Spontaneous bacterial infections in cirrhosis and portal hypertension have been attributed to tra... more Spontaneous bacterial infections in cirrhosis and portal hypertension have been attributed to trans- location of gut-derived bacteria, a process promoted by intestinal bacterial overgrowth and disruption of the gut mucosal barrier. Bacteriotherapy with Lactobacillus has been reported to correct bacterial overgrowth, stabilize mucosal barrier function, and decrease bacterial translocation in rat models of acute liver injury and failure. In this
In recent years it has become well established that nitric oxide (NO) plays a crucial role in the... more In recent years it has become well established that nitric oxide (NO) plays a crucial role in the hemodynamic abnormalities that develop in chronic portal hypertension. The purpose of this review is to summarize the available data and current concepts regarding the involvement of NO in the pathophysiologic changes in the micro-circulation of the liver and the splanchnic and systemic circulation that associate portal hypertension.
Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dy... more Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY) is a sympathetic neurotransmitter facilitating adrenergic vasoconstriction via Y1-receptors on the vascular smooth muscle. Therefore, we investigated its role for vascular reactivity in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham operated rats. In vitro perfused SMA vascular beds of rats were tested for the cumulative dose-response to NPY dependent on the presence and level of alpha1-adrenergic vascular tone (methoxamine MT: 0.3-10 microM). Moreover, the effect of NPY (50 nM) on vascular responsiveness to alpha1-adrenergic stimulation (MT: 0.3-300 microM) was evaluated. Y1-receptor function was tested by Y1-selective inhibition using BIBP-3226 (1 microM). NPY dose-dependently and endothelium-independently enhanced MT-pre-constriction in SMA. This potentiation was increasingly effective with increasing...
&... more &Aims: Patients with liver cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective, randomized trial to compare prevention of rebleeding in patients given small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. We performed an open-label study of patients with liver cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were randomly assigned more than 5 days after variceal hemorrhage to groups given a small intrahepatic stent shunt (cTIPS, 8mm; n=90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n=95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with adequate reduction in HVPG (responders) remained on the drugs whereas non-responders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary endpoint was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the SF-36 health survey) were secondary outcome measures. A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 y (7%) than the medical group (26%) (P=.002). A slightly higher proportion of patients in the TIPS group had adverse events, including encephalopathy (18% vs 8% for medical treatment, P=.05). Rebleeding occurred in 6/23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in non-responders who received variceal band ligation (31%) (P=.06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. Placement of a small-diameter cTIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required a step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events.
To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoemboliz... more To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with a new real-time imaging fusion technique of contrast-enhanced ultrasound (CEUS) with multi-slice detection computed tomography (CT) in comparison to conventional post-interventional follow-up. 40 patients with HCC (26 male, ages 46-81 years) were evaluated 24 hours after TACE using CEUS with ultrasound volume navigation and image fusion with CT compared to non-enhanced CT and follow-up contrast-enhanced CT after 6-8 weeks. Reduction of tumor vascularization to less than 25% was regarded as "successful" treatment, whereas reduction to levels >25% was considered as "partial" treatment response. Homogenous lipiodol retention was regarded as successful treatment in non-enhanced CT. Post-interventional image fusion of CEUS with CT was feasible in all 40 patients. In 24 patients (24/40), post-interventional image fusion with CEUS revealed residual tumor...
Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the comp... more Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the complications of cirrhosis. Research on the pathogenesis of BT and its clinical significance transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review delineates multiple mechanisms involved in the process of BT, with an emphasis on alterations in intestinal flora and mucosal barrier function, particularly immunological defense mechanisms. Current knowledge on the innate and adaptive immune response that allows a "friendly" communication between bacteria and host is summarized, and alterations occurring in cirrhosis that may facilitate BT are discussed. In addition, definition of a "pathological" BT is proposed together with an analysis of the anatomical site and route of BT. Finally, therapeutic approaches for the prevention of BT in experimental and human cirrhosis are reviewed. Future research in the f...
