Chronic Active Hepatitis Type Research Articles

Long-term Therapy With Adefovir Dipivoxil for HBeAg-Negative Chronic Hepatitis B for up to 5 Years

Treatment with adefovir dipivoxil for 48 weeks resulted in clinical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B that was lost when treatment was discontinued. We investigated the efficacy, safety, and resistance profile of adefovir dipivoxil treatment for up to 240 weeks. HBeAg-negative patients were treated double blind with placebo or adefovir dipivoxil 10 mg once daily for 48 weeks, followed by adefovir dipivoxil from week 49 to 96. At week 97, 125 patients enrolled in a 144-week, open-label phase. Patients received adefovir dipivoxil for up to 192 or 240 weeks. Serum hepatitis B virus (HBV) DNA levels were less than 1000 copies per milliliter in 67% of patients, and alanine aminotransferase (ALT) levels normalized in 69% after 240 weeks. After 192 or 240 weeks of treatment, over 83% of patients had improvement in necroinflammation, and over 73% had improvement in fibrosis. Ishak fibrosis scores improved compared with baseline in 35%, 55%, and 71% of patients after 48, 192, and 240 weeks of adefovir dipivoxil, respectively. After 240 weeks, the cumulative probability of HBV polymerase mutations was 29%, but the cumulative probability of mutations with virologic resistance was 20% and of mutations, virologic resistance, and ALT elevations was 11%. Slight elevations in creatinine were confirmed in 4 (3%) patients. Treatment with adefovir dipivoxil for up to 240 weeks was well tolerated and produced significant, increasing improvement in hepatic fibrosis, durable suppression of HBV replication, normalization of liver enzymes, and delayed development of resistance.

Bone marrow transplantation in patients with thalassemia

In this study we report the long-term results of bone marrow transplantation (BMT) in 113 patients (M 56, F 57) with thalassemia major (TM) who were given 117 transplants from HLA identical sibling donor between May 1983 and September 2005. The median age was 9.09 years (0.11-28.11). The median number of transfusions given before BMT was 136 (2-900). The pretransplant liver biopsy performed in 78 patients showed: chronic persistent hepatitis in 35, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. All patients received the same preparative therapy consisting of busulphan (BU) (13-14 mg/kg) and cyclophosphamide (200 mg/kg), preceded by an hypertransfusion regimen for 2-3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 38 patients were given cyclosporine (CSA) alone and 75 received CSA and short course methotrexate. The median number of transplanted nucleated cells was 4.8 × 108/kg (2.3-10.1). Marrow engraftment was evident in 111 patients. The median time to achieve 0.5 × 109/L neutrophils and 50 × 109/L platelets was 19 (11-37) and 24 (10-55) days respectively. Four patients had an autologous reconstitution and are currently alive under transfusion therapy. The probability of graft rejection was 6.6%. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively. Transplant related mortality was 8.8%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3, encephalopathy in 2, aGvHD in 1. Two late deaths occurred, one for septic shock 54 months post-BMT and one for parotitis carcinoma 138 months after BMT. As of October 2005, 101 patients are alive and 97 of them are cured after a median follow-up of 158 months (1-269). The 10-year actuarial probability of survival and disease-free survival (DFS) was 91% and 87% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. This study confirms the feasibility of curing the majority of patients with TM by BMT. In this study we report the long-term results of bone marrow transplantation (BMT) in 113 patients (M 56, F 57) with thalassemia major (TM) who were given 117 transplants from HLA identical sibling donor between May 1983 and September 2005. The median age was 9.09 years (0.11-28.11). The median number of transfusions given before BMT was 136 (2-900). The pretransplant liver biopsy performed in 78 patients showed: chronic persistent hepatitis in 35, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. All patients received the same preparative therapy consisting of busulphan (BU) (13-14 mg/kg) and cyclophosphamide (200 mg/kg), preceded by an hypertransfusion regimen for 2-3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 38 patients were given cyclosporine (CSA) alone and 75 received CSA and short course methotrexate. The median number of transplanted nucleated cells was 4.8 × 108/kg (2.3-10.1). Marrow engraftment was evident in 111 patients. The median time to achieve 0.5 × 109/L neutrophils and 50 × 109/L platelets was 19 (11-37) and 24 (10-55) days respectively. Four patients had an autologous reconstitution and are currently alive under transfusion therapy. The probability of graft rejection was 6.6%. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively. Transplant related mortality was 8.8%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3, encephalopathy in 2, aGvHD in 1. Two late deaths occurred, one for septic shock 54 months post-BMT and one for parotitis carcinoma 138 months after BMT. As of October 2005, 101 patients are alive and 97 of them are cured after a median follow-up of 158 months (1-269). The 10-year actuarial probability of survival and disease-free survival (DFS) was 91% and 87% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. This study confirms the feasibility of curing the majority of patients with TM by BMT.

