Makoto Kako

Transmission of Hepatitis C Virus from Mothers to Infants

Background Although there are case reports of vertical transmission of hepatitis C virus (HCV), it remains uncertain to what extent infected mothers transmit this virus to their infants. Methods We investigated the transmission of HCV from infected mothers to their babies by analyzing HCV RNA in the blood. Three independent studies were performed. First, 7698 parturient women were tested for anti-HCV antibodies; 53 were positive. Their 54 infants (including one set of twins) were followed prospectively for at least six months and tested for HCV infection. Second, the babies of six women with known HCV disease were prospectively studied. Third, the families of three HCV-infected infants were examined retrospectively. Results Of the 53 antibody-positive mothers, 31 were also positive for serum HCV RNA. Three of the 54 babies born to these mothers (5.6 percent) became positive for HCV RNA during the follow-up period. None of the babies of the 22 women who were antibody-positive but HCV RNA-negative became po...

Indirect evidence of TTV replication in bone marrow cells, but not in hepatocytes, of a subacute hepatitis/aplastic anemia patient

The presence of a new DNA virus (TTV) has been reported in sera from patients with posttransfusion hepatitis of unknown etiology. The precise replication site of TTV, however, has not been established. In this study, the presence of TTV in liver autopsy material, and in bone marrow biopsy and autopsy samples taken from a subacute hepatitis/aplastic anemia patient was determined by PCR and Southern blot analyses. Liver cells were found to contain only TTV DNA and not mRNA. Bone marrow material, especially that taken at biopsy, contained high levels of TTV DNA. It is suggested that the TTV replication site was in the bone marrow rather than in the liver, and that TTV infection was the cause of this patients aplastic anemia. The precise etiological association of TTV with hepatitis remains to be established. J. Med. Virol. 61:165–170, 2000.

Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture

BackgroundThe prevalence of antimitochondrial antibody (AMA) in humans and its relationship to the development of primary biliary cirrhosis (PBC) are not well known. We have estimated the frequency of AMA in the general population, and studied its association with PBC.MethodsWe studies 1714 corporate workers (median age, 48 years; range, 30 to 59 years) who had an annual health check from 1998 to 1999 at Kawasaki Social Insurance Hospital in Japan. We used an indirect immunofluorescence method for screening serum AMA. We applied the prevalence of AMA-positive people in the study group to the general population in Japan. Then the inferred AMA-positive population was compared to the actual number of patients with PBC in statistics published by the Japanese Government.ResultsAMA was detected in 11 of 1714 people (0.64%; 95% confidence interval, 0.26% to 1.02%). All these 11 sera reacted with 2-oxoacid-dehydrogenase complex by immunoblotting. Of these 11 individuals, none had subjective symptoms, all had normal serum bilirubin levels, and 6 had abnormal liver function test results. Using published statistics for the Japanese population, we inferred that there were approximately 336 472 AMA-positive people in Japan from age 30 to 59 years. The number of patients with symptomatic PBC recorded by the nationwide epidemiological survey of the Japanese Government was 2459. Thus, we inferred the rate of symptomatic PBC among AMA-positive persons to be about 0.73% (2459/336 472).ConclusionsAMA is not a rare antibody in the general population, but few people develop recognizable PBC even if they have AMA.

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study.

Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis.

Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis

To determine whether “autoimmune hepatitis type IIb” should be categorized as a subgroup of autoimmune hepatitis, we conducted a clinicopathological study of 25 adult Japanese patients who were positive for anti-liver/kidney microsome-1 (anti-LKM-1) antibody and infected with the hepatitis C virus (HCV). Anti-LKM-1 was determined by indirect immunofluo-rescence and by the double immunodiffusion assays we have developed. Twenty-two patients did not present any unusual symptoms or any associated diseases during the course of their chronic HCV infection. The spectrum of HCV genotypes of these patients did not significantly differ from that of anti-LKM-1-negative Japanese patients with chronic hepatitis C. Histological examination of liver biopsy specimens showed the usual characteristics of chronic hepatitis C and lack of characteristics of autoimmune hepatitis type I. No disease-specific HLA haplotypes were noted, and HLA-DR4, which is detectable in 88.7% of Japanese patients with autoimmune hepatitis type I, was detected in only 50.0% of our group, the same rate as the background frequency. Prednisolone was effective in none of the six patients treated, but interferon was effective in six of ten treated patients (60%). From these results, we conclude that “autoimmune hepatitis type IIb” should not be categorized as autoimmune hepatitis, and that this subgroup is essentially chronic hepatitis C in which an autoantibody has been produced during the course of chronic HCV infection.

