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A case of acute hepatitis A associated with fibrin-ring granulomas in the liver is presented. Because a relationship between acute hepatitis A infection and granuloma formation had not previously been established, liver specimens were examined from both the hepatitic and recovery phases. Numerous fibrin-ring granulomas were observed in the parenchyma during the hepatitic phase. The cellular components of the granulomas were largely macrophages and CD4-positive T-cells. Granulomas had disappeared completely by the recovery phase. These results suggest that fibrin-ring granulomas were caused by hepatitis A virus infection. This virus may activate macrophages and CD4-positive T-cells through an as-yet undetermined mechanism.

B型肝硬変5例 (男性3例, 女性2例, 年齢28-53, 中央値44歳) に対してラミブジンを投与し, その有用性について検討した. ラミブジン投与開始時と投与9カ月目の比較では, 総ビリルビンが0.7-6.2中央値3.1mg/dlから0.8-3.1中央値0.8mg/dlへ, ALTが50-268中央値74IU/lから19-44中央値30IU/lへ, TTTが20.1-33.1中央値29.9 Kunkel から5.5-19.8中央値14.3 Kunkel へ, アルブミンが3.1-4.8中央値3.5g/dlから3.1-5.1中央値3.9g/dlへ, コリンエステラーゼが79-211中央値94IU/lから118-315中央値206IU/lへ, HBV DNAが108.00-108.92中央値108.32copies/mlから102.00未満-105.30中央値102.00copies/ml未満へと改善した. 肝硬変症例に対するラミブジン投与は, 肝炎を鎮静化するだけでなく, 肝予備能の改善をも期待し得る治療法であると考えられた.

Simultaneous measurements of serum α-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma

OBJECTIVE We evaluated the measurements of serum alpha-fetoprotein (AFP) and the protein induced by vitamin K absence (PIVKA-II) in 734 patients with chronic hepatitis (CH) and liver cirrhosis (LC) who had been followed-up for the development of hepatocellular carcinoma (HCC). METHODS Serum AFP and PIVKA-II were measured every month and abdominal ultrasonography was performed every 3 months. Youden's index (sensitivity + specificity -1) was calculated. RESULTS On an average follow-up period of 374.5 days, HCC was detected in three HBsAg-positive LC patients (10.0%/yr), four anti-HCV-positive CH patients (1.35%/yr), 21 anti-HCV-positive LC patients (7.8%/yr), and one patient with both HBsAg- and anti-HCV-positive LC (22.7%/yr). At the time of HCC detection, the size of HCC was 4.7+/-0.6 (mean +/- SD) cm in HBsAg-positive patients and 2.4+/-1.3 cm in anti-HCV-positive patents. Cut-off values of 20 ng/ml for AFP (Youden's index = 0.422) and 60 mAU/ml for PIVKA-II (Youden's index = 0.316) gave the highest index for each marker. When these two markers were combined, cut-off values of 40 ng/ml for AFP and 80 mAU/ml for PIVKA-II gave the highest index (Youden's index = 0.500, sensitivity = 65.5%, specificity = 85.5%, positive predictable value = 14.8%, negative predictable value = 98.3%). The levels of AFP or PIVKA-II increased within three months before the detection of HCC. CONCLUSIONS Simultaneous measurements of serum AFP and PIVKA-II levels that are performed every 3 months are useful for detecting a developing HCC. The optimal cut-off values for AFP and PIVKA-II may be 40 ng/ml and 80 mAU/ml, respectively.

The route of hepatitis B virus (HBV) infection and subsequent clinical course vary widely. It is not clear if the prevalence of HBV genotypes differs in the different clinical features of HBV carriers. The genotype of HBV was determined by direct sequencing of HBV DNA amplified with a PCR method from 310 Japanese HBV carriers (189 male and 121 female, aged from 14 to 82 years). Genotype A was detected in eight (2.6%) of 310 HBV carriers, genotype B was detected in 92 (29.7%) and genotype C was detected in 210 (67.7%). None of them had genotype D, E or F. Among the eight patients infected with genotype A, one patient had been infected with HBV in his adulthood. Furthermore, both of one married couple also had genotype A. On the other hand, a HBeAg-negative state and HBeAg-negative healthy carrier state were significantly more common in patients infected with genotype B than those with genotype C by univariate analysis (P