Autoimmune-type chronic active hepatitis in children. A report of 23 cases at a Hospital in Northwestern Mexico

Introduction: Autoimmune type chronic active hepatitis (AI-CAH) is a rare pediatric disorder whose principal characteristics include hepatocellular dysfunction and active tissue damage with evolution to cirrhosis in 25-30% of cases. Objective: Our aim was to ascertain the evolution of 23 children with AI-CAH treated between 1978 and 2004 at the Hospital Infantil del Estado de Sonora in the Sonora State capital of Hermosillo in northern Mexico. Materials and methods: We conducted a retrospective review that included the following variables: age; sex; personal antecedents; signs and symptoms; laboratory and medical office studies; histologic tissue pattern obtained by biopsy; treatment; evolution, and mortality. Results: Thirteen males and 10 females participated in the study; predominant signs were hyporexia, fatigue-hepatomegalia, and icterus. Ten patients presented moderate anemia and six patients, leukopenia and thrombocytopenia. Eighteen patients presented hypergammaglobulinemia. Twenty three patients had percutaneous (p.c.) liver biopsy, and we observed the following histologic pattern: rupture of the limiting plate; necrotic foci; cholangiolar proliferation, and fibrotic bridges; in addition, four patients demonstrated precirrhotic changes. Twenty one children received prednisone for periods of between 1 and 12 years; in seven cases, children were administered azatioprine. Six children presented histologic, biochemical, and clinical remission, nine experienced biochemical remission but presented inflammatory activity, five abandoned treatment, and three died due to cirrhosis, liver insufficiency, and other complications. Discussion: To date, AI-CAH etiology continues to be unknown, while treatment has not been importantly modified in 50 years and continues to consist of prednisone alone or in association with azathioprine.

Graves' Hyperthyroidism Showing Transient Hypothyroidism during Interferon Therapy for Chronic Hepatitis Type C

We report a patient with Graves' disease in whom thyroid function was changed from initial hyperthyroidism to transient hypothyroidism and back to hyperthyroidism during interferon (IFN) therapy. A 43-year-old man was admitted to our hospital to receive IFN treatment for chronic active hepatitis (type C) in June 1998. His thyroid function was normal and testing for thyroid gland antibodies (TSH binding inhibitor immunoglobulins; TBII, anti-thyroglobulin antibodies; TgAb and anti-thyroid peroxidase antibodies; TPOAb) was negative before IFN therapy. The patient had neither history of thyroid disease nor any particular family history. He developed hyperthyroidism four months after its initiation of IFN therapy. When he was hyperthyroid, TBII, the activity of thyroid-stimulating antibodies (TSAb) and thyroid stimulation-blocking antibodies (TSBAb) were 40.2% (normal range, -15 approximately +15.0%), 1201% (normal range, <or=180%) and 52.0% (normal range, <or=45.6%), respectively. Thyroid 99mTc(technetium)-uptake ratio (Tc-UTR) was 1.07% (normal range, 0.5-3.0%). He transiently developed hypothyroidism in December 1998 and recurrent hyperthyroidism in February 1999. When he was hypothyroid, TBII, TSAb and TSBAb were 74.3%, 769% and 95.9%, respectively. To investigate the mechanism of his fluctuating thyroid status, we serially assessed the serum levels of cytokines (TNF-alpha, IFN-gamma, IL-1beta, IL-2, IL-4) and the soluble form of ICAM-1 (sICAM-1) as well as the activities of two types of TSH receptor antibodies (TRAb), TSAb and TSBAb, before and after IFN therapy. There were no characteristic changes of cytokines or sICAM-1 during the follow-up period. The transient hypothyroid state may be explained by two possible mechanisms: one may be due to the shift in the balance between the stimulating and blocking types of TRAb, and the other may be due to the complication of destructive thyroiditis that developed during IFN therapy.

