, Fonds Europeen de Developpement Regional (FEDER). The first author was financed by a fund provided by the Regional Health Agency. Declaration of Interests: The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this paper Ethics Approval Statement: All patients gave written informed consent. The study was carried out in accordance with the principles of the Helsinki declaration and was approved in 2008 by the local ethics committee (agreement n°2008/09); the French drug safety agency (Agence Nationale de Securite des Medicaments et des Produits de Sante: agreement n° 2008-A00023-52) and the National Commission for Data Processing and Liberties. The CiRCE study was registered at clinicaltrials.gov as NCT01798173.