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406A AASLD ABSTRACTS HEPATOLOGY October 1995 1197 CHANGES IN THE ACTIVATION STATUS OF T LYMPHOCYTE SUBPOPULATIONS ASSOCIATED WITH ACUTE CELLULAR REJECTION FOLLOWING LIVER TRANSPLANTATION. O. Crosbie; S. Norris. P. Costello. C. O'Farrellv. 1. Hegarty Liver Unit & ERC, St. Vincents Hospital, Dublin, Ireland. Acute cellular rejection (ACR) occurs in 60-80% of patients following liver transplantation (OLT) the diagnosis of which is routinely confirmed by liver biopsy. Previous studies in renal transplant patients have shown an increase in activated CDS+ ceils associated with ACR. We examined changes in lymphocyte subpopulations and their activation status to see if similar changes occur in patients following liver transplantation. Patients: Eight patients were included in the study during which time six episodes of histologically proven ACR rejection developed in five patients. Flow cytometric analysis of peripheral blood lymphocytes was performed every 3-5 days (total of 40 samples). CD3+, CD4+ and CDS+ cells were quantified and coexpression of HLA- DR used to define .their activation status. Results: (1) Consistent changes were not observed in the HLA-DR negative CD4+ and CD8+ populations or the ratio of CD4+:CD8+ cells during ACR. (2) All six episodes of ACR were associated with a significant increase in the activation status of the CD3+, CD4+ and CD8+ populations (mean % CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+ prior to and during ACR was 11:8 vs 27.45%, 6.6vs 23.6% and 19.5 vs 39.1% respectively, p<0.05). (3) Successful rreatment'of 6 episodes of rejection was accompanied by a decrease in the activation status of the three populations: mean % CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+ during ACR and fonowing treatment was 29.7 vs 22:4%, 26.9 vs 17.2% and 49.8 vs 41.4% respectively. (4) No changes in the activation status of T cell subsets were deter:ted in the two subjects who did not experience ACR. In conclusion, we have identified consistent patterns of change in T lymphocyte activation markers following liver transplantation related to significant clinical events. Serial measurements of these markers may be of use in evaluating patients following transplantation and may predict those at risk of ACR. 1198 GENETIC PREDISPOSITIONS FOR IMMUNOLOGIC FEATURES IN CHRONIC LIVER DISEASES OTHER THAN TYPE 1 AUTOIMMUNE HEPATITIS. AJ Czaia. HA Can~nter. PJ Santraeh. and SI3 Moore. Mayo Clinic, Rochester, MN. The human leukocyte antigens (HLA) DR3 and DR4 have been identified as independent risk factors for autoimmune hepatitis and they have been associated with immunologic manifestations. Other chronic liver diseases can have immune features that resemble those of : autoimmune hepatitis and it is possible that these clinical expressions of autoimmunity have a genetic basis that also relates to DR3 and DR4. AIM/METHODS: To assess the existence of an autoimmune genotype that is not disease-specific, 178 patients with chronic liver diseases other than type 1 autoimmune hepatitis were assessed prospectively for immune features and HLA DR3 and DR4. The study population included 89 patients had chronic hepatitis C, 19 with chronic hepatitis B, 20 with primary biliary cirrhosis, 13 with primary sclerosing eholangitis, 13 with non-alcoholic steatohepatitis, and 24 with other chronic liver conditions. HLA typing was performed by restriction fragment length polymorphism. Eighty normal subjects were typed in a similar fashion. RESULTS: Antinuclear (28%), smooth muscle (8%), antinuclear and/or smooth muscle (33%), and thyroid (18%) antibodies were found with similar frequency in all diagnostic categories. One or more autoantibodies were present in 92 patients (52%). Concurrent immunologic diseases (30%) were also identified in all subgroups. Patients with antinuclear antibodies (ANA) had a higher frequency of the A 1-B8-DR3 haplotype than seronegative patients (27% vs 12%, p=0.04). Similarly,patients with concurrent immunologic diseases had a greater occurrence of HLA DR4 than patients without these findings (51% vs 26%, p--0.003). Patients with ANA were more commonly DR3 positive than normal subjects (35% vs 16%, p=0.03). Indeed, DR3 occurred more frequently in patients expressing any autoantibody than in normals (30% vs 16%, p--0.04) and patients with concurrent immunologic diseases were more commonly DR4 positive than normals (51% vs 30%, p=0.02). CONCLUSIONS: Autoantibody expression and concurrent immunologic diseases are associated with HLA DR3 and DR4 outside the context of autoimmune hepatitis. These clinical manifestations of autoimmunity have a genetic basis that is not disease-specific. 