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Interferon treatmnet of a patient with chronic hepatitis B infection and idiopathic thrombocytopenic purpura: A case report
A1486 AASLD ABSTRACTS
GASTROENTEROLOGY Vol. 118, No.4
6726
6728
INTERFERON TREATMNET OF A PATIENT WITH CHRONIC HEPATITIS B INFECTION AND IDIOPATHIC THROMBOCYTOPENIC PURPURA: A CASE REPORT. Muhammet Cemil Savas, Gonca Tatar, Ibrahim Celalettin Haznedaroglu, Halis Simsek, HACETTEPE Univ, Ankara, Turkey.
SOLUBLE ADHESION MOLECULES (SICAM-l AND SVCAM-l) IN LIVER TRANSPLANTATION - BENEFICIAL OR DELETERIOUS EFFECTS ON GRAFT FUNCTION? Martin Schenk, Annette Zipfel, Oliver Kinder, Werner Lauchart, Horst Dieter Becker, Richard Viebahn, Univ Hosp, Dept Gen Surg, Tuebingen, Germany.
Idiopathic or immune thrombocytopenic purpura (lTP) is a disease characterized by immune destruction of platelets primarily in the spleen and recurrent bleeding episodes. The stantard therapy for chronic hepatitis B infection is interferon alpha (IFN). One of the most serious side effects of the drug is thrombocytopenia which may necessitate cessation of therapy. Some studies report beneficial effect of IFN therapy in patients with ITP. So we decided to try IFN treatment in a patient with chronic active hepatitis B infection and ITP. 36 year-old man was followed by Hacettepe University, hematology unit with the diagnosis of ITP since the age of six. He had episodes of bleedings and took multiple blood transfusions and steroid treatment in various intervals. He referred to gastroenterology unit due to liver enzyme elevation and diagnosed as HBs Ag, HBe Ag and HBV DNA positive. After six months follow-up, liver enzymes were still elevated and diagnosis of chronic active hepatitis B infection was made. Liver biopsy was not taken due to low platelet count. IFN therapy was planned but platelet count was 25.000/mm 3 . Steroid for ITP could not be given due to replicative hepatitis B virus infection. So iv immunglobulin I gr/kg for two days given and platelet count increased from 25.000/mm 3 to 110 OOO/mm3 . IFN therapy started at a dose of 5 MU three times a week for six months. During the entire course of therapy no decrease in platelet number was observed, it stayed between llO.OOO-128.000/mm 3 . At the end of treatment, liver enzymes normalized and HBV DNA becomes negative. After three months, relapse occurred with elevation of liver enzymes, HBV DNA (+ ) and platelet count of 30.000/mm 3 . IFN retreatment was given at a dose of 10 MU three times a week for four months without prior iv imrnunglobulin. Platelet count increased to 120.000/mm3 with IFN therapy and remain above 100.OOO/mm3 during course of treatment. At the end of treatment, liver enzymes normalized and HBV DNA (-). At the third month of follow-up, he was still in remission with normal enzymes, but platelet count decreased to 55.000/mm 3 . Side effects of IFN therapy include fever, flu-like syndrome, myalgias, neuropsychiatric and autoimmun side effects. The most important dose limiting adverse effect is the bone marrow supression and resulting thrombocytopenia and leukopenia. In this case eport, we observed that thrombocytopenia due to ITP is not a contraindication and even a good indication for IFN treatment of chronic hepatitis B infection.
