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1.
Biochim Biophys Acta Mol Basis Dis ; 1865(5): 1019-1030, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30055295

ABSTRACT

Chronic liver diseases ultimately lead to cirrhosis and portal hypertension (PHT). Indeed, PHT is a major cause of severe complications, while medical treatment is limited to non-selective beta blockers. Sophisticated animal models are needed to investigate novel treatment options for different etiologies of liver disease, effective anti-fibrotic agents as well as vasoactive drugs against PHT. In this review, we present some of the most common animal models of liver disease and PHT - including pre-hepatic, intra-hepatic and post-hepatic PHT in rodents. Methodology for induction, considerations for disease etiology, advantages and limitations and practical issues of these animal models are discussed. The appropriate and sensible use of animal models in preclinical research supporting the 3R concept of replacement, reduction and refinement is highlighted.


Subject(s)
Disease Models, Animal , Hypertension, Portal/pathology , Animals , Humans , Hypertension, Portal/chemically induced , Hypertension, Portal/drug therapy , Hypertension, Portal/genetics , Mice , Research Design/standards
2.
Aliment Pharmacol Ther ; 48(4): 451-459, 2018 08.
Article in English | MEDLINE | ID: mdl-29956823

ABSTRACT

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.


Subject(s)
Hypertension, Portal/genetics , Hypertension, Portal/mortality , Lipase/genetics , Liver Failure/genetics , Liver Failure/mortality , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Cross-Sectional Studies , Fatty Liver/complications , Fatty Liver/genetics , Fatty Liver/mortality , Female , Genetic Predisposition to Disease , Genotype , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/mortality , Hepatitis C, Chronic/pathology , Humans , Hypertension, Portal/complications , Liver Failure/complications , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Survival Rate
3.
Aliment Pharmacol Ther ; 47(7): 966-979, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29388229

ABSTRACT

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.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Endoscopy, Gastrointestinal/methods , Esophageal and Gastric Varices/mortality , Esophageal and Gastric Varices/therapy , Gastrointestinal Hemorrhage/mortality , Gastrointestinal Hemorrhage/therapy , Adult , Aged , Chemoprevention/methods , Combined Modality Therapy , Esophageal and Gastric Varices/complications , Esophageal and Gastric Varices/drug therapy , Female , Gastrointestinal Hemorrhage/drug therapy , Gastrointestinal Hemorrhage/etiology , Humans , Ligation , Liver Cirrhosis/drug therapy , Middle Aged , Primary Prevention/methods , Retrospective Studies , Secondary Prevention/methods , Survival Analysis , Treatment Outcome
4.
Aliment Pharmacol Ther ; 47(7): 980-988, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29377193

ABSTRACT

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.


Subject(s)
Bacterial Translocation , Blood Coagulation Disorders/diagnosis , Hypertension, Portal/diagnosis , Inflammation/diagnosis , von Willebrand Factor/metabolism , Biomarkers/blood , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/physiopathology , Blood Coagulation Factors/metabolism , Esophageal and Gastric Varices/blood , Esophageal and Gastric Varices/complications , Esophageal and Gastric Varices/diagnosis , Female , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/complications , Gastrointestinal Hemorrhage/diagnosis , Humans , Hypertension, Portal/complications , Hypertension, Portal/microbiology , Hypertension, Portal/pathology , Inflammation/blood , Inflammation/etiology , Liver Cirrhosis/blood , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Liver Cirrhosis/microbiology , Male , Middle Aged , Portal Pressure , Predictive Value of Tests , Prognosis , Retrospective Studies , Severity of Illness Index
7.
Aliment Pharmacol Ther ; 45(1): 139-149, 2017 01.
Article in English | MEDLINE | ID: mdl-27910154

ABSTRACT

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-ß) 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.


Subject(s)
HIV Infections/pathology , Hepatitis C, Chronic/pathology , Hypertension, Portal/pathology , Interferons , Liver Cirrhosis/pathology , Adult , Coinfection , Disease Progression , Female , HIV Infections/blood , HIV Infections/epidemiology , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/epidemiology , Humans , Hypertension, Portal/blood , Hypertension, Portal/epidemiology , Interferons/therapeutic use , Liver Cirrhosis/blood , Liver Cirrhosis/epidemiology , Male , Middle Aged , Portal Pressure/physiology
8.
Aliment Pharmacol Ther ; 42(6): 707-18, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26179884

ABSTRACT

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.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hypertension, Portal/etiology , Liver Cirrhosis/etiology , Portal Pressure/drug effects , Adult , Aged , Antiviral Agents/administration & dosage , Carbamates , Drug Therapy, Combination , Female , Humans , Imidazoles/therapeutic use , Male , Middle Aged , Pyrrolidines , Retrospective Studies , Ribavirin/therapeutic use , Simeprevir/therapeutic use , Sofosbuvir/therapeutic use , Treatment Outcome , Valine/analogs & derivatives
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