1199 MEDIATOR PRODUCTION AND PHAGOCYTIC ACTIVITY OF MACROPHAGES FROM CIRRHOTIC RAT LIVERS, R Daroel, S Vogl, and H Pctermann. Institute of Pathobiochemistry, Medical Faculty of Fried- rieh-Sehiller-Unlversity, 07740 Jena, Germany. The importance of sessile hepatic macrophages for the pathogenesis of liver cirrhosis is not yet sufficiently clear. Therefore, we developed a method to iso- late and cultivate maerophages from cirrhotic livers in order to characterize them bioehemieally by comparing different functional parameters of macro- phages from controls and cirrhotic livers. - Liver cirrhosis was obtained by treatment with thioacetamide fib.A) for 6 months. Cells were prepared by me- arts of an enzymic digestion method. The production of superoxide anions by maerephages from cirrhotic livers stimulated by zymosan was significantly lo- wer when compared with the controls. Unstimulated NO production was low in both maerophage cultures and did not differ between controls and ceils from TAA-treated rats. Stimulation of NO formation by LPS was more markedly expressed in cultures from cirrhotic livers than in those from controls amoun- ting to 252+_39 nmol/10 ~ cells/72 hr in the former in comparison with 58_+9 in the controls. When stimulated by IFN-7 the amount of NO measured after 72 hr incubation did not differ between cultures of macrophages from normal and cirrhotic livers. However, the induction of the NO synthase occurred more ra- pidly in macmphage cultures from cirrhotic livers than in controls. Unstimula- ted macrephages from cirrhotic livers delivered a manifold of IL~6 in compari- son with the controls. However, IFN-7 or LPS only slightly enhanced its pro- duction in macrophages from cirrhotic livers. The incorporation of 31-1- thymidine into DNA significantlyincreased about twofold in cultivated macro- phages from TAA treated rats in comparison with controls. In contrast to the findings in isolated perfused livers the zymosan-stimulated phagocytic activity of cultivated maerophages from cirrhotic livers measured as uptake of latex partieles or colloidal carbon did not show distinct differences when compared with the controls. -The data provide evidence that it is possible to isolate and to cultivate maerophages from macronodular-cirrhotic livers with high yield and vitality. The latter are characterized by enhanced proliferation, reduced forma- tion of superoxide anions, and increased production of NO and IL-6. 1200 LACRIMAL DISFUNCTION IN PATIENTS WITH CHRONIC HCV INFECTION. JR Daruich. M Zas. JA Finder, MT Santarelli. C Demetrio.J Bar. Hospital de Clfnicas San Martfn, University of Buenos Aires. Buenos Aires, Argentina. Background: Lacrimal disfunction was reported in several hepatic diseases. Objective: To evaluate the prevalence of this condition in chronic HCV infected patients (pts) and its possible relation to interferon alpha (IFN a-2a) treatment. Material and Methods: 55 unselected pts, mean age 55.9 years ( ± 13.5), 39 females and 16 males withproved chronic HCV hepatitis (anti HCV +ve by EIA and HCV RNA +ve by n- PCR) were included in this study. 21 pts in this serie were under IFN therapy for at least three months (Group A) and the remaining 34 pt were feee of treatment (Group B). The liver biopsy showed chronic hepatitis in 10pts (48%) and cirrhosis in 11 (52%) in group A, while in group B chronic hepatitis was observed in 14 pts (41%) and cirrhosis in 20 (59%)(p = 5946). All of them were examined in the ophthalmologic clinic by visual acuity, ocular pressure, slit lamp examination, ocular fundus, visual field, fluorescein angiography, tear break up time (BUT) and rose bengal stain tests. The criteria for lacrimal disfunction were BUT __% 10 seconds and a positive rose bengal stain. Statistical analysis: It was performed by the x 2 test with Yates correction. Results: One pt in group B and none of group A showed xerophthalmia. Lacrimal disfunction was detected in 30/55 pts (54%); 13/21 (62%) of group A and 17134 (50%) in group B (p=0.5600). No relation was found between the finding of lacrimal disfunction and the severity of the histological lesion, age or gender. Four pts (12%) m group B and none of group A showed elevated ocular pressure. No significant changes were observed in visual acuity, ocular pressure, slit lamp examination, ocular fundus, visual field and fluorescein angiography in both groups. Conclusion: 1- Lacrimal disfunctlon seems to be a frequent finding in chronic HCV related liver disease in spite of the lack of ocular symptoms. 2- No relation to IFN a-2a treatment was established. 3- Age, gender or degree of histological lesion were not related to the presence of lacrimal disfunction.