Alterations in carbohydrate metabolism associated with liver cirrhosis are characterized by a high serum insulin level and prolonged hyperglycemia on oral glucose tolerance test (OGTT). We measured plasma glucose, immunoreactive insulin (IRI), and C-peptide immunoreactivity (CPR) levels during a 75-g OGTT before and after varices obliteration in 10 cirrhotic patients with gastric varices. After obliteration, the indocyanine green retention rate was decreased and the portal flow velocity was increased. A significant decline in plasma glucose and IRI levels was also noted on OGTT. Moreover, the plasma glucose and IRI levels declined at 90 and 120 min in OGTT while they increased progressively by 120 min before obliteration. The levels of CPR were similar before and after treatment. These results indicate that decreased portal flow due to extrahepatic shunt and consequent impairment of insulin metabolism play a role in glucose intolerance observed in cirrhotic patients and that shunt occlusion improves glucose metabolism.

A controlled trial was conducted to compare the efficacy of interferon (IFN) between two groups of patients with type C liver. Thirty-five patients were randomly assigned to group A (17 patients) or group B (18 patients). The former received 3 megaunits (MU) of human lymphoblastoid IFN six days per week for two weeks, followed by three days per week for 50 weeks; the latter group received 6 MU six days per week for two weeks followed by three days per week for 24 weeks. The percentages of biological sustained responders (B-SR) and virological sustained responders (V-SR) were 29.4 and 23.5%, respectively, in group B, and 17.6% for both in group A. The therapeutic effects were not different between two groups. HCV genotype 2 accounted for significantly higher percentage of B-SR and V-SR (both 57.1%, respectively). These findings indicate that IFN is effective in type C cirrhosis with genotype 2.

Aims/Background: Transcatheter arterial chemoembolization (TAE) of hepatocellular carcinoma (HCC) causes anoxia. Escape of cancer cells from anoxic injury may be enhanced by induction of proteins which provide resistance to apoptosis. Methods: We examined HCCs immuno-histochemically for Bcl-2, vascular endothelial growth factor (VEGF), p53, and Ki67. The staining intensity for VEGF, a protein induced by anoxia, was assessed morphometrically with a computer-assisted image-analyzer. Results: The frequency of Bcl-2 positive cells was higher in HCCs that had undergone TAE (TAE HCC) than that in HCCs that had not undergone TAE (41.75 ± 15.06 vs. 1.01 ± 0.79 cells/1000 cells, p=0.0173). The frequency of p53- or Ki67-positive cells was not increased after TAE. Of 12 TAE HCCs, 7 had Bcl-2 positive HCC cells and 6 had clusters of Bcl-2 positive cells. In contrast, 2 of 11 HCCs that had not undergone TAE had only a few, sporadically distributed, Bcl-2-positive cells. The staining intensity for VEGF was higher in Bcl-2 positive than in Bcl-2 negative areas (1.208 ± 0.091 vs. 1.071 ± 0.017, p=0.0222). Furthermore, the VEGF staining intensity in Bcl-2 positive areas of TAE HCCs was higher than in Bcl-2 negative areas (1.296 ± 0.126 vs. 1.066 ± 0.024, p= 0.0186), while in HCCs that had not undergone TAE the staining intensity was similar. Conclusions: TAE of HCC can induce Bcl-2 expression, possibly through anoxic stress.

Helper T cells (Th) are classified as type 1 (Th1) and type 2 (Th2) according to the cytokines they produce; interferon-gamma is produced by Th1, and interleukin-4 by Th2. We counted the circulating CD4-positive Th cells that produce interferon-gamma or interleukin-4 with an enzyme-linked immunospot assay. CD4-positive T cells isolated from patients with chronic hepatitis B (n = 10), chronic hepatitis C (n = 16), and healthy subjects (n = 10) were stimulated with anti-CD3 antibody in vitro. The number of interferon-gamma-producing Th cells was significantly lower in patients with chronic hepatitis C than in healthy subjects (P = 0.0024), whereas in patients with chronic hepatitis B, the number was similar to that in healthy subjects (P = 0.8530). The number of interleukin-4-producing Th cells was significantly higher in patients with chronic hepatitis C (P = 0.0010) and chronic hepatitis B (P = 0.0089) than in healthy subjects. In chronic hepatitis C, the number of interferon-gamma-producing Th cells was increased after incubation of the cells with interferon-alpha (P = 0.008) or with recombinant interferon-gammala (P = 0.024), but not with interferon-beta (P = 0.051). The number of interleukin-4-producing Th cells was decreased after incubation with interferon-alpha (P = 0.0004), with interferon-beta (P = 0.003), and with recombinant interferon-gammala (P = 0.0004). Changes in the numbers of interferon-gamma- or interleukin-4-producing Th cells in vitro were more evident in sustained responders to interferon therapy than in non-responders. These results suggest that Th2 cells are the predominant cell type in chronic hepatitis C, and that their activity may be suppressed by the administration of interferon.

