Yukihisa Ueno

Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection

BACKGROUND Hepatocellular carcinoma (HCC) commonly develops in patients with chronic hepatitis or cirrhosis of the liver caused by hepatitis-C-virus (HCV) infection. We prospectively studied whether irregular regeneration of hepatocytes is a risk factor for HCC in these patients. METHODS 242 patients were enrolled after liver biopsy and followed up by ultrasonographic scanning every 3 months. We examined age, sex, platelet count, the diagnosis of cirrhosis or chronic hepatitis, liver-cell dysplasia, and irregular regeneration. We classified irregular regeneration as slight or severe, based on histological expression of pleiomorphism, anisocytosis, bulging, and map-like distribution of hepatocytes. FINDINGS 37 of 63 patients with cirrhosis and 26 of 179 with chronic hepatitis were judged to have severe irregular regeneration. HCC was diagnosed in 33 of 63 patients with cirrhosis (29 had severe irregular regeneration) and 12 of 179 patients with chronic hepatitis (11 had severe irregular regeneration) during mean follow-up of 5.5 years (SD 4.1; range 1-16). Multivariate analysis with a proportional-hazards model showed severe irregular regeneration (relative risk 15.1 [95% CI 5.6-40.7], p<0.0001) and a diagnosis of cirrhosis (3.8 [1.7-8.2], p=0.0008) to be significant risk factors for HCC. Within the diagnostic categories, irregular regeneration was also significant (cirrhosis 6.8 [2.1-21.9], p=0.0014; chronic hepatitis 28.5 [2.9-276.4], p=0.0038). INTERPRETATION We recommend that liver biopsy to look for irregular regeneration should be done in patients with HCV-related chronic liver diseases. Those with severe irregular regeneration should be followed up carefully.

Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study

Primary biliary cirrhosis (PBC) sera contain antibodies which recognize various nuclear envelope proteins of which antibody against gp210 has been proven to be diagnostic for disease. In contrast, the clinical significance of another nuclear envelope antibody, anti-p62 antibody has not been well investigated. In the present study, we have analyzed anti-nuclear envelope antibodies by indirect immunofluorescence and immunoblot using rat liver nuclear envelope proteins and wheat germ agglutinin-bound fraction. Test sera were obtained from 175 patients with PBC and from 120 controls. Anti-gp210, anti-lamina associated polypeptide 2, anti-lamin B receptor, and anti-p62 complex antibodies were detected with a frequency of 26% (46 of 175), 6% (11 of 175), 9% (16 of 175), and 13% (15 of 115), respectively. The confirmation of Scheuers stage IV was made with a frequency of 27% (4 of 15) in PBC patients with anti-p62 complex antibody, in contrast to only 2% (2 of 100) in PBC patients without anti-p62 complex antibody. This difference was found to be statistically significant. The presence of anti-p62 complex antibody may be related with the progressive or advanced state of PBC.

Clinicopathological study of proliferating cell nuclear antigen (PCNA) of hepatocytes in primary biliary cirrhosis

The DNA synthesis activities of hepatocytes in primary biliary cirrhosis (PBC) and other chronic liver diseases and control subjects were examined by staining proliferating cell nuclear antigen (PCNA) with anti-PCNA monoclonal antibody. The number of PCNA-positive cells (PCNA value) was significantly higher in PBC (375±281 parts per thousand; ppt) than in other chronic liver diseases, i.e., chronic hepatitis (95±83 ppt), liver cirrhosis (72±71 ppt), and alcoholic liver disease (73±56 ppt), and in control subjects (11±14 ppt). The PCNA value of PBC in stages I-III of Scheuers classification was remarkably high, while in stage IV it was low. Even in identical, Scheuers stages, the PCNA value of PBC was higher in patients who were not given ursodeoxycholic acid (UDCA) than in those who received UDCA. In identical patients, the PCNA value was lowered significantly after UDCA treatment. It was concluded that the DNA synthesis activity of PBC in stages I-III was accelerated and that UDCA can alleviate the abnormality in DNA synthesis activity.

