Yoshitaka Fukuzawa

Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection.

Background : Tumour immunity does not seem to be induced effectively in tumour‐bearing hosts, including in patients with hepatocellular carcinoma (HCC). One possible reason is that function of dendritic cells (DC) is decreased in such hosts.

Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus.

Background: To examine the relationship between hepatitis C virus (HCV) infection and diabetes mellitus (DM) in Japanese populations, a retrospective study was done in 866 patients with chronic viral disease. Methods: The present study included 707 HCV-infected and 159 hepatitis B virus (HBV)-infected patients. The prevalences of HBV- and HCV-related cirrhosis were 32% and 33%, respectively. A case-control study was also conducted to determine the seroprevalence of HCV infection in a cohort of 459 diabetics. Results: The prevalence of DM was higher in HCV-infected patients (20.9%; P < 0.02) than in HBV-infected subjects (11.9%). In the cirrhotic patients, DM was observed in 30.8% of the subjects with HCV compared with 11.8% of those with HBV (P < 0.01). Multivariate analysis revealed that the major independent variables associated with type II DM were male sex (odds ratio, 1.54; p = 0.020) and cirrhosis (odds ratio, 1.97; P = 0.0007). The relative odds of the development of DM were calculated to be 3.2 times higher in HCV-infected cirrhotic patients than in HBV-infected ones. In the case-control study of the diabetic cohort, 10.5% of patients were infected with HCV compared with 1.1% with HBV (P < 0.0001). The results indicate that HCV infection is closely associated with DM, compared with HBV infection. Cirrhosis was an independent risk factor for DM. Conclusions: Taken together, the findings indicate that cirrhosis appears to be a more important predictor of glucose intolerance than HCV infection, and the combination of both factors increases the risk of DM in our populations.

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection

Background and Aim:  Evidence showing a higher prevalence of diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection has been accumulating. However, the reason why chronic HCV infection promotes DM remains unknown. In the present study, the authors focused on non‐cirrhotic and non‐diabetic patients with chronic HCV infection and evaluated the factors responsible for increases in insulin resistance.

Expression of Toll-like receptors in chronic hepatitis C virus infection

Background:  Toll‐like receptors (TLRs) are involved in innate immunity. Certain viruses interact with TLRs and mediate antiviral effects as well as immune responses. The aim of this study was to investigate the effect of TLRs on pathogenesis in hepatitis C virus (HCV)‐infected patients.

Gene mutation of transforming growth factor β1 type II receptor in hepatocellular carcinoma

Alteration of transforming growth factor β1 (TGF‐β1) type II receptor (RII) appears to cause unresponsiveness to TGF‐β1 in tumorigenic cells. Defect in the mononucleotide repeat sequence, i.e., poly A region of TGF‐β1RII gene has been reported to be related to replication error‐positive cancer cells. We examined if there is any TGF‐β1RII mutation in a coding microsatellite in hepatocellular carcinoma (HCC). Genomic DNAs were extracted from formalin‐fixed, paraffin‐embedded liver tissues obtained at surgery or autopsy in 3 normal individuals and 96 patients with hepatitis C virus‐induced chronic liver disease; 3 with chronic hepatitis, 20 with liver cirrhosis and 73 with HCC. The DNA was PCR‐amplified at 2 segments of TGF‐β1RII: poly A region which includes the (A)10 microsatellite sequence, and poly GT region. PCR products were directly sequenced. DNA from normal and patients with chronic liver disease contained the 10 wild‐type adenines but 3 cases with liver cirrhosis in whom there were only 9 adenines within poly A tract. This microdeletion of one A resulted in a frameshift and truncated a predicted length of amino acids. In HCC lesions, the same deletion was noted in 4 cases (25%) of well‐differentiated type, 10 (40%) of moderately differentiated type, 18 (53%) of poorly differentiated type. None of the lesions had mutations within the GT region. Our findings indicate that one adenine deletion of poly A microsatellite tract within TGF‐β1RII is frequently detected in patients with HCC, and the mutation may cause the abrogation of the function of TGF‐β1RII gene. Int. J. Cancer 81:851–853, 1999.