Purpose: To assess the arterial supply to hepatocellular carcinomas (HCCs) by inferior phrenic arteries (IPA). Material and Methods: A total of 126 consecutive cases of HCC were studied by contrast-enhanced CT and conventional arteriography. Blood supply from an IPA was suspected when the size of the HCC mass as seen on contrast-enhanced CT did not match the size of the tumor mass as seen on hepatic arteriography. Inferior phrenic arteriography was employed to confirm these findings. HCCs fed by the IPA were analyzed in terms of size, location, and history of prior treatment. Results: In 14 (11%) of the 126 cases, the tumor was found to have a blood supply from an IPA. Eleven of these tumors were located in segments 2 and 7. Three tumors, which had not been treated previously, had a blood supply from an IPA. Six tumors were almost exclusively fed by an IPA and were located in segments 7, 1, and 4. Conclusion: HCCs located in segments which form the bare area of the liver (S1, S2, S7) can be supplied by an IPA. This should be suspected when a lesion or part of a lesion is identified on contrast-enhanced CT but not on hepatic arteriography.

A recently discovered non-A non-B hepatitis virus has been designated hepatitis G virus (HGV). Blood contamination has been proposed as its mode of transmission. We studied the genoprevalence of HGV in Japanese people at high risk. HGV was identified in serum by a reverse-transcription polymerase chain reaction. HGV was detected in 16.0% of intravenous drug users (IDUs) (n = 25), 16.2% of those with tattoos (n = 37), 10.9% of IDUs with tattoos (n = 55), 5.7% of chronic hepatitis (CH)-C patients (n = 87), and in none of the CH-B (n = 50) or CH non-B non-C (n = 46) patients. Serum alanine aminotransferase (ALT) levels of those infected with HGV alone (n = 3) were all within normal range. In the patients with CH-C, serum ALT levels of those coinfected with HGV were similar to serum ALT levels of those without HGV infection. A phylogenetic tree of isolated HGV clones showed that the HGVs of these subjects bore only a distant-resemblance to clones reported from Africa and North America, and that variation in the phylogenetic index of HGV clones was small. These results suggest that HGV clones from different areas have genetic heterogeneity and that HGV causes no or mild hepatitis.

Rationale and Objectives. Currently available treatments for hepatocellular carcinoma are not satisfactory in terms of recurrence rates. In this study, we injected ethanolamine oleate (EO) into a portal branch in an attempt to cause necrosis of a liver segment in which hepatocellular carcinoma might be located. Methods. Nine dogs received EO injections via a balloon catheter into a segmental portal branch of the liver. Results. Immediately after injection, 80–100% of the liver cells in the EO-injected segment underwent coagulative necrosis. After 1 week, the EO-injected segment had become completely necrotic in two dogs. Only a few viable hepatocytes were still observed around the arteries and beneath the liver capsule in another dog. No pathologic changes were observed in the lungs, kidneys, or heart of any dog. There was a correlation between the EO dosages and the volume of the EO-injected liver tissue. Conclusion. EO injection into a portal branch results in the pharmacologic destruction of the corresponding liver segment. This procedure may be beneficial in the treatment of hepatic malignancies.

To evaluate the efficacy of pegylated interferon alpha-2b (peg-IFN alpha-2b) plus ribavirin (RBV) therapy in Japanese patients with chronic hepatitis C (CHC) genotype Ib and a high viral load.One hundred and twenty CHC patients (58.3% male) who received peg-IFN alpha-2b plus RBV therapy for 48 wk were enrolled. Sustained virological response (SVR) and clinical parameters were evaluated.One hundred (83.3%) of 120 patients completed 48 wk of treatment. 53 patients (44.3%) achieved SVR. Early virological response (EVR) and end of treatment response (ETR) rates were 50% and 73.3%, respectively. The clinical parameters (SVR vs non-SVR) associated with SVR, ALT (108.4 IU/L vs 74.5 IU/L, P = 0.063), EVR (76.4% vs 16.4%, P0.0001), adherence to peg-IFN (or= 80% of planned dose) at week 12 (48.1% vs 13.6%, P = 0.00036), adherence to peg-IFN at week 48 (54.7% vs 16.2%, P0.0001) and adherence to RBV at week 48 (56.1% vs 32.1%, P = 0.0102) were determined using univariate analysis, and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis. In the older patient group (56 years), SVR in females was significantly lower than that in males (17% vs 50%, P = 0.0262). EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR.Peg-IFN alpha-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%. Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFN alpha-2b is important in improving the SVR rate.

