- Email: [email protected]
Clinical and angiographic characteristics of Budd-Chiari syndrome associated with primary antiphospholipid antibody syndrome
438A
AASLD ABSTRACTS
1325
CLINICAL A N D ANGIOGRAPHIC C H A R A ~ C $ OF BUDD-CHIARI SYNDROM][~ r ASSOCIATED WITH PRIMARY ANTIPHOSPHOLIPID ANTIBODY SYNDROME K K/m, Y-H Chung, DW Seo, B Yoo, IH Song, MS Koh, YS Lee, DI Suh. Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea Many patients with Budd-Chiari syndrome (BCS) have no evident etiological factor especially in Asian countries. And various obstructive patterns of inferior vena eava (IVC) and hepatic veins have been reported suggesting several different causes may be involved. Receudy primary antiphospholipid antibody syndrome (APAS) has been d e s c r i b e d as a characteristic clinical entity with multiple thromboembolitic episodes and typical laboratory features such as serum antiphospholipid antibody, not being associated with any collagen disease. To evaluate the etiological role of prim,~ APAS in BCS and clarify the clinical features of BCS patients with primary APAS, we analized clinical and angiographic data of 27 consecutive patients with BCS (Age :47+12 years, M:F=14:13). Underlying etiological factors were identified only in 6 (22%) ; 4 (17%) were associated with primary APAS. Most of patients with BCS showed superficial venous collaterals, ascites, symmetrical lower leg edema and hepatosplenomegaly with laboratory features of liver cirrhosis, regardless the association of primary APAS. However, only out of 4 with primary APAS, 2 had asymmetrical lower leg edema with ulcer ; 2 complained of unexplained long-standing dry cough, 1 of intermittent fever. In both with lower leg ulcer, thrombotic obstructions of deep veins were identified. Another one with primary APAS was proved to have pulmonary hypertension without definite vascular obstruction. All of 4 patients (100%) with APAS in contrast to only 8 out of 23 (35%) without it showed broad obstruction of IVC and all three hepatic veins (Suginra type II ; p<0.05). These data suggested that primary APAS is one of common etiological factors in patients with BCS, and that especially in BCS patients who present asymmetrical lower leg edema with ulcer, long-standing dry cough, unexplained fever, pulmonary hypertension of unknown cause or broad obslruction of IVC, the possibility of association with APAS should be considered.
1327 I M M U N O H I S T O C H E M I C A L STUDY OF FAS IN THE LIVER OF PRIMARY BILIARY CIRRHOSIS. F Kishi, G Yamada, H Tsu[geno, M Takatani, H Endo, K Manabe, M Takahashi, M Mizuno and T Tsuii. First Dept. of Internal Medicine, Okayama University Medical School, Okayama, Japan. Previously, we reported that in primary biliary cirrhosis (PBC) cytotoxic T cells (CD8+, CDllb-) frequently infiltrate into the intraepitheliaI space of the bile ducts (Hepatology 1986;6:385-391). In this study, we have examined the expression of Fas, which mediates apoptosis, in PBCusing immunohistochemistry. Patients and methods Liver biopsy specimens were obtained from 8 patients with PBC (Scheuer's criteria ; gradeI:4, gradelI:3, gradelII:l), and from 24 patients with chronic hepatitis B or C (CH-B:13, CH-C: 11 ). Indirect peroxidase-labeled antibody method was performed using mouse monoclonal antibodies to Fas, HLA-ABCAg, HLA-DR Ag, CD4 and CD8 at light and electron microscopic levels. Results In all PBC, F.~s was expressed stronger on the surface of the epithelial cells of interlobular bile ducts than those in chronic hepatitis B or C. On the other hand, the expression of Fas on hepatocytes was rather weaker in PBC than in chronic hepatitis B or C. In the immtmoelectron microscopic observation, electrondense reaction products of Fas were present on the basolateral membrane as well as in the endoplasmic reticulum of the bile duct epithelial cells. In these bile ducts, infiltration of CD8+ and/or CD4+ lymphocytes, increased expression of HLA-ABC Ag and neo-expression of HLA-DR Ag on the epithelial cells were often observed. Conclusion These findings suggest apoptosis mediated by CDS+/CD4+ lymphocytes may play some role in the pathogenesis of bile duct injury in PBC.
