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To determine whether detection of IgM type antibody (Ab) to hepatitis C virus (HCV) antigens would be useful in the early diagnosis of type C acute hepatitis (AH) or fulminant hepatitis (FH), we assayed serum IgM and IgG type Abs to nonstructural (C100-3) and core (AR 142) antigens of HCV in patients with type C hepatitis. Of 8 patients with AH, anti-C100-3 IgM and anti-AR 142 IgM were positive in 1 and 6 patients, respectively. Early appearance of Anti-AR 142 IgM was observed in all of these 6 patients, and in 4 anti-AR 142 IgM was the sole serological marker of HCV infection during the acute-phase. However, the anti-AR 142 IgM response was rather persistent, not transient in AH. Only 1 patient with AH was positive for anti-C100-3 IgM, and this patient became positive for anti-AR 142 IgM 3 months before the appearance of anti-C100-3 IgM. The titre of anti-AR 142 IgM in AH was not dependent on the activity of hepatitis or on the duration. Anti-AR 142 IgM was also positive in 30-75% cases with chronic HCV carriers. Thus it is suggested that the detection of anti-AR 142 IgM may contribute to the early diagnosis of type C AH, although the appearance of this marker in chronic HCV carriers limits its usefulness as the sole serological marker of acute HCV infection.

The clinical and biochemical features of patients with autoimmune hepatitis (AIH) in Japan during the 15-year period, 1975 to 1990, were evaluated by a nationwide survey using a questionnaire prepared by the Intractable Diseases Study Group organized by the Ministry of Health and Welfare. Data on a total of 866 cases with AIH were collected and analyzed, and of these, 632 cases underwent follow-up study. AIH was predominant in females, with a male:female ratio of approximately 2:19. Biochemical investigation on the occasion of the first examination showed abnormalities of liver function tests, including increased serum total bilirubin, transaminase activity and gamma-globulin levels. The main complications of autoimmune diseases were rheumatoid arthritis, Sjögren's syndrome and chronic thyroiditis. All patients with complications were female. Of 253 AIH patients, 50 were positive for anti-C100-3 antibody. ICG clearance and platelet count, which are stigmata of liver cirrhosis, were the main factors of prognostic importance in AIH. Therefore, early diagnosis prior to the development of liver cirrhosis is important to improve the prognosis of AIH.

To determine whether identification of subclasses of anti-HCV IgG would help distinguish between acute and fulminant hepatitis, we assayed serum IgG subclasses of anti-HCV (C100-3) in non-A, non-B hepatitis. Anti-HCV IgG was restricted to two subclasses in different diagnostic conditions; anti-HCV IgG1 and anti-HCV IgG3. Anti-HCV IgG1 was the main subclass in acute hepatitis (AH), and was positive in all the cases and only one case was positive for anti-HCV IgG3. Anti-HCV IgG3 was the dominant subclass in fulminant hepatitis (FH). Out of the total 12 cases of FH, who were positive for either anti-HCV IgG or for any of it's subclasses, in 10 cases (83%), anti-HCV IgG3 had higher optical density (OD) values than anti-HCV IgG1 and in 6 cases (50%) was the only subclass of anti-HCV IgG being positive. In 5 cases with FH, anti-HCV IgG3 became positive even when anti-HCV IgG was negative. These findings from the basis of a new observation and are likely to be helpful in the diagnosis of non-A, non-B fulminant hepatitis.

To study the intrafamilial transmission of hepatitis C virus (HCV), 36 family members of 16 patients with anti-HCV (anti-C100-3)-positive chronic liver disease were screened for anti-HCV by an enzyme-linked immunosorbent assay (ELISA). Clusters of anti-HCV-positive individuals were observed in 2 of 16 families (12.5%). Four of 35 family members (11.4%) with no history of blood transfusion were positive for anti-HCV. Two of 17 offspring (11.8%) of anti-HCV-positive females were positive for anti-HCV, while 1 of 5 spouses (20.0%) was positive for anti-HCV. These data suggest that intrafamilial transmission is one of the possible routes of infection for HCV.

To clarify the relationship between autoimmune hepatitis (AIH) and the hepatitis C virus (HCV), we investigated the prevalence of antibodies to HCV (anti-HCV) by an enzyme-linked immunosorbent assay in patients with AIH, primary biliary cirrhosis (PBC), rheumatoid arthritis and multiple myeloma. The antibody was detected in 9 out of 18 patients with AIH (50%), in 3 out of 23 with PBC (23%), in 2 out of 10 with rheumatoid arthritis (20%), and in 5 out of 9 with multiple myeloma (56%). However, the optical density values in these patients were lower than those observed in non-A, non-B hepatitis (NANBH). Anti-HCV became negative immediately after the initiation of glucocorticoid therapy in all four antibody-positive AIH patients tested. The extracted immunoglobulin G fraction from sera of 5 anti-HCV negative AIH patients became positive for the antibody. This phenomenon was not observed in 5 normal volunteer sera. The 9 family members of three anti-HCV positive AIH patients showed no anti-HCV positivity. These results suggest that autoantibodies in AIH patients may cross-react with the HCV-related antigen. Direct association of the HCV influencing the development of AIH is unlikely. Therefore, care should be taken in the evaluation of anti-HCV positivity in patients with autoimmune diseases and multiple myeloma.

