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Thrombopoietin-deficiency, DIC, thrombocyte consumption, and thrombocytopenia in cirrhosis
Cirrhosis and its complications, pathophysiology
and cliniculaspects
77
1P/CO2/0291
1 P/CO2/031
THROMBOPOIETIN-DEFICIENCY, DIG, THROMBOCYTE CONSUMPTION, AND THROMBOCYTOPENIA IN CIRRHOSIS
CHOLYL LYSYLFLUORESCEIN (CLF) PLASMA CLEARANCE IN PATIENTS WITH LlVER DISEASES: A NEW DYNAMIC LIVER FUNCTION TEST?
M Peck-Radosavlievic, M Wichlas, J Zacherl, G Stiegler. P Stohlawetz, S Panzer, R Steininaer. P Ferenci. J Pidlich, A Gangl. Dept of Gastroenterology, University of Vienna, Austria. Insufficient Thrombopoietin (TPO) production by the cirrhotic liver is important for thrombocytopenia, but disseminated intravascular coagulation (DIC) and thrombocyte consumption have been discussed as etiologic factors, too. In 1 I patients with liver cirrhosis (Child B, C) and thrombocytopenia, markers of coagulation (thrombin-AT Ill complex TAT, prothrombin fragment F 1+2) and thrombocyte activation (P-thromboglobulin p-TG) were studied, as well as individual clotting factors, TPO serum levels and reticulated platelets (RP) as indicators of bone marrow (BM) production of platelets before and after orthotopic liver transplantation (OLT). Thrombocyte counts increased significantly to normal values within two weeks after OLT. A significant TPO-peak preceeded this increase together with a peak of RP. TAT and F I +2 were within the range of normal before OLT and increased significantly after OLT. Factor V (liver derived) was low before OLT and increased significantly, while factor VIII (endothelium derived) was already in the high range of normal before OLT. b-TG was within the range of normal in most patients with cirrhosis but increased significantly after OLT. Normal markers of coagulation and thrombocyte activation and high plasma levels of clotting factor VIII before OLT on one hand, together with consumption of clotting factors and thrombocytes but still rapid resolution of thrombocytopenia through increased bone marrow production of RP and thrombocytes post OLT on the other hand suggest decreased BM production rather than DIC and thrombocyte consumption as major factor in the etiology of thrombocytopenia in liver disease. Restitution of adequate TPO production by OLT rapidly restores normal platelet counts through an increase in BM production of thrombocytes, even against increased platelet consumption in the immediate postoperative phase.
P.Milkiewicz. S.Saksena, T.Cardenas. CO.Mills. E.Elias.Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. Background. In our recent study we showed that CLF plasma clearance in healthy volunteers is similar to the clearance of natural cholyl glycine (J Hepatol in press] and therefore may provide the basis for a new dynamic liver function test. The aim of this study was to analyze the CLF plasma clearance in groups with normal liver(n=5), fatty liver without cirrhosis (n=7) and cirrhosis of differing aetiologies(n=l 1) Methods: CLF in the dose of 0.02 mg/kg b.w. was injected i.v. as a bolus. Blood samples were collected before injection and every 10 min. over 90 min. Plasma fluorescence was measured by spectrometer and residual fluorescence (RF) 30 min after injection was compared in each group. Routine liver function tests (rLFT’s) and total bile acid (TBA) levels were done before each injection Results: RF 30 mm after injection was significantly htgher in cirrhotics than in pts with fatty livers or healthy controls (see table). In cirrhosics correlation-coefficient analysis did not show any significant correlation with rLFT‘s or Child-Pugh score. CLF clearance was much more sensitive than rLFT’s in distinguishing healthy subjects from pts WC Group
of patients
1.Cirrhotics 2. Fatty liver y 3. Health
