Periostin Circulating Levels and Genetic Variants in Patients with Non-Alcoholic Fatty Liver Disease

Circulating periostin has been suggested as a possible biomarker in non-alcoholic fatty liver disease (NAFLD) in Asian studies. In the present study, we aimed to test its still controversial relevance in a Caucasian population. In patients with histologically-proven NAFLD (N. = 74; 10 with hepatocellular carcinoma, HCC) plasma periostin concentrations were analyzed. POSTN haplotype analysis was based on rs9603226, rs3829365, and rs1029728. Hepatitis C patients (N. = 81, 7 HCC) and healthy subjects (N. = 27) were used as controls. The median plasma periostin concentration was 11.6 ng/mL without differences amongst groups; it was not influenced by age, liver fibrosis or steatosis. However, possession of haplotype two (rs9603226 = G, rs3829365 = C, rs1028728 = A) was associated with lower circulating periostin compared to other haplotypes. Moreover, periostin was higher in HCC patients. At multivariate analysis, HCC remained the only predictor of high periostin. In conclusion, plasma periostin concentrations in Caucasians NAFLD patients are not influenced by the degree of liver disease, but are significantly higher in HCC. Genetically-determined differences may account for some of the variability. These data suggest extreme caution in predicting a possible future role of periostin antagonists as a rational therapeutic alternative for NAFLD, but show a potential periostin role in the management of NAFLD-associated HCC

17β-Oestradiol Protects from Hepatitis C Virus Infection through Induction of Type I Interferon

Background and Aims: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17β-oestradiol controls HCV’s life cycle. We investigated the mechanism(s) behind oestrogen’s antiviral effect. Methods: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17β-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. Results: Stimulation of 17β-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. Conclusion: Resulting in viral control and suppression, 17β-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling

Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment

The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as "seeds " in peripheral blood, then reach the target organ as dormant cells which could be subsequently "awakened " and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice

Gas6 as a predictor of esophageal varices in patients affected by hepatitis C virus related-chronic liver disease

Aim: Plasma Gas6 was tested as an alternative to Baveno VI criteria (liver stiffness &lt;20 kPa and platelet count &gt;150 × 109/l) in an endoscopy-sparing strategy. Methods: A total of 160 patients with chronic hepatitis C and advanced fibrosis/cirrhosis underwent, on the same occasion, liver elastography, upper endoscopy, a platelet count and serum Gas6 measurement. Results: A total of 74/160 (46%) patients had esophageal varices, that were small (diameter &lt;5 mm) in 57/160 (34%) and large in 17/160 (11%) cases. A total of 34/160 (21%) patients satisfied Baveno VI criteria, according to which screening for esophageal varices could have been omitted; 1/34 had large varices (sensitivity 94%). A plasma Gas6 value &lt;45 ng/ml, detected in 34/160 (21%) patients, was also 94% sensitive. Conclusion: Plasma Gas6 might represent a feasible alternative to Baveno VI criteria when transient elastography is unavailable/unsuccessful. </jats:p

Interplay of PNPLA3 and HSD17B13 Variants in Modulating the Risk of Hepatocellular Carcinoma among Hepatitis C Patients

A single-nucleotide polymorphism causing a C to G change in the PNPLA3 gene (rs738409) is associated with disease severity and development of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease; the insertion variant rs72613567:TA of the 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13) mitigates this detrimental effect. Our aim was to evaluate if the same holds true in chronic hepatitis C virus infection (HCV). With a case control retrospective study design, we selected 110 patients who developed HCC on a background of HCV infection, matching each patient for sex and age (±30 months) to three HCV-infected, non-HCC patients. All participants underwent genotyping for PNPLA3 and HSD17B13 gene variants. Both univariate and multivariate analyses of risk factors for advanced disease and HCC were performed. Carriage of PNPLA3 G∗ allele was associated with a trend of progressively more severe liver disease, from mild fibrosis to significant fibrosis, cirrhosis, and HCC (p=0.007). When the HSD17B13:TA status of these patients was taken into account, the abovementioned trend was strengthened among HSD17B13 major allele homozygotes and completely blunted among carriers of the minor allele (p=0.0003 and 0.953, respectively). In a conditional logistic regression model including diabetes and AST to platelet ratio index among predictor variables, the unfavourable genetic profile characterized by the coexistence of the PNPLA3 minor allele and HSD17B13 major allele (vs. all other possible combinations) was an independent risk factor for HCC (OR=2.00, 95% CI: 1.23-3.26) together with a history of alcohol abuse. In conclusion, carriage of the combination PNPLA3 minor allele and HSD17B13 major allele may represent a risk factor for HCC among HCV-infected patients. The interplay between the two genes may explain some of the controversy on this topic and may be exploited to stratify HCC risk in hepatitis C