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Summary: Background: The rs738409 C>G p.I148M variant in the patatin‐like phospholipase domain containing 3 (PNPLA3)‐gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis. Aim: To investigate its impact on hepatic decompensation and (liver‐related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter. Methods: We performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease‐induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014‐2017; n = 153; cross‐sectional study). Results: While survival was similar between PNPLA3‐C/C and ‐C/G patients, we observed substantially increased mortality in PNPLA3‐G/G patients. PNPLA3‐G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3‐G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1‐4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22‐3.98; P = 0.009; liver‐related: aSHR: 2.2, 95% CI: 1.08‐4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3‐G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27‐4.29; P = 0.006). PNPLA3‐genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m. Conclusion: PNPLA3‐G/G‐genotype seems to double the risks of hepatic decompensation and (liver‐related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis. [ABSTRACT FROM AUTHOR]

Summary: Background: Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. Aims: To assess the rates of HVPG response to different doses of carvedilol. Methods: Consecutive patients with cirrhosis undergoing HVPG‐guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25 mg/d was administered and HVPG response (HVPG‐decrease ≥20% or to ≤12 mm Hg) was assessed after 3‐4 weeks. In case of nonresponse, carvedilol dose was increased to 12.5 mg/d and a third HVPG‐measurement was performed after 3‐4 weeks. We also assessed HVPG‐response rates according to the Baveno VI consensus (HVPG decrease ≥10% or to ≤12 mm Hg) and changes in systolic arterial pressure (SAP). Results: Seventy‐two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG‐decrease ≥ 20% with carvedilol 6.25 mg/d and another 10 (14%) with carvedilol 12.5 mg/d. Forty (56%) patients had a HVPG decrease ≥10% with carvedilol 6.25 mg/d and 24 (33%) with carvedilol 12.5 mg/d. Thus, in total, a HVPG‐response of ≥20% and ≥10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n = 4 with ascites) did not tolerate an increase to 12.5 mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP < 90 mm Hg at the final HVPG measurement. Conclusion: Carvedilol 12.5 mg/d was more effective than 6.25 mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG‐response of ≥ 10% to carvedilol 12.5 mg/d, however, arterial hypotension might occur, especially in patients with ascites. [ABSTRACT FROM AUTHOR]

Summary: Background: Endoscopic band ligation (EBL) is used for primary (PP) and secondary prophylaxis (SP) of variceal bleeding. Current guidelines recommend combined use of non‐selective beta‐blockers (NSBBs) and EBL for SP, while in PP either NSBB or EBL should be used. Aim: To assess (re‐)bleeding rates and mortality in cirrhotic patients receiving EBL for PP or SP for variceal bleeding. Methods: (Re‐)bleeding rates and mortality were retrospectively assessed with and without concomitant NSBB therapy after first EBL in PP and SP. Results: Seven hundred and sixty‐six patients with oesophageal varices underwent EBL from 01/2005 to 06/2015. Among the 284 patients undergoing EBL for PP, n = 101 (35.6%) received EBL only, while n = 180 (63.4%) received EBL + NSBBs. In 482 patients on SP, n = 163 (33.8%) received EBL only, while n = 299 (62%) received EBL + NSBBs. In PP, concomitant NSBB therapy neither decreased bleeding rates (log‐rank: P = 0.353) nor mortality (log‐rank: P = 0.497) as compared to EBL alone. In SP, similar re‐bleeding rates were documented in EBL + NSBB vs EBL alone (log‐rank: P = 0.247). However, EBL + NSBB resulted in a significantly lower mortality rate (log‐rank: P<0.001). A decreased risk of death with EBL + NSBB in SP (hazard ratio, HR: 0.50; P<0.001) but not of rebleeding, transplantation or further decompensation was confirmed by competing risk analysis. Overall NSBB intake reduced 6‐months mortality (HR: 0.53, P = 0.008) in SP, which was most pronounced in patients without severe/refractory ascites (HR: 0.37; P = 0.001) but not observed in patients with severe/refractory ascites (HR: 0.80; P = 0.567). Conclusions: EBL alone seems sufficient for PP of variceal bleeding. In SP, the addition of NSBB to EBL was associated with an improved survival within the first 6 months after EBL. [ABSTRACT FROM AUTHOR]

Summary: Background: Elevated plasma von Willebrand factor antigen (vWF) has been shown to indicate the presence of clinically significant portal hypertension, and thus, predicts the development of clinical events in patients with cirrhosis. Aim: To investigate the impact of bacterial translocation and inflammation on vWF, as well as the association between vWF and procoagulant imbalance. Moreover, we assessed whether vWF predicts complications of cirrhosis, independent of the severity of portal hypertension. Methods: Our study population comprised 225 patients with hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg without active bacterial infections or hepatocellular carcinoma. Results: vWF correlated with markers of bacterial translocation (lipopolysaccharide‐binding protein [LBP; ρ = 0.201; P = 0.021]), inflammation (interleukin 6 [IL‐6; ρ = 0.426; P < 0.001] and C‐reactive protein [CRP; ρ = 0.249; P < 0.001]), and procoagulant imbalance (factor VIII/protein C ratio; ρ = 0.507; P < 0.001). Importantly, the associations between vWF and these parameters were independent of HVPG. Moreover, vWF (per 10%) independently predicted variceal bleeding (hazard ratio [HR]: 1.08 [95% confidence interval (95% CI): 1.01‐1.16]; P = 0.023), requirement of paracentesis (HR: 1.05 [95% CI: 1.01‐1.1]; P = 0.023) and bacterial infections (HR: 1.04 [95% CI: 1‐1.09]; P = 0.04) including spontaneous bacterial peritonitis (HR: 1.09 [95% CI: 0.999‐1.18]; P = 0.053) on a trend‐wise level. After backward elimination, vWF (HR: 1.05 [95% CI: 1.02‐1.08]; P = 0.003) and CRP (per 10 mg/L; HR: 1.53 [95% CI: 1.14‐2.05]; P = 0.005) remained in the final model for transplant‐free mortality. Finally, the independent prognostic value of vWF/CRP groups for mortality was confirmed by competing risk analysis. Conclusion: Our results demonstrate that vWF is not only a marker of portal hypertension but also independently linked to bacterial translocation, inflammation and procoagulant imbalance, which might explain its HVPG‐independent association with most clinical events. Prognostic groups based on vWF/CRP efficiently discriminate between patients with a poor 5‐year survival and patients with a favourable prognosis. [ABSTRACT FROM AUTHOR]