Long-Term Results of Bone Marrow Transplantation for Thalassemia Major in Pescara.

In this study we report the long-term results of bone marrow transplantation (BMT) in 111 patients (M 56, F 55) with thalassemia major (TM) who were given 115 transplants in Pescara between May 1983 and February 2004. The median age was 10.06 years (0.11–28.11). The median number of transfusions given before BMT was 139 (2–900). The median level of ferritin at time of BMT was 1328 (258–6640). Twenty-three patients showed evidence of HBV infection and 59 of HCV infection. A pretransplant liver biopsy was performed in 78 patients. On the basis of Knodell classification, results of liver biopsy were: mild siderosis with normal histology in 1 patient, chronic persistent hepatitis in 34, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. Results of liver fibrosis were: no fibrosis in 4 patients, mild fibrosis in 39, moderate in 25 and severe in 10. All patients showed normal ejection fraction evaluated by echocardiogram (median 62%, range 56% to 70%). One hundred and seven patients received their marrow from HLA identical siblings, 3 from HLA identical parent and 1 from HLA identical uncle. All patients received the same preparative therapy consisting of Busulphan (BU) (13–14 mg/Kg) and Cyclophosphamide (CY) (200 mg/Kg), preceded by an hypertransfusion regimen for 2–3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 37 patients were given Cyclosporine (CSA) alone and 74 received CSA in association with short course Methotrexate. The median number of transplanted nucleated cells was 4.7 x 108/Kg (2.3–10.1). Marrow engraftment was evident in 109 patients. The median time to achieve 0.5x109/L neutrophils and 50x109/L platelets was 19 (11–37) and 24 (10–55) days respectively. Four patients showed graft rejection and were given a second BMT from the same donor. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively.Transplant related mortality was 9%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3 patients, encephalopathy in 2, aGvHD in 1. The median day of death was day 41 (12–212). Two late deaths occurred. One patient died of septic shock 54 months post-BMT. One patient died for parotitis carcinoma 138 months after BMT. As of July 2004, 99 patients are alive. Ninety five are cured after a median follow-up of 160 months (5–254). Four patients had an autologous reconstitution and are currently alive under transfusion therapy. To-date, 4 patients are receiving immunosuppressive therapy for active chronic GvHD. The 10-year actuarial probability of survival and disease-free survival (DFS) was 90% and 86% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. Three studies were activated in the post-transplant course in order to normalize the serum ferritin with phlebotomy (28 patients), to treat HCV related CAH (9 patients) and to ameliorate the growth velocity with recombinant human growth hormone (7 patients).

The effect of Silybum marianum on the viral load of hispanic patients with chronic hepatitis C

The aim of the present study was to obtain erythrocyte membrane fractions from patients with chronic active hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Na+,K+ ATPase activities were significantly lower (P<0.005) in HBV related chronic active hepatitis (n=20, 0.134±0.073 μmol P/mg protein per h) and in HCV hepatitis (n=11, 0.144±0.049 μmol P/mg protein per h) when compared to control group (n=10, 0.219±0.055 μmol P/mg protein per h). Both types of chronic active hepatitis B and C have markedly altered erythrocyte membrane Na+,K+ ATPase activities that can be indicative of hepatic cell damage in humans. Although HBV and HCV infections are based on diverse mechanisms of action on their effect in liver injury, they cause similar effects on membrane ATPase activities.

Erythrocyte membrane ATPase activities in patients with chronic active hepatitis B and C virus infections

The aim of the present study was to obtain erythrocyte membrane fractions from patients with chronic active hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Na +,K + ATPase activities were significantly lower ( P<0.005) in HBV related chronic active hepatitis ( n=20, 0.134±0.073 μmol P/mg protein per h) and in HCV hepatitis ( n=11, 0.144±0.049 μmol P/mg protein per h) when compared to control group ( n=10, 0.219±0.055 μmol P/mg protein per h). Both types of chronic active hepatitis B and C have markedly altered erythrocyte membrane Na +,K + ATPase activities that can be indicative of hepatic cell damage in humans. Although HBV and HCV infections are based on diverse mechanisms of action on their effect in liver injury, they cause similar effects on membrane ATPase activities.

