PRO-C3-Levels in Patients with HIV/HCV-Co-Infection Reflect Fibrosis Stage and Degree of Portal Hypertension

Abstract

BackgroundLiver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection.MethodsFifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen).ResultsAs expected, HVPG showed strong and significant correlations with FIB4-index (rs = 0.628; p = 7*10−7). Interestingly, PRO-C3 significantly correlated with HVPG (rs = 0.354; p = 0.02), alanine aminotransferase (rs = 0.30; p = 0.038), as well as with FIB4-index (rs = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg).ConclusionPRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection.

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

“…As with previous observations4, 10, 12, 13 in patients with liver fibrosis and/or compensated liver cirrhosis, patients with high Pro‐C3 levels had a poorer outcome than patients with lower levels (Fig. 2A).…”

“…Interestingly, not only the formation marker Pro‐C3 but also the degradation marker C3M is correlated with increased liver fibrosis in human immunodeficiency virus /hepatitis C virus coinfected patients with early liver disease as well as in another cohort with compensated advanced liver disease 4, 10. The present work confirms these findings in the animal model, demonstrating the robustness of these markers.…”

“…Besides the animal data directly comparing the soluble and indirect but noninvasive markers of liver fibrosis, we have previously shown that patients with compensated chronic liver disease show increased collagen type III turnover, i.e., formation and degradation 4, 26. Interestingly, not only the formation marker Pro‐C3 but also the degradation marker C3M is correlated with increased liver fibrosis in human immunodeficiency virus /hepatitis C virus coinfected patients with early liver disease as well as in another cohort with compensated advanced liver disease 4, 10.…”

“…Progressive fibrosis, increased hepatic vascular tone, and ongoing inflammation due to permanent liver injury are major causes of decompensation, morbidity, and mortality. These processes incite continuous extracellular matrix (ECM) protein remodeling, which reflects the progression of liver disease 2, 3, 4, 5, 6. During ECM remodeling, matrix metalloproteinases (MMPs) generate small peptide fragments, known as neoepitopes, that are released into the circulation.…”

“…They can be measured with protein fingerprint technology using specific antibodies 7. The levels of these ECM markers depend on the degree of fibrosis4, 8, 9, 10 and also reflect antifibrotic therapy 5, 11. Degradation markers and collagen type III formation, in particular, mirror progression of fibrosis and diagnosis of portal hypertension4, 10, 12, 13; however, the roles of these markers in decompensation of liver cirrhosis have not been assessed.…”