Chemerin is a well-established modulator of immune cell function and its serum levels are induced... more Chemerin is a well-established modulator of immune cell function and its serum levels are induced in inflammatory diseases. Liver cirrhosis is associated with inflammation which is aggravated by portal hypertension. The objective of this study was to evaluate whether chemerin is induced in patients with more severe liver cirrhosis and portal hypertension. Chemerin has been measured by ELISA in the portal venous serum (PVS), systemic venous serum (SVS) and hepatic venous serum (HVS) of 45 patients with liver cirrhosis. Chemerin is higher in HVS compared to PVS in accordance with our recently published finding. SVS, HVS and PVS chemerin decline in patients with more advanced liver injury defined by the CHILD-PUGH score. Hepatic chemerin has been determined in a small cohort and is similarly expressed in normal and cirrhotic liver. MELD score and serum markers of liver and kidney function do not correlate with chemerin. There is a positive correlation of chemerin in all compartments with Quick prothrombin time and of SVS chemerin with systolic blood pressure. PVS chemerin is induced in patients with modest/massive ascites but this does not translate into higher HVS and SVS levels. Chemerin is not associated with variceal size. Reduction of portal pressure by transjugular intrahepatic portosystemic shunt does not affect chemerin levels. These data show that low chemerin in patients with more severe liver cirrhosis is associated with reduced Quick prothrombin time.
Connective tissue growth factor (CTGF) is a profibrotic protein whose systemic levels are increas... more Connective tissue growth factor (CTGF) is a profibrotic protein whose systemic levels are increased in liver cirrhosis. Here, association of CTGF with stages of liver injury and complications of cirrhotic liver disease has been analyzed in patients with different aetiologies of hepatic injury. CTGF is significantly increased in portal venous serum (PVS), hepatic venous serum (HVS) and systemic venous serum (SVS) of 46 patients with liver cirrhosis compared to eight liver-healthy controls. In patients´ blood samples CTGF in HVS is about 6% higher than PVS levels indicating that CTGF produced in the liver is released to the circulation. CTGF is not associated with stages of liver cirrhosis defined by CHILD-PUGH or MELD score nor with secondary complications of portal hypertension (varices, ascites, spontaneous bacterial peritonitis). Transforming growth factor β (TGFβ) induces CTGF synthesis in hepatocytes and a positive association of systemic TGFβ1 and SVS and HVS CTGF is found. Three months after placing transjugular intrahepatic portosystemic shunt (TIPS) hepatic venous pressure gradient is reduced whereas CHILD-PUGH score, TGFβ1 and CTGF are not altered in serum of 15 patients. Current data show that the cirrhotic liver releases little CTGF but SVS, HVS and PVS CTGF levels are not associated with residual liver function and complications of cirrhosis.
Spontaneous bacterial infections in cirrhosis and portal hypertension have been attributed to tra... more Spontaneous bacterial infections in cirrhosis and portal hypertension have been attributed to trans- location of gut-derived bacteria, a process promoted by intestinal bacterial overgrowth and disruption of the gut mucosal barrier. Bacteriotherapy with Lactobacillus has been reported to correct bacterial overgrowth, stabilize mucosal barrier function, and decrease bacterial translocation in rat models of acute liver injury and failure. In this
In recent years it has become well established that nitric oxide (NO) plays a crucial role in the... more In recent years it has become well established that nitric oxide (NO) plays a crucial role in the hemodynamic abnormalities that develop in chronic portal hypertension. The purpose of this review is to summarize the available data and current concepts regarding the involvement of NO in the pathophysiologic changes in the micro-circulation of the liver and the splanchnic and systemic circulation that associate portal hypertension.
Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dy... more Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY) is a sympathetic neurotransmitter facilitating adrenergic vasoconstriction via Y1-receptors on the vascular smooth muscle. Therefore, we investigated its role for vascular reactivity in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham operated rats. In vitro perfused SMA vascular beds of rats were tested for the cumulative dose-response to NPY dependent on the presence and level of alpha1-adrenergic vascular tone (methoxamine MT: 0.3-10 microM). Moreover, the effect of NPY (50 nM) on vascular responsiveness to alpha1-adrenergic stimulation (MT: 0.3-300 microM) was evaluated. Y1-receptor function was tested by Y1-selective inhibition using BIBP-3226 (1 microM). NPY dose-dependently and endothelium-independently enhanced MT-pre-constriction in SMA. This potentiation was increasingly effective with increasing...
&... more &Aims: Patients with liver cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective, randomized trial to compare prevention of rebleeding in patients given small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. We performed an open-label study of patients with liver cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were randomly assigned more than 5 days after variceal hemorrhage to groups given a small intrahepatic stent shunt (cTIPS, 8mm; n=90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n=95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with adequate reduction in HVPG (responders) remained on the drugs whereas non-responders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary endpoint was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the SF-36 health survey) were secondary outcome measures. A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 y (7%) than the medical group (26%) (P=.002). A slightly higher proportion of patients in the TIPS group had adverse events, including encephalopathy (18% vs 8% for medical treatment, P=.05). Rebleeding occurred in 6/23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in non-responders who received variceal band ligation (31%) (P=.06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. Placement of a small-diameter cTIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required a step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events.