Objective: To report on a patient with Hashimoto’s encephalopathy induced by lithium. Patient and interventions: A 61-year-old woman with a type II bipolar disorder and a history of lithium-induced thyrotoxicosis associated with silent thyroiditis was hospitalized to treat a severe major depressive episode. Given long-term treatment with levothyroxine for hypothyroidism that had resulted from silent thyroiditis, endogenous hormone in thyroid follicles was assumed to be minimized by the negative feedback, decreasing risk of recurrent thyrotoxicosis if lithium were restarted. Results: Lithium clearly relieved the patient’s depressive symptoms, but after 40 days encephalopathy developed. Thyrotoxicosis was ruled out, and serum antithyroid antibody titers were elevated. In the cerebrospinal fluid, protein content was substantially elevated and antithyroid antibodies were detected. Encephalopathy resolved dramatically after course of intravenous pulse therapy with methylprednisolone. Conclusions: We believe that autoantibodies against antigens shared by the thyroid gland and the brain were induced by exposure to lithium, causing the patient to develop Hashimoto’s encephalopathy.

Ribavirin and interferon-alpha induce Th1 polarization of human CD4+ T cells. The study was conducted to investigate the whether cellular immune response during ribavirin/interferon-alpha therapy is associated with viral eradication by examining mRNA expression of molecules relevant to Th1 and Th2 polarization in CD4+ cells of 13 patients with chronic hepatitis C (seven patients with sustained viral response and six with transient response). Peripheral CD4+ T lymphocytes at 0, 4 and 24 weeks of treatment were tested. There were no significant differences in the mRNA levels at each point of time of the treatment between patients with sustained viral response and those with transient response. The percent increase in mRNA level of the IL-12R beta2 chain from the baseline to the end of the treatment was significantly higher in patients with sustained viral response (15.3+/-6.1%) than in those with transient response (-1.6+/-4.7%, p0.05). There was no significant difference in percent changes in level of IL-12R beta1 chain mRNA between the two groups. In conclusion, the results of this study indicate that the increase of Th1 response is related to the inflammatory activity in the liver and possibly to ribavirin and interferon-alpha therapy. It is also suggested that the measurement of Th1 response has the potential to distinguish patients with relapse from those with sustained virus response.

We investigated the responses of peripheral blood mononuclear cells (PBMCs) to hepatitis C virus core protein in ten patients with chronic hepatitis C during interferon (IFN)-beta treatment to determine if the modulation of the immune reaction to hepatitis C virus by IFN treatment is associated with the viral clearance. Interleukin-2, interleukin-4, interleukin-10, and interferon-gamma in the supernatant of the patients' PBMC co-cultured with the HCV core antigen-presenting autologous PBMCs were measured by ELISA. Serum levels of soluble CD (sCD) 8 and sCD30 in these patients were also measured by ELISA. The production of interleukin-2 and interferon-gamma by PBMCs of sustained responders (SRs) increased after IFN-treatment, although it did not reach a significant level. Interleukin-10 was detected only in non-responders (NRs) at 0 and 4 weeks after the start of IFN treatment. Serum sCD8 level increased significantly in SR with IFN treatment. A close correlation between the serum sCD8 levels and interferon-gamma levels in the supernatant at week 8 was observed in SR. These results suggest that IFN treatment potentiates the cellular immune reaction against HCV core protein more efficiently in SR than in NR.

