Markers of liver fibrosis and apoptosis in patients with HIV mono-infection and HIV/HCV co-infection

Abstract

Introduction: Human immunodeficiency virus (HIV)/hepatits C virus (HCV) co-infection has a significant impact on liver-related morbidity and mortality. Among many other pathogenic mechanisms leading to accelerated hepatic disease are liver fibrosis and hepatocyte apoptosis. Hence the objective of this investigator-initiated cross-sectional study was to analyse the plasma levels of hyaluronic acid, cytokeratin-18, and cytochrome c in order to assess their impact on progression of liver disease in patients with HIV/HCV co-infection comparing to those with HIV mono-infection. Material and methods: There were 80 patients with HIV infection included in the study. HCV co-infection was in 46 (57.5%) patients and HIV mono-infection in 34 patients. Blood levels of hyaluronic acid were tested using a Hyaluronic Acid test Kit, cytokeratin-18 neoepitope levels using M30-Apoptose ELISA test, and cytochrome c using human Cytochrome c ELISA test. Results: The levels of cytokeratin-18 and of hyaluronic acid were significantly higher in the group of patients with HIV/HCV co-infection. The differences in the level of cytochrome c were not significant. The analysis revealed that the main effect of HCV co-infection on the level of cytokeratin-18 is indirect. It is mediated by the level of hyaluronic acid. Conclusions: The progression of liver disease in patients with HIV/HCV co-infection is more pronounced compared to those with HIV mono-infection. It is shown by the higher plasma levels of hyaluronic acid, which is a relevant liver fibrosis marker and hepatocyte apoptosis marker cytokeratin-18 in patients with HIV/HCV co-infection. The hyaluronic acid level is important in assessing the impact of HCV co-infection on liver apoptosis.

The Level of Cytokeratin 18 in Patients with HIV and Viral Hepatitis C Co-Infection in Latvia

“…Correlation between CK18 and HA confirms the theoretical relationship between hepatocyte apoptosis and liver fibrosis, described by Canbay et al (2004), Guicciardi and Gores (2005) and Friedman (2010). A clinical study (Vîksna et al, 2019) also indicated that HIV/HCV co-infection impacts CK18 indirectly through the level of HA.…”

“…At the same time, there was no association between CK18 and other markers of liver fibrosis in this group. Higher levels of CK18 in HIV/HCV patients than in HIV mono-infected patients have been shown previously in two studies in Latvian cohorts (Vîksna et al, 2019;Madelâne et al, 2019). Our study merges data from both Latvian studies and provides CK18 levels in a relatively large group of HIV/HCV coinfected and HIV mono-infected patients, and the association of CK18 levels with other non-invasive markers of liver fibrosis, and describes CK18 dynamics in a fourmonth-long period.…”

“…It should be noted that the re-lationship between apoptosis and fibrosis is bidirectional (Canbay et al, 2004). Evidence of this was demonstrated in a recent experimental study (Ganesan et al, 2018) and a clinical study (Vîksna et al, 2019).…”

Improvement of liver metabolic activity in people with advanced HIV after antiretroviral therapy initiation

“…In a preclinical model of HIV, the dual-reconstituted humanized mouse, HIV infection resulted in hepatocyte dysfunction and death with reduction of albumin levels [13]. Clinically, HIV was found to exacerbate hepatocyte apoptosis in patients with HBV and HCV infection with higher number of hepatocytes expressing the death receptor Fas in co-infected patients [32][33][34]. In our PWH, transaminases decreased significantly after initiation of ART, even though their pre-ART levels were not too high to begin with and albumin levels increased, positively correlating with increasing FDG uptake.…”

Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment

“…There is clinical evidence of the importance of hepatocyte apoptosis in the development of liver disease in HIV patients. In this sense, a recent study has shown the correlation between high plasma levels of hyaluronic acid, a relevant liver fibrosis marker, and caspase-cleaved CK-18 in patients with HIV/HCV co-infection [ 40 ]. Similarly, biopsies from HCV/HIV co-infected patients show that higher number of hepatocytes express the death receptor Fas (CD95, a member of a subgroup of the tumor necrosis factor (TNF) receptor superfamily) and undergo irreversible apoptosis compared to biopsies from HCV-infected patients [ 41 ].…”