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Relation between portosystemic hydrostatic and osmotic pressure gradients in patients with portal hypertension
Cirrhosis and its complications, pathophysiology and clinical aspects
C02/13 ] COMPARISON OF THROMBOPOIETIN LEVELS IN PATIENTS WITH CHRONIC LIVER DISEASE T.E Tu~lular, E. Av~ar, M. Ekenel, E Uras, N. T6ztin Marmara University Gastroenterology Institute, Istanbul, Turkey. Thrombocytopenia is a well known hematologic complication of liver cirrhosis. Splenic sequestration and antibody mediated destruction of platelets are blamed in the etiology of thromboeytopenia seen in chronic liver diseases. Thrombopoietin is the key regulatory cytokine in the production and proliferation of platelets. It is mainly produced in the liver, so thromboeytopenia associated with liver cirrhosis can be related to inadequate production of thrombopoietin by the liver. Aim: The aim of our study is to compare thrombopoietin levels in thrombocytopenias with different etiologies. Materials and methods: We measured peripheral platelet counts and thrombopoietin levels in 20 patients with chronic hepatitis (CH), 17 patients with cirrhosis and 20 patients with chemotherapy induced thrombocytopenia (CIT) with normal liver functions. Serum thrombopoietin levels were measured by ELISA. Results: Mean serum thrombopoietin levels in patients with chronic hepatitis, cirrhosis and chemotherapy induced thromboeytopenia were 89~48.8, 69.7~-45.8 and 1541.8±893.0 pg/ml. Respectively. Levels of serum thrombopoietin in CH and cirrhosis were significantly lower, when compared to patients with CIT (p<0.0001). There were no differences beetween the levels of thrombopoietin in patients with CH and cirrhosis. There was no correlation between platelet count and serum thrombopoietin levels in patients with CH and cirrhosis, but we found a slight correlation in CIT patients (p<0.0658). Conclusions: Although there may be other contributing factors, it seems that reduced production of the thrombopoietin by the liver is the major pathophysiologic factor in the etiology of thrombocytopenia seen in cirrhosis.
C02/14 ] RELATION BETWEEN PORTOSYSTEMIC HYDROSTATIC AND OSMOTIC PRESSURE GRADIENTS IN PATIENTS WITH PORTAL HYPERTENSION K.G. Petersen, V. Siegerstetter, A. Ochs, M. R6ssle Dept. of Gastroenterology and Hepatology, University Hospital, Freiburg, Germany. Hydrostatic and oneotic pressures determine the exchange of small osmolytes and water fi'om the vascular bed to the interstitium and vize versa. Accordingly, a change in the hydrostatic pressure as in portal hypertension may result in splamhnic filtration and s)~temic reabsorption of osmolytes and ~ater. Assuming the existence of osmotic receptors in the portal and hepatic vascular bed the degree of portal hypertension may directly modulate the release of hormones involved in water and sodium handling. To test this hypothesis we determined the portal and venous concentrations of the choline esterase (CHE), a large molecule which can be measured with high aeeuracT, and the systemic plasma concentrations ofantidiuretic hormone (ADI-1),renine and aldosterone in patients receiving TIPS implantation. Blood sampling ~as performed in 11 patients with refractory ascites (5 Ins) or variceal bleeding (8 pts) before shunt opening, 15 minutes therea.--~r, and 30 minutes after balloon occlusion of the shunt. Results: A mean reduction of the portosystemie pressure gradient by 11 _+2 mmHg decreased the concentration of CHE by 4.8 + 0.3%. Subsequent closure of the shunt led to an increase in the CHE concentration by 7.2 + 3.4% together with a significant increase in the ADH but not renine and aldosterone concentration. The estimated filtration volume, calculated from the changes of the CHE concentration, was 10 ml/min or 1.5 L/24 hrs. Conclusion: 1. Changes in the portal osmolarity may be involved in x~naterand electrolyte regulation. 2. Our approach allows estimation of splanehnic filtration volume in patients with portal hypertension.