Background/aims Cholangitis in rats induced by N-formyl L-methionine L-leucine L-tyrosine (fMLT) is characterized by infiltration of mononuclear cells around bile ducts in portal tracts. Methods We investigated the initial process in fMLT-induced cholangitis histochemically. Results Administration of fMLT into the colons of adult male Wistar rats with acetate-induced colitis resulted in an infiltration of mostly macrophages and granulocytes into the portal tracts on day 1. Abnormal peroxidation as demonstrated by the nitro blue tetrazolium (NBT) reaction occurred in bile duct cells as well, although no apparent necrosis of the bile duct cells was observed. On day 4, the majority of the inflammatory cells in the portal tracts were CD4+ or CD8+ T lymphocytes. The oxidative products of the NBT reaction also disappeared from the bile duct cells. Administration of carrageenan, a potent inhibitor of macrophage function, resulted in a significant decrease in lymphocyte infiltration into the portal tracts. On day 8, portal inflammation subsided. Conclusions In formyl peptide-induced cholangitis, macrophages and granulocytes may injure bile ducts transiently. Further, macrophages are necessary for the subsequent migration of T lymphocytes around the bile ducts.

OBJECTIVE: 1,25(OH)2 vitamin D3 can affect immune cells. However, the mechanism responsible for the favorable effects of 1(OH) vitamin D3, which becomes 1,25(OH)2 vitamin D3 in the liver, is not clear. The aim of this study is to analyze the immunological response of 1(OH) vitamin D3 supplementation in CH-C patients. DESIGN: Forty-two CH-C patients were treated with 1(OH) vitamin D3/Peg-IFNα/RBV. Forty-two case-matched controls were treated with Peg-IFNα/RBV. The expression of Interferon-stimulated genes (ISGs)-mRNA in the liver biopsy samples and JFH-1 replicating Huh-7 cells were quantified by real-time PCR. Ten kinds of cytokines in the plasma were quantified during treatment by using a suspension beads array. A trans-well co-culture system with peripheral blood mononuclear cells (PBMCs) and Huh-7 cells was used to analyze the effect of 1(OH) vitamin D3. The activities of the Th1 response were compared between subjects treated with 1(OH) vitamin D3/Peg-IFN/RBV and those treated with Peg-IFN/RBV therapy alone. RESULTS: 1(OH) vitamin D3/Peg-IFN/RBV treatment could induce rapid viral reduction, especially in IL28B T/T polymorphism. Several kinds of cytokines including IP-10 were significantly decreased after 4 weeks of 1(OH) vitamin D3 treatment (p

Concanavalin A (Con A) can induce an immune-mediated hepatitis. Since direct evidence of immune mechanism for this hepatitis is lacking, we employed adoptive transfer to study the mechanism of Con A-induced hepatitis. Intravenous administration of Con A (20 mg/kg) to Balb/c mice was accompanied by elevations of serum alanine aminotransferase (ALT) levels and midzonal necrosis with lymphocyte infiltration in the liver. None of the Balb/c nu/nu mice showed biochemical or pathologic hepatic abnormalities with the same dose of Con A. In the area of midzonal necrosis, CD4-positive T lymphocytes appeared at 24 hr after injection, and then both CD4-positive and CD8-positive T lymphocytes were found at the margin of zonal necrosis at 48 hr. Pretreatment with carrageenan, a potent inhibitor of macrophages, prevented these biochemical and pathologic changes. Mononuclear cells infiltrating in the liver of Balb/c mice 24 hr after priming with Con A were harvested and injected into Balb/c nu/nu mice injected with Con A 24 hr previously. Serum ALT levels elevated and the same pathologic changes observed in Con A-treated Balb/c mice were observed. These changes were not observed when the splenic cells from Con A-treated Balb/c mice were transferred to Con A-treated nude mice. These results suggest that Con A-induced hepatic injury is mediated by macrophages and T lymphocytes sensitized by Con A or its metabolites.

Antibodies against hepatitis B surface antigen and against anti-hepatitis B surface antigen idiotype were assayed after immunization with hepatitis B vaccine both in sera, by enzyme-linked immunosorbent assay (ELISA), and in peripheral blood mononuclear cells, by enzyme-linked immunospot (ELISPOT) assay. After vaccination of 19 subjects, antibody to the idiotype of anti-hepatitis B surface antigen was detected in none of the sera tested with ELISA, but anti-idiotypic antibody-secreting cells were detected by ELISPOT assay in 4 (36.4%) of the 11 vaccine recipients who were positive for anti-hepatitis B surface antigen with ELISPOT assay. On the other hand, these cells were detected in none of those who remained seronegative for anti-hepatitis B surface antigen, or in the 7 normal subjects or the 2 chronic hepatitis type C patients. These results suggest that anti-idiotypic antibody production is more sensitively detected by ELISPOT assay than by ELISA, and anti-idiotypic antibodies to anti-hepatitis B surface antigen may be present in those with anti-hepatitis B surface antigen.