1326
HEPATOLOGY October 1995
ANTIBODIES AGAINST ADHESION MOLECULES SUPPRESS PRIMARY BILIARY CIRRHOSIS (PBC) LIKE LESIONS INDUCED BY GRAFT-VERSUS-HOST REACTION (GVHR) ACROSS MHC CLASS II DIFFERENCE. T Kimura, Y Matsuzaki, S Inada, S Ito, J Shoda, M Abel, N Tanaka, and M Fujiwara* Institute of Clinical Medicine, University of Tsukuba, TsukubaCity, Ibarakiand *Animal Center for Biomedical Research, Faculty of Medicine, Universityof Tokyo, Tokyo, Japan Increasedexpression of many kinds of adhesion molecules was detected immunohistochemicallyin the liver tissue of patients with PBC. Therefore, it was speculated that these molecules play important roles on the pathogenesisof PBC. AIM: Thisstudy was aimed to assess whether monoclonal antibodies (mAbs) against adhesion molecules could suppress PBC-like lesions employingour PBC animal model. METHODS: To induce GVHR with MHC class II disparity, 1-2x107 of C57BL/6 (B6) spleen T cells were injected twice intravenously into F1 mice which were obtained by mating B6. C=H-2 ~,~12 mutant mice with B6 mice. Histological findings of the liver in these mice resemble PBC (Am. J. Pathol. 1988; 135: 301). Each 50/~g of KBA, anti-mouse c¢ chain of LFA-I mAb, YNI/1.7, anti-mouse ICAM-I mAb and isotype-match control rat antibody (M18/2) were administered intraperit0neally per mouse prior to cell transfer. All mice were killed at 2 weeks after the first cell transfer and histological examination of the liver was performed. RESULTS: The induction of GVHR was not altered in these groupsby mAbs. grade of cellular percentageof infiltration of portal NSDC-Iike n mAb area lesion (%)
Group 1 Group 2 Group3 Group4 Group 5
10 11 KBA+YN1/1.7 5 YNI/I.7 5 KBA 4 M18/2
2.3±0.48 0.5±0.5§ 1.8±0.45 0.6±0.55 § 2.3±0.5
70.8±11.2 29.1±9.3 § 77.2+11.5 32.2±11.7 § 76.0+17.5
Results representmean+SDof each experimental group. § P<0.05 vs. Group 1 CONCLUSION: These results demonstrate LFA-1 may be crucial for the formation of PBC-like lesionsand also suggest a possibilityof therapy for PBC using mAbs againstadhesion molecules.
1328
EXPRESSION OF HEPARIN-BINDING EGF-LIKE G R O W T H FACTOR IN CIRRHOTIC RAT LIVER S Kisol. S Kawata 1. S Tamura 1. J Mivac,awa1. N Ito 1, H Tsushima 1. A Yamada1. O Oshikawa 1. S Tat~qa1-1. S t-Iiga~hiyama2, N Tanimachi2° Y Matsuzawa1 1Second Dept. of Int. Med., 2Dept. of Biochem., Osaka University Medical School, Osaka 565, Japan
It is well known that hepatocellular carcinoma (HCC) and cirrhosis coexist in the same liver. It is reported that the hepatocytes in cirrhotic liver proliferate more rapidly than those in the normal liver. We reported that heparin-bindlng EGF-like growth factor (HB-EGF), a new hepatotrophic factor, expressed in non-parenchymal liver cells but not in hepatocytes in regenerating rat liver after partial hepatectomy. However, in human HCC tissues, HCC cells express HB-EGF gene. In this study, we investigated the expression of HBEGF in the cirrhotic rat. MATERIALS AND METHODS (1) Cirrhosis was induced in male Sprague-Dawley rats by means of oral administration of 0.05% thioacetamide in drinking water for 4 mo. (2) Hepatocytes were isolated by in situ perfusion with collagenase. (3) Gene expression and protein production of HB-EGF were investigated by Northern hybridization and immunohistochemical methods, respectively. (4) Expression of glutathione S-transferase P (GST-P) gene, which is closely related to the process of neoplastic transformation of the rat liver, was also investigated. RESULTS (1) By an immunohistochemical study of HB-EGF, hepatocytes in the cirrhotic rat liver were stained for HB-EGF, but those in normal rat liver were not stained. (2) The gene expression of HB-EGF was present in the isolated hepatoeytes from cirrhotic rat liver. (3) GST-P gene overexpressed in the isolated hepatocytes from cirrhotic rat liver, which indicated that the isolated hepatocytes from cirrhotic liver might be in a process of neoplastic transformation. (4) On the other hand, HB-EGF and GST-P gene were not detected in the isolated hepatocytes from normal rats. CONCLUSION The expression of HB-EGF in the cirrhotic hepatocytes suggests a possible role of HBEGF in the growth of cirrhotic hepatocytes.