6727 LONG-TERM FOLLOW-UP OF CHILDREN WITH CHRONIC HEPATITIS B WHO WERE TREATED WITH IFN. Atsushi Sawada, Hitoshi Tajiri, Kosuke Kozaiwa, Hiroki Kondou, Yoko Miyoshi, Kanae Tada, Yuri Etani, Sotaro Mushiake, Shintaro Okada, Med Sch, Osaka Univ, Suita, Japan. Aims: We have followed 24 children with chronic hepatitis B who were treated with interferon (IFN) and evaluated the long-term efficacy ofIFN. Non-responders to IFN were further treated with a combination of IFN and immunopotentiating agents and its efficacy was also assessed. Patients and treatments: We administered natural IFN alpha for 12 weeks trice a week in 24 children with chronic hepatitis B (18 male, 6 female: age 3 to 16 years old) and followed them for one year or more after the end of the treatment. Responders were defined by loss of HBeAg (seronegative, SN) within one year after the end of IFN therapy. Next we retreated 7 of 12 cases who failed to respond to the first IFN therapy; IFN +rIL-2 3, IFN + propagermanium (PG) 3, IFN I. Result: 12 of IFN-treated 24 cases were responders and seroconversion eventually occurred in all the responders. Two (IFN + PG, IFN +rIL-2) of 7 retreated cases cleared HBeAg. The remaining 5 cases retreated cases did not respond to the treatment. One case who was treated with IFN and PG became SN once but HBeAg reappeared during enterocolitis. However after this episode HBeAg decreased gradually and DNA polymerase turned negative with sustained administration ofPG. One case with chronic liver disease of 10-year-duration was first treated with IFN, followed by IFN +IL-2, IFN + PG, and long-term administration of PG. Because his liver disease has advanced to cirrhosis despite these treatments, lamivudine was introduced and HBeAg was cleared and DNApolymerase became negative. At one year of lamivudine therapy liver biopsy showed a marked improvement. Discussion: In this study IFN therapy was effective in 14/24 (50%). This efficacy is higher than those reported in adults (20-25%). Furthermore, in combination with IFN, we administered three immunopotentiating agents to IFN non-responders in order to promote clearance of HBV. However, many of them were found to be intractable to combination therapy. Since the occurrence of hepatocellular carcinoma in children and young adults with chronic hepatitis B was reported, we should pursue new treatments, including long-term administration of lamivudine, for pediatric cases with chronic hepatitis B who are refractory to IFN therapy.
The expression of adhesion molecules on endothelial tissues is a fundamental step in immunological activation leading to the dysfunction of a liver graft. Caused either by shearing forces or by active secretion, beside of the membranous form, soluble forms (sICAM-l, sVCAM-I) are found in the serum. In this study the role of these molecules was evaluated in terms of beneficial or deleterious effects on graft function in clinical liver transplantation (LTX). In a series of 72 LTX the concentrations of sICAM-l and sVCAM-l were determined pre- (incl. 52 donor sera), intraand postoperatively in the serum by an ELISA procedure. Graft function rate was analyzed during 100 days post-TX according to the Kaplan-Maier method. The function rate of grafts from donors with sICAM-1 concentrations above 230 ng/ml (n = 35) was 83% compared to 47% from donors (n = 17) below that threshold (p = 0.003). No correlation to the sVCAM-l concentration in the donor was found. Like in the donor, high sICAM-1 levels in the recipient before TX resulted in an improved graft function rate (~ 1100 ng/ml: 54%, n = 41; > 1100 ng/ml: 91%, n = 32). An additive effect was observed by combining the results of donor and recipient sICAM-l levels. Elevated levels (> 1100 ng/ml) of sVCAM-l in the recipient before TX also had a less significant but also positive impact on graft function (p = 0.04). Additive effects of sICAM-l and sVCAM-l in the recipient were observed as well. In the post-operative course an increase of ICAM-l levels above 1.5-fold the level before TX was observed in the context of a bad function prognosis (63% vs. 90%; p = 0.005). The intra- and post-operative levels of sVCAM-l were strongly suppressed by the intraoperative administration of pentoxifylline - without a correlation to the graft function rate. It is concluded that high levels of soluble adhesion molecules (especially sICAM-l) in the donor as well as in the recipient indicate a protective environment for liver grafts. However, these findings cannot be generalized: The postoperatively fast increasing levels of sICAM-l in the context of deleterious influences might reflect the beginning of an immunological activation.