Lacrimal disfunction in patients with chronic HCV infection . Hospital de Cl�nicas San Mart�n, University of Buenos Aires, Buenos Aires, Argentina

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Page 1: Lacrimal disfunction in patients with chronic HCV infection . Hospital de Cl�nicas San Mart�n, University of Buenos Aires, Buenos Aires, Argentina

4 0 6 A A A S L D A B S T R A C T S HEPATOLOGY O c t o b e r 1995

1197 CHANGES IN THE ACTIVATION STATUS OF T LYMPHOCYTE SUBPOPULATIONS ASSOCIATED WITH ACUTE CELLULAR REJECTION FOLLOWING LIVER TRANSPLANTATION. O. Crosbie; S. Norris. P. Costello. C. O'Farrellv. 1. Hegarty Liver Unit & ERC, St. Vincents Hospital, Dublin, Ireland.

Acute cellular rejection (ACR) occurs in 60-80% of patients following liver transplantation (OLT) the diagnosis of which is routinely confirmed by liver biopsy. Previous studies in renal transplant patients have shown an increase in activated CDS+ ceils associated with ACR. We examined changes in lymphocyte subpopulations and their activation s t a t u s to see if similar changes occur in patients following liver transplantation. Patients: Eight patients were included in the study during which time six episodes of histologically proven ACR rejection developed in five patients. Flow cytometric analysis of per iphera l blood lymphocytes was performed every 3-5 days (total o f 40 samples). CD3+, CD4+ and CDS+ cells were quantified and coexpression of HLA- DR used to define .their activation status. Results: (1) Consistent changes were not observed in the HLA-DR negative CD4+ and CD8+ populations or the ratio of CD4+:CD8+ cells during ACR. (2) All six episodes of ACR were associated with a significant increase in the activation status of the CD3+, CD4+ and CD8+ populations (mean % CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+ prior to and during ACR was 11:8 vs 27.45%, 6.6vs 23.6% and 19.5 vs 39.1% respectively, p<0.05). (3) Successful rreatment 'of 6 episodes of rejection was accompanied by a decrease in the activation status of the three populations: mean % CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+ during ACR and fonowing treatment was 29.7 vs 22:4%, 26.9 vs 17.2% and 49.8 vs 41.4% respectively. (4) No changes in the activation status of T cell subsets were deter:ted in the two subjects who did not experience ACR.

In conclusion, we have identified consistent patterns of change in T lymphocyte activation markers following liver transplantation related to significant clinical events. Serial measurements of these markers may be of use in evaluating patients following transplantation and may predict those at risk of ACR.

1198 GENETIC PREDISPOSITIONS FOR IMMUNOLOGIC FEATURES IN CHRONIC LIVER DISEASES OTHER THAN TYPE 1 AUTOIMMUNE HEPATITIS. AJ Czaia. HA Can~nter. PJ Santraeh. and SI3 Moore. Mayo Clinic, Rochester, MN.

The human leukocyte antigens (HLA) DR3 and DR4 have been identified as independent risk factors for autoimmune hepatitis and they have been associated with immunologic manifestations. Other chronic liver diseases can have immune features that resemble those of : autoimmune hepatitis and it is possible that these clinical expressions of autoimmunity have a genetic basis that also relates to DR3 and DR4. AIM/METHODS: To assess the existence of an autoimmune genotype that is not disease-specific, 178 patients with chronic liver diseases other than type 1 autoimmune hepatitis were assessed prospectively for immune features and HLA DR3 and DR4. The study population included 89 patients had chronic hepatitis C, 19 with chronic hepatitis B, 20 with primary biliary cirrhosis, 13 with primary sclerosing eholangitis, 13 with non-alcoholic steatohepatitis, and 24 with other chronic liver conditions. HLA typing was performed by restriction fragment length polymorphism. Eighty normal subjects were typed in a similar fashion. RESULTS: Antinuclear (28%), smooth muscle (8%), antinuclear and/or smooth muscle (33%), and thyroid (18%) antibodies were found with similar frequency in all diagnostic categories. One or more autoantibodies were present in 92 patients (52%). Concurrent immunologic diseases (30%) were also identified in all subgroups. Patients with antinuclear antibodies (ANA) had a higher frequency of the A 1-B8-DR3 haplotype than seronegative patients (27% vs 12%, p=0.04). Similarly,patients with concurrent immunologic diseases had a greater occurrence of HLA DR4 than patients without these findings (51% vs 26%, p--0.003). Patients with ANA were more commonly DR3 positive than normal subjects (35% vs 16%, p=0.03). Indeed, DR3 occurred more frequently in patients expressing any autoantibody than in normals (30% vs 16%, p--0.04) and patients with concurrent immunologic diseases were more commonly DR4 positive than normals (51% vs 30%, p=0.02). CONCLUSIONS: Autoantibody expression and concurrent immunologic diseases are associated with HLA DR3 and DR4 outside the context of autoimmune hepatitis. These clinical manifestations of autoimmunity have a genetic basis that is not disease-specific.