STUDY OF THE CORRELATION THE DEVELOPMENT OF LIVER FIBROSIS AND HEMODYNAMIC CHANGES IN PATIENTS WITH I&INFECTION an. C. Deaott. C. Denie. D. Valla. A. Gadano. S. Yank F. P. Soani. R. M0reau.S. E lineer. D. Leb ec INSERM, See d’hepatologie and knatomo-path:logie, h6pital Beaujon, Clichy, France In patients with chronic HCV infection, the correlation between portal hypertension, the hyperdynamic syndrome and biological measurements and the development of fibrosis has not been demonstrated. Eighty-nine consecutive patients with chronic HCV infection, referred for transjugular liver biopsy, were included in the study. Plasma, bilirubin, ALAT, prothrombin and albumin levels were measured. Liver biopsies were graded according to the Knodell score of fibrosis (stage: 0 to 4). The hepatic venous pressure gradient (mmHg) and systemic hemodynamics were determined. Plasma aldosterone, renin and TNFa levels were measured. Results (meamtSD) are shown in the following table. stage 3 stage 0 stage 1 stage 4 Fibrosis stage (n=45) (;n=&j 4@=;;) (J-l? 54*11* Age (yr) 80f25 8M13* 68fl3” Prothrombin (%) 83f24 4.2f2.8 7.2f3.7+ 14*3.9+ Hepatic pressure 3.1f1.2 3M.6 3.5fo.8 3.2i0.8 3.5fl Cardiac index 1158f287 1252f379 1301f490 1124f414 RVS Significantly different from: *stage 1. “stage 0,1,3. +stage 1,2. The stage of fibrosis was not correlated with plasma aldosterone, renin or TNFn levels. In conclusion, in patients with chronic HCV infection, the stage of fibrosis is onlv associated with age and the henatic ven’ous pressure gradient. In this series of patients,- the hynerkinetic syndrome occurred in 22% of patients with cirrhosis. _
Residual fluorescence 30 min after inj.(y/o),,,_ 74ti 49ti
P (lvs.2)= 0.0004; P (1vs.3)=0.0000007; P (2vs.3)=0.003. The difference in rLFT’s between group 2 and 3 were not statistically significant. Conclusions: (i) CLF clearance seems to be more sensitive than rLFT’s in detecting mild abnormalities of liver function.(ii) in pts with liver cirrhosis it does not correlate with Child-Pugh score or rLF’T’s and therefore may have a role as an independent indicator of prognosis (iii) test is safe, simple to perform and analyze and has potential to become a widely used dynamic liver function test.
1 P/CO2/032 PROSPECTIVE BETWEEN
1
1
A RANDOMlZED TRIAL COMPARING ENDOSCOPIC WITH NADOLOL PLUS ISOSORBIDE-5-MONONITRATE
LIGATION
FOR THE PREVENTION OF VARICEAL REBLEEDING. PRELIMINARY RESULTS. A.Gallego, CVillanueva, J.Ortiz, J.Mifiana, GSoriano. E.Ricart, X.Torras, S.Sainz, L.Kolle, C.Guarner, J.Balanz6. Bleeding Unit. Gastroenterology Department. Hospital Sant Pau. Barcelona. Spain. It have been shown that both endoscopic ligation (EL) and combined drug therapy with 8-blockers and isosorbide-5mononitrate (Is-5-Mn) are superior to sclerotherapy for the prevention of variceal rebleeding. The aim of the present study is to assess the efficacy of EL as compared with DT with nadolol plus Is-B-Mn (DT) in this setting. METHODS: Cirrhotic patients admitted because of esophageal variceal bleeding were randomized into two treatment groups: one was treated with EL (repeating sessions regularly until the varices were obliterated) and the other group received combined therapy with nadolol plus Is-5-mn. The present interim analysis was performed after the inclusion of the first 50 patients (27 into EL group and 23 into DT group). RESULTS: The groups were well matched for baseline data. The mean follow-up was similar (13+6 months). Slightly more ELtreated patients had variceal rebleeding during the study (40% vs 18%; 95% Cl= -1% to 47%) with a lower actuarial probability of remaining free of rebleeding (60% vs 83% at 1 year, P= 0.07). Therapeutic failure was also slightly more frequent in EL group with a l-year actuarial probability of 23%~~ 7% (P= 0.08). The number of rebleeding episodes per patient during the follow-up and rebleeding index were also improved by DT, although the difference was not significant. Complications rate was 22% in EL group vs 9% in DT group (P NS). Five vs 6 patients died respectively. CONCLUSIONS: As compared with endoscopic ligation, there is a trend towards a greater efficacy and lower complications rate favouring the combined drug therapy with nadolol and Is-5-Mn, that may be verified by the final results of this ongoing study.
and cliniculaspects
77
1P/CO2/0291
1 P/CO2/031
THROMBOPOIETIN-DEFICIENCY, DIG, THROMBOCYTE CONSUMPTION, AND THROMBOCYTOPENIA IN CIRRHOSIS
CHOLYL LYSYLFLUORESCEIN (CLF) PLASMA CLEARANCE IN PATIENTS WITH LlVER DISEASES: A NEW DYNAMIC LIVER FUNCTION TEST?