AASLD ABSTRACTS
1325
CLINICAL A N D ANGIOGRAPHIC C H A R A ~ C $ OF BUDD-CHIARI SYNDROM][~ r ASSOCIATED WITH PRIMARY ANTIPHOSPHOLIPID ANTIBODY SYNDROME K K/m, Y-H Chung, DW Seo, B Yoo, IH Song, MS Koh, YS Lee, DI Suh. Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea Many patients with Budd-Chiari syndrome (BCS) have no evident etiological factor especially in Asian countries. And various obstructive patterns of inferior vena eava (IVC) and hepatic veins have been reported suggesting several different causes may be involved. Receudy primary antiphospholipid antibody syndrome (APAS) has been d e s c r i b e d as a characteristic clinical entity with multiple thromboembolitic episodes and typical laboratory features such as serum antiphospholipid antibody, not being associated with any collagen disease. To evaluate the etiological role of prim,~ APAS in BCS and clarify the clinical features of BCS patients with primary APAS, we analized clinical and angiographic data of 27 consecutive patients with BCS (Age :47+12 years, M:F=14:13). Underlying etiological factors were identified only in 6 (22%) ; 4 (17%) were associated with primary APAS. Most of patients with BCS showed superficial venous collaterals, ascites, symmetrical lower leg edema and hepatosplenomegaly with laboratory features of liver cirrhosis, regardless the association of primary APAS. However, only out of 4 with primary APAS, 2 had asymmetrical lower leg edema with ulcer ; 2 complained of unexplained long-standing dry cough, 1 of intermittent fever. In both with lower leg ulcer, thrombotic obstructions of deep veins were identified. Another one with primary APAS was proved to have pulmonary hypertension without definite vascular obstruction. All of 4 patients (100%) with APAS in contrast to only 8 out of 23 (35%) without it showed broad obstruction of IVC and all three hepatic veins (Suginra type II ; p<0.05). These data suggested that primary APAS is one of common etiological factors in patients with BCS, and that especially in BCS patients who present asymmetrical lower leg edema with ulcer, long-standing dry cough, unexplained fever, pulmonary hypertension of unknown cause or broad obslruction of IVC, the possibility of association with APAS should be considered.
1327 I M M U N O H I S T O C H E M I C A L STUDY OF FAS IN THE LIVER OF PRIMARY BILIARY CIRRHOSIS. F Kishi, G Yamada, H Tsu[geno, M Takatani, H Endo, K Manabe, M Takahashi, M Mizuno and T Tsuii. First Dept. of Internal Medicine, Okayama University Medical School, Okayama, Japan. Previously, we reported that in primary biliary cirrhosis (PBC) cytotoxic T cells (CD8+, CDllb-) frequently infiltrate into the intraepitheliaI space of the bile ducts (Hepatology 1986;6:385-391). In this study, we have examined the expression of Fas, which mediates apoptosis, in PBCusing immunohistochemistry. Patients and methods Liver biopsy specimens were obtained from 8 patients with PBC (Scheuer's criteria ; gradeI:4, gradelI:3, gradelII:l), and from 24 patients with chronic hepatitis B or C (CH-B:13, CH-C: 11 ). Indirect peroxidase-labeled antibody method was performed using mouse monoclonal antibodies to Fas, HLA-ABCAg, HLA-DR Ag, CD4 and CD8 at light and electron microscopic levels. Results In all PBC, F.~s was expressed stronger on the surface of the epithelial cells of interlobular bile ducts than those in chronic hepatitis B or C. On the other hand, the expression of Fas on hepatocytes was rather weaker in PBC than in chronic hepatitis B or C. In the immtmoelectron microscopic observation, electrondense reaction products of Fas were present on the basolateral membrane as well as in the endoplasmic reticulum of the bile duct epithelial cells. In these bile ducts, infiltration of CD8+ and/or CD4+ lymphocytes, increased expression of HLA-ABC Ag and neo-expression of HLA-DR Ag on the epithelial cells were often observed. Conclusion These findings suggest apoptosis mediated by CDS+/CD4+ lymphocytes may play some role in the pathogenesis of bile duct injury in PBC.