Background The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis. Aim To assess the haemodynamic effects of taurine supplementation in patients with cirrhosis and varices. Methods Patients with hepatic venous pressure gradient ( HVPG) ≥12 mm Hg were included in this prospective proof of concept study. Concomitant nonselective beta-blockers therapy was not allowed. Patients received either 4 weeks of oral taurine (6 g/day), or placebo, prior to evaluation of HVPG response. Results Thirty patients were screened and 22 included in the efficacy analysis (12 taurine/10 placebo; 64% male, mean age: 52 ± 11 years, Child A: 9%, B:64%, C:27%, ascites:68%). In the taurine group, mean HVPG dropped from 20 mm Hg (±4) at baseline to 18 mm Hg (±4) on day 28 (mean relative change: −12%, P = .0093). In the placebo group, mean HVPG increased from 20 mm Hg (±5) at baseline to 21 mm Hg (±5) on day 28 (mean relative change:+2%, P = .4945). Taurine had no significant effects on systemic haemodynamics. Seven of 12 patients (58%) on taurine achieved a HVPG response >10%, compared to none in the placebo group ( P = .0053). In a multivariate linear model, HVPG reduction was significantly larger in the taurine group compared to placebo group ( P = .0091 and P = .0109 for absolute and relative change respectively). Treatment-related adverse events included gastrointestinal discomfort and fatigue, and were usually mild and comparable between treatment groups. Conclusion Taurine is safe and may reduce portal pressure in cirrhotic patients. More studies on the underlying mechanisms of action and long-term effects of taurine supplementation are warranted. [ABSTRACT FROM AUTHOR]

Background HIV/ HCV co-infected patients show accelerated fibrosis progression and higher risk for complications of portal hypertension ( PHT). Aim To assess the effects of interferon-free therapy on portal pressure, liver histology and plasma biomarkers in HIV/ HCV-coinfected patients with PHT. Methods Twenty-two patients with paired hepatic venous pressure gradient ( HVPG) measurements prior and after successful treatment ( SVR) with interferon-free regimens were included. Liver stiffness was assessed by transient elastography and biopsies were scored according to METAVIR. Plasma biomarkers were determined by ELISA. Results Overall, HVPG decreased from 10.7 ± 4.1 mmHg at baseline to 7.4 ± 4.2 mmHg after HCV treatment (Δ:-3.3 ± 2.7 mmHg; p < 0.001). In patients with clinically significant PHT ( HVPG≥10 mmHg, n = 11), HVPG decreased from 14.1 ± 2.9 to 10.4 ± 3.9 mmHg (Δ:-3.7 ± 3.3 mmHg; p = 0.004) and a haemodynamic response ( HVPG decrease ≥10%) was observed in 73%. In 64% of patients with subclinical PHT ( HVPG 6-9 mmHg, n = 11), portal pressure normalised at SVR. Mean liver stiffness decreased from 20.8 kPa to 11.5 kPa (Δ:-8.8 ± 7.4 kPa; p < 0.001). Fifty percent (7/14) of patients with cirrhosis were re-classified as METAVIR ≤F3 and all patients with decompensated cirrhosis improved their Child-Pugh stage. After successful HCV treatment, 39% still had persistent histological necroinflammatory activity ( METAVIR A1), which correlated with less HVPG response and more steatosis. While most biomarkers improved with SVR, METAVIR A1 patients had significantly higher plasma levels of fibrogenic ( PDGF, TGF-β) and angiogenic ( VEGF, Angiopoietin1) biomarkers. Conclusions Interferon-free therapy reduces PHT and halts histological necroinflammatory activity in the majority of HIV/ HCV-coinfected patients after SVR, which may lead to re-compensation of liver function in cirrhosis. Biomarkers could identify patients with persisting hepatic necroinflammation. [ABSTRACT FROM AUTHOR]

Background: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC).Methods: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined.Results: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]).Conclusions: Nintedanib may have similar efficacy to sorafenib in aHCC. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely “silent pandemic,” its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high‐level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week. [ABSTRACT FROM AUTHOR]

Background Portal hypertension is the strongest predictor of virological response to pegylated interferon ( IFN)/ribavirin in patients with chronic hepatitis C ( CHC)-related cirrhosis. Aim To investigate the effects of portal pressure assessed by hepatic venous pressure gradient ( HVPG) measurement on virological responses in patients treated with IFN-free regimens outside of clinical trials. Methods Fifty-six patients with CHC and cirrhosis who underwent HVPG measurement before starting an IFN-free therapy were retrospectively studied. Patients were treated with sofosbuvir in combination with daclatasvir ( n = 32), ribavirin ( n = 12) or simeprevir ( n = 11), or the combination of simeprevir/daclatasvir ( n = 1), for 12-24 weeks. Results Hepatic venous pressure gradient values ≥10 mmHg and ≥16 mmHg were observed in 41 (73%) and 31 (55%) patients respectively. The distributions of treatment regimens and durations were comparable between patients with or without portal hypertension. Patients with portal hypertension had lower platelet counts and albumin levels, while bilirubin levels, INR, MELD and Child-Pugh scores were higher than in patients without portal hypertension. Importantly, rates of on-treatment virological response and viral kinetics, as well as the rates of sustained virological response 12 weeks after the end of therapy [96% (54/56)] were not affected by portal hypertension. Anti-viral therapy improved liver stiffness, platelet count, serum albumin and bilirubin levels, as well as prothrombin time. Conclusions This is the first study to demonstrate that IFN-free regimens overcome the negative effect of portal hypertension on virological responses and viral kinetics. Improvements in liver stiffness and platelet count might reflect an anti-portal hypertensive effect of IFN-free treatments. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV-/HIV)-coinfected patients receiving HBV-active combined antiretroviral therapy ( cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV-active cART in a cohort of 59 HIV-/HBV-coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan-Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg-positive [HBeAg(+); n = 36] and HBeAg-negative [HBeAg(−); n = 23] patients. HBeAg(+) patients with an HBsAg on-treatment decline ≥1 log IU/mL per year achieved higher HBsAg loss rates ( P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(−) patients, a pretreatment baseline cut-off level of HBsAg ≤100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(−) HIV-/HBV-coinfected patients receiving HBV-active cART. [ABSTRACT FROM AUTHOR]