To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoemboliz... more To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with a new real-time imaging fusion technique of contrast-enhanced ultrasound (CEUS) with multi-slice detection computed tomography (CT) in comparison to conventional post-interventional follow-up. 40 patients with HCC (26 male, ages 46-81 years) were evaluated 24 hours after TACE using CEUS with ultrasound volume navigation and image fusion with CT compared to non-enhanced CT and follow-up contrast-enhanced CT after 6-8 weeks. Reduction of tumor vascularization to less than 25% was regarded as "successful" treatment, whereas reduction to levels >25% was considered as "partial" treatment response. Homogenous lipiodol retention was regarded as successful treatment in non-enhanced CT. Post-interventional image fusion of CEUS with CT was feasible in all 40 patients. In 24 patients (24/40), post-interventional image fusion with CEUS revealed residual tumor...
Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the comp... more Gut flora and bacterial translocation (BT) play an important role in the pathogenesis of the complications of cirrhosis. Research on the pathogenesis of BT and its clinical significance transcends established boundaries between microbiology, cell biology, intestinal pathophysiology, and immunology. This review delineates multiple mechanisms involved in the process of BT, with an emphasis on alterations in intestinal flora and mucosal barrier function, particularly immunological defense mechanisms. Current knowledge on the innate and adaptive immune response that allows a "friendly" communication between bacteria and host is summarized, and alterations occurring in cirrhosis that may facilitate BT are discussed. In addition, definition of a "pathological" BT is proposed together with an analysis of the anatomical site and route of BT. Finally, therapeutic approaches for the prevention of BT in experimental and human cirrhosis are reviewed. Future research in the f...
Chemerin is a well-established modulator of immune cell function and its serum levels are induced... more Chemerin is a well-established modulator of immune cell function and its serum levels are induced in inflammatory diseases. Liver cirrhosis is associated with inflammation which is aggravated by portal hypertension. The objective of this study was to evaluate whether chemerin is induced in patients with more severe liver cirrhosis and portal hypertension. Chemerin has been measured by ELISA in the portal venous serum (PVS), systemic venous serum (SVS) and hepatic venous serum (HVS) of 45 patients with liver cirrhosis. Chemerin is higher in HVS compared to PVS in accordance with our recently published finding. SVS, HVS and PVS chemerin decline in patients with more advanced liver injury defined by the CHILD-PUGH score. Hepatic chemerin has been determined in a small cohort and is similarly expressed in normal and cirrhotic liver. MELD score and serum markers of liver and kidney function do not correlate with chemerin. There is a positive correlation of chemerin in all compartments with Quick prothrombin time and of SVS chemerin with systolic blood pressure. PVS chemerin is induced in patients with modest/massive ascites but this does not translate into higher HVS and SVS levels. Chemerin is not associated with variceal size. Reduction of portal pressure by transjugular intrahepatic portosystemic shunt does not affect chemerin levels. These data show that low chemerin in patients with more severe liver cirrhosis is associated with reduced Quick prothrombin time.
Connective tissue growth factor (CTGF) is a profibrotic protein whose systemic levels are increas... more Connective tissue growth factor (CTGF) is a profibrotic protein whose systemic levels are increased in liver cirrhosis. Here, association of CTGF with stages of liver injury and complications of cirrhotic liver disease has been analyzed in patients with different aetiologies of hepatic injury. CTGF is significantly increased in portal venous serum (PVS), hepatic venous serum (HVS) and systemic venous serum (SVS) of 46 patients with liver cirrhosis compared to eight liver-healthy controls. In patients´ blood samples CTGF in HVS is about 6% higher than PVS levels indicating that CTGF produced in the liver is released to the circulation. CTGF is not associated with stages of liver cirrhosis defined by CHILD-PUGH or MELD score nor with secondary complications of portal hypertension (varices, ascites, spontaneous bacterial peritonitis). Transforming growth factor β (TGFβ) induces CTGF synthesis in hepatocytes and a positive association of systemic TGFβ1 and SVS and HVS CTGF is found. Three months after placing transjugular intrahepatic portosystemic shunt (TIPS) hepatic venous pressure gradient is reduced whereas CHILD-PUGH score, TGFβ1 and CTGF are not altered in serum of 15 patients. Current data show that the cirrhotic liver releases little CTGF but SVS, HVS and PVS CTGF levels are not associated with residual liver function and complications of cirrhosis.
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