- Email: [email protected]
Natural history of compensated cirrhosis
Category 2: Cirrhosis and its complications, pathophysiology and clinical aspects
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randomly to either standard of care medical therapy (SOC 12 pts.) or additionally albumin dialysis (MARS 12 pts.). Method: After incubating patients serum samples with a binding site II (diazepam binding site) specific fluorescence marker (Dansylsarcosine, DS) the amount of unbound DS was determined by fluorescence detection after ultrafiltration. In parallel, the same procedure was done with a standard albumin for reference. Results: Whereas ABiC was reduced at baseline in all patients (SOC 42% 4- 13%; MARS 53% 4- 27%). After one week ABiC was improved significantly in the MARS group (73 4- 16%) compared to SOC (43 4- 13%; p < 0.001). In addition, during each single MARS treatment an improvement of the ABiC was observed (pre: 68 4- 20%, post 78 4- 18%; p < 0.001). Conclusions: Impaired albumin function in severe liver failure can be improved significantly by elimination of albumin bound substances compared to conventional therapy.
Results: 54.9% of the patients were males, 47.06% were <64 years old. 56 had alcoholic cirrhosis, 17 had alcoholic cirrhosis with a viral infection, 45 had HBV cirrhosis, 145 had HCV cirrhosis and 43 had cryptogenic cirrhosis. 150 patients (49.02%) became decompensated within the study period. Median time to decompensation was 58 months (95% C151 and 65 months). Patients with HCV cirrhosis had longer times to decompensation than the other groups (81 months). 65% of all patients remain compensated 3 years after diagnosis, reduced to 34% after 7 years. 70 patients (22.88%) died within the study period. The median survival time was 126 months (95% CI 103 to 149 months). The prognostic factors available at diagnosis that were found to have a significant effect on decompensation and survival time were sex (p = 0.0024 and p = 0.0007) and etiology of cirrhosis (p < 0.0001 and p = 0.0024). Conclusions: Females with HCV cirrhosis have the longest time until decompensation and the longest survival times.
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THE ROLE OF THE IL6/gp130 SYSTEM FOR LIVER DISEASE PROGRESSION
Konrad L. Streetz 1, Torsten Wuestefeld I , L. Leifeld 3, F. Tacke 1, A. Graw 1, K. Kamino 2, G. Schuetz 4, W. Mueller 5, M.P. Manns I , C. Trautwein I. 1Departmentof Gastroenterology, Medical School of
Hannover; 2Departmentof Pathology, Medical School of Hannover; 3Department of Gastroenterology, University of Bonn; 4DKFZ, Heidelberg; 5Departmentof Experimental Immunology, GBF Braunschweig, Germany In this study we investigated the impact of IL6 and gpl30-dependent pathways for liver disease progression in patients and in animal models of acute and chronic liver injury. Liver immunhistochemistry showed a 10 fold (acute liver failure) and 4 fold (chronic liver disease; CLD) increase in IL6 expression compared to controls. IL6 positive signals were allocated to infiltrating lymphocytes and Kupffer cells. Additionally, in CLD patients 1L6 serum levels correlated with the Child-Pugh-stage and other serum parameters. In order to proof the relevance of our clinical findings for liver physiology we generated hepatocyte-specific knockout animals where the common signal transducer for all IL6 family members - gpl30 - was deleted using the Cre/loxP system. Hepatocyte-specific (using an albumin specific cre-recombinase; Alb-cre) gpl30 loxP knockout mice displayed hypersensitivity against LPS resulting in enhanced apoptosis. Thereby STAT3 activation and induction of the acute-phase-genes was totally suppressed. Inflammatory cytokines (IL6, TNFa) were substantially more elevated in hepatocyte specific gpl30-deleted animals. Additionally we showed that conditional gpl301oxP knockout mice using the ubiquitous expressed mx-Cre promoter - in contrast to Alb-Cre mice - displayed enhanced fibrosis progression after chronic CCL4 induced injury. This suggests during fibrosis progression a protective role of gpl30 in nonparenchymal and not parenchymal liver cells. In summary, we demonstrate that activation of the IL6/gpl30 system is involved in disease progression during acute and chronic liver injury by parenchymal and non-parenchymal liver cells. Therefore it has to be evaluated if stimulation of this system can be a potential therapeutic option.