Background Staging of liver fibrosis in patients with chronic hepatitis C (CHC) is recommended prior to anti-viral therapy. As vWF-Ag was shown as a predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis, we performed this study to investigate if vWF-Ag is able to predict different fibrosis stages and if it is comparable to other fibrosis scores. Aim To investigate if vWF-Ag is able to predict different fibrosis stages and if it is comparable to other fibrosis scores. Methods We analysed 294 patients with chronic hepatitis C who underwent biopsy. We assessed stage of liver fibrosis according to Metavir, measured vWF-Ag and calculated different fibrosis scores (APRI, FCI, FORNS, FI, Fib-4) and compared them by AUCs. We also calculated a new score: vWF-Ag/thrombocytes (VITRO score) for prediction of fibrosis. Results vWF-Ag levels were increasing with stage of fibrosis: F0: vWF-Ag was median 136.5%, FI 140.6%, FII 157.5%, FIII 171.0%, FIV 252.0%; P < 0.001. vWF-Ag and VITRO score produced AUCs of 0.7 and 0.72 for ≥F2, comparable to the AUCs of APRI, Fib-4, FORNS with 0.75, 0.65 and 0.64 ( P > 0.05). For ≥F3 AUCs were 0.79 and 0.86 for vWF-Ag and VITRO score, comparable with AUCs of 0.79, 0.86 and 0.87 for APRI, Fib-4 and FORNS. Cirrhosis shows AUCs of 0.84 and 0.89 for vWF-Ag and VITRO score, APRI, Fib-4 and FORNS showed similar results with AUCs of 0.82, 0.88 and 0.87. Conclusions vWF-Ag and VITRO score offer an easy possibility to evaluate the stage of fibrosis to diagnose subclinical cirrhosis in patients with chronic hepatitis C. Both vWF-Ag and VITRO score show equal performance in comparison to other fibrosis scores assessed in our study. [ABSTRACT FROM AUTHOR]

Evaluation of metabolic factors and elevated γ-glutamyltransferase ( GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/ HCV-coinfected patients ( HIV/ HCV). Sixty-four HIV/ HCV patients treated with pegylated interferon-α-2a plus ribavirin ( PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/ HCV from the AIFA- HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance ( IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/μL, respectively. HCV-genotype 1/4 ( OR26.3; P = 0.006), advanced liver fibrosis ( OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP ( OR8.27; P = 0.02) and GGT elevation ( OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR ( OR3.51; P = 0.106) and low CD4 + nadir ( OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse ( r = 0.259; P = 0.039), liver steatosis ( r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol ( r = −0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort ( OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/ HCV that can easily be incorporated into predictive algorithms. [ABSTRACT FROM AUTHOR]

. Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg− patients (5962 ± 3663 vs 20 ± 19 × 106 IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- ( P = 0.042 vs LAM) and in 57% of TDF + FTC ( P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg− patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV-DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One-third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity. [ABSTRACT FROM AUTHOR]

Background: Liver stiffness (LS) correlates with portal pressure (hepatic venous pressure gradient, HVPG). However, the dynamic components of portal hypertension (PHT) in advanced cirrhosis may not be adequately assessed by TE. The influence of treatment with non-selective β-blockers (NSBB) on the correlation of HVPG and LS has not been investigated. Methods: One hundred and twenty-two patients with esophageal varices were included. LS, hemodynamic parameters, and HVPG were recorded at baseline (BL) and after 6 weeks of treatment with NSBB (FU). The correlation of LS and HVPG was compared to control patients with HVPG ≤ 12 mmHg. Results: Patients with higher Child-Pugh stages (A:88/B:25/C:9) had higher levels of liver stiffness (47.4 ± 16.5 vs. 70.3 ± 7.9 vs. 73.7 ± 2.1 kPa) and HVPG (21 ± 5 vs. 26 ± 5 vs. 26 ± 4 mmHg). The correlation of LS and HVPG was stronger in controls with HVPG ≤ 12 mmHg ( R = 0.951; P < 0.0001) than in patients with HVPG > 12 mmHg ( R = 0.538; P = 0.0004). The association of HVPG with LS became stronger under treatment with NSBB, which finally restored the linear correlation of HVPG and LS ( R = 0.930; P < 0.0001). Forty-three percent (53/122) of patients were hemodynamic responders to NSBB. The improvement in the correlation of LS and HVPG under NSBB was mainly noted in hemodynamic responders ( R = 0.864), but not in nonresponders ( R = 0.535), whereas changes in LS, heart rate, and MAP were similar in responders and nonresponders. Conclusions: Targeting the hyperdynamic circulation and the increased splanchnic blood inflow by treatment with NSBB unmasks the linear (mechanical) correlation of HVPG and LS in patients with HVPG > 12 mmHg. Measurement of LS by TE is not a feasible method to assess the dynamic components of PHT. [ABSTRACT FROM AUTHOR]

Background: Liver stiffness (LS) correlates with portal pressure (hepatic venous pressure gradient, HVPG). However, the dynamic components of portal hypertension (PHT) in advanced cirrhosis may not be adequately assessed by TE. The influence of treatment with non-selective β-blockers (NSBB) on the correlation of HVPG and LS has not been investigated.Methods: One hundred and twenty-two patients with esophageal varices were included. LS, hemodynamic parameters, and HVPG were recorded at baseline (BL) and after 6 weeks of treatment with NSBB (FU). The correlation of LS and HVPG was compared to control patients with HVPG ≤ 12 mmHg.Results: Patients with higher Child-Pugh stages (A:88/B:25/C:9) had higher levels of liver stiffness (47.4 ± 16.5 vs. 70.3 ± 7.9 vs. 73.7 ± 2.1 kPa) and HVPG (21 ± 5 vs. 26 ± 5 vs. 26 ± 4 mmHg). The correlation of LS and HVPG was stronger in controls with HVPG ≤ 12 mmHg (R = 0.951; P < 0.0001) than in patients with HVPG > 12 mmHg (R = 0.538; P = 0.0004). The association of HVPG with LS became stronger under treatment with NSBB, which finally restored the linear correlation of HVPG and LS (R = 0.930; P < 0.0001). Forty-three percent (53/122) of patients were hemodynamic responders to NSBB. The improvement in the correlation of LS and HVPG under NSBB was mainly noted in hemodynamic responders (R = 0.864), but not in nonresponders (R = 0.535), whereas changes in LS, heart rate, and MAP were similar in responders and nonresponders.Conclusions: Targeting the hyperdynamic circulation and the increased splanchnic blood inflow by treatment with NSBB unmasks the linear (mechanical) correlation of HVPG and LS in patients with HVPG > 12 mmHg. Measurement of LS by TE is not a feasible method to assess the dynamic components of PHT. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2012; 35: 83-91 Summary Background Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome. Aim To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes. Methods Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), RhoA, tumour necrosis factor-alpha (TNF-α) and placental growth factor (PlGF) were evaluated. Results Thirteen patients (m/f = 12/1; Child-Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption ( n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF-α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43-85%) mRNA decrease of all five investigated genes. Conclusion Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Introduction: The impact of highly active antiretroviral therapy (HAART) on CD4+ cell course during treatment with pegylated interferon plus ribavirin (PegIFN-RBV) in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is unknown.Methods: We determined CD4(+) cell count in 94 HIV-HCV coinfected patients undergoing treatment with pegylated interferon plus RBV at baseline, treatment weeks 4-48 (W4-W48), and months 1, 3, and 6 of follow-up. Of the 94 patients, 70 underwent concomitant HAART (group A) and 24 did not (group B).Results: Group A showed smaller CD4(+) cell decreases from W24-W48 (P = .027) and greater CD4(+) cell increases after cessation of pegylated interferon plus ribavirin therapy (P = .002) than group B showed.Conclusions: Concomitant HAART leads to smaller decreases and faster recovery of CD4(+) cells during and after pegylated interferon plus RBV therapy. [ABSTRACT FROM AUTHOR]

Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV–HCV co-infection. Data of 74 interferon-naïve HIV–HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV–HCV patients had rapid progression of fibrosis [0.201 ± 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 ± 13 years), high HCV viral loads (4.83 × 106 IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression ( R = −0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV–HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/μL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV–HCV co-infection and largely preserved CD4+ cell counts. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the fifth leading cause of cancer death worldwide, is a tumour with dismal prognosis [1]. In recent years, significant advances have been made and survival of patients with HCC has been prolonged and even cure can be achieved in a sizeable number of patients. The biggest advances are viable through screening and surveillance programmes of the population at risk, which includes all patients with cirrhosis of the liver and patients chronically infected with hepatitis B virus. Through regular ultrasound screening at 6-month intervals, detection rates and through this treatment and survival have been improved dramatically [2]. Through these surveillance programmes, at least 80% of the patients with HCC in western countries will undergo treatment for HCC of any kind with proven efficacy on survival. Only about 20% of patients with endstage tumours at the time of diagnosis will have no other option left than supportive care [3]. [ABSTRACT FROM AUTHOR]

Background The liver is the site for synthesis of the vast majority of proteins that play a central role in maintaining hemostasis, by participating in the regulation of coagulation and fibrinolysis. Aim To summarize the available data on the impact of coagulation disorders in patients with chronic liver disease. Results Hepatocellular damage in patients with severe liver disease can lead to abnormalities in the production and function of coagulation and fibrinolytic factors, disrupting the balance between coagulation and anticoagulation systems. Conclusions Hemostatic abnormalities (eg. impaired synthesis of clotting factors, heightened fibrinolysis, disseminated intravascular coagulation, thrombocytopenia, and platelet dysfunction) can increase the risk of bleeding in cirrhotic patients. [ABSTRACT FROM AUTHOR]

TIPS is currently only a second-line treatment for prevention of rebleeding in patients with variceal bleeding, second to drug therapy and endoscopic therapy. Technological advances, however, were able to improve both patency rates and rates of hepatic encephalopathy in patients undergoing TIPS placement. Thus new trials about the possible use of TIPS in variceal bleeding are warranted. Even though this is not the case at the moment, it could well be that in the future TIPS will play a much bigger role for prevention of variceal rebleeding. [ABSTRACT FROM AUTHOR]

Background: Treatment of chronic hepatitis C with interferon (IFN)-α and ribavirin has haematotoxic effects. We evaluated the effects of four different IFN/lFN-ribavirin treatment regimens on haematopoiesis. Methods: Haematopoiesis was studied in 133 patients with chronic hepatitis C receiving IFN-α2b alone (group A) or in combination with ribavirin (group B), pegylated IFN-α2a (group C), or pegylated IFN-α2b (group D) in combination with ribavirin. Results: At week 4, haemoglobin levels were diminished in all groups receiving combination therapy. In the monotherapy group, haemoglobin decreased slightly after eight weeks. In all groups, haemoglobin remained diminished throughout therapy. In all patients, leucocytes (while blood cells) decreased after four weeks and remained low during treatment. Platelets (peripheral platelet count (PPC)) were decreased in all groups after four weeks and remained below baseline levels during therapy in group A, C, and D whereas in group B PPC recovered early and reached baseline levels at week 16 of therapy. Concomitantly with the decreases in haemoglobin and PPC, erythropoietin increased in all groups receiving combination therapy and thrombopoietin in all groups. Patients treated with pegylated IFN-α2a and those who received pegylated IFN-α2b combination therapy differed only in leucopoiesis, whereas erythropoiesis and thrombopoiesis were comparable. Conclusion: IFN-α based therapies are associated with a decrease in all three haematopoietic lineages, irrespective of the type of therapy used. The stronger suppressive effect of pegylated IFN-α2a on leucopoiesis could be due to a dose effect. Overall, concentrations of endogenous haematopoietic growth factors are increased but can only partially alleviate haematotoxicity. Potential uses of exogenous haematopoietic growth factors and their impact on the virological response need to be explored. [ABSTRACT FROM AUTHOR]

: A pegylated interferon-alpha-induced decrease in platelet counts may become a limiting factor for continuation of therapy.: To evaluate the effect of pegylated interferon-α administration on platelet plug formation and von Willebrand factor antigen release in patients with chronic hepatitis C.: Thirty patients with chronic hepatitis C (genotype 1; fibrosis 1–3:n = 16, cirrhosis:n = 14) received a single dose of 9 MU interferon-α2a, followed by weekly administration of 180 μg of pegylated interferon-α2a/ribavirin for 48 weeks. Platelet counts, platelet function (collagen–epinephrine-induced closure time) and von Willebrand factor antigen were measured.: Platelet counts and collagen–epinephrine-induced closure time decreased by 13% and 16%, respectively, 24 h after the first dose of interferon-α2a, and von Willebrand factor antigen levels increased by 31% (P < 0.01) compared with baseline. During a 48-week observation period, platelet counts decreased by a maximum of 33% (P < 0.001), von Willebrand factor antigen levels increased by 69% (P < 0.001) whereas collagen–epinephrine-induced closure time did not change. In noncirrhotic patients, the increase of von Willebrand factor antigen levels was maintained throughout therapy without a change in collagen–epinephrine-induced closure time. In contrast, in cirrhotics, von Willebrand factor antigen levels did not increase, while collagen–epinephrine-induced closure time was prolonged.: Single-dose interferon-α decreases platelet counts but improves platelet function, possibly by the release of von Willebrand factor antigen. Accordingly, long-term antiviral treatment had no effect on collagen–epinephrine-induced closure time, despite the decrease in platelet count in noncirrhotic patients. Such a compensation of decreased platelet counts by increased von Willebrand factor antigen level did not occur in cirrhotics. [ABSTRACT FROM AUTHOR]