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INCREASED HEPATIC NITROTYROSINE LEVELS IN CIRRHOSIS M. Frost l, B. Halliwell L2, K. Moore3 1Dept. of Pharmacology, King's College, London. 2Dept. of Biochemistry, National University of Singapore, Kent Ridge Crescent, Singapore 119260. 3Centre for Hepatology, Royal Free and University College Medical School, London. Liver disease is associated with increased formation of superoxide or nitric oxide, which can react together to form peroxynitrite, a highly reactive free radical. Once formed peroxynitrite reacts rapidly with proteins causing nitration of tyrosine residues to form nitrotyrosine, or lipids to induce lipid oxidation. More recently peroxynitrite has been proposed as a signalling molecule during sheer stress in endothelial cells. Measurement of tissue nitrotyrosine levels reflects the formation of peroxynitrite or reactive nitrogen species in vivo. We have ~cently developed a gas chromatography mass spectrometric method for the determination of protein bound nitmtyrosine concentrations in tissues. Nitrotyrosine levels were measured in liver tissue obtained from patients undergoing liver transplantation. Normal liver tissue was obtained from 2 un-used donors~ and from 1 subject with primary hyperoxaluria in which the liver is structurally normal. Hepatic nitrotyrosine levels were increased in patients with alcoholic cirrhosis (8.2 ± 2.0 ng/mg, n=7), primary biliary cirrhosis (8.5 ± 2.0 ng/mg, n=5) and HCV related cirrhosis (6.3 ± 1.0 ng/mg) compared with normal controls (2.6 ± 0.6 ng/mg protein, n=3). Work is currently in progress to localise sites of nitration by immunohistochemistry, and to identify nitrated proteins by western analysis. We conclude that liver disease is associated with increased nitration of liver proteins indicative of increased formation of reactive nitrogen species,
I C02/16 I HOST FACTORS ARE MORE IMPORTANT THAN VIRAL LOAD OR HCV GENOTYPES FOR PROGRESSION TOWARDS CIRRHOSIS G.M. DeSanctis, D. Sebastiano, A. Magnapera, M.T. Napoli, A.M. lalungo, L.V. Chircu Viral Hepatitis Unit, Department of Infectous Diseases, University La Sapienza, Rome, Italy. Aim: to compare host factors (age,duration of infection,daily alcohol intake above 20 g x die,presence of cryoglobulins ,NS5 abs and alpha FP normal levels),HCV load in untreated cases, genotypes, and SR (more than 24 months after end of Tx), between cirrhotic (CIRR) versus non CIRR cases. Patients: 299 CIRR ( 75% Child A,15% Child B) and 1493 non CIRR. Methods :HCV RNA by Amplicor(Roehe), genotyping by Irmo.LIPA,Innogenetics. Results:among CIRR significative prevalence of cryoglobulins:n, 15,6% versus 10,7%,p <0,001,age above 65 yrs 58,2%versus 28,1% p<0,001,presence ofNS5 abs 73,3% versus 56,5% p< 0,001,daily alcohol intake 25,1% versus 15,8% p<0,001,and duration of infection above 20 years in 70% of CIRR versus 50%of non CIRR, whereas higher than 10x6 copies x ml viral 1oad(37,5% versus 31,3%),genotype(3a:5,6% versus 8,8%,1b 56,6% versus 51,8% and 2a2c 37,8<5 versus 39,4%),and normal alpha FP levels(72,2% versus 70,3%) were not related to more severe liver disease .SR to IFN Tx was observed in 9,9% of CIRR and 37,3% of non CIRR. Conclusions: among our cases,outcome in CIRR was related to individual or co-risk factors such as increasing age, duration of disease,daily alcohol intake,presence of NS5 abs and cryoglobulins,whereas viral load and genotypes did nor predict a more severe evolution. SR to IFN Tx was 4-fold more frequent among non CIRR.Thus individual(immune response and co-risk factors) rather than virological aspects are more important as prognostic factors.Further more, anti-viral Tx cannot be denied to Child A patients,as nearly 10% of them showed a SR.
