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Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population. In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured. Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes. Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.

BackgroundMutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4.AimAs these four genes have been poorly studied in young people and adults, we investigated them in this context here.MethodsIn patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces.ResultsOf 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244–27.060, p = 0.025).ConclusionsMutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching.

Background and Aims: Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide. Six-month imaging along with alpha-fetoprotein (AFP) serum levels detection are the current gold standard to exclude HCC. Protein induced by vitamin K absence (PIVKA-II) has been proposed as a potential screening biomarker for HCC. This study was designed to evaluate the role of PIVKA-II as diagnostic HCC marker, and the correlation between PIVKA-II levels and HCC stage. Methods: PIVKA-II levels were assessed on serum samples of Italian patients. The study population included 80 patients with HCC, 111 with liver cirrhosis (LC), and 111 with chronic hepatitis C (CHC). Results: PIVKA-II serum levels progressively increase from patients with CHC to patients with HCC. In the HCC group, PIVKA-II values are higher in the more advanced stages of the disease, assessed by the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC-B vs. BCLC-A vs. BCLC-0). Youden’s index analysis identified a value >37 mAU/mL as the optimal threshold for the best combination of sensitivity and specificity (80% and 76%, respectively) and, at the best cut-off of 5.2 ng/mL, AFP yielded 53% specificity and 78% sensitivity. The combination of PIVKA-II and AFP reached positive and negative predictive values of 73.9% and 94.2%, respectively. Conclusions: PIVKA-II levels are increased in the HCC patients, compared to control groups. The increase is more evident in patients with advanced HCC. The diagnostic performance of PIVKA-II seems more sensitive than AFP while the combination of PIVKA-II and AFP resulted in the best diagnostic accuracy, reaching 73.9% positive predictive value and 94.2% negative predictive value, thus improving the diagnostic capability of the single marker.

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To evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs). Ninety-six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated. A sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05). Monitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective.

Chronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men. A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis. Liver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001). The severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.

Ischemia–reperfusion injury (IRI) is a mechanism based on inflammatory mediators’ release and activation of effectors of damage. Studies showed a correlation between cytokine, severity of damage, and post-operative outcomes. Ex situ perfusion may work as a platform for the treatment of IRI mechanisms, such as the removal of cytokines using cytokine adsorption (CA). We assessed the safety and benefits of an integrated CA during ex situ dual-oxygenated hypothermic (D-HOPE) and normothermic perfusion (NMP). During the period of July 2021–December 2023, 84 octogenarian liver grafts, suitable for transplantation, were considered: 12 were randomized to D-HOPE or NMP with or without CA (D-HOPE + CA, D-HOPE, NMP + CA, NMP groups, n = 3 each) and compared to 72 performed using grafts preserved in static cold storage (SCS). IL-1, IL-6, IL-10, and TNF-a perfusate concentrations were evaluated together with perfusion parameters and post-operative outcomes. Perfusion procedures were unaffected by CA integration. In NMP, cytokine levels were 10–40 times higher than in healthy subjects and 20–50 times higher than D-HOPE. Cytokines were removed both in D-HOPE and NMP, but the concentration-dependent mechanisms of action of CA led to more remarkable removal in NMP. IL-10 and TNF-a concentrations were significantly lower in NMP + CA than in NMP. The application of CA was associated with significantly higher arterial flows both in D-HOPE and NMP, and reduced neutrophil infiltration in NMP. No differences in post-operative outcomes were found among groups. In conclusion, cytokine adsorption during ex situ machine perfusion of liver grafts from elderly donors is safe and feasible and is associated with modulation of inflammatory mediators and perfusion dynamics. These findings are hypothesis-generating, and larger studies are required to determine the clinical impact of this strategy.

Background: The risk of hepatocarcinoma in HCV cirrhotic patient responders after treatment with DAAs decrease, but HCC still occurs. A correlation between specific miRNAs and the development of hepatocarcinoma have been highlighted. Aim: To investigate miRNA expression in HCV-infected cirrhotic patients treated with DAAs, regarding whether or not they developed HCC at follow-up. Methods: A total of 73 outpatients with HCV-related cirrhosis treated with DAAs were enrolled, 28 of which had HCC. Samples were collected at the start and at the end of treatment. In the screening phase, 172 miRNAs were analyzed at baseline. Differentially expressed miRNAs were validated in the entire cohort. Results: In the validation phase, at baseline and in patients treated for 12 weeks, miR-28-5p was confirmed to be more highly expressed in the HCC group compared to the non-HCC group. In all of the patients treated for 12 weeks, at end of the treatment we found a significant downregulation in miR-132-3p, miR-133b-3p, miR-221-3p and miR-324-3p. In the HCC group, miR-28-5p was significantly downregulated after DAA therapy as well as in HCC patients treated for 24 weeks. Conclusion: In the HCC group, miR28-5p was differently expressed both at baseline and at the end of therapy with DAAs. This difference in expression should suggest its involvement in HCC development.

To attain a deeper understanding of diseases like cancer, it is critical to couple genetics with biomolecular mechanisms. High-throughput sequencing has identified thousands of somatic mutations across dozens of cancers, and there is a pressing need to identify the few that are pathologically relevant. Here we use protein structure and interaction data to interrogate nonsynonymous somatic cancer mutations, identifying a set of 213 molecular interfaces (protein-protein, -small molecule or –nucleic acid) most often perturbed in cancer, highlighting several potentially novel cancer genes. Over half of these interfaces involve protein-small-molecule interactions highlighting their overall importance in cancer. We found distinct differences in the predominance of perturbed interfaces between cancers and histological subtypes and presence or absence of certain interfaces appears to correlate with cancer severity.

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.