Primary sclerosing cholangitis (PSC) frequently accompanies inflammatory bowel diseases. In an attempt to increase our understanding of the pathogenesis of PSC, we studied bile duct changes in rats with colitis which had been given N-formyl L-methionine L-leucine L-tyrosine (fMLT) rectally; fMLT is one of the chemotactic peptides produced by Escherichia coli, and is secreted into the bile by hepatocytes after it enters the portal blood. Transrectal administration of fMLT induced a marked inflammation in the portal triad and mild hepatocyte necrosis on the 4th day. The infiltrating leukocytes in the portal tract were mostly mononuclear cells, which densely infiltrated around the bile ducts. These mononuclear cells appeared to attach to bile duct epithelial cells, and they were more numerous in the smaller bile ducts. Electron microscopy revealed that lymphocytes were in direct contact with bile duct lining cells and that some epithelial cells had degenerated or collapsed. These results suggest that this E. coli-derived peptide may induce cholangitis in the small bile duct through cell-mediated mechanisms. Since these pathologic changes resemble those of the bile duct observed in the early stage of PSC, it can be concluded that bacterial chemotactic peptides may play a role in the pathogenesis of small-duct PSC.

SAITOH, Y., MIURA, M., NIITSUMA, H., NUMATA, N., OHORI, H., ISHII, M. and TOYOTA, T. Changes of Serum Hepatitis C Virus Levels in Patients with Chronic Hepatitis C Treated with Two Courses of Interferon Administration. Tohoku J. Exp. Med., 1994, 173 (4), 361-369-To assess the efficacy of repeated interferon (IFN) administration in patients with chronic hepatitis C unresponsive to initial therapy, serum hepatitis C virus (HCV)-RNA levels were measured in 12 patients who had failed prior IFN therapy. Serum HCV-RNA was assayed by measuring DNA complementary to HCV-RNA using a quantitative reverse transcription-polymerase chain reaction assay. The mean total dose of IFN was 227.8 megaunits for first treatment and 270.7 mega-units for second treatment. Five responders with a normal alanine aminotransferase (ALT) concentration (less than 40IU/liter) at the end of the first treatment also had a normal ALT concentration at the end of the second treatment. By contrast, all nonresponders with an elevated ALT concentration during the first treatment likewise had an elevated ALT concentration at the end of the second treatment. HCV-RNA levels before the first treatment varied from 106 to 108 copies/μl. The serum HCV-RNA levels fell in 9 out of 10 patients after the first treatment and in 11 out of 12 patients after the second treatment. One patient had unchanged normal serum ALT levels after two courses of IFN treatment. These results suggested that the outcome of a second course of IFN treatment was similar biochemically and virologically to a first course, and that patients who did not respond initially seldom respond to additional IFN therapy. Therefore, readministration of IFN should be restricted to patients who respond biochemically and virologically to initial treatment. The optimal second dose shall be determined with further studies.

The mechanism of bile duct destruction observed in primary biliary cirrhosis (PBC) is still not clear. Recent study regarding cell death suggests the contribution of perforinor Fas-related apoptosis in the pathogenesis of immune-mediated cholangiopathy. The measurement of Fas-ligand (Fas-L) has been available recently and serum Fas-L level is reportedly related to the various inflammatory processes. However, its importance in immunemediated cholangiopathy is not known. Also, the usefulness of measuring Fas-L for evaluation of the clinical stage or activity is not known. Thus the Aims of this study are; (1) to measure the Fas-L in the serum from patients with PBC and compare their Fas-L levels to clinical parameters, (2) to compare Fas-L levels in PBC patients with those in other autoimmune liver disease patients (autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC)), and (3) to examine the relationship between serum Fas-L levels and histological Fas-L expression of the liver-infiltrating lymphocytes. [Methods] Histologically diagnosed 43 PBC cases, 5 AIH cases, and 2 PSC cases were enrolled in this study. The clinical parameters analyzed included serum ALT, ALP, IgG, IgM levels and histological staging of PBC by Scheuer. Serum Fas-L level was measured by ELISA. The Fas-L expression in liver specimens from PBC patients was evaluated by indirect immunohistochemistry using anti-Fas-L antibody. The density of Fas-L positive cells in the portal tract were calculated using NIH image, and evaluated in accordance with the degree of cholangitis and fibrosis in routine HE PBC 0.55 1.01, AIH 0.84 + 0.62, PSC 2.20--. 2.54, and the difference was not significant. (2) There was no statistical corelation between serum Fas-L levels and other clinical parameters (serum ALT, ALP, IgG, IgM levels). (3) In PBC, scattered Fas-L-positive cells were observed. The number of Fas-L positive cells per portal tract (mean_+ SD) was 2.79 +-1.21 (range 1.29 to 5.14). However, there was no statistical corelation of those positivities of histological Fas-L expression with serum Fas-L levels or degree of fiborsis/cholangitis. [Conclusions] Measurement of serum Fas-L levels were possible in human cholangiopathies including PBC. However, its relationship to other clinical factors and histological Fas-L expression was not proved. This research was funded by the grant from the Ministry of Education of Japan #07670555 and #09770339.