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NATURAL HISTORY OF COMPENSATED CIRRHOSIS
J. Moschandrea, M. Koulentaki, E. Oekonomaki, C.H. Leontidis, D. Samonakis, E Skordilis, E. Kouroumalis. Gastroenterology
Department, University of Crete, Greece Aim: To define the natural history of compensated cirrhosis and analyze age, sex and cirrhosis etiology at diagnosis to identify prognostic factors available at diagnosis which might influence the time or decompensation or survival. Patients-Methods: We retrospectively analyzed data of 306 compensated cirrhotic patients from diagnosis to decompensation and, death, using the log rank test and univariate Cox PH models.
URSODEOXYCOLIC ACID (UDCA) INCREASES SURVIVAL OF PRIMARY BILIARY CIRRHOSIS (PBC) AND AUTOIMMUNE CHOLANGITIS (AIC) PATIENTS
M. Koulentaki, J. Moschandrea, P.H. Dimoulios, K. Hatzikostas, E Skordilis, E. Kouroumalis. Gastroenterology Department, University of
Crete, Greece Aim" We conducted the present study to assess the effect of UDCA treatment on survival of PBC and AIC patients. Patients a n d Methods: We analyzed the data of 85 patients with PBC and 19 patients with AIC, diagnosed between 1989 and 2000 and followed up until March 2001. All patients were on treatment with UDCA 15 mg/kg/day. As non treatment control groups we used without treatment with a predicted survival from the statistical updated Mayo model The untreated group calculated survival was compared with the actual survival of the patients within the study period. Results: Median follow-up was 64 months (range 12-141 months). 57.6% of patients were Ludwig stage I-I, 42.4% III-V. 20 patients died within the study period (39 deaths were expected p < 0.001). At 1 year after diagnosis the observed percentage of survivors was 95% for both PBC and AIC patients similar to the one predicted (95% and 94% respectively), whereas at 7 years the observed survival rate was 83% for the PBC and 80% for the AIC patients compared to the expected 63% for the PBC and 58% for the AIC patients. Conclusions: For both groups and for every year after the first the survival chances without treatment were found lower than the actual ones. UDCA treatment therefore has a beneficial effect on long-term survival
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SERUM HYALURONIC ACID AS A MARKER OF HEPATIC FIBROSIS IN PATIENTS WITH CHRONIC LIVER DISEASES
Viera Kupcova ] , Martina Valkova I , Ladislav Turecky 2, Maria Szantova ] .
13.rd Dept. of Medicine, Derer Hospital, Limbova 5, Bratislava; 2Dept. of Biochemistry, Medical School of Comenius University, Bratislava, SR, Slovakia Hepatic fibrosis is a reversible accumulation of extracellular matrix in response to chronic injury. There is a major need for noninvasive reliable serum markers of liver fibrosis to monitor both static and dynamic aspects of liver fibrosis. Elevated serum levels of glykosaminoglykan - hyaluronic acid (HA) in chronic liver diseases (LD) reflect both increased synthesis by stellate cells and reduced clearance - as a result of endothelial cell dysfunction associated with advanced disease. Aim of the study was to evaluate the relationship between serum HA and hepatic fibrosis in liver biopsy samples in patients with chronic LD and to determine whether HA is a reliable predictor of liver cirrhosis and significant fibrosis. We have examined serum HA concentration (Hyaluronic acid 'Chugai', sandwich HA binding protein assay), in 34 patients with histologically verified chronic LD and 8 healthy blood donors. Serum HA levels increased with the progress of LD.