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C02/13 ] COMPARISON OF THROMBOPOIETIN LEVELS IN PATIENTS WITH CHRONIC LIVER DISEASE T.E Tu~lular, E. Av~ar, M. Ekenel, E Uras, N. T6ztin Marmara University Gastroenterology Institute, Istanbul, Turkey. Thrombocytopenia is a well known hematologic complication of liver cirrhosis. Splenic sequestration and antibody mediated destruction of platelets are blamed in the etiology of thromboeytopenia seen in chronic liver diseases. Thrombopoietin is the key regulatory cytokine in the production and proliferation of platelets. It is mainly produced in the liver, so thromboeytopenia associated with liver cirrhosis can be related to inadequate production of thrombopoietin by the liver. Aim: The aim of our study is to compare thrombopoietin levels in thrombocytopenias with different etiologies. Materials and methods: We measured peripheral platelet counts and thrombopoietin levels in 20 patients with chronic hepatitis (CH), 17 patients with cirrhosis and 20 patients with chemotherapy induced thrombocytopenia (CIT) with normal liver functions. Serum thrombopoietin levels were measured by ELISA. Results: Mean serum thrombopoietin levels in patients with chronic hepatitis, cirrhosis and chemotherapy induced thromboeytopenia were 89~48.8, 69.7~-45.8 and 1541.8±893.0 pg/ml. Respectively. Levels of serum thrombopoietin in CH and cirrhosis were significantly lower, when compared to patients with CIT (p<0.0001). There were no differences beetween the levels of thrombopoietin in patients with CH and cirrhosis. There was no correlation between platelet count and serum thrombopoietin levels in patients with CH and cirrhosis, but we found a slight correlation in CIT patients (p<0.0658). Conclusions: Although there may be other contributing factors, it seems that reduced production of the thrombopoietin by the liver is the major pathophysiologic factor in the etiology of thrombocytopenia seen in cirrhosis.
C02/14 ] RELATION BETWEEN PORTOSYSTEMIC HYDROSTATIC AND OSMOTIC PRESSURE GRADIENTS IN PATIENTS WITH PORTAL HYPERTENSION K.G. Petersen, V. Siegerstetter, A. Ochs, M. R6ssle Dept. of Gastroenterology and Hepatology, University Hospital, Freiburg, Germany. Hydrostatic and oneotic pressures determine the exchange of small osmolytes and water fi'om the vascular bed to the interstitium and vize versa. Accordingly, a change in the hydrostatic pressure as in portal hypertension may result in splamhnic filtration and s)~temic reabsorption of osmolytes and ~ater. Assuming the existence of osmotic receptors in the portal and hepatic vascular bed the degree of portal hypertension may directly modulate the release of hormones involved in water and sodium handling. To test this hypothesis we determined the portal and venous concentrations of the choline esterase (CHE), a large molecule which can be measured with high aeeuracT, and the systemic plasma concentrations ofantidiuretic hormone (ADI-1),renine and aldosterone in patients receiving TIPS implantation. Blood sampling ~as performed in 11 patients with refractory ascites (5 Ins) or variceal bleeding (8 pts) before shunt opening, 15 minutes therea.--~r, and 30 minutes after balloon occlusion of the shunt. Results: A mean reduction of the portosystemie pressure gradient by 11 _+2 mmHg decreased the concentration of CHE by 4.8 + 0.3%. Subsequent closure of the shunt led to an increase in the CHE concentration by 7.2 + 3.4% together with a significant increase in the ADH but not renine and aldosterone concentration. The estimated filtration volume, calculated from the changes of the CHE concentration, was 10 ml/min or 1.5 L/24 hrs. Conclusion: 1. Changes in the portal osmolarity may be involved in x~naterand electrolyte regulation. 2. Our approach allows estimation of splanehnic filtration volume in patients with portal hypertension.