M Peck-Radosavlievic, M Wichlas, J Zacherl, G Stiegler. P Stohlawetz, S Panzer, R Steininaer. P Ferenci. J Pidlich, A Gangl. Dept of Gastroenterology, University of Vienna, Austria. Insufficient Thrombopoietin (TPO) production by the cirrhotic liver is important for thrombocytopenia, but disseminated intravascular coagulation (DIC) and thrombocyte consumption have been discussed as etiologic factors, too. In 1 I patients with liver cirrhosis (Child B, C) and thrombocytopenia, markers of coagulation (thrombin-AT Ill complex TAT, prothrombin fragment F 1+2) and thrombocyte activation (P-thromboglobulin p-TG) were studied, as well as individual clotting factors, TPO serum levels and reticulated platelets (RP) as indicators of bone marrow (BM) production of platelets before and after orthotopic liver transplantation (OLT). Thrombocyte counts increased significantly to normal values within two weeks after OLT. A significant TPO-peak preceeded this increase together with a peak of RP. TAT and F I +2 were within the range of normal before OLT and increased significantly after OLT. Factor V (liver derived) was low before OLT and increased significantly, while factor VIII (endothelium derived) was already in the high range of normal before OLT. b-TG was within the range of normal in most patients with cirrhosis but increased significantly after OLT. Normal markers of coagulation and thrombocyte activation and high plasma levels of clotting factor VIII before OLT on one hand, together with consumption of clotting factors and thrombocytes but still rapid resolution of thrombocytopenia through increased bone marrow production of RP and thrombocytes post OLT on the other hand suggest decreased BM production rather than DIC and thrombocyte consumption as major factor in the etiology of thrombocytopenia in liver disease. Restitution of adequate TPO production by OLT rapidly restores normal platelet counts through an increase in BM production of thrombocytes, even against increased platelet consumption in the immediate postoperative phase.
P.Milkiewicz. S.Saksena, T.Cardenas. CO.Mills. E.Elias.Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. Background. In our recent study we showed that CLF plasma clearance in healthy volunteers is similar to the clearance of natural cholyl glycine (J Hepatol in press] and therefore may provide the basis for a new dynamic liver function test. The aim of this study was to analyze the CLF plasma clearance in groups with normal liver(n=5), fatty liver without cirrhosis (n=7) and cirrhosis of differing aetiologies(n=l 1) Methods: CLF in the dose of 0.02 mg/kg b.w. was injected i.v. as a bolus. Blood samples were collected before injection and every 10 min. over 90 min. Plasma fluorescence was measured by spectrometer and residual fluorescence (RF) 30 min after injection was compared in each group. Routine liver function tests (rLFT’s) and total bile acid (TBA) levels were done before each injection Results: RF 30 mm after injection was significantly htgher in cirrhotics than in pts with fatty livers or healthy controls (see table). In cirrhosics correlation-coefficient analysis did not show any significant correlation with rLFT‘s or Child-Pugh score. CLF clearance was much more sensitive than rLFT’s in distinguishing healthy subjects from pts WC Group
of patients
1.Cirrhotics 2. Fatty liver y 3. Health