6729 CYTOKlNE RELEASE FROM LIVER GRAFTS DURING COLD ISCHEMIA. Martin Schenk, Annette Zipfel, Almut Grenz, Stefan Hofer, Harald Weng, Horst Dieter Becker, Richard Viebahn, Univ Hosp, Dept Gen Surg, Tuebingen, Germany. Cytokines playa crucial role in leukocyte-endothelial interaction (e.g. in the regulation of the expression of adhesion molecules). Since the de-novo synthesis of cytokines by cells kept under ischemic conditions is thought to be quite unlikely, the presence of only marginal concentrations of cytokines during that period was assumed. This assumption was assessed in the current study. The concentration of cytokines and their soluble receptors were determined by ELISA procedure in serum samples from the donor as well as in perfusates from the right liver vein, obtained by flushing via the portal vein during the preparation of 35 liver grafts in the recipient center. Other serologic parameters were obtained by routine laboratory methods. Correlation was assessed using the Spearman Rank Correlation test. The median concentration in the graft perfusate ranged between the 0.2-fold for sIL-6R to the 56-fold (IL-lf3) of the donor serum concentration (see table). Strong correlations (p > 0.5; P < 0.01) were found between the concentration of IL-6, IL-lf3, TNF-RI and TNF-RlI. An increasing release correlating to ischemic time was observed only for TNF-RI, TNF-RII and IL-6 (p < 0.05). The number of leukocytes found in the perfusate correlated to the concentration of TNF-Rl, -RlI as well as IL-6, whereas the concentration of IL-l f3 was closely associated to hepatocellular damage indicated by AST and ALT concentrations. A considerable amount of cytokines and receptors was released into the perfusate during the conservation period in liver transplantation. The origin may be leukocytes emerging from the tissue or hepatocytes being damaged. Therefore, intra-graft cytokine levels will have to be included into considerations concerning immunological activation in clinical liver transplantation.
Median concentration ofcytokines and soluble receptors in thedonor and thegraft perfusate
Donor Perfusate
TNF·(J.
sTNF·RI
sTNF·RII
IL·6
sIL·6R
IL·1Jl
lpg/mil
lng/mil
lng/mil
lpg/mil
lng/mil
lpg/mil
253 73
38 4.3
7.0 5.1
197 108
65.0 11.8
0.2 11.2
GASTROENTEROLOGY Vol. 118, No.4
6726
6728
INTERFERON TREATMNET OF A PATIENT WITH CHRONIC HEPATITIS B INFECTION AND IDIOPATHIC THROMBOCYTOPENIC PURPURA: A CASE REPORT. Muhammet Cemil Savas, Gonca Tatar, Ibrahim Celalettin Haznedaroglu, Halis Simsek, HACETTEPE Univ, Ankara, Turkey.
SOLUBLE ADHESION MOLECULES (SICAM-l AND SVCAM-l) IN LIVER TRANSPLANTATION - BENEFICIAL OR DELETERIOUS EFFECTS ON GRAFT FUNCTION? Martin Schenk, Annette Zipfel, Oliver Kinder, Werner Lauchart, Horst Dieter Becker, Richard Viebahn, Univ Hosp, Dept Gen Surg, Tuebingen, Germany.