57
randomly to either standard of care medical therapy (SOC 12 pts.) or additionally albumin dialysis (MARS 12 pts.). Method: After incubating patients serum samples with a binding site II (diazepam binding site) specific fluorescence marker (Dansylsarcosine, DS) the amount of unbound DS was determined by fluorescence detection after ultrafiltration. In parallel, the same procedure was done with a standard albumin for reference. Results: Whereas ABiC was reduced at baseline in all patients (SOC 42% 4- 13%; MARS 53% 4- 27%). After one week ABiC was improved significantly in the MARS group (73 4- 16%) compared to SOC (43 4- 13%; p < 0.001). In addition, during each single MARS treatment an improvement of the ABiC was observed (pre: 68 4- 20%, post 78 4- 18%; p < 0.001). Conclusions: Impaired albumin function in severe liver failure can be improved significantly by elimination of albumin bound substances compared to conventional therapy.
Results: 54.9% of the patients were males, 47.06% were <64 years old. 56 had alcoholic cirrhosis, 17 had alcoholic cirrhosis with a viral infection, 45 had HBV cirrhosis, 145 had HCV cirrhosis and 43 had cryptogenic cirrhosis. 150 patients (49.02%) became decompensated within the study period. Median time to decompensation was 58 months (95% C151 and 65 months). Patients with HCV cirrhosis had longer times to decompensation than the other groups (81 months). 65% of all patients remain compensated 3 years after diagnosis, reduced to 34% after 7 years. 70 patients (22.88%) died within the study period. The median survival time was 126 months (95% CI 103 to 149 months). The prognostic factors available at diagnosis that were found to have a significant effect on decompensation and survival time were sex (p = 0.0024 and p = 0.0007) and etiology of cirrhosis (p < 0.0001 and p = 0.0024). Conclusions: Females with HCV cirrhosis have the longest time until decompensation and the longest survival times.
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THE ROLE OF THE IL6/gp130 SYSTEM FOR LIVER DISEASE PROGRESSION
Konrad L. Streetz 1, Torsten Wuestefeld I , L. Leifeld 3, F. Tacke 1, A. Graw 1, K. Kamino 2, G. Schuetz 4, W. Mueller 5, M.P. Manns I , C. Trautwein I. 1Departmentof Gastroenterology, Medical School of
Hannover; 2Departmentof Pathology, Medical School of Hannover; 3Department of Gastroenterology, University of Bonn; 4DKFZ, Heidelberg; 5Departmentof Experimental Immunology, GBF Braunschweig, Germany In this study we investigated the impact of IL6 and gpl30-dependent pathways for liver disease progression in patients and in animal models of acute and chronic liver injury. Liver immunhistochemistry showed a 10 fold (acute liver failure) and 4 fold (chronic liver disease; CLD) increase in IL6 expression compared to controls. IL6 positive signals were allocated to infiltrating lymphocytes and Kupffer cells. Additionally, in CLD patients 1L6 serum levels correlated with the Child-Pugh-stage and other serum parameters. In order to proof the relevance of our clinical findings for liver physiology we generated hepatocyte-specific knockout animals where the common signal transducer for all IL6 family members - gpl30 - was deleted using the Cre/loxP system. Hepatocyte-specific (using an albumin specific cre-recombinase; Alb-cre) gpl30 loxP knockout mice displayed hypersensitivity against LPS resulting in enhanced apoptosis. Thereby STAT3 activation and induction of the acute-phase-genes was totally suppressed. Inflammatory cytokines (IL6, TNFa) were substantially more elevated in hepatocyte specific gpl30-deleted animals. Additionally we showed that conditional gpl301oxP knockout mice using the ubiquitous expressed mx-Cre promoter - in contrast to Alb-Cre mice - displayed enhanced fibrosis progression after chronic CCL4 induced injury. This suggests during fibrosis progression a protective role of gpl30 in nonparenchymal and not parenchymal liver cells. In summary, we demonstrate that activation of the IL6/gpl30 system is involved in disease progression during acute and chronic liver injury by parenchymal and non-parenchymal liver cells. Therefore it has to be evaluated if stimulation of this system can be a potential therapeutic option.