A multi-center double-blind controlled trial of ursodeoxycholic acid (UDCA) for treatment of primary biliary cirrhosis (PBC) was carried out. Twenty two and 23 patients were treated with 600 mg/day UDCA and placebo, respectively, for 24 weeks. In UDCA-treated patients, fall of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma-glutamyltranspeptidase activities started within 4 weeks after start of the trial and continued throughout the trial period. The serum IgM level fell in 7 UDCA-treated patients examined but not in 10 placebo-treated patients examined. Serum bilirubin concentration showed no significant change at the end of the study in either of UDCA- and placebo-treated group of patients. There was no significant difference between these two groups with respect to the frequency of improvement of pruritus. In UDCA-treated patients, serum bile acid composition changed markedly, though its concentration showed no significant change. The percentage of total bile acid which ursodeoxycholic acid took up increased, whereas those which cholic acid, chenodeoxycholic acid and deoxycholic acid took up were decreased.

The effect of sera from 8 patients with fulminant hepatitis, including 2 survival cases, on DNA and protein synthesis in primary cultured rat hepatocytes was studied. The serum from patients at an early stage or within 10 days after onset tended to intensify DNA synthesis in isolated hepatocytes, whereas the serum from patients with a history of over 50 days distinctly inhibited synthesis. When the serum was fractionated by gel filtration or free-flow electrophoresis, only the albumin fraction inhibited DNA synthesis in cultured hepatocytes. The suppressive effect of the albumin fraction was demonstrated even in patients suffering for only a short period of time. The inhibitory activity against DNA and protein synthesis in cultured hepatocytes was demonstrated in a substance extracted with a chloroform and methanol mixture from the albumin fraction of patients with fulminant hepatitis. The extract from the patients' sera also inhibited acceleration of DNA synthesis by epidermal growth factor (EGF) in the same cells.

The immunoelectron microscopic localization of actin in hepatocytes was studied in normal, common bile duct-ligated, and phalloidin treated rats. We used the low temperature embedding procedure with Lowicryl K4M and protein A-gold technique was applied to demonstrate the localization of actin. The tissues embedded in Lowicryl K4M at low temperature provided good preservation of ultrastructure and antigenicity of actin. In control rats bile canaliculi were clearly visualized and most of the gold particles were observed on the bile canalicular microvilli, at the pericanalicular ectoplasm, at the cell border, and on the sinusoidal microvilli. In common bile duct-ligated rats and phalloidin treated rats, pericanalicular ectoplasm was thickened and many gold particles were seen there.

The cytoskeletons of hepatocytes and biliary epithelial cells in bile duct ligated rate livers were investigated by transmission and scanning electron microscopy. The three dimensional organization of the intermediate filaments (IFs) of hepatocytes and biliary epithelial cells was clearly demonstrated by scanning electron microscopy. Cell borders and dilated bile canaliculi were well preserved after perfusion with detergent solution. A very dense filamentous network of IFs was seen throughout the cytoplasm, especially around the dilated bile canaliculi and at the cell borders. IFs in biliary epithelial cells were more numerous compared with hepatocytes. Morphometric analysis showed that the IFs of hepatocytes significantly (p greater than 0.001) increased in amount in bile duct ligated rats. The IFs of biliary epithelial cells showed no significant changes in bile duct ligated rats compared to controls. These results suggest that the increase in IFs in hepatocytes results from the adaptation of the hepatocytes to the stress imposed by bile duct ligation. It may be that the resulting intracanalicular pressure and back diffusion of bile induces a metaplastic change in hepatocytes so that they acquire more IFs to function like the bile duct epithelium to conduct bile flow.

A case study is presented of a 57-year-old male who showed typical clinical features of Cronkhite-Canada syndrome. Numerous polypoid lesions were found in the stomach, duodenum, ileum, colon and rectum accompanied with characteristic ectodermal changes. Tests indicated a protein-losing gastroenteropathy. Intestinal lactase deficiency was demonstrated by the lactose tolerance test. Scanning electronmicroscopy of the gastric and colonic mucosa revealed prominent secretion of mucoid substances and distortion in the gastric pits and colonic crypts. These abnormal findings were interpreted as having a direct relationship to the loss of protein into the gastrointestinal tract.