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BACKGROUND Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of the sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established. AIM To examine the occurrence of HCC or death from any cause in a retrospective-prospective study of patients treated with DAAs. METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders. RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for the SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, the independent predictors of SVR achievement were absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively). CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death. A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.

Background: NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) are emerging conditions that sequentially affect hepatocyte metabolism. Fibroblast Growth Factor 21 (FGF21) is produced by the liver and has autocrine and paracrine actions on liver energy metabolism while serpinB3 (SCCA) is produced by damaged liver cells and is considered a marker of progression to cirrhosis and hepatocellular carcinoma. Aim of the study: A first aim of this study is to investigate expression profile of FGF21 and its receptor/coreceptor in liver biopsies of patients with NAFLD and NASH. A second aim is to assess whether circulating concentration of SCCA-IgM is increased in patients with NASH compared to patients with pure fatty liver. Materials and methods: Expression of FGF21 and its receptor was measured by real-time PCR in liver biopsies of 42 patients with NAFLD/NASH and 16 matched controls. Moreover in a separate group of patients with NAFLD (n = 39) and NASH (n = 45) serum concentration of SCCA-IgM was measured. Results: A significant lower expression of FGF21 (53±3.1 u.a. vs 27.2±1 u.a., p < 0.05), FGF21-R1 (4.7±0.2 u.a. vs 2.7±0.1 u.a., p < 0.02) and its coreceptor-klotho (107.6±6.4 u.a. vs 64.0±1 u.a., p < 0,03) was found in patients with NAFLD/NASH. SCCA-IgM serum concentration was significantly increased in patients with NASH compared with those with NAFLD (9.2±1.8 vs 31.0±7.2 u.a./mL, p = 0.007). Conclusions: Downregulation of FGF21, FGF21-R1 and-klotho suggests that both low hormonal levels and its membrane receptor and coreceptor might contribute to detrimental metabolic effect in hepatocytes of NAFLD/NASH patients. Moreover higher circulating levels of SCCA-IgM in patients with NASH compared to those with pure fatty liver suggest that this protein might represent a possible marker of hepatic damage before the progression to cirrhosis and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is often diagnosed after the tumor manifests clinical signs and symptoms. Early diagnosis is usually performed thanks to HCC screening programs for patients affected by liver cirrhosis or chronic viral hepatopathies using ultrasound and serum alfa-fetoprotien. In most HCC cases, clinical signs and symptoms of this tumor may occur several months after development, when therapy can not be curative, given the advanced tumor stage and underlying liver disease, which preclude curative options, such as ablation, resection, or liver transplantation.