From MASH to HCC: the role of Gas6/TAM receptors.

Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.

HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment.

BACKGROUND: Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) after hepatitis C treatment. Whether this holds true taking into account carriage of the HSD17B13:TA splice variant, also affecting lipogenesis, and achievement of viral clearance (SVR), is unknown. METHODS: PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 variants were determined in a cohort of 328 cirrhotic patients free of HCC before starting treatment with direct acting antivirals (DAA). RESULTS: SVR in the study cohort was 96%. At the end of follow-up, N = 21 patients had been diagnosed an HCC; none of the genes included in the GRS was individually associated with HCC development. However, in a Cox proportional hazards model, a GRS > 0.457 predicted HCC independently of sex, diabetes, albumin, INR and FIB4. The fit of the model improved adding treatment outcome and carriage of the HSD17B13:TA splice variant, with sex, GRS > 0.457, HSD17B13:TA splice variant and failure to achieve an SVR (hazard ratio = 6.75, 4.24, 0.24 and 7.7, respectively) being independent predictors of HCC. CONCLUSION: Our findings confirm that genes modulating liver fat and lipogenesis are important risk factors for HCC development among cirrhotics C treated with DAA.

Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis.

BACKGROUND AND AIMS: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. METHODS: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. RESULTS: Median OS of SBRT patients was 18.1 (10.3-25.9) months compared to 8.8 (8.2-9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8-23.2) months compared to 9.6 (8.6-10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. CONCLUSIONS: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.

Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.

Liver Stiffness, Not Fat Liver Content, Predicts the Length of QTc Interval in Patients with Chronic Liver Disease.

The severity of fatty liver at ultrasound has been associated with QT length, a finding invoked to explain the excess cardiovascular risk of patients with fatty liver. However, the ability of ultrasound to stage accurately the severity of fatty liver is limited, with fibrosis a major confounder. Here, we aimed to verify the alleged relationship between fat liver content and QT length using a technique apt at discriminating steatosis from fibrosis noninvasively, i.e., transient elastography (TE) with measure of liver stiffness (LS) and controlled attenuation parameter (CAP). A prospectively collected derivation cohort of 349 patients with chronic liver disease (CLD) of any etiology (N = 105 with nonalcoholic fatty liver) was studied to identify clinical, laboratory, and instrumental predictors of the corrected QT interval (QTc) and QTc prolongation, including LS and CAP. The results were validated on a subgroup of patients belonging to the derivation cohort (out of sample validation), as well as on a completely different group of N = 149 subjects with CLD (out of time validation). QTc values were directly related to liver stiffness (LS; ρ = 0.137; p = 0.011), heart rate (HR; ρ = 0.307; p < 0.001), and age (ρ = 0.265; p < 0.001) and were significantly longer in females (p < 0.001). In contrast, QTc was not associated with the value of controlled attenuation parameter (ρ = 0.019; p = 0.718); moreover, no discernible differences in QTc length were noted based on CLD etiology. QTc was prolonged in 24/349 patients (6.9%); age, HR, and LS were independent predictors of QTc prolongation (χ 2 = 23.7, p < 0.001). Furthermore, QTc values (after logarithmic transformation) were predicted by a model including age, gender, HR, and LS (F = 14.1, R 2 = 0.198, p < 0.001). These latter results were validated by both out-of-sample and out-of-time methods. In conclusion, TE findings strongly suggest that among patients with CLD, fibrosis, not steatosis, is a major determinant of QTc length.

B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD).

Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4+ T-lymphocytes. Furthermore, TACI-Ig mice showed milder steatohepatitis and a decreased progression to fibrosis. Similarly, mice treatment with the BAFF-neutralizing monoclonal antibody Sandy-2 prevented hepatic B2-cell responses and ameliorated steatohepatitis. From these data we conclude that B2-lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T-cells. Furthermore, combined clinical and experimental data suggest that elevated circulating anti-OSE IgG can identify a subset of NAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis.

Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study.

BACKGROUND: Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogeneity in efficacy exists due to varying clinicopathologic features of the disease. AIM: We evaluated whether prior treatment with curative or locoregional therapies influences sorafenib-specific survival. METHODS: From a prospective data set of 785 consecutive patients from international specialist centres, 264 patients (34%) were treatment naïve (TN) and 521 (66%) were pre-treated (PT), most frequently with transarterial chemoembolization (n = 413; 79%). The primary endpoint was overall survival (OS) from sorafenib initiation with prognostic factors tested on uni- and multivariate analyses. RESULTS: Median OS for the entire cohort was 9 months; the median sorafenib duration was 2.8 months, with discontinuation being secondary to progression (n = 454; 58%) or toxicity (n = 149; 19%). PT patients had significantly longer OS than TN patients (10.5 vs. 6.6 months; p < 0.001). Compared to TN patients, PT patients had a better Child-Pugh (CP) class (CP A: 57 vs. 47%; p < 0.001) and a lower BCLC stage (BCLC A-B, 40 vs. 30%; p = 0.007). PT status preserved an independent prognostic role (p = 0.002) following adjustment for BCLC stage, α-fetoprotein, CP class, aetiology, and post-sorafenib treatment status. PT patients were more likely to receive further anticancer treatment after sorafenib (31 vs. 9%; p < 0.001). CONCLUSION: Patients receiving sorafenib after having failed curative or locoregional therapies survive longer and are more likely to receive further treatment after sorafenib. This suggests an incremental benefit to OS from sequential exposure to multiple lines of therapy, justifying treatment stage migration in eligible patients.