Comparative efficacy of interferon alfa in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis

Background/Aims: Because the effects of interferon in the presence and absence of cirrhosis are still debated in chronic active hepatitis type non-A, non-B, C (NANB/ C), the aim of this study was to determine to what extent the presence of cirrhosis influences the response to interferon. Methods: We compared the response to interferon alfa in 108 patients with chronic active hepatitis NANB/C with or without cirrhosis. The patients were randomly assigned to one of the two regimens: one group received 6 months of interferon 3 MU 3 times weekly, while the second group received a 12-month course, 3 MU three times weekly during the first 6 months, 2 MU for the following 3 months, and 1 MU for the last 3 months. Results: In both regimens, the proportion of patients with normal alanine aminotransferase at the end of treatment was significantly lower in the cirrhotic than in the noncirrhotic patients. In males, abnormal serum alkaline phosphatase levels and gamma glutamyl transpeptidase were also related to a lesser response independent of cirrhosis. The response at the end of treatment was not significantly different between the two regimens in either the cirrhotic or the noncirrhotic patients. However, the 12-month regimen gave a significantly higher rate of sustained response 6 months after the end of treatment in patients without cirrhosis. Conclusions: It is suggested that the presence of cirrhosis markedly reduces the rate of response to interferon and that in noncirrhotic patients, a 1-year treatment regimen could improve the beneficial effect of interferon.

Clinical aspects of incomplete septal cirrhosis in comparison with macronodular cirrhosis

Background/Aims: Incomplete septal cirrhosis (ISC) is a form of macronodular cirrhosis characterized by slender, incomplete septa that demarcate inconspicuous nodules. Its clinical features have not been investigated in a large series. The aims of this study were to review the clinical symptoms and evolution of ISC in 42 patients. Methods: Forty-two patients with at least one liver biopsy strongly suggestive of ISC were selected for the study covering a period between 1968 and 1987. Data for these patients were compared with the evolution of 49 patients with classical macronodular cirrhosis after chronic active hepatitis type B or C. Results: Possible etiological factors for ISC were alcohol abuse, arsenic treatment, and hepatitis B infection. In three cases, a genetic factor could not be excluded. Patients with ISC had significantly lower serum concentrations of transaminases and bilirubin at diagnosis. Compared with macronodular cirrhosis, bleeding varices were more frequent (57% vs. 22%) in ISC. Ten-year survivals in the ISC and the macronodular cirrhosis groups were 54% and 57%, respectively. Conclusions: ISC represents a relatively stable burnt-out form of macronodular cirrhosis with an unusually high incidence of variceal bleeding. This could be explained by a superimposed insufficiency of the portal vascular supply.

Expression of the fim and ldlr domains of factor I for structure/function studies

Genetic determinants of the autoimmune type of chronic active hepatitis include the major histocompatibility complex alleles HLA-B8 and HLA-DR3, which are usually present as the haplotype A1, B8, DR3. In certain other autoimmune diseases, an extended haplotype including complement alleles confers a greater relative risk than does B8, DR3. Hence, extended haplotypes were ascertained in autoimmune chronic active hepatitis by typing for HLA, complement alleles C4A, C4B, and Bf, and glyoxalase type 1 or 2. Eight of the 10 B8, DR3 haplotypes were A1, B8, DR3. Of the 8, 7 had the extended haplotype A1, B8, C4AQ0, C4B1, BfS, DR3, but this haplotype occurred in four instances with glyoxalase 2 and in three with glyoxalase 1. Thus, we find that in autoimmune chronic active hepatitis there is a high frequency of null alleles for complement but an extended haplotype does not cause any greater risk for disease than B8, DR3 alone.