Autoantibodies against nuclear envelope in patients with primary biliary cirrhosis

Abstract Antinuclear antibodies (autoantibodies) specific for nuclear envelope (NE) have been identified in patients with primary biliary cirrhosis (PBC). Using an indirect immunofluorescence method, we determined the sensitivity and specificity of these autoantibodies for the diagnosis of PBC and examined their clinical significance. Autoantibodies against NE (anti-NE) were detected in 19 (33%) of 57 patients with PBC and 2 (0.4%) of 523 control individuals. Out of 21 patients positive for anti-NE, 19 (90%) patients suffered from PBC and 16 of them had antimitochondrial antibodies (AMA). The presence of anti-NE had a sensitivity of 33% and specificity of 90% for the diagnosis of PBC. Using western blotting of HeLa cell extracts we found that sera from 12 (63%) out of 19 patients with PBC positive for anti-NE recognized antigens with a molecular weight of approximately 200 kilodaltons (kDa). Anti 200 kDa proteins were detected in 12 (27%) out of 44 patients with PBC by immunoblotting. There were a few significances in the clinical, immunological, biochemical and histological features between the patients with and without anti-NE. Anti 200 kDa proteins were found in 3 (50%) out of 6 patients with PBC negative for AMA, whereas these antibodies were detected in 9 (24%) out of 38 patients with PBC positive for AMA. Anti-NE are specific for the diagnosis of PBC and can be considered as a new marker of a subset of PBC, being present in some patients even when AMA are absent.

A patient with hepatitis C-related liver cirrhosis and hepatocellular carcinoma who was cured with an orthotopic liver transplantation and interferon therapy

A patient with hepatitis C virus (HCV)-related liver cirrhosis and hepatocellular carcinoma (HCC) was treated successfully with an orthotopic liver transplantation (OLT) followed by interferon therapy. The 36-year-old Japanese man was diagnosed as having liver cirrhosis in 1983. HCC was detected in 1991, and by 1994, jaundice and ascites had developed. The patient underwent OLT in June 1995, after which hepatitis C recurred, with elevated aminotransferases. His liver biopsy specimen showed chronic active hepatitis. He was given interferon-alpha three times weekly for 24 weeks in 1999. Six months after the end of the interferon treatment, the patients serum HCV RNA became negative, with normalization of aminotransferases, and his liver histology exhibited amelioration of fibrosis and inflammation. At the present time, he remains free of HCC (more than 6.5 years after the OLT) and free of HCV RNA (more than 2.5 years since interferon therapy was completed). This is the first Japanese patient whose HCC was cured by OLT and HCV was eradicated by interferon therapy.

Laparoscopic Findings of Asymptomatic Primary Biliary Cirrhosis —Particular investigation in early PBC—

Abstract: of 17 cases of asymptomatic primary biliary cirrhosis (PBC), seven cases whose ALP (alkaline phosphatase) was less than twice the upper limit of the normal range were defined as being “early PBC”, and ten cases whose ALP was more than twice the upper limit of the normal range were defined as being “classical PBC” in order to investigate their clinical pictures and laparoscopic findings.

Laparoscopic Findings of the Liver of Adult T cell Leukemia with Hepatic Injury— A Case Report

Abstract: A 54 year‐ old man was admitted to our hospital because of general fatigue and marked hepato ‐splenomegaly. Laboratory findings revealed marked leukocytosis including atypical lymphocytosis and abnormalities in the hepatic function tests. A diagnosis of acute stage of adult T‐cell leukemia (ATL) was made from his positive serum anti‐ATL (HTLV‐1). Since the complication of alcoholic liver disease could not be ruled out because of his heavy consumption of alcohol, hepato ‐ splenomegaly and abnormal liver function tests, a laparoscopic examination was performed. The laparoscopic findings of the liver revealed it was yellow / brown in color, and showed swelling of both lobes, granular unevenness and diffuse white markings on the surface. Histological findings of the liver biopsy specimen revealed an enlargement of the portal areas with diffuse infiltration of ATL cells but no evidence of alcoholic liver diseases. It is suggested that the white markings on the liver surface, which showed slight elevation unlike those seen in chronic hepatitis, might reflect an infiltration of ATL cells.