Summary Background Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). Aim To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. Methods In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. Results In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [ n = 76]) vs. 6.4 (BSC [ n = 17]) months ( P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [ n = 55]) vs. 1.9 (BSC [ n = 22]) months ( P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [ n = 58]) vs. 3.9 (≥100 U/L [ n = 15]) months for CP-A patients ( P = 0.127), and 6.5 (<100 U/L [ n = 33]) vs. 2.1 (≥100 U/L [ n = 21]) months for CP-B patients ( P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). Conclusions Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib. [ABSTRACT FROM AUTHOR]

Background Originally, aetiology of liver disease has been incorporated into the computation of the Model of End-stage Liver Disease (MELD) score. Clinical observations prompted us to hypothesize that patients with viral and alcoholic cirrhosis may differ in predicted survival rates. Until now, no large representative studies evaluated the impact of aetiology on long-term survival predicted by the Child–Pugh and MELD scores. Materials and methods Four hundred and ninety-three patients who underwent transjugular intrahepatic portosystemic shunt implantation in Vienna, Austria, and Palermo, Italy, were included in this retrospective study. The main analyses were a logistic regression model and a Cox proportional hazards regression model calculating the interaction of the aetiology with the scores. Results Both groups had similar survival rates (median 1377 and 1721 days for viral and alcoholic cirrhosis, respectively; P = 0.58), but patients with viral cirrhosis had significantly lower MELD scores ( P = 0.002). In the Cox analysis, aetiology had a significant impact on the prediction of overall survival by MELD score. For 3-month survival, MELD score was adequately predictive for both groups. For 1-year survival, aetiology had a significant impact on survival, indicating that patients with identical scores but different aetiologies differed in survival rates. When stratifying patients into high- and low-risk patients (MELD < 16 vs. MELD ≥ 16), aetiology of cirrhosis had no impact on the predictive value for low-risk patients; high-risk-patients (MELD ≥ 16) with viral cirrhosis had significantly lower survival rates than patients with alcoholic cirrhosis and identical scores. With regard to Child–Pugh Score, no significant differences between the two patient groups and in the prediction of 3-month and 1-year survival could be observed. Conclusions Our study suggests that aetiology of cirrhosis has an impact on 1-year survival predicted by the MELD score. This becomes more apparent in patients with advanced stage of liver disease (MELD ≥ 16). Since MELD score is used for ranking patients for liver transplantation and waiting times are regularly longer than 3 months, our observations suggest that with increasing time on the waiting list and severity of disease, patients with viral cirrhosis may have a disadvantage in the current allocation policy. [ABSTRACT FROM AUTHOR]

Background Interferon (IFN)-based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV–HCV co-infection. Differences in early viral kinetics have not been compared in these patients. Materials and methods We retrospectively analysed 76 patients (31 OLT, 20 HIV–HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN-α2a (180 µg week−1) plus ribavirin (0·8–1·2 g day−1) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV–HCV patients on treatment response. Results Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls ( P = 0·003). The same trend was present in HIV–HCV ( P = 0·09). The log-drop after test dose was less in OLT compared to HCV ( P = 0·02), while no significant difference was found between HIV–HCV and HCV. In HIV–HCV patients viral load log-drop correlated significantly with CD4+ cell counts ( P = 0·001). No difference in viral load pretherapy, log-drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV–HCV and 56% in HCV patients. Conclusions Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV–HCV with largely preserved CD4+ cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV–HCV patients with relatively high CD4+ cell counts. [ABSTRACT FROM AUTHOR]

Objective: Patients before orthotopic liver transplantation usually show a reduced physical performance status, which impacts on their daily life and social participation. This pilot study aimed to evaluate endurance capacity, muscle strength, and quality of life before and after orthotopic liver transplantation in patients in an Austrian transplantation centre.Subjects: Fifteen patients (male/female = 10:5) were included in the pilot study.Methods: Exercise testing, strength testing of knee extensor muscles and of handgrip, and quality of life (SF-36 health survey) were assessed before and after orthotopic liver transplantation (after 1-2 months). Results: The oxygen uptake at the anaerobic threshold (VO2AT) and isokinetic strength testing of quadriceps femoris muscle did not change significantly from baseline, before transplantation to follow-up after orthotopic liver transplantation. Before orthotopic liver transplantation, quality of life was hampered concerning functional status, emotional role, vitality, and general health perception. Significant improvements of social functioning (p=0.032), vitality (p=0.006), mental health (p=0.004) and general health perception (p=0.002) could be found for this study population after orthotopic liver transplantation.Conclusion: The results of this pilot study including a population of an Austrian transplantation centre indicate deficits of physical performance as well as reduced quality of life in patients before and after orthotopic liver transplantation. [ABSTRACT FROM AUTHOR]

Background Plasma haptoglobin determination is clinically used as parameter for haemolysis. To date, however, the influence of the mode of haemolysis (extravascular vs. intravascular) and of nonhaemolytic conditions on haptoglobin concentration and its reliability as a haemolysis marker remain poorly defined. Materials and methods In a total of 479 individuals, the influence of haemolytic and nonhaemolytic conditions on plasma haptoglobin levels was investigated. Results All studied types of haemolytic disease ( n = 16) were associated with markedly decreased plasma haptoglobin levels, without significant differences between intravascular vs. predominantly extravascular haemolysis. Diminished haptoglobin values were also observed in patients with liver cirrhosis, which normalized after liver transplantation. In contrast, markedly increased haptoglobin levels were found in patients with inflammation. In patients with haemolysis and a concomitant acute-phase response, however, haemolysis-dependent haptoglobin depletion was not attenuated. Interestingly, patients with a strongly positive direct antiglobulin test or high cold agglutinin titre but no further evidence for haemolysis had normal haptoglobin values. Likewise, anaemia owing to bone marrow failure, acute gastrointestinal or chronic diffuse blood loss, and end-stage kidney disease were associated with normal haptoglobin levels. Conclusions Plasma haptoglobin depletion is a reliable marker for the instant diagnosis of accelerated red cell destruction irrespective of the site of haemolysis or the presence of inflammation. The capacity of this parameter to predict haemolysis appears to be limited in patients with liver cirrhosis and decreased haptoglobin production only. [ABSTRACT FROM AUTHOR]