Variability in the expression of a β2-microglobulin epitope on hepatocytes in chronic type C hepatitis on treatment with interferon

Cytotoxic CD8+ T lymphocytes recognize viral antigens in the context of human leukocyte antigen class I molecule coexpression by target cells. Analysis of beta 2-microglobulin reactivity is useful in evaluating changes in human leukocyte antigen class I antigen distribution. In this study we analyzed liver biopsy specimens obtained from 15 patients with chronic active hepatitis type C who underwent a clinical trial with recombinant interferon-alpha 2b. We comparatively studied by immunohistochemical analysis the expression of human leukocyte antigen class I antigens in frozen liver samples obtained before entry in the protocol and in specimens taken 8 mo after initiation of treatment. Six normal liver samples were used as controls. For immunohistochemical analysis, a panel of several human leukocyte antigen class I monoclonal antibodies, specific for beta 2-microglobulin or different heavy-chain determinants, was used. In addition, we included a novel monoclonal antibody (HP-1H8), characterized in this report, which is specific for a distinct beta 2-microglobulin epitope. On entry, mean serum ALT was 240 +/- 89 IU/L and mean Knodell's index was 9.9 +/- 2.4, whereas at the time of the second biopsy mean values had diminished to 45 +/- 22 IU/L and 4.7 +/- 3.0, respectively. Liver sections from controls and patients expressed human leukocyte antigen class I light- and heavy-chain determinants in hepatocytes, biliary duct epithelium, sinusoidal lining cells and lymphocytes. Remarkably, the beta 2-microglobulin epitope recognized by the HP-1H8 monoclonal antibody was undetectable on hepatocytes from normal livers but clearly evident on hepatocytes from patients with chronic active hepatitis C before interferon treatment. Positive staining was more intense in areas of piecemeal and lobular necrosis. Double immunostaining with a CD2 monoclonal antibody demonstrated that labeling with HP-1H8 was predominantly associated with T-cell infiltration. Interestingly, the reactivity of HP-1H8 with hepatocytes was diminished or disappeared in specimens obtained during interferon treatment; the pattern of reactivity then resembled that of samples from normal controls. Our data indirectly suggest that, in addition to the increased expression of human leukocyte antigen class I molecules on hepatocytes in viral infections, conformational changes may take place in these antigens. These changes can be revealed by immunostaining with the HP-1H8 monoclonal antibody. Interferon therapy could down-regulate this expression through its effect in reducing the histological activity resulting from the lysis of virus-infected hepatocytes by cytotoxic T cells.

Variability in the expression of a β2-microglobulin epitope on hepatocytes in chronic type C hepatitis on treatment with interferon

Cytotoxic CD8+ T lymphocytes recognize viral antigens in the context of human leukocyte antigen class I molecule coexpression by target cells. Analysis of β2-microglobulin reactivity is useful in evaluating changes in human leukocyte antigen class I antigen distribution. In this study we analyzed liver biopsy specimens obtained from 15 patients with chronic active hepatitis type C who underwent a clinical trial with recombinant interferon-α2b. We comparatively studied by immunohistochemical analysis the expression of human leukocyte antigen class I antigens in frozen liver samples obtained before entry in the protocol and in specimens taken 8 mo after initiation of treatment. Six normal liver samples were used as controls. For immunohistochemical analysis, a panel of several human leukocyte antigen class I monoclonal antibodies, specific for β2-microglobulin or different heavy-chain determinants, was used. In addition, we included a novel monoclonal antibody (HP-1H8), characterized in this report, which is specific for a distinct β2-microglobulin epitope. On entry, mean serum ALT was 240 ± 89 IU/L and mean Knodell's index was 9.9 ± 2.4, whereas at the time of the second biopsy mean values had diminished to 45 ± 22 IU/L and 4.7 ± 3.0, respectively. Liver sections from controls and patients expressed human leukocyte antigen class I light- and heavy-chain determinants in hepatocytes, biliary duct epithelium, sinusoidal lining cells and lymphocytes. Remarkably, the β2-microglobulin epitope recognized by the HP-1H8 monoclonal antibody was undetectable on hepatocytes from normal livers but clearly evident on hepatocytes from patients with chronic active hepatitis C before interferon treatment. Positive staining was more intense in areas of piecemeal and lobular necrosis. Double immunostaining with a CD2 monoclonal antibody demonstrated that labeling with HP-1H8 was predominantly associated with T-cell infiltration. Interestingly, the reactivity of HP-1H8 with hepatocytes was diminished or disappeared in specimens obtained during interferon treatment; the pattern of reactivity then resembled that of samples from normal controls. Our data indirectly suggest that, in addition to the increased expression of human leukocyte antigen class I molecules on hepatocytes in viral infections, conformational changes may take place in these antigens. These changes can be revealed by immunostaining with the HP-1H8 monoclonal antibody. Interferon therapy could down-regulate this expression through its effect in reducing the histological activity resulting from the lysis of virus-infected hepatocytes by cytotoxic T cells. (HEPATOLOGY 1993;17:372–382.)