•
]
NATURAL HISTORY OF COMPENSATED CIRRHOSIS
J. Moschandrea, M. Koulentaki, E. Oekonomaki, C.H. Leontidis, D. Samonakis, E Skordilis, E. Kouroumalis. Gastroenterology
Department, University of Crete, Greece Aim: To define the natural history of compensated cirrhosis and analyze age, sex and cirrhosis etiology at diagnosis to identify prognostic factors available at diagnosis which might influence the time or decompensation or survival. Patients-Methods: We retrospectively analyzed data of 306 compensated cirrhotic patients from diagnosis to decompensation and, death, using the log rank test and univariate Cox PH models.
URSODEOXYCOLIC ACID (UDCA) INCREASES SURVIVAL OF PRIMARY BILIARY CIRRHOSIS (PBC) AND AUTOIMMUNE CHOLANGITIS (AIC) PATIENTS
M. Koulentaki, J. Moschandrea, P.H. Dimoulios, K. Hatzikostas, E Skordilis, E. Kouroumalis. Gastroenterology Department, University of
Crete, Greece Aim" We conducted the present study to assess the effect of UDCA treatment on survival of PBC and AIC patients. Patients a n d Methods: We analyzed the data of 85 patients with PBC and 19 patients with AIC, diagnosed between 1989 and 2000 and followed up until March 2001. All patients were on treatment with UDCA 15 mg/kg/day. As non treatment control groups we used without treatment with a predicted survival from the statistical updated Mayo model The untreated group calculated survival was compared with the actual survival of the patients within the study period. Results: Median follow-up was 64 months (range 12-141 months). 57.6% of patients were Ludwig stage I-I, 42.4% III-V. 20 patients died within the study period (39 deaths were expected p < 0.001). At 1 year after diagnosis the observed percentage of survivors was 95% for both PBC and AIC patients similar to the one predicted (95% and 94% respectively), whereas at 7 years the observed survival rate was 83% for the PBC and 80% for the AIC patients compared to the expected 63% for the PBC and 58% for the AIC patients. Conclusions: For both groups and for every year after the first the survival chances without treatment were found lower than the actual ones. UDCA treatment therefore has a beneficial effect on long-term survival
•]
SERUM HYALURONIC ACID AS A MARKER OF HEPATIC FIBROSIS IN PATIENTS WITH CHRONIC LIVER DISEASES
Viera Kupcova ] , Martina Valkova I , Ladislav Turecky 2, Maria Szantova ] .
13.rd Dept. of Medicine, Derer Hospital, Limbova 5, Bratislava; 2Dept. of Biochemistry, Medical School of Comenius University, Bratislava, SR, Slovakia Hepatic fibrosis is a reversible accumulation of extracellular matrix in response to chronic injury. There is a major need for noninvasive reliable serum markers of liver fibrosis to monitor both static and dynamic aspects of liver fibrosis. Elevated serum levels of glykosaminoglykan - hyaluronic acid (HA) in chronic liver diseases (LD) reflect both increased synthesis by stellate cells and reduced clearance - as a result of endothelial cell dysfunction associated with advanced disease. Aim of the study was to evaluate the relationship between serum HA and hepatic fibrosis in liver biopsy samples in patients with chronic LD and to determine whether HA is a reliable predictor of liver cirrhosis and significant fibrosis. We have examined serum HA concentration (Hyaluronic acid 'Chugai', sandwich HA binding protein assay), in 34 patients with histologically verified chronic LD and 8 healthy blood donors. Serum HA levels increased with the progress of LD.