1326
HEPATOLOGY October 1995
ANTIBODIES AGAINST ADHESION MOLECULES SUPPRESS PRIMARY BILIARY CIRRHOSIS (PBC) LIKE LESIONS INDUCED BY GRAFT-VERSUS-HOST REACTION (GVHR) ACROSS MHC CLASS II DIFFERENCE. T Kimura, Y Matsuzaki, S Inada, S Ito, J Shoda, M Abel, N Tanaka, and M Fujiwara* Institute of Clinical Medicine, University of Tsukuba, TsukubaCity, Ibarakiand *Animal Center for Biomedical Research, Faculty of Medicine, Universityof Tokyo, Tokyo, Japan Increasedexpression of many kinds of adhesion molecules was detected immunohistochemicallyin the liver tissue of patients with PBC. Therefore, it was speculated that these molecules play important roles on the pathogenesisof PBC. AIM: Thisstudy was aimed to assess whether monoclonal antibodies (mAbs) against adhesion molecules could suppress PBC-like lesions employingour PBC animal model. METHODS: To induce GVHR with MHC class II disparity, 1-2x107 of C57BL/6 (B6) spleen T cells were injected twice intravenously into F1 mice which were obtained by mating B6. C=H-2 ~,~12 mutant mice with B6 mice. Histological findings of the liver in these mice resemble PBC (Am. J. Pathol. 1988; 135: 301). Each 50/~g of KBA, anti-mouse c¢ chain of LFA-I mAb, YNI/1.7, anti-mouse ICAM-I mAb and isotype-match control rat antibody (M18/2) were administered intraperit0neally per mouse prior to cell transfer. All mice were killed at 2 weeks after the first cell transfer and histological examination of the liver was performed. RESULTS: The induction of GVHR was not altered in these groupsby mAbs. grade of cellular percentageof infiltration of portal NSDC-Iike n mAb area lesion (%)
Group 1 Group 2 Group3 Group4 Group 5
10 11 KBA+YN1/1.7 5 YNI/I.7 5 KBA 4 M18/2
2.3±0.48 0.5±0.5§ 1.8±0.45 0.6±0.55 § 2.3±0.5
70.8±11.2 29.1±9.3 § 77.2+11.5 32.2±11.7 § 76.0+17.5
Results representmean+SDof each experimental group. § P<0.05 vs. Group 1 CONCLUSION: These results demonstrate LFA-1 may be crucial for the formation of PBC-like lesionsand also suggest a possibilityof therapy for PBC using mAbs againstadhesion molecules.
1328
EXPRESSION OF HEPARIN-BINDING EGF-LIKE G R O W T H FACTOR IN CIRRHOTIC RAT LIVER S Kisol. S Kawata 1. S Tamura 1. J Mivac,awa1. N Ito 1, H Tsushima 1. A Yamada1. O Oshikawa 1. S Tat~qa1-1. S t-Iiga~hiyama2, N Tanimachi2° Y Matsuzawa1 1Second Dept. of Int. Med., 2Dept. of Biochem., Osaka University Medical School, Osaka 565, Japan
It is well known that hepatocellular carcinoma (HCC) and cirrhosis coexist in the same liver. It is reported that the hepatocytes in cirrhotic liver proliferate more rapidly than those in the normal liver. We reported that heparin-bindlng EGF-like growth factor (HB-EGF), a new hepatotrophic factor, expressed in non-parenchymal liver cells but not in hepatocytes in regenerating rat liver after partial hepatectomy. However, in human HCC tissues, HCC cells express HB-EGF gene. In this study, we investigated the expression of HBEGF in the cirrhotic rat. MATERIALS AND METHODS (1) Cirrhosis was induced in male Sprague-Dawley rats by means of oral administration of 0.05% thioacetamide in drinking water for 4 mo. (2) Hepatocytes were isolated by in situ perfusion with collagenase. (3) Gene expression and protein production of HB-EGF were investigated by Northern hybridization and immunohistochemical methods, respectively. (4) Expression of glutathione S-transferase P (GST-P) gene, which is closely related to the process of neoplastic transformation of the rat liver, was also investigated. RESULTS (1) By an immunohistochemical study of HB-EGF, hepatocytes in the cirrhotic rat liver were stained for HB-EGF, but those in normal rat liver were not stained. (2) The gene expression of HB-EGF was present in the isolated hepatoeytes from cirrhotic rat liver. (3) GST-P gene overexpressed in the isolated hepatocytes from cirrhotic rat liver, which indicated that the isolated hepatocytes from cirrhotic liver might be in a process of neoplastic transformation. (4) On the other hand, HB-EGF and GST-P gene were not detected in the isolated hepatocytes from normal rats. CONCLUSION The expression of HB-EGF in the cirrhotic hepatocytes suggests a possible role of HBEGF in the growth of cirrhotic hepatocytes.