Idiopathic or immune thrombocytopenic purpura (lTP) is a disease characterized by immune destruction of platelets primarily in the spleen and recurrent bleeding episodes. The stantard therapy for chronic hepatitis B infection is interferon alpha (IFN). One of the most serious side effects of the drug is thrombocytopenia which may necessitate cessation of therapy. Some studies report beneficial effect of IFN therapy in patients with ITP. So we decided to try IFN treatment in a patient with chronic active hepatitis B infection and ITP. 36 year-old man was followed by Hacettepe University, hematology unit with the diagnosis of ITP since the age of six. He had episodes of bleedings and took multiple blood transfusions and steroid treatment in various intervals. He referred to gastroenterology unit due to liver enzyme elevation and diagnosed as HBs Ag, HBe Ag and HBV DNA positive. After six months follow-up, liver enzymes were still elevated and diagnosis of chronic active hepatitis B infection was made. Liver biopsy was not taken due to low platelet count. IFN therapy was planned but platelet count was 25.000/mm 3 . Steroid for ITP could not be given due to replicative hepatitis B virus infection. So iv immunglobulin I gr/kg for two days given and platelet count increased from 25.000/mm 3 to 110 OOO/mm3 . IFN therapy started at a dose of 5 MU three times a week for six months. During the entire course of therapy no decrease in platelet number was observed, it stayed between llO.OOO-128.000/mm 3 . At the end of treatment, liver enzymes normalized and HBV DNA becomes negative. After three months, relapse occurred with elevation of liver enzymes, HBV DNA (+ ) and platelet count of 30.000/mm 3 . IFN retreatment was given at a dose of 10 MU three times a week for four months without prior iv imrnunglobulin. Platelet count increased to 120.000/mm3 with IFN therapy and remain above 100.OOO/mm3 during course of treatment. At the end of treatment, liver enzymes normalized and HBV DNA (-). At the third month of follow-up, he was still in remission with normal enzymes, but platelet count decreased to 55.000/mm 3 . Side effects of IFN therapy include fever, flu-like syndrome, myalgias, neuropsychiatric and autoimmun side effects. The most important dose limiting adverse effect is the bone marrow supression and resulting thrombocytopenia and leukopenia. In this case eport, we observed that thrombocytopenia due to ITP is not a contraindication and even a good indication for IFN treatment of chronic hepatitis B infection.
6727 LONG-TERM FOLLOW-UP OF CHILDREN WITH CHRONIC HEPATITIS B WHO WERE TREATED WITH IFN. Atsushi Sawada, Hitoshi Tajiri, Kosuke Kozaiwa, Hiroki Kondou, Yoko Miyoshi, Kanae Tada, Yuri Etani, Sotaro Mushiake, Shintaro Okada, Med Sch, Osaka Univ, Suita, Japan. Aims: We have followed 24 children with chronic hepatitis B who were treated with interferon (IFN) and evaluated the long-term efficacy ofIFN. Non-responders to IFN were further treated with a combination of IFN and immunopotentiating agents and its efficacy was also assessed. Patients and treatments: We administered natural IFN alpha for 12 weeks trice a week in 24 children with chronic hepatitis B (18 male, 6 female: age 3 to 16 years old) and followed them for one year or more after the end of the treatment. Responders were defined by loss of HBeAg (seronegative, SN) within one year after the end of IFN therapy. Next we retreated 7 of 12 cases who failed to respond to the first IFN therapy; IFN +rIL-2 3, IFN + propagermanium (PG) 3, IFN I. Result: 12 of IFN-treated 24 cases were responders and seroconversion eventually occurred in all the responders. Two (IFN + PG, IFN +rIL-2) of 7 retreated cases cleared HBeAg. The remaining 5 cases retreated cases did not respond to the treatment. One case who was treated with IFN and PG became SN once but HBeAg reappeared during enterocolitis. However after this episode HBeAg decreased gradually and DNA polymerase turned negative with sustained administration ofPG. One case with chronic liver disease of 10-year-duration was first treated with IFN, followed by IFN +IL-2, IFN + PG, and long-term administration of PG. Because his liver disease has advanced to cirrhosis despite these treatments, lamivudine was introduced and HBeAg was cleared and DNApolymerase became negative. At one year of lamivudine therapy liver biopsy showed a marked improvement. Discussion: In this study IFN therapy was effective in 14/24 (50%). This efficacy is higher than those reported in adults (20-25%). Furthermore, in combination with IFN, we administered three immunopotentiating agents to IFN non-responders in order to promote clearance of HBV. However, many of them were found to be intractable to combination therapy. Since the occurrence of hepatocellular carcinoma in children and young adults with chronic hepatitis B was reported, we should pursue new treatments, including long-term administration of lamivudine, for pediatric cases with chronic hepatitis B who are refractory to IFN therapy.
