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  • 1
    Online Resource
    Online Resource
    Cirrhosis-Associated RAS-Inflammation-Coagulation Axis Anomalies: Parallels to Severe COVID-19
    MDPI AG ; 2021
    In:  Journal of Personalized Medicine Vol. 11, No. 12 ( 2021-12-01), p. 1264-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 11, No. 12 ( 2021-12-01), p. 1264-
    Abstract: (1) Background: Cirrhotic patients have an increased risk for severe COVID-19. We investigated the renin-angiotensin-aldosterone system (RAS), parameters of endothelial dysfunction, inflammation, and coagulation/fibrinolysis in cirrhotic patients and in COVID-19 patients. (2) Methods: 127 prospectively characterized cirrhotic patients (CIRR), along with nine patients with mild COVID-19 (mild-COVID), 11 patients with COVID-19 acute respiratory distress syndrome (ARDS; ARDS-COVID), and 10 healthy subjects (HS) were included in the study. Portal hypertension (PH) in cirrhotic patients was characterized by hepatic venous pressure gradient (HVPG). (3) Results: With increased liver disease severity (Child−Pugh stage A vs. B vs. C) and compared to HS, CIRR patients exhibited higher RAS activity (angiotensin-converting enzyme (ACE), renin, aldosterone), endothelial dysfunction (von Willebrand-factor (VWF) antigen), inflammation (C-reactive protein (CRP), interleukin-6 (IL-6)), and a disturbed coagulation/fibrinolysis profile (prothrombin fragment F1,2, D-dimer, plasminogen activity, antiplasmin activity). Increased RAS activity (renin), endothelial dysfunction (vWF), coagulation parameters (D-dimer, prothrombin fragment F1,2) and inflammation (CRP, IL-6) were significantly altered in COVID patients and followed similar trends from mild-COVID to ARDS-COVID. In CIRR patients, ACE activity was linked to IL-6 (ρ = 0.26; p = 0.003), independently correlated with VWF antigen (aB: 0.10; p = 0.001), and was inversely associated with prothrombin fragment F1,2 (aB: −0.03; p = 0.023) and antiplasmin activity (aB: −0.58; p = 0.006), after adjusting for liver disease severity. (4) Conclusions: The considerable upregulation of the RAS in Child−Pugh B/C cirrhosis is linked to systemic inflammation, endothelial dysfunction, and abnormal coagulation profile. The cirrhosis-associated abnormalities of ACE, IL-6, VWF antigen, and antiplasmin parallel those observed in severe COVID-19.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm11121264
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662248-8
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  • 2
    Online Resource
    Online Resource
    Vascular Complications in Patients with Hepatocellular Carcinoma Treated with Sorafenib
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 10 ( 2020-10-13), p. 2961-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 10 ( 2020-10-13), p. 2961-
    Abstract: VEGF(R)-targeted therapies are associated with an increased risk of thromboembolism and bleeding, which might be pronounced in patients with increased cardiovascular risk. Nevertheless, sorafenib represents an important treatment option in patients with hepatocellular carcinoma (HCC). We retrospectively investigated the risk of arterial/venous thromboembolic and bleeding events in 252 patients treated with sorafenib for HCC between 05/2006 and 03/2020 at the Medical University of Vienna. Cardiovascular risk was assessed using Framingham score. Eight patients (3.2%) experienced 11 arterial/venous thromboembolic events. Only two patients (0.8%) developed arterial thromboembolism even though cardiovascular risk was low, intermediate, and high in 15 (8.7%), 104 (60%), and 54 (31.2%) of 173 assessable patients. Median overall survival (OS) was shorter in the high risk vs. low/intermediate risk group 7.4 (95% CI: 3.4–11.3) vs. 10.0 (95% CI: 6.8–13.2 months) and independently associated with OS in multivariable analysis HR: 1.53 (95% CI: 1.07–2.19; p = 0.019). Forty-eight (19%) patients experienced a bleeding, most commonly gastrointestinal bleeding (14%) followed by epistaxis (4.7%). Advanced liver dysfunction was not associated with an increased incidence of bleeding/venous thromboembolism. Sorafenib represents a safe treatment option even in patients with increased cardiovascular risk. Bleeding complications were comparable with previous reports, even though patients with more advanced liver disease were included.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12102961
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 3
    Online Resource
    Online Resource
    De-Ritis Ratio Improves Long-Term Risk Prediction after Acute Myocardial Infarction
    MDPI AG ; 2018
    In:  Journal of Clinical Medicine Vol. 7, No. 12 ( 2018-11-23), p. 474-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 7, No. 12 ( 2018-11-23), p. 474-
    Abstract: Background: Recent evidence suggested levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and AST/ALT ratio (De-Ritis ratio) were associated with a worse outcome after acute myocardial infarction (AMI). However, their value for predicting long-term prognosis remained unknown. Therefore, we investigated the prognostic potential of transaminases on patient outcome after AMI from a long-term perspective. Methods: Data of a large AMI registry including 1355 consecutive patients were analyzed. The Cox regression hazard analysis was used to assess the impact of transaminases and the De-Ritis ratio on long-term mortality. Results: The median De-Ritis ratio for the entire study population was 1.5 (interquartile range [IQR]: 1.0–2.6). After a median follow-up time of 8.6 years, we found that AST (crude hazard ratio (HR) of 1.19 per 1-SD [95% confidence interval (CI): 1 .09–1.32; p 〈 0.001]) and De-Ritis ratio (crude HR of 1.31 per 1-SD [95% CI: 1.18–1.44; p 〈 0.001]), but not ALT (p = 0.827), were significantly associated with long-term mortality after AMI. After adjustment for confounders independently, the De-Ritis ratio remained a strong and independent predictor for long-term mortality in the multivariate model with an adjusted HR of 1.23 per 1-SD (95% CI: 1.07–1.42; p = 0.004). Moreover, the De-Ritis ratio added prognostic value beyond N-terminal pro-B-Type Natriuretic Peptide, Troponin T, and Creatine Kinase. Conclusion: The De-Ritis ratio is a strong and independent predictor for long-term mortality after AMI. As a readily available biomarker in clinical routine, it might be used to identify patients at risk for fatal cardiovascular events and help to optimize secondary prevention strategies after AMI.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm7120474