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)

Background. This study was conducted to examine the expression of Fas/Fas ligand (FasL), to elucidate its relationship with tumor-infiltrating lymphocytes (TILs), and to detect possible gene mutation of Fas/FasL in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). Methods. Indirect immunohistochemical staining was performed on formalin-fixed, paraffin-embedded sections of liver biopsy and surgery specimens from five normal livers, and from the livers of 30 patients with HCC. Fas/FasL mRNA-expressing cells and apoptotic cells were detected by in situ hybridization and DNA nick end labeling (TUNEL), respectively. We also performed polymerase chain reaction (PCR)-amplifying and direct sequencing for the Fas/FasL gene. Results. Fas/FasL and its mRNA were localized on the membrane or in the cytoplasm in some HCC cells, as well as hepatocytes. Their expression was enhanced in areas with infiltrating inflammatory cells in the noncancerous regions of liver tissue and on the margins of the cancerous tissue. The positivity rate for TUNEL was elevated along these margins. The labeling index of Fas/FasL was lower in the cancerous liver tissue than in the surrounding noncancerous region (P < 0.01), and tended to decrease in proportion to the malignancy of tumor cells; Fas/FasL expression was not found on poorly differentiated type cancer cells. Fas(−)/FasL(+), FasL-mRNA(+) HCC cells were seen in one specimen of moderately differentiated type. Some CD8+T lymphocytes were TUNEL-positive around the cancerous region. In this study, cancerous and noncancerous tissues in HCC revealed no genetic mutations in any exons of Fas/FasL. Conclusions. These findings suggest that Fas/FasL expression was decreased in proportion to the malignancy of tumor cells, and that infiltrating CD8+T lymphocytes play a role in apoptosis in HCC. The apoptosis in HCC could be regulated by the suppression of Fas/FasL expression, or, sometimes, by the enhancement of FasL expression.

Nutritional status and quality of life in current patients with liver cirrhosis as assessed in 2007-2011.

Current guidelines recommended adequate nutritional support for patients with liver cirrhosis to improve clinical outcome and quality of life (QOL). However, these evidences were obtained more than 10 years ago when malnutrition prevailed. In recent years, the impact of obesity on liver damage and carcinogenesis has grown. We attempted to elucidate the nutritional state and QOL in present cirrhotics.

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trials

OBJECTIVES Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. METHODS PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. RESULTS According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. CONCLUSIONS Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH.

Connective tissue configuration in the human liver hilar region with special reference to the liver capsule and vascular sheath

BACKGROUND/PURPOSE We carried out this study to examine the validity of the accepted dogma that: (1) the human liver capsule does not extend along the fissures for the hepatic veins; (2) the hilar vasculobiliary sheath does not connect to the liver capsule; and (3) the hilar plate is a thickening of the vasculobiliary sheath. METHODS Using cadaveric specimens, we identified composite fibers and other structures in the sheath and capsule histologically. RESULTS The liver capsule, Glissons sheath, and the sheath for the hepatic vein tributaries were characterized by a high content of thin, wavy elastic fibers. However, the hilar vasculobiliary sheath of the thick vessels and ducts did not contain elastic fibers. Along the roof of the hilar region, vaginal ductuli were identified as a chain of cross-sectional bile ducts with a relatively thick wall, because of their tortuous course with abundant small pouches budding from the surface. The ductuli were separated from the liver capsule by abundant lymphatic vessels. CONCLUSIONS The sheath for hepatic veins and Glissons sheath appear to connect to, and be continuous with, the liver capsule. During surgery and dissection, it should be borne in mind that the hilar plate is likely to be artificially developed when, without intention, surgeon bundle collagenous fibers with vaginal ductuli forming a core.

Pleuroperitoneal Canal Closure and the Fetal Adrenal Gland

Pleuroperitoneal canal (PP canal) closure is generally considered to result from an increase in the height, and subsequent fusion, of the bilateral pleuroperitoneal folds (PP folds). However, the folds develop in the area ventral to the adrenal, in contrast to the final position of the diaphragm, which extends to the dorsal side of the adrenal (the “retro‐adrenal” diaphragm). We examined the semiserial histology of 20 human embryos and fetuses (crown‐rump length 11–40 mm). We started observations of the canal at the stage through which the lung bud extends far caudally along the dorsal body wall to the level of the future adrenal, and the phrenic nerve has already reached the PP fold. Subsequently, the developing adrenal causes narrowing of the dorsocaudal parts of the canal, and provides the bilateral midsagittal recesses or “false” bottoms of the pleural cavity. However, at this stage, the PP fold mesenchymal cells are still restricted to the ventral side of the adrenal, especially along the liver and esophagus. Thereafter, in accordance with ascent of the lung, possibly due to anchoring of the liver to the adrenal, the PP fold mesenchymal cells seem to migrate laterally along the coelomic mesothelium covering some sheet‐like loose mesenchymal tissue behind the adrenal. Final closure of the PP canal by lateral