AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the ...AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.展开更多
BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines ...BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content.AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein.METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group(MR-G)with soy-yogurt-honey preparation or to guided lifestyle change group(LC-G)with endurance activity and nutrition counselling. Serum alanine transaminase(ALT), aspartate transaminase(AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod? device. Pre-and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median(interquartile range).RESULTS Twenty-two subjects(MR-G, n = 11 and LC-G, n = 11) completed the study(9 women, 13 men; age 52.1(15.0) years, body mass index(BMI) 32.3(3.3) kg/m^2).In both groups a significant weight loss was achieved(MR-G:-6.4(3.6) kg, P <0.01; LC-G:-9.1(10.4) kg, P < 0.01). BMI dropped in both groups(MR-G:-2.3(1.5)kg/m^2, P = 0.003; LC-G:-3.0(3.4) kg/m^2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT.Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes.CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.展开更多
Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis.Inhibitors of phosphodiesterase-5(PDE-5-inhibitors)reduce portal pressure in the acute setting by>10%which ...Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis.Inhibitors of phosphodiesterase-5(PDE-5-inhibitors)reduce portal pressure in the acute setting by>10%which may suggest a long-term beneficial effect.Currently,there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors.This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored.In the acute setting,the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%.The portal blood flow increased by 28%based onDoppler sonography and by 16%using MRI technique.As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow.There were no recurrence of bleeding and no formation of new varices.Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.展开更多
文摘AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver cirrhosis.METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.RESULTS Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.
基金(in part)Almased^(®)? Wellness Company,Bienenbuettel,GermanyThe planning,organisation,monitoring and analysis of the study were performed independently by the investigators+1 种基金a study grant from Almased^(®)? Wellness Companya study grant from Helmholtz Alliance ICEMED
文摘BACKGROUND Non-alcoholic steatohepatitis(NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content.AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein.METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group(MR-G)with soy-yogurt-honey preparation or to guided lifestyle change group(LC-G)with endurance activity and nutrition counselling. Serum alanine transaminase(ALT), aspartate transaminase(AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod? device. Pre-and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median(interquartile range).RESULTS Twenty-two subjects(MR-G, n = 11 and LC-G, n = 11) completed the study(9 women, 13 men; age 52.1(15.0) years, body mass index(BMI) 32.3(3.3) kg/m^2).In both groups a significant weight loss was achieved(MR-G:-6.4(3.6) kg, P <0.01; LC-G:-9.1(10.4) kg, P < 0.01). BMI dropped in both groups(MR-G:-2.3(1.5)kg/m^2, P = 0.003; LC-G:-3.0(3.4) kg/m^2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT.Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes.CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.
文摘Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis.Inhibitors of phosphodiesterase-5(PDE-5-inhibitors)reduce portal pressure in the acute setting by>10%which may suggest a long-term beneficial effect.Currently,there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors.This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored.In the acute setting,the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%.The portal blood flow increased by 28%based onDoppler sonography and by 16%using MRI technique.As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow.There were no recurrence of bleeding and no formation of new varices.Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.
