Liver steatosis without alcohol consumption, namely, nonalcoholic fatty liver disease (NAFLD), is a common hepatic condition that encompasses a wide spectrum of presentations, ranging from simple accumulation of triglycerides in the hepatocytes without any liver damage to inflammation, necrosis, ballooning, and fibrosis (namely, nonalcoholic steatohepatitis) up to severe liver disease and eventually cirrhosis and/or hepatocellular carcinoma. The pathophysiology of fatty liver and its progression is influenced by multiple factors (environmental and genetics), in a “multiple parallel-hit model,” in which oxidative stress plays a very likely primary role as the starting point of the hepatic and extrahepatic damage. The aim of this review is to give a comprehensive insight on the present researches and findings on the role of oxidative stress mechanisms in the pathogenesis and pathophysiology of NAFLD. With this aim, we evaluated the available data in basic science and clinical studies in this field, reviewing the most recent works published on this topic.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its incidence is definitely increasing. NAFLD is a metabolic disease with extensive multi-organ involvement, whose extra-hepatic manifestations include type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, chronic kidney disease, osteoporosis, and polycystic ovarian syndrome. Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis, and urolithiasis. The most common cause of mortality in NAFLD is represented by cardiovascular disease, followed by liver-related complications. Therefore, clinicians should learn to screen and initiate treatment for these extra-hepatic manifestations, in order to provide appropriate multidisciplinary assessments and rigorous surveillance. This review evaluates the current evidence regarding extra-hepatic associations of NAFLD, focusing on the pathogenic hypothesis and the clinical implications.

The association of hepatitis C virus (HCV) with non-Hodgkin's lymphoma (NHL) has been demonstrated throughout the world. The new interferon-free direct antiviral agents (DAAs) showed high efficacy and safety, and preliminary data seem to confirm their activity on low-grade NHL. The question arises as whether or not-and how-to treat the HCV-positive patients suffering from diffuse large B-cell lymphomas (DLBCLs). The aim of this observational study was to evaluate whether DAA antiviral treatment of DLBCL/HCV-infected patients in concomitance with chemotherapy is a safe and effective option. Twenty (13 males and 7 females) HCV genotype 1b-positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all patients underwent antiviral therapy (AVT) with sofosbuvir/ledipasvir and chemotherapy (14 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and 6 cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL. Complete hematological (Revised European-American Lymphoma classification, Ann Arbor, and International Prognostic Index [IPI] scores) and hepatological (viral markers, liver stiffness, and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV-positive patients not undergoing AVT was enrolled for comparison. DAA-treated and untreated patients were similar for sex distribution, IPI score, and NHL stage, and differed for age (older in treated), chemotherapy and use of AVT. Overall survival (OS) and disease-free survival (DFS) were evaluated among a 52-week of follow-up. No statistical difference was found in OS after 52 weeks (P 5 0.122), whereas a statistically significant higher DFS was achieved in treated patients (P 5 0.036). At the multivariate analysis, only IPI score and AVT were independently correlated with a better DFS. No differences in adverse events were reported. Conclusion: DAA treatment in concomitance with chemotherapy was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients. (HEPATOLOGY 2018;67:48-55). SEE EDITORIAL ON PAGE 4I n the last 20 years, the treatment of (HCV)-related chronic hepatitis saw the development of multiple different therapeutic regimens, with an increase of their efficacy overtime. The most recent treatments with direct antiviral agents (DAAs) are the extraordinary peak of this scientific progress, with 80%-100% of patients experiencing sustained virological response (SVR) to the therapy, depending on the stage of the disease and the virus genotype.

Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.

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Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

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Background and Aims Chronic hepatitis C virus (HCV) infection increases the risk of incident chronic kidney disease (CKD) and progression to end‐stage renal disease (ESRD). Previously available direct‐acting antiviral regimens are not approved for patients with advanced CKD across all HCV genotypes. Methods EXPEDITION‐5 is a phase 3 study to evaluate efficacy and safety of the fixed‐dose combination of glecaprevir and pibrentasvir (G/P) for chronic HCV infection (genotype 1 through 6) in adults without cirrhosis or with compensated cirrhosis and with stage 3b, 4 or 5 CKD. Patients received approved duration of G/P according to HCV genotype, cirrhosis status and prior HCV treatment experience. The primary efficacy endpoint was percentage of patients with sustained virologic response at 12 weeks post‐treatment (SVR12). Results Among the 101 patients enrolled in the study, 24% had predialysis CKD and 76% were on dialysis. Eighty‐four patients were treated with G/P for 8 weeks, 13 patients for 12 weeks and four patients for 16 weeks. Fifty‐five per cent of patients had genotype 1, 27% had genotype 2, 15% had genotype 3 and 4% had genotype 4, and none had genotype 5 or 6 infection. The SVR12 rate was 97% (98/101, 95% confidence interval, 91.6‐99.0). No patients experienced virologic failure. Adverse events (AEs) reported in at least 5% of the patients were pruritus, bronchitis, hypertension and generalized pruritus. Serious AEs were reported in 12% of patients; none related to study drug. Conclusions G/P treatment yielded high SVR12 rates irrespective of the presence of stage 3b, 4 or 5 CKD. No safety signals were detected. Clinicaltrials.gov identifier This Phase 3 clinical trial was funded by AbbVie and registered with http://www.clinicaltrials.gov as NCT03069365 (EXPEDITION‐5).