: Patients with liver cirrhosis have a complex haemostasis disturbance including thrombocytopenia and abnormal bleeding time. Erythropoietin is the primary stimulator for erythrocyte production and also induces megakaryocyte formation. In healthy men erythropoietin increased platelet count and platelet reactivity. : As patients with liver cirrhosis often undergo invasive procedures, we were interested to study whether erythropoietin could improve platelet function in addition to thrombocytopenia. : In total, 22 thrombocytopenic (platelet counts < 120 g/L) patients with alcoholic liver cirrhosis received either 100 IE/kg erythropoietin or placebo on days 1, 3 and 5 in a 2:1 randomized, placebo-controlled double-blind fashion. Platelet counts and platelet reactivity (activator-stimulated expression of P-selectin on platelets measured by flow cytometry) were determined on study days 1, 3, 5 and 9. : Median platelet count was 80 g/L which is borderline for major elective surgical interventions. Baseline values were not different between groups ( P > 0.05). Treatment with erythropoietin increased platelet count by 25% ( P = 0.01) and platelet reactivity twofold ( P < 0.01) vs. baseline. The increase in platelet count vs. baseline was more pronounced in patients with platelet counts <80 g/L. No significant effect was observed in the placebo group. : Treatment with erythropoietin significantly increased platelet counts and platelet reactivity in patients with alcoholic liver cirrhosis. Preoperative treatment with erythropoietin is therefore expected to yield higher platelet levels and better platelet function. [ABSTRACT FROM AUTHOR]

Percutaneous ethanol injection (PEI) is an established method in the treatment of hepatocellular carcinoma (HCC) and considered a safe procedure, with severe complications occurring rarely. Cardiac arrhythmias have not been reported to date. Aim of the study was to investigate the occurrence of dysrhythmias during PEI. Twenty-six consecutive patients with inoperable HCC were included. During ultrasound-guided PEI with 95% ethanol, electrocardiogram (ECG) monitoring was performed before starting and continuously during PEI. During PEI a significant reduction in mean heart rate (> 20%) was seen in 15 of 26 (58%) patients. In 11 of 26 patients (42%) occurrence of sinuatrial block (SAB) or atrioventricular block (AVB) was observed after a median time of 9 s (range 4–50) from the start of PEI with a median length of 24 s (range 12–480). Clinical symptoms were seen in two patients, including episodes of unconsciousness, seizure-like symptoms in both and a respiratory arrest during PEI in one patient, requiring mechanical ventilation. In four of 12 patients with repeat interventions, dysrhythmias were reproducible during monthly performed procedures. There was a significant association between the occurrence of SAB or AVB and the amount of instilled alcohol ( P = 0·03) and post-PEI serum ethanol levels ( P = 0·03). Bradycardia and block formation occur frequently during PEI. These symptoms could be explained by a vasovagal reaction and/or the direct effect of ethanol on the sinus node or the right atrial conduction system. Ethanol dose is an important factor for the occurrence of SAB/AVB. ECG-monitoring seems mandatory during PEI. Prophylactic use of intravenously administered Atropine might be useful. Eur J Clin Invest 2004; 34 (3): 218–223 [ABSTRACT FROM AUTHOR]

Twenty-six men on a liver transplant waiting list (12 had alcoholic cirrhosis, 8 suffered from posthepatitic cirrhosis, and 6 from cirrhosis of other etiologies) were eligible for this observation. Nineteen subjects underwent exercise testing to determine oxygen uptake at anaerobic threshold. In all patients dynamometry was performed to determine isokinetic muscle strength of knee extensor muscles, and handgrip. Quality of life was evaluated in all patients with the MOS SF-36 questionnaire. Child-Pugh A patients showed 54 +/- 8%, Child-Pugh B patients 36 +/- 2%, and Child-Pugh C patients 31 +/- 4% of VO2 max predicted at the anaerobic threshold (Kruskal-Wallis ANOVA, p < 0.05). Isokinetic muscle strength of the quadriceps femoris (left/right) was 149 +/- 20/134 +/- 14 Nm in Child-Pugh A, 108 +/- 16/114 +/- 19 Nm in Child-Pugh B, and 89 +/- 10/81 +/- 11 Nm in Child-Pugh C patients (Kruskal-Wallis ANOVA, p < 0.05). MOS-SF36 revealed a Child-Pugh class dependent reduced functional status (Kruskal-Wallis ANOVA, p < 0.05). No significant differences in target parameters were found when analysed according to the etiology of cirrhosis. Patients on the liver transplant waiting list do have a stage dependent reduction in physical health. These data are the basis for longitudinal studies measuring the effects of preoperative rehabilitation programs in these patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the primary forms of liver cancer and is currently the sixth most prevalent malignancy worldwide. In addition to surgical interventions, effective drug treatment is essential for treating HCC. With an increasing number of therapeutic drugs for liver cancer undergoing clinical studies, the therapeutic strategies for advanced HCC are more diverse than ever, leading to improved prospects for HCC patients. Molecular targeted drugs and immunotherapies have become crucial treatment options for HCC. Treatment programs include single-agent molecular-targeted drugs, immunotherapies, combinations of immunotherapies with molecular-targeted drugs, and dual immune checkpoint inhibitors. However, further exploration is necessary to determine the optimal pharmacological treatment regimens, and the development of new effective drugs is urgently needed. This review provides an overview of the current globally approved drugs for liver cancer, as well as the latest advances in ongoing clinical research and drug therapies. Additionally, the review offers an outlook and discussion on the prospects for the development of drug therapy approaches for HCC. [ABSTRACT FROM AUTHOR]

