PCSK9 Levels Are Raised in Chronic HCV Patients with Hepatocellular Carcinoma

Abstract

Background: Since emerging evidence suggests a protective role of proprotein convertase subtilisin/kexin type 9 (PCSK9) on hepatitis C virus (HCV) infection, the aim of the present study was to evaluate the correlation between PCSK9 and HCV infection in hepatocellular carcinoma (HCC) patients. Methods: In this retrospective study, PCSK9 levels were evaluated by ELISA, in plasma samples from control (n = 24) and 178 patients diagnosed for HCC, cirrhosis, or chronic hepatitis, either positive or negative for HCV. Results: HCV positive patients (HCV+) presented with higher PCSK9 levels compared to HCV negative individuals (HCV-), 325.2 ± 117.7 ng/mL and 256.7 ± 139.5 ng/mL, respectively. This difference was maintained in the presence of HCC, although this disease significantly reduced PCSK9 levels. By univariate analysis, a positive correlation between PCSK9 and HCV viral titer was found, being G2 genotype the most-potent inducer of PCSK9 among other genotypes. This induction was not associated with changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). A negative correlation was also found between PCSK9 levels and liver impairment, assessed by Model for End-Stage Liver Disease (MELD). Finally, a multivariate correlation analysis corrected for age, TC, LDL-C, and sex, demonstrated, in the whole cohort, a positive association between PCSK9 and HCV and a negative with HCC. Conclusions: taken together, our study reveals that HCV raised PCSK9 in both the presence and absence of HCC.

Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy

“…In HIV-infected patients, coinfection with HCV increased plasma PCSK9 levels [ 35 ]. Fasolato et al observed higher plasma PCSK9 in HCV-infected patients than in non-infected controls [ 22 ]. Our study identified elevated PCSK9 levels in serum of patients with chronic HCV compared to non-infected patients without severe liver diseases.…”

“…Serum PCSK9 levels were moreover induced by dietary saturated fat, fructose and cholesterol [ 37 ]. The studies cited above regarding systemic PCSK9 levels in HCV-infected patients used fasting plasma [ 22 , 24 , 35 ]. Fasting serum was obtained from the patients in the current analysis.…”

“…A diurnal rhythm, with the lowest PCSK9 levels between 3 and 9 p.m. and a peak at about 4:30 a.m., was also reported [ 38 ]. Samples of our cohort were all obtained in the morning, and this may also apply to the studies cited above [ 22 , 24 , 35 ].…”

“…Of clinical relevance, HCV-infected patients had higher serum PCSK9 levels, whereas LDL did not increase in parallel [ 22 ]. Serum PCSK9 negatively correlated with the model for end-stage liver disease (MELD) score, which is the state-of-the-art scoring model of liver disease severity [ 22 , 23 ]. In addition, HCV genotype-dependent regulation of plasma PCSK9 levels has been described.…”

Profibrotic Signaling and HCC Risk during Chronic Viral Hepatitis: Biomarker Development

“…This was recently consolidated by a retrospective study, which showed that combining DCP and AFP serum levels in NUC-treated HBV Caucasian cirrhotic individuals, represents a potential surveillance strategy for HCC [ 49 ]. Additional candidate biomarkers for HCC in the blood have been suggested, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) [ 54 , 55 ], glypican 3 (GPC3), squamous cell carcinoma antigen (SCCA), cytokeratine-19, osteopontin (OPN), Golgi protein-73 (GP73), alpha-L-fucosidase (AFU) [ 56 ], heat shock 70 kD protein (HSP-70) [ 57 ], annexin A2, midkine (MDK), aldo-keto reductase family 1 member B10 (AKR1B10) [ 58 ], and HCC-responsive miRNAs and cell-free DNA (for a more detailed review, see [ 59 ]). However, even if these candidate biomarkers are promising, to date, none of them have been adopted in the current clinical practice, and they need to be externally validated.…”