A case of primary biliary cirrhosis associated with chronic active hepatitis type C improved by the injection of interferon and the administration of ursodeoxycholic acid

A case of primary biliary cirrhosis associated with chronic active hepatitis type C improved by the injection of interferon and the administration of ursodeoxycholic acid

The relationship between LeY antigen and the therapeutic efficacy of interferon in chronic hepatitis C.

The expression of LeY antigen (Fuc alpha 1-->2Gal beta 1-->4 [Fuc alpha-->3] GlcNAc beta 1-->R), recognized by the monoclonal antibody BM-1, was studied in peripheral blood T-lymphocyte subpopulations in patients with viral hepatitis, and in liver tissue of patients with acute viral hepatitis. The relationship between the expression of LeY antigen on peripheral blood T-lymphocytes and the effects of interferon (IFN) therapy for chronic hepatitis type C were also evaluated. LeY antigen is not markedly expressed in B or T-lymphocytes of healthy individuals. However, it was strongly expressed in CD8 and CD4 T-lymphocytes in patients with viral hepatitis. In the acute phase of acute viral hepatitis, the expression of LeY antigen was more markedly expressed on peripheral CD8 T-lymphocytes than on CD4 T-lymphocytes. In chronic hepatitis type B and type C, it was significantly expressed more often on CD4 T-lymphocytes. In the liver tissues of patients with acute viral hepatitis, LeY antigen was expressed on hepatocytes and infiltrating lymphocytes. IFN therapy for chronic active hepatitis type C proved most effective when LeY antigen was more markedly expressed on the patient's CD4 and CD8 peripheral blood T-lymphocytes before treatment. Further studies are needed to clarify the relationship between the mechanisms of hepatic cell injury and LeY antigen.

Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis.

An autoantibody to liver cytosol was previously described in childhood autoimmune chronic active hepatitis type 2. The antigen, liver cytosol antigen type 1, was for the first time partially purified using gel filtration and ion exchange chromatography, and it was characterized using immunodiffusion, immunoblot and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the immunoprecipitate. Immunoblot detected a unique antigenic peptide at 62 kD from human cytosol and at 58 kD from rat cytosol. The same peptides were also detected when immunoprecipitates of liver cytosol antigen type 1 and autoantibodies to liver cytosol antigen were submitted to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A polymeric structure, probably a tetramer, is suggested for native liver cytosol antigen type 1 because in gel filtration chromatography liver cytosol antigen type 1 was eluted as a protein of a molecular weight between 240 and 290 kD when human liver cytosol was fractionated and between 220 and 270 kD from rat liver cytosol. Liver cytosol antigen type 1 is probably poor in carbohydrates because it was not stained by periodic acid-Schiff stain. The autoantibodies to liver cytosol were frequently found in association with antiliver kidney microsomal autoantibodies type 1, which are directed against the cytochrome P-450 of the IID6 subfamily. Antiliver kidney microsomal autoantibodies type 1 but not antiliver cytosol autoantibodies were found in association with antibodies to hepatitis C virus. Autoantibodies to liver cytosol antigen type 1 seem to be a more specific marker for autoimmune hepatitis type 2 than antiliver kidney microsomal antibodies type 1 autoantibodies.

Intrahepatic up-regulated expression of extracellular matrix protein receptors in chronic active hepatitis type B

The aim of the present study was to investigate the differences in expression of β1 integrins between normal liver and the inflamed livers of patients with chronic active hepatitis B. Immunohistochemical staining with monoclonal antibodies that specifically recognize the common β1 chain and five different α subunits has been performed in frozen liver biopsy sections from 10 patients with chronic active hepatitis B and from 4 patients with normal livers. The major findings of our study were de novo expression in liver with chronic active hepatitis B of α2 and α3 subunits on both periportal hepatocytes and on lobular hepatocytes in close proximity to lymphocyte infiltrates. These results indicate the existence of an up-regulatory process in the expression of β1 integrins, especially the α2 and α3 subunits, in the inflamed liver tissue from patients with chronic active hepatitis B, suggesting that these integrins could play an important role in the development of liver fibrosis and in regulating intrahepatic lymphocyte migration.