Coagulation screening tests including prothrombin time, hepaplastin test, kaolin-activated partial thromboplastin time, serial thrombin time 30', fibrinogen, fibrinogen and fibrin degradation products (FDP), and platelet count seem to be influenced by the capacity of the liver to produce proteins such as serum albumin, cholinesterase, and almost of all coagulo-fibrinolytic factors.So we studied the correlation between coagulation screening tests and histological pictures of biopsy specimens of liver in chronic liver diseases. Then we designed coagulation disturbance score (CDS) to express the severity of hepatic parenchyma damage by the degree of deteriolation of coagulation screening tests. On the other hand, histological findings were classified as liver cell damage score (LCDS) and liver fibrosis score (LFS) according to degrees of liver cell necrosis and liver fibrosis. And histological diagnoses of chronic liver diseases used were liver cirrhosis, active stage (LC (a)), liver cirrhosis, inactive stage (LC (i)), chronic active hepatitis with lobular disorganization (CH (a)) c LD), chronic active hepatitis (CH (a)), and chronic inactive hepatitis (CH (i)).In LC (a), compared with other types of chronic liver diseases, CDS was significantly high and also platelet count below 10×104/cμ, cholinesterase below normal value in our laboratory (4.4IU/ml). In LC (i) and CH (i), the lower the CDS, the higher the LCDS. It was postulated that hyperproduction of coagulation factors might be induced by the regeneration of liver cell after inflammation or by the inflammatory stimulation on hepatic parenchyma. In CH (a) c LD, which is a histological stage from chronic hepatitis to liver cirrhosis, CDS was significantly correlated with LCDS. On the other hand, CDS wasn't dependent on LFS in all types of chronic liver diseases.CDS had significant correlation with serum albumin, cholinesterase and ICG 15'.Conclusively, in chronic liver diseases, especially in liver cirrhosis, increase of CDS means that functional capacity of the liver gets worse.

In order to establish the virological significance of HBeAg subtypes (HBeAg/1 and HBeAg/2) during hepatitis B virus infection, HBsAg, HBeAg and hepatitis B virus DNA in serum and HBcAg in liver were determined quantitatively in relation to the detection of HBeAg subtypes in agar gel diffusion. Thirty-eight chronic HBsAg carriers with HBeAg, including 16 non-specific reactive hepatitis, 8 chronic persistent hepatitis, 11 chronic active hepatitis and 3 liver cirrhosis, who were seen at Tohoku University Hospital from 1983 to 1985, were examined. Significantly larger amounts of HBsAg, HBeAg and hepatitis B virus DNA in serum and HBcAg in liver were found in patients positive for both HBeAg/1 and HBeAg/2 in serum than in those positive for only HBeAg/1 or negative for both subtypes. These results suggest that the presence of HBeAg/2 in serum may reflect the occurrence of active viral replication. When the detection pattern of HBeAg subtypes was examined during serial follow-up for at least 1 year, three groups of patients were classified with respect to the presence of HBeAg/2, i.e., Type I, consistently positive for HBeAg/2; Type II, consistently negative for HBeAg/2, and Type III, intermittently positive for HBeAg/2. More than 80% of Type I patients were histologically diagnosed having as nonspecific reactive hepatitis, while more than 80% of Type II and III patients had more progressive liver diseases such as chronic persistent hepatitis, chronic active hepatitis and liver cirrhosis. These results suggest that the serial examination of HBeAg subtypes in serum may be important for more detailed evaluations of type B hepatitis.