Our previous manuscript showed that thrombocytopenia predicts all-cause mortality in Chinese hemodialysis (HD) patients. Based on the role of platelets in coagulation, clot formation, and systemic inflammation, we speculate that high platelets increase risk of thrombo-embolic events, hence the mortality. However, research evidence is currently lacking. Therefore, we utilized data from a very large international cohort study to explore the association of platelet counts with mortality and cardiovascular (CV) death in hemodialysis (HD) patients. International data from 396 facilities enrolled in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012–2015) were analyzed. Participants were divided into 3 groups according to their platelet counts (low: <100, normal: 100–300, high: >300*109). Associations between platelet counts and all-cause and CV mortality were analyzed using Cox regression, adjusted for confounders. There were 13,631 patients with median age of 65 years old. Males accounted for 61.2%. Mean platelet count was 205*109/L overall and ranged from 173 *109/L in China to 227 *109/L in Sweden. Overall, 2,348 (17.2%) patients died and 1017 (7.5%) died from CV disease. Both low (HR:1.48, 95% CI 1.21–1.80, p < 0.001) and high (HR:1.17, 95% CI 1.00- 1.35, p = 0.044) platelet counts were associated with higher all-cause mortality after adjustment for covariates; results for CV death were consistent. Platelet count has a U-shaped association with all-cause and CV mortality in HD patients, and thus may be used as an outcome predictor that is readily available among HD patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that poses significant challenges regarding morbidity and mortality rates. In the context of HCC, immune cells play a vital role, especially concerning the presentation of antigens. This review explores the intricate interactions among immune cells within HCC, focusing on their functions in antigen presentation and the modulation of T-cell responses. We begin by summarizing the strategies that HCC uses to escape immune recognition, emphasizing the delicate equilibrium between immune surveillance and evasion. Next, we investigate the specific functions of various types of immune cells, including dendritic cells, natural killer (NK) cells, and CD8+ T cells, in the process of antigen presentation. We also examine the impact of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the pathways involving programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), on antigen presentation, while taking into account the clinical significance of checkpoint inhibitors. The review further emphasizes the importance of immune-based therapies, including cancer vaccines and CAR-T cell therapy, in improving antigen presentation. In conclusion, we encapsulate the latest advancements in research, propose future avenues for exploration, and stress the importance of innovative technologies and customized treatment strategies. By thoroughly analyzing the interactions of immune cells throughout the antigen presentation process in HCC, this review provides an up-to-date perspective on the field, setting the stage for new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. Materials and Methods: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. Results: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). Conclusions: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials. [ABSTRACT FROM AUTHOR]

The development of new drugs for the inhibition of hepatocellular carcinoma (HCC) development and progression is a critical and urgent need. The median survival rate for HCC patients remains disappointingly low. Vinpocetine is a safe nootropic agent that is often used to enhance cognitive function. The impact of vinpocetine on HCC development and progression has not been fully explored. Our main objective was to investigate the possible inhibitory role of vinpocetine in rats exposed to diethylnitrosamine. We observed that vinpocetine increased the survival rate of these rats and improved the ultrastructure of their livers. Additionally, vinpocetine reduced the liver weight index, mitigated liver oxidative stress, and improved liver function. In both in vitro and in vivo settings, vinpocetine demonstrated antiproliferative and apoptotic properties. It downregulated the expression of CCND1 and Ki-67 while exhibiting anti-BCL-2 effects and enhancing the levels of Bax and cleaved caspase-3. Vinpocetine also successfully deactivated NF-κB, STAT3, and HIF-1α, along with their associated transcription proteins, thereby exerting anti-inflammatory and anti-angiogenic role. Furthermore, vinpocetine showed promise in reducing the levels of ICAM-1 and TGF-β1 indicating its potential role in tissue remodeling. These findings strongly suggest that vinpocetine holds promise as a hepatoprotective agent by targeting a range of oncogenic proteins simultaneously. However, further approaches are needed to validate and establish causal links between our observed effects allowing for a more in-depth exploration of the mechanisms underlying vinpocetine's effects and identifying pivotal determinants of outcomes. [ABSTRACT FROM AUTHOR]

Background: Cirrhosis comprises a significant health challenge in the Middle East and North African (MENA) region impacting healthcare systems and communities. This study sought to investigate trends in the burden of cirrhosis and other chronic liver disease, different etiologies, deaths, and the disability burden utilizing data from the Global Burden of Disease (GBD) database. Methods: Analyzing epidemiological trends from 1990 to 2021 across 21 MENA countries, this research utilized data on age-standardized incidence rates (ASIR), age-standardized death rates, and age-standardized disability-adjusted life years (DALYs) to evaluate the burden of cirrhosis and other chronic liver disease. The study also examined national variations and sociodemographic relationships. Results: The study identified a 114.9% increase in cirrhosis and other chronic liver disease incidence within the MENA region between 1990 and 2021, with 7,344,030 incident cases reported in 2021. The ASIR showed a steeper rise in females (9.6%) compared to males (7.0%). Etiology-specific analysis revealed an increase in the ASIR for MASLD related cirrhosis and other chronic liver disease by 22.2%, while those due to alcohol as well as hepatitis B and C decreased by 28.1%, 59.3%, and 30%, respectively. Despite the rising incidence, overall age-standardized death rates across all etiologies decreased by 54.3%, with DALYs showing a 51.4% decrease during the same period. Country-specific trends varied significantly, with Oman recording the highest annual ASIR increase (0.64%), and Qatar observing the most substantial annual reduction in age-standardized death rates (-2.88%). Conclusion: The study highlights evolving trends in cirrhosis and other chronic liver disease within the MENA region, emphasizing the necessity for comprehensive, etiology, and gender-specific interventions. Despite an increasing incidence, the observed improvements in mortality rates and age-standardized disability burden indicate progress in public health efforts to mitigate cirrhosis's impact. These findings point to the complex nature of cirrhosis outcomes and the urgent need for tailored strategies to manage its increasing burden effectively. [ABSTRACT FROM AUTHOR]