1199 MEDIATOR PRODUCTION AND PHAGOCYTIC ACTIVITY OF MACROPHAGES FROM CIRRHOTIC RAT LIVERS, R Daroel, S Vogl, and H Pctermann. Institute of Pathobiochemistry, Medical Faculty of Fried- rieh-Sehiller-Unlversity, 07740 Jena, Germany.

The importance of sessile hepatic macrophages for the pathogenesis of liver cirrhosis is not yet sufficiently clear. Therefore, we developed a method to iso- late and cultivate maerophages from cirrhotic livers in order to characterize them bioehemieally by comparing different functional parameters of macro- phages from controls and cirrhotic livers. - Liver cirrhosis was obtained by treatment with thioacetamide fib.A) for 6 months. Cells were prepared by me- arts of an enzymic digestion method. The production of superoxide anions by maerephages from cirrhotic livers stimulated by zymosan was significantly lo- wer when compared with the controls. Unstimulated NO production was low in both maerophage cultures and did not differ between controls and ceils from TAA-treated rats. Stimulation of NO formation by LPS was more markedly expressed in cultures from cirrhotic livers than in those from controls amoun- ting to 252+_39 nmol/10 ~ cells/72 hr in the former in comparison with 58_+9 in the controls. When stimulated by IFN-7 the amount of NO measured after 72 hr incubation did not differ between cultures of macrophages from normal and cirrhotic livers. However, the induction of the NO synthase occurred more ra- pidly in macmphage cultures from cirrhotic livers than in controls. Unstimula- ted macrephages from cirrhotic livers delivered a manifold of IL~6 in compari- son with the controls. However, IFN-7 or LPS only slightly enhanced its pro- duction in macrophages from cirrhotic livers. The incorporation of 31-1- thymidine into DNA significantly increased about twofold in cultivated macro- phages from TAA treated rats in comparison with controls. In contrast to the findings in isolated perfused livers the zymosan-stimulated phagocytic activity of cultivated maerophages from cirrhotic livers measured as uptake of latex partieles or colloidal carbon did not show distinct differences when compared with the controls. -The data provide evidence that it is possible to isolate and to cultivate maerophages from macronodular-cirrhotic livers with high yield and vitality. The latter are characterized by enhanced proliferation, reduced forma- tion of superoxide anions, and increased production of NO and IL-6.

1200 LACRIMAL DISFUNCTION IN PATIENTS WITH CHRONIC HCV INFECTION. JR Daruich. M Zas. JA Finder, MT Santarelli. C Demetrio.J Bar. Hospital de Clfnicas San Martfn, University of Buenos Aires. Buenos Aires, Argentina.

Background: Lacrimal disfunction was reported in several hepatic diseases. Objective: To evaluate the prevalence of this condition in chronic HCV infected patients (pts) and its possible relation to interferon alpha (IFN a-2a) treatment. Material and Methods: 55 unselected pts, mean age 55.9 years ( ± 13.5), 39 females and 16 males withproved chronic HCV hepatitis (anti HCV +ve by EIA and HCV RNA +ve by n- PCR) were included in this study. 21 pts in this serie were under IFN therapy for at least three months (Group A) and the remaining 34 pt were feee of treatment (Group B). The liver biopsy showed chronic hepatitis in 10pts (48%) and cirrhosis in 11 (52%) in group A, while in group B chronic hepatitis was observed in 14 pts (41%) and cirrhosis in 20 (59%)(p = 5946). All of them were examined in the ophthalmologic clinic by visual acuity, ocular pressure, slit lamp examination, ocular fundus, visual field, fluorescein angiography, tear break up time (BUT) and rose bengal stain tests. The criteria for lacrimal disfunction were BUT __% 10 seconds and a positive rose bengal stain. Statistical analysis: It was performed by the x 2 test with Yates correction. Results: One pt in group B and none of group A showed xerophthalmia. Lacrimal disfunction was detected in 30/55 pts (54%); 13/21 (62%) of group A and 17134 (50%) in group B (p=0.5600). No relation was found between the finding of lacrimal disfunction and the severity of the histological lesion, age or gender. Four pts (12%) m group B and none of group A showed elevated ocular pressure. No significant changes were observed in visual acuity, ocular pressure, slit lamp examination, ocular fundus, visual field and fluorescein angiography in both groups. Conclusion: 1- Lacrimal disfunctlon seems to be a frequent finding in chronic HCV related liver disease in spite of the lack of ocular symptoms. 2- No relation to IFN a-2a treatment was established. 3- Age, gender or degree of histological lesion were not related to the presence o f lacrimal disfunction.