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIMS: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. RESULTS: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival. METHODS: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. CONCLUSION: The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.

17,ß-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle.

BACKGROUND & AIMS: Oestrogen and oestrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens. METHODS: Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17ß-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17ß-estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo-particle system (viral entry), the subgenomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. RESULTS: Progesterone and testosterone showed no inhibitory effect on hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17ß-estradiol inhibited infection by 64%-67% (IC50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17ß-estradiol in a dose-dependent manner. 17ß-estradiol exerted only a slight inhibition (<20%) on hepatitis C virus pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. CONCLUSIONS: 17ß-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.

The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma.

BACKGROUND & AIMS: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.

[Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy]. / Scelte terapeutiche e trattamento con sorafenib nell'epatocarcinoma: analisi finale dello studio GIDEON in Italia.

INTRODUCTION: Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. METHODS: Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. RESULTS: In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. DISCUSSION: The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.

Evaluation of the red cell distribution width as a biomarker of early mortality in hepatocellular carcinoma.

BACKGROUND: The red cell distribution width is a biomarker of early mortality across various disease states. AIM: To verify whether it may refine estimates of survival in hepatocellular carcinoma. METHODS: The red cell distribution width measured at diagnosis was analyzed in relationship to mortality by any cause both in a retrospective training cohort (N=208), and in an independent prospectively collected validation cohort (N=106) of patients with hepatocellular carcinoma. Based on Cox proportional hazards modelling, a prognostic index was validated. RESULTS: In the training and the validation cohort, median survival time was respectively 1026 and 868 days in patients with red cell distribution width ≤14.6%, vs. 282 and 340 days in patients with red cell distribution width >14.6%; the corresponding hazard ratios were 0.43 (95% CI: 0.31-0.60), p<0.0001 and 0.28 (95% CI: 0.17-0.47), p<0.0001. At multivariate analysis, the red cell distribution width remained an independent predictor of survival (p<0.001) in a Cox model including other widely accepted prognostic factors. Applying to the validation dataset the prognostic index derived from the training dataset, the ability of the model to discriminate the survival probabilities of patients was confirmed (Harrell's C=0.769). CONCLUSIONS: The red cell distribution width is a novel, reproducible, prospectively validated predictor of survival in patients with hepatocellular carcinoma.

Fibrosis progression in HCV carriers with mild hepatitis who possess the high-repetition variant of the DRD4 gene, a genetic marker for binge-drinking and risk-seeking behavior: a longitudinal study.

BACKGROUND: Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome. METHODS: A cohort of HCV patients with normal or near-normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology. RESULTS: HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up. CONCLUSIONS: The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.

IL28B polymorphism, blood interferon-alpha concentration, and disease stage of HCV mono-infected and HCV-HIV co-infected patients.

Interferon (IFN) preactivation, interleukin-28B (IL28B) alleles, and liver fibrosis act as predictors of response to antiviral therapy against hepatitis C. We aimed to verify if blood IFN concentration, a putative biomarker of interferon preactivation, might depend on carriage of a given IL28B genotype and/or advanced hepatic fibrosis. The study population included 187 hepatitis C patients (75 of whom were HIV coinfected), who were genotyped for the rs12979860 polymorphism and staged non-invasively by transient elastography. Blood IFN, measured by an enzyme immunoassay, was detectable in 68/187 patients (36%). Seventy-three patients (39%) were C/C homozygotes, 25 (13%) were T/T homozygotes, and 89 (48%) were heterozygotes. The fibrosis stage was F0-F1 in 70 patients (37%), F2-F3 in 54 patients (29%), and F4 in 63 patients (34%). IFN levels were higher among patients with HIV coinfection (p=0.044) and patients with better renal function (p=0.041), without association with the IL28B genotype or the hepatitis C stage. From the multivariate analysis, the only independent predictor of higher level of IFN was the age of patients (p=0.019), whereas independent predictors of a fibrosis stage ≥ F2 were age (p=0.007), belonging to the HIV/HCV group (p=0.048) and current alcohol consumption (p=0.008). In conclusion, a sizable proportion of HCV carriers have detectable IFN levels that do not indicate a greater severity of disease or display any relationships to specific rs12979860 variants.

Hepatitis C virus cell entry: role of lipoproteins and cellular receptors.

Hepatitis C virus (HCV), a major cause of chronic liver disease, is a single-stranded positive sense virus of the family Flaviviridae. HCV cell entry is a multi-step process, involving several viral and cellular factors that trigger virus uptake into the hepatocyte. Tetraspanin CD81, human scavenger receptor SR-BI, and tight junction molecules Claudin-1 and occludin are the main receptors that mediate HCV entry. In addition, the virus may use glycosaminoglycans and/or low density receptors on host cells as initial attachment factors. A unique feature of HCV is the dependence of virus replication and assembly on host cell lipid metabolism. Most notably, during HCV assembly and release from the infected cells, virus particles associate with lipids and very-low-density lipoproteins. Thus, infectious virus circulates in patient sera in the form of triglyceride-rich particles. Consequently, lipoproteins and lipoprotein receptors play an essential role in virus uptake and the initiation of infection. This review summarizes the current knowledge about HCV receptors, mechanisms of HCV cell entry and the role of lipoproteins in this process.