Caracterización integral de las alteraciones moleculares generadas durante la cirrosis avanzada en pacientes coinfectados por el VHC y el VIH

Resumen

Infection with the hepatitis C virus (HCV) is able to cause a chronic liver disease that can lead to cirrhosis and whose course is altered by coinfection with the human immunodeficiency virus (HIV). The disease may progress to an advanced stage, developing clinically significant portal hypertension (CSPH). In this work, we have characterized molecular alterations occurring in patients coinfected with HCV and HIV during advanced cirrhosis, which include plasmatic markers, as well as metabolic and transcriptomic alterations. Firstly, the inflammation plasmatic markers IP-10, IL-8, IL-6, and OPG, those of endothelial dysfunction, sVCAM-1 and sICAM-1, and of thrombotic risk such as D-dimer, were found to be higher in those patients with more severe cirrhosis. Secondly, advanced stages of cirrhosis were associated with changes in the metabolomic profile. On the one hand, fatty acids, bile acids, aromatic and sulfur-containing amino acids, butyrate derivatives, oxidized phospholipids, and those metabolites related to energy and to bacterial fermentation were found to be increased. On the other hand, lysophosphatidylcholines (LPC) and lysophosphatidylethanolamines, branched-chain amino acids and tricarboxylic acid cycle metabolites decreased. In addition, patients with advanced cirrhosis monoinfected with HCV and those who are coinfected with HCV/HIV do not show significant differences in terms of plasmatic biomarkers or metabolic alterations. Thirdly, patients at high risk for developing CSPH (LSM ≥ 25 kPa) presented a differential expression signature comprising 38 overexpressed and 22 underexpressed transcripts. Lastly, the different molecular alterations studied made it possible to distinguish subgroups of patients of clinical interest. The combination of IL-6 and IP-10 and, separately, the metabolites glycolic acid, LPC (16:0), and taurocholic acid differentiated patients with decompensated cirrhosis. In addition, STAG3L2 and MDK transcripts showed a good ability to discriminate patients at high risk of developing CSPH. In conclusion, this work helps broaden our knowledge of the underlying processes of this disease. It opens the door for new developments that facilitate and improve the management of these patients.