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INCREASED HEPATIC NITROTYROSINE LEVELS IN CIRRHOSIS M. Frost l, B. Halliwell L2, K. Moore3 1Dept. of Pharmacology, King's College, London. 2Dept. of Biochemistry, National University of Singapore, Kent Ridge Crescent, Singapore 119260. 3Centre for Hepatology, Royal Free and University College Medical School, London. Liver disease is associated with increased formation of superoxide or nitric oxide, which can react together to form peroxynitrite, a highly reactive free radical. Once formed peroxynitrite reacts rapidly with proteins causing nitration of tyrosine residues to form nitrotyrosine, or lipids to induce lipid oxidation. More recently peroxynitrite has been proposed as a signalling molecule during sheer stress in endothelial cells. Measurement of tissue nitrotyrosine levels reflects the formation of peroxynitrite or reactive nitrogen species in vivo. We have ~cently developed a gas chromatography mass spectrometric method for the determination of protein bound nitmtyrosine concentrations in tissues. Nitrotyrosine levels were measured in liver tissue obtained from patients undergoing liver transplantation. Normal liver tissue was obtained from 2 un-used donors~ and from 1 subject with primary hyperoxaluria in which the liver is structurally normal. Hepatic nitrotyrosine levels were increased in patients with alcoholic cirrhosis (8.2 ± 2.0 ng/mg, n=7), primary biliary cirrhosis (8.5 ± 2.0 ng/mg, n=5) and HCV related cirrhosis (6.3 ± 1.0 ng/mg) compared with normal controls (2.6 ± 0.6 ng/mg protein, n=3). Work is currently in progress to localise sites of nitration by immunohistochemistry, and to identify nitrated proteins by western analysis. We conclude that liver disease is associated with increased nitration of liver proteins indicative of increased formation of reactive nitrogen species,
I C02/16 I HOST FACTORS ARE MORE IMPORTANT THAN VIRAL LOAD OR HCV GENOTYPES FOR PROGRESSION TOWARDS CIRRHOSIS G.M. DeSanctis, D. Sebastiano, A. Magnapera, M.T. Napoli, A.M. lalungo, L.V. Chircu Viral Hepatitis Unit, Department of Infectous Diseases, University La Sapienza, Rome, Italy. Aim: to compare host factors (age,duration of infection,daily alcohol intake above 20 g x die,presence of cryoglobulins ,NS5 abs and alpha FP normal levels),HCV load in untreated cases, genotypes, and SR (more than 24 months after end of Tx), between cirrhotic (CIRR) versus non CIRR cases. Patients: 299 CIRR ( 75% Child A,15% Child B) and 1493 non CIRR. Methods :HCV RNA by Amplicor(Roehe), genotyping by Irmo.LIPA,Innogenetics. Results:among CIRR significative prevalence of cryoglobulins:n, 15,6% versus 10,7%,p <0,001,age above 65 yrs 58,2%versus 28,1% p<0,001,presence ofNS5 abs 73,3% versus 56,5% p< 0,001,daily alcohol intake 25,1% versus 15,8% p<0,001,and duration of infection above 20 years in 70% of CIRR versus 50%of non CIRR, whereas higher than 10x6 copies x ml viral 1oad(37,5% versus 31,3%),genotype(3a:5,6% versus 8,8%,1b 56,6% versus 51,8% and 2a2c 37,8<5 versus 39,4%),and normal alpha FP levels(72,2% versus 70,3%) were not related to more severe liver disease .SR to IFN Tx was observed in 9,9% of CIRR and 37,3% of non CIRR. Conclusions: among our cases,outcome in CIRR was related to individual or co-risk factors such as increasing age, duration of disease,daily alcohol intake,presence of NS5 abs and cryoglobulins,whereas viral load and genotypes did nor predict a more severe evolution. SR to IFN Tx was 4-fold more frequent among non CIRR.Thus individual(immune response and co-risk factors) rather than virological aspects are more important as prognostic factors.Further more, anti-viral Tx cannot be denied to Child A patients,as nearly 10% of them showed a SR.
149