The expression of adhesion molecules on endothelial tissues is a fundamental step in immunological activation leading to the dysfunction of a liver graft. Caused either by shearing forces or by active secretion, beside of the membranous form, soluble forms (sICAM-l, sVCAM-I) are found in the serum. In this study the role of these molecules was evaluated in terms of beneficial or deleterious effects on graft function in clinical liver transplantation (LTX). In a series of 72 LTX the concentrations of sICAM-l and sVCAM-l were determined pre- (incl. 52 donor sera), intraand postoperatively in the serum by an ELISA procedure. Graft function rate was analyzed during 100 days post-TX according to the Kaplan-Maier method. The function rate of grafts from donors with sICAM-1 concentrations above 230 ng/ml (n = 35) was 83% compared to 47% from donors (n = 17) below that threshold (p = 0.003). No correlation to the sVCAM-l concentration in the donor was found. Like in the donor, high sICAM-1 levels in the recipient before TX resulted in an improved graft function rate (~ 1100 ng/ml: 54%, n = 41; > 1100 ng/ml: 91%, n = 32). An additive effect was observed by combining the results of donor and recipient sICAM-l levels. Elevated levels (> 1100 ng/ml) of sVCAM-l in the recipient before TX also had a less significant but also positive impact on graft function (p = 0.04). Additive effects of sICAM-l and sVCAM-l in the recipient were observed as well. In the post-operative course an increase of ICAM-l levels above 1.5-fold the level before TX was observed in the context of a bad function prognosis (63% vs. 90%; p = 0.005). The intra- and post-operative levels of sVCAM-l were strongly suppressed by the intraoperative administration of pentoxifylline - without a correlation to the graft function rate. It is concluded that high levels of soluble adhesion molecules (especially sICAM-l) in the donor as well as in the recipient indicate a protective environment for liver grafts. However, these findings cannot be generalized: The postoperatively fast increasing levels of sICAM-l in the context of deleterious influences might reflect the beginning of an immunological activation.
6729 CYTOKlNE RELEASE FROM LIVER GRAFTS DURING COLD ISCHEMIA. Martin Schenk, Annette Zipfel, Almut Grenz, Stefan Hofer, Harald Weng, Horst Dieter Becker, Richard Viebahn, Univ Hosp, Dept Gen Surg, Tuebingen, Germany. Cytokines playa crucial role in leukocyte-endothelial interaction (e.g. in the regulation of the expression of adhesion molecules). Since the de-novo synthesis of cytokines by cells kept under ischemic conditions is thought to be quite unlikely, the presence of only marginal concentrations of cytokines during that period was assumed. This assumption was assessed in the current study. The concentration of cytokines and their soluble receptors were determined by ELISA procedure in serum samples from the donor as well as in perfusates from the right liver vein, obtained by flushing via the portal vein during the preparation of 35 liver grafts in the recipient center. Other serologic parameters were obtained by routine laboratory methods. Correlation was assessed using the Spearman Rank Correlation test. The median concentration in the graft perfusate ranged between the 0.2-fold for sIL-6R to the 56-fold (IL-lf3) of the donor serum concentration (see table). Strong correlations (p > 0.5; P < 0.01) were found between the concentration of IL-6, IL-lf3, TNF-RI and TNF-RlI. An increasing release correlating to ischemic time was observed only for TNF-RI, TNF-RII and IL-6 (p < 0.05). The number of leukocytes found in the perfusate correlated to the concentration of TNF-Rl, -RlI as well as IL-6, whereas the concentration of IL-l f3 was closely associated to hepatocellular damage indicated by AST and ALT concentrations. A considerable amount of cytokines and receptors was released into the perfusate during the conservation period in liver transplantation. The origin may be leukocytes emerging from the tissue or hepatocytes being damaged. Therefore, intra-graft cytokine levels will have to be included into considerations concerning immunological activation in clinical liver transplantation.
Median concentration ofcytokines and soluble receptors in thedonor and thegraft perfusate
Donor Perfusate
TNF·(J.
sTNF·RI
sTNF·RII
IL·6
sIL·6R
IL·1Jl
lpg/mil
lng/mil
lng/mil
lpg/mil
lng/mil
lpg/mil
253 73
38 4.3
7.0 5.1
197 108
65.0 11.8
0.2 11.2