STUDY OF THE CORRELATION THE DEVELOPMENT OF LIVER FIBROSIS AND HEMODYNAMIC CHANGES IN PATIENTS WITH I&INFECTION an. C. Deaott. C. Denie. D. Valla. A. Gadano. S. Yank F. P. Soani. R. M0reau.S. E lineer. D. Leb ec INSERM, See d’hepatologie and knatomo-path:logie, h6pital Beaujon, Clichy, France In patients with chronic HCV infection, the correlation between portal hypertension, the hyperdynamic syndrome and biological measurements and the development of fibrosis has not been demonstrated. Eighty-nine consecutive patients with chronic HCV infection, referred for transjugular liver biopsy, were included in the study. Plasma, bilirubin, ALAT, prothrombin and albumin levels were measured. Liver biopsies were graded according to the Knodell score of fibrosis (stage: 0 to 4). The hepatic venous pressure gradient (mmHg) and systemic hemodynamics were determined. Plasma aldosterone, renin and TNFa levels were measured. Results (meamtSD) are shown in the following table. stage 3 stage 0 stage 1 stage 4 Fibrosis stage (n=45) (;n=&j 4@=;;) (J-l? 54*11* Age (yr) 80f25 8M13* 68fl3” Prothrombin (%) 83f24 4.2f2.8 7.2f3.7+ 14*3.9+ Hepatic pressure 3.1f1.2 3M.6 3.5fo.8 3.2i0.8 3.5fl Cardiac index 1158f287 1252f379 1301f490 1124f414 RVS Significantly different from: *stage 1. “stage 0,1,3. +stage 1,2. The stage of fibrosis was not correlated with plasma aldosterone, renin or TNFn levels. In conclusion, in patients with chronic HCV infection, the stage of fibrosis is onlv associated with age and the henatic ven’ous pressure gradient. In this series of patients,- the hynerkinetic syndrome occurred in 22% of patients with cirrhosis. _
Residual fluorescence 30 min after inj.(y/o),,,_ 74ti 49ti
P (lvs.2)= 0.0004; P (1vs.3)=0.0000007; P (2vs.3)=0.003. The difference in rLFT’s between group 2 and 3 were not statistically significant. Conclusions: (i) CLF clearance seems to be more sensitive than rLFT’s in detecting mild abnormalities of liver function.(ii) in pts with liver cirrhosis it does not correlate with Child-Pugh score or rLF’T’s and therefore may have a role as an independent indicator of prognosis (iii) test is safe, simple to perform and analyze and has potential to become a widely used dynamic liver function test.
1 P/CO2/032 PROSPECTIVE BETWEEN
1
1
A RANDOMlZED TRIAL COMPARING ENDOSCOPIC WITH NADOLOL PLUS ISOSORBIDE-5-MONONITRATE
LIGATION
FOR THE PREVENTION OF VARICEAL REBLEEDING. PRELIMINARY RESULTS. A.Gallego, CVillanueva, J.Ortiz, J.Mifiana, GSoriano. E.Ricart, X.Torras, S.Sainz, L.Kolle, C.Guarner, J.Balanz6. Bleeding Unit. Gastroenterology Department. Hospital Sant Pau. Barcelona. Spain. It have been shown that both endoscopic ligation (EL) and combined drug therapy with 8-blockers and isosorbide-5mononitrate (Is-5-Mn) are superior to sclerotherapy for the prevention of variceal rebleeding. The aim of the present study is to assess the efficacy of EL as compared with DT with nadolol plus Is-B-Mn (DT) in this setting. METHODS: Cirrhotic patients admitted because of esophageal variceal bleeding were randomized into two treatment groups: one was treated with EL (repeating sessions regularly until the varices were obliterated) and the other group received combined therapy with nadolol plus Is-5-mn. The present interim analysis was performed after the inclusion of the first 50 patients (27 into EL group and 23 into DT group). RESULTS: The groups were well matched for baseline data. The mean follow-up was similar (13+6 months). Slightly more ELtreated patients had variceal rebleeding during the study (40% vs 18%; 95% Cl= -1% to 47%) with a lower actuarial probability of remaining free of rebleeding (60% vs 83% at 1 year, P= 0.07). Therapeutic failure was also slightly more frequent in EL group with a l-year actuarial probability of 23%~~ 7% (P= 0.08). The number of rebleeding episodes per patient during the follow-up and rebleeding index were also improved by DT, although the difference was not significant. Complications rate was 22% in EL group vs 9% in DT group (P NS). Five vs 6 patients died respectively. CONCLUSIONS: As compared with endoscopic ligation, there is a trend towards a greater efficacy and lower complications rate favouring the combined drug therapy with nadolol and Is-5-Mn, that may be verified by the final results of this ongoing study.