自己免疫型の病型を示し，インターフェロン治療が有効であったＣ型慢性肝炎の１症例

症例は53歳女性で1991年3月検診時にGOT 329, GPT 306とトランスアミナーゼの上昇を指摘され精査加療目的にて当科入院.検査成績では血沈65mm/hrと亢進,γ-glb 3.5g/dl,IgG 5.5g/dlと上昇,抗核抗体が160倍と陽性,また抗C100-3抗体,PCR法にてHCV RNAが陽性であり,自己免疫型の病型を示すC型慢性肝炎と診断した.プレドニゾロン(PSL) 40mgより加療するも改善は認めず,PSL漸減後α-インターフェロン(α-IFN)投与を開始した.α-IFN投与後GPT値は速やかに正常化し,また,γ-glb値は2.1g/dlまで減少した.一方,抗核抗体は持続陽性であったが,抗体価の上昇は認めなかった.なおIFN投与後22日目の時点で測定したHCV抗体,HCV RNAはいずれも陽性であった.C型慢性肝炎の一部に自己免疫型の病型を示す症例が存在し,また,IFNが有効な症例が存在することを示す貴重な症例と思われ報告した.

Severe chronic active hepatitis (autoimmune type) mimicked by coinfection of hepatitis C and human immunodeficiency viruses.

Severe chronic active hepatitis, defined as the presence of a fivefold increase in serum aminotransferases and a twofold rise in gamma globulin for at least 10 weeks, is considered a progressive immunological liver disease requiring corticosteroid treatment, particularly when serum autoantibodies and a severe lymphoplasmacellular periportal infiltrate are found in the liver biopsy specimen. A 38 year old man who fulfilled the criteria for severe chronic active hepatitis is described. His sex, his homosexuality, and the presence of antibodies against HIV, however, led to the suspicion of a coinfection with hepatitis C virus (HCV) rather than autoimmune disease. The rapid and complete response to alpha interferon treatment and a recently available positive antibody test for HCV supported this view. These findings indicate that a HCV related chronic active hepatitis can present as the severe autoimmune type of chronic active hepatitis. Moreover, as in HBV infection, the response to treatment differs from that of autoimmune severe chronic active hepatitis.

Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals

To identify factors contributing to the pathogenesis of autoimmune chronic active hepatitis (CAH) healthy relatives of 13 patients with the disorder were followed prospectively for 4 years. 58 relatives were monitored for various serological markers and for T-lymphocyte migration inhibitory activity every 2 months. 3 cases of subclinical acute hepatitis A occurred during the study. In 2 of the 3 subjects, before hepatitis A virus (HAV) infection, there was a defect in suppressor-inducer T lymphocytes specifically controlling immune responses to the asialoglycoprotein receptor, an antigen expressed on the hepatocyte surface. In these 2 subjects, specific helper T cells and antibodies to the asialoglycoprotein receptor persisted and increased after acute hepatitis A, and autoimmune CAH type 1 developed within 5 months. Thus, in susceptible individuals HAV is a trigger for autoimmune CAH.

Identification of cytochrome P450IA2 as a human autoantigen

Autoantibodies occurring in a patient with idiopathic autoimmune type chronic active hepatitis (CAH) were found to react with purified rabbit cytochrome P450IA2 and to a much lesser extent with P450IA1. Both cytochrome P450s are known to be inducible by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in the rabbit, and the expression of the microsomal protein recognized by the patient serum was induced in adult rabbit livers after treatment with TCDD. This protein is only weakly detected in liver microsomes from neonatal rabbits exposed to TCDD in utero, which is consistent with the age-dependent induction of P450IA2 by TCDD. The serum specifically reacted with a protein of similar size in microsomes prepared from COS-1 cells transfected with an expression vector containing the full length human P450IA2 cDNA. This reactivity was not detected in the cells transfected with the vector alone, indicating that the antibody recognizes human P450IA2. In addition, the serum extensively inhibited 7-ethoxyresorufin O-deethylation catalyzed by isolated human liver microsomes. This catalytic activity is associated with class IA P450s in other species. A screen of sera from patients with various hepatic and nonhepatic diseases indicates that the autoantibody to P450IA2 occurs rarely in CAH. Cytochrome P450IA2 becomes the third P450 identified as an autoantigen in inflammatory liver diseases.