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2662592-1
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  • 4
    Online Resource
    Online Resource
    Recent Advances in Practical Methods for Liver Cell Biology: A Short Overview
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 6 ( 2020-03-16), p. 2027-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 6 ( 2020-03-16), p. 2027-
    Abstract: Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21062027
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Long-Term Outcome of HBV-Infected Patients with Clinically Significant Portal Hypertension Achieving Viral Suppression
    MDPI AG ; 2022
    In:  Journal of Personalized Medicine Vol. 12, No. 2 ( 2022-02-08), p. 239-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 12, No. 2 ( 2022-02-08), p. 239-
    Abstract: Background: Nucleos(t)ide analog (NA) treatment for hepatitis B virus (HBV) infection may improve clinically significant portal hypertension (CSPH). Data on hepatic venous pressure gradient (HVPG) and non-invasive tests (NITs) for risk re-stratification in virally suppressed HBV-infected patients with pre-treatment CSPH are limited. Methods: We retrospectively included patients with long-term ( 〉 12 months) suppression of HBV replication and pre-treatment CSPH (i.e., varices, collaterals on cross-sectional imaging, or ascites). Patients were monitored by on-treatment liver stiffness measurement (LSM) and HVPG assessment. The primary outcome was (further) hepatic decompensation (including liver-related mortality). Results: Forty-two patients (n = 12 (28.6%) with previous decompensation, HBeAg-negative: n = 36 (85.7%)) were included and followed for 2.1 (0.6; 5.3) years. The median HVPG (available in n = 17) was 15 (10; 22) mmHg and the median LSM 22.5 (12.5; 41.0) kPa. LSM correlated strongly with HVPG (Spearman’s ρ: 0.725, p 〈 0.001) and moderately with the model for end-stage liver disease (MELD) score (ρ: 0.459, p = 0.002). LSM, MELD and albumin levels had good prognostic value for decompensation (area under the receiver operated characteristics curve (AUROC) 〉 0.850 for all). LSM predicted (further) decompensation in competing risk regression (subdistribution hazard ratio (SHR): 1.05 (95% confidence interval(CI) 1.03–1.06); p 〈 0.001), even after adjusting for other factors. An LSM cut-off at 25kPa accurately stratified patients into a low-risk (n = 23, zero events during follow-up) and a high-risk (n = 19; n = 12 (63.2%) developed events during follow-up) group. Conclusions: Patients with HBV-induced CSPH who achieved long-term viral suppression were protected from decompensation, if LSM was 〈 25 kPa. LSM ≥ 25 kPa indicates a persisting risk for decompensation, despite long-term HBV suppression.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm12020239
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662248-8
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  • 6
    Online Resource
    Online Resource
    Treatment of Chronic Hepatitis D with Bulevirtide—A Fight against Two Foes—An Update
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 22 ( 2022-11-08), p. 3531-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 22 ( 2022-11-08), p. 3531-
    Abstract: HDV infection frequently causes progression to cirrhosis and hepatocellular carcinoma (HCC). In summer 2020, the first potentially effective drug Bulevirtide (BLV) has been approved for the treatment of HDV by the EMA. BLV is a synthetic N-acylated pre-S1 lipopeptide that blocks the binding of HBsAg-enveloped particles to the sodium taurocholate co-transporting polypeptide (NTCP), which is the cell entry receptor for both HBV and HDV. In this review, we discuss the available data from the ongoing clinical trials and from “real world series”. Clinical trials and real-world experiences demonstrated that BLV 2 mg administered for 24 or 48 weeks as monotherapy or combined with pegIFNα reduces HDV viremia and normalizes ALT levels in a large proportion of patients. The combination of BLV and pegIFNα shows a synergistic on-treatment effect compared with either one of the monotherapies.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11223531
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 7
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    Online Resource
    The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model
    MDPI AG ; 2021
    In:  Biomedicines Vol. 9, No. 1 ( 2021-01-09), p. 60-
    Details
    In: Biomedicines, MDPI AG, Vol. 9, No. 1 ( 2021-01-09), p. 60-
    Abstract: Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines9010060
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2720867-9
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  • 8
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    Online Resource
    Influence of Genetic Variants on Disease Regression and Outcomes in HCV-Related Advanced Chronic Liver Disease after SVR
    MDPI AG ; 2021
    In:  Journal of Personalized Medicine Vol. 11, No. 4 ( 2021-04-07), p. 281-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 11, No. 4 ( 2021-04-07), p. 281-
    Abstract: Genetic variants including PNPLA3-rs738409 C 〉 G, TM6SF2-rs58542926 C 〉 T, MBOAT7-rs641738 C 〉 T, and HSD17B13-rs72613567 T 〉 TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)] ) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm11040281
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662248-8
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