Interferon-α2a for chronic hepatitis B with e antigen or antibody: comparable antiviral effects on wild-type virus and precore mutant

Summary. Recombinant interferon‐α2a (IFN‐α2a) in a total dose of 702 MU was given to 31 patients: nine with wild‐type hepatitis B virus (HBV) and hepatitis B e antigen (HBeAg) (A); four with HBeAg and a mixed infection with wild‐type HBV and precore mutants (B); 11 with antibody to HBeAg (HBeAb) and a mixed infection (C); and seven with HBeAb and precore mutants alone (D). HBV DNA was not cleared in any patient in groups A and B. By contrast, in patients with HBeAb, HBV DNA was ultimately lost in four patients in group C, as well as in 10 patients in group D. Thus, patients with HBeAb and infected with precore mutants alone (D) lost serum HBV DNA more often than those with HBeAg and wild‐type HBV (A). Patients with low pre‐treatment levels of HBV DNA cleared virus more frequently, and the response of precore mutant to IFN was comparable with that of wild‐type HBV in patients who had a mixed infection. Based on these results, precore mutants do respond to IFN, and therefore, IFN is indicated in patients with HBeAb, especially those with low serum HBV DNA levels.

CASE REPORT: Vanishing Bile Duct Syndrome Associated with Chronic EBV Infection

We reported here an adult patient with vanishing bile duct syndrome due to chronic EBV infection. A 22-year-old male was admitted to a nearby hospital complaining of a sore throat and jaundice. He received a high dose of prednisolone for bile stasis of acute viral hepatitis. However, the hepatitis did not improve, and he was transferred to our hospital. He had exhibited jaundice for one year as well as hemophagocytic syndrome and intestinal perforation. Subtotal intestinal resection was successfully performed. Three follow-up biopsied liver specimens indicated vanishing bile duct syndrome. Positive results of EBV-DNA in his serum and mRNA of EBV by in situ hybridization of his liver indicated that massive doses of prednisolone caused chronic EBV infection and vanishing bile duct syndrome.

Serial changes of serum anti-M2 proteins in patients with primary biliary cirrhosis: a follow-up study by immunoblotting

Abstract To investigate the pathogenic role of M2 components in primary biliary cirrhosis (PBC), we studied the serial changes of serum anti-M2 protein profiles by immunoblotting in 21 patients with PBC who were observed for at least 3 years. Immunoblotting was done using bovine heart mitochondrial fraction as the antigen. First, we confirmed the antigen specificity by inhibition tests using recombinant proteins associated with two types of major M2 proteins. At the initial examination, 15 patients showed positivity for the 74-kDa protein corresponding to anti-PDC-E2, and 19 patients showed the 50-kDa protein corresponding to anti-BCOADC-E2. In subsequent examinations, four of the 21 patients continuously did not show the 74-kDa protein and only one patient showed the 50-kDa protein although it was not detected at the initial examination. The anti-M2s other than 74-kDa protein, especially 50-kDa protein, showed almost no changes from the initial examinations. These data indicate that part of the onset and development of PBC is highly associated with M2 proteins other than PDC-E2.

Detection of anti-LKM-1(anti-CYP2D6) by an enzyme-linked immunosorbent assay in adult patients with chronic liver diseases

Anti-liver kidney microsome-1 (LKM-1) autoantibody, which is a serological marker for autoimmune hepatitis type II, recognizes Cytochrome P450 IID6 (CYP2D6). This autoantibody is also detected in a portion of patients with chronic hepatitis C. Anti-LKM-1 has been measured by indirect immunofluorescence (IF) using rat liver and kidney sections. However, this method has some problems in specificity and is so laborious to handle with many samples. In this study, in order to determine anti-LKM-1, we established an enzyme-linked immunosorbent assay (ELISA) for anti-CYP2D6 using a recombinant CYP2D6 fusion protein. We studied sera from 29 patients positive for anti-LKM-1 by the new ELISA. We further studied sera from a total of 301 patients with various liver diseases and 100 sera from normal controls negative for anti-LKM-1 by the new ELISA. The specificity of the ELISA was ascertained by absorption tests using sera positive for anti-LKM-1. In 29 sera from patients positive for anti-LKM-1 by IF, we found a good correlation between the logarithms of the antibody titers determined by IF and ELISA indexes obtained by our new method. Anti-CYP2D6 was positive in 12 of 12 (100%) patient with autoimmune hepatitis type II and 16 of 17(94.1%) with chronic hepatitis C positive for anti-LKM-1 by IF. In other 401 sera negative for anti-LKM-1 by IF, anti-CYP2D6 was all negative except a few sera. We established a new ELISA for anti-LKM-1 (anti-CYP2D6). This ELISA system is sensitive, antigen-specific and easy to be done. Therefore, this assay allows a routine test of many serum samples, especially for diagnosing autoimmune hepatitis type II.

Ursodeoxycholic acid therapy for chronic type C hepatitis: A multicenter, dose-finding trial

Abstract Ursodeoxycholic acid (UDCA) was administered orally for 12 weeks to 40 patients with chronic type C hepatitis. Patients were randomly assigned to receive UDCA 150 mg/day (n = 20) or 450 mg/day (n = 20). In the 450-mg group, alanine aminotransferase (ALT) decreased significantly ( P P P P