Background: EphrinA5 belongs to a subclass of ephrin ligands. Abnormal signal transduction of EFNA5 shows a relationship to the development of various tumors. In this study, we explored the level of EFNA5 in hepatoma cells and the influence of up regulation of EFNA5 expression level on the proliferation, invasion, and migration of HepG2 and LM3 cells. Additionally, this work focused on examining its possible mechanism of action, and future impacts on clinical practice. Methods: Immunohistochemistry was utilized to explore the connection between EFNA5 and hepatoma. Real-time quantitative polymerase chain reaction was used for determining the expression levels of EFNA5 in several hepatoma cell lines and normal hepatocytes. Cells were transfected with a pCMV3-EFNA5-flag plasmid and an EFNA5 plasmid. The expression efficiency of EFNA5 was identified through qRT-PCR. For the purpose of further identifying cell proliferation, the Cell Counting Kit-8 assay was applied. To identify changes of cell migration and invasion ability, Transwell and Boyden tests were utilized. Western blot was employed to identify the expressions mof EFNA5 and possible downstream molecules. Results: Data acquired from The Cancer Genome Atlas demonstrated that the level of EFNA5 in hepatoma was significantly downregulated in relative to the normal hepatocytes (P < 0.05). Upregulation of EFNA5 expression in hepatoma cells hindered the proliferative, invasive, and migratory ability of cells (P < 0.05). Additionally, EFNA5 downregulated the level of epithelial–mesenchymal transition-related molecules and EGFR. Conclusions: The expression of EFNA5 was low in hepatoma cells. An increase in EFNA5 levels hinders the proliferation, invasion, and migration of hepatoma cells. These effects may occur through inhibition of hepatoma epithelial–mesenchymal transition by EFNA5. Moreover, the study on the mechanisms of proliferation, invasion and metastasis of hepatoma provides a novel theoretical basis, and may influence the clinical practice of tumor treatment in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to a shortage of reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) following treatment with atezolizumab plus bevacizumab (Ate/Bev), we assessed the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. We prospectively enrolled 32 patients, analyzing changes in IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels from blood samples collected before the first and second Ate/Bev treatments. Patients with increased IL-10, IL-17, and TNF-α levels demonstrated significantly better survival and marginally improved progression-free survival compared to those with decreased cytokine levels. Additionally, a positive correlation was found between changes in IL-10 and TNF-α levels. Multivariable analysis confirmed that increases in these cytokines are significant predictors of improved survival (p = 0.005). Early increases in IL-10 and TNF-α levels post-Ate/Bev treatment may thus serve as effective biomarkers for clinical outcomes in advanced HCC patients. Background/Objectives: Reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev) are still lacking. Cytokines, which play a crucial role in immune regulation and HCC progression, have potential as predictive markers, but data supporting their use are limited. This study aimed to evaluate the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. Methods: We prospectively enrolled 32 advanced HCC patients, collecting blood samples before the first and second Ate/Bev treatments. These samples were analyzed for IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels to assess changes post-treatment. The primary outcome was overall survival, with a secondary focus on progression-free survival (PFS) at 6 months. Results: The mean age of the participants was 64.2 years, with the majority being male (93.8%). Patients showing increased IL-10, IL-17, and TNF-α levels had significantly better survival (p < 0.05) and marginally improved PFS compared to those with decreased cytokine levels. Interestingly, a positive correlation was noted between changes in IL-10 and TNF-α levels (p = 0.009). Furthermore, a multivariable analysis revealed that increased levels of IL-10 and TNF-α were significant predictors of enhanced survival (hazard ratio, 0.07; 95% confidence interval, 0.01–0.46; p = 0.005). Conclusions: An early increases in IL-10 and TNF-α after Ate/Bev treatment may serve as effective biomarkers for clinical outcomes in advanced HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Diet is a fundamental determinant of health and longevity. This relationship is complex. Historically, among the most investigated variables have been quality and quantity of food. However, over the past 2 decades increasing attention has been devoted to dietary rhythms, including time of food consumption during the day and length of fasting intervals. In this respect, contrasting evidence has recently emerged in the literature regarding the effect of adequate intervals of fasting on the evolution of diet-related chronic liver diseases, including hepatocellular carcinoma. In this review, we briefly refer to this evidence and propose a hypothesis that may help reconcile apparently conflicting observations. Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing. [ABSTRACT FROM AUTHOR]

Liver disease is a global public problem, and the cost of its therapy is a large financial burden to governments. It is well known that drug therapy plays a critical role in the treatment of liver disease. However, present drugs are far from meeting clinical needs. Lots of efforts have been made to find novel agents to treat liver disease in the past several decades. Acacetin is a dihydroxy and monomethoxy flavone, named 5,7-dihydroxy-4′-methoxyflavone, which can be found in diverse plants. It has been reported that acacetin exhibits multiple pharmacological activities, including anti-cancer, anti-inflammation, anti-virus, anti-obesity, and anti-oxidation. These studies indicate the therapeutic potential of acacetin in liver disease. This review discussed the comprehensive information on the pathogenesis of liver disease (cirrhosis, viral hepatitis, drug-induced liver injury, and hepatocellular carcinoma), then introduced the biological source, structural features, and pharmacological properties of acacetin, and the possible application in preventing liver disease along with the pharmacokinetic and toxicity of acacetin, and future research directions. We systemically summarized the latest research progress on the potential therapeutic effect of acacetin on liver disease and existing problems. Based on the present published information, the natural flavone acacetin is an anticipated candidate agent for the treatment of liver disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the primary forms of liver cancer and is currently the sixth most prevalent malignancy worldwide. In addition to surgical interventions, effective drug treatment is essential for treating HCC. With an increasing number of therapeutic drugs for liver cancer undergoing clinical studies, the therapeutic strategies for advanced HCC are more diverse than ever, leading to improved prospects for HCC patients. Molecular targeted drugs and immunotherapies have become crucial treatment options for HCC. Treatment programs include single-agent molecular-targeted drugs, immunotherapies, combinations of immunotherapies with molecular-targeted drugs, and dual immune checkpoint inhibitors. However, further exploration is necessary to determine the optimal pharmacological treatment regimens, and the development of new effective drugs is urgently needed. This review provides an overview of the current globally approved drugs for liver cancer, as well as the latest advances in ongoing clinical research and drug therapies. Additionally, the review offers an outlook and discussion on the prospects for the development of drug therapy approaches for HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the primary forms of liver cancer and is currently the sixth most prevalent malignancy worldwide. In addition to surgical interventions, effective drug treatment is essential for treating HCC. With an increasing number of therapeutic drugs for liver cancer undergoing clinical studies, the therapeutic strategies for advanced HCC are more diverse than ever, leading to improved prospects for HCC patients. Molecular targeted drugs and immunotherapies have become crucial treatment options for HCC. Treatment programs include single-agent molecular-targeted drugs, immunotherapies, combinations of immunotherapies with molecular-targeted drugs, and dual immune checkpoint inhibitors. However, further exploration is necessary to determine the optimal pharmacological treatment regimens, and the development of new effective drugs is urgently needed. This review provides an overview of the current globally approved drugs for liver cancer, as well as the latest advances in ongoing clinical research and drug therapies. Additionally, the review offers an outlook and discussion on the prospects for the development of drug therapy approaches for HCC. [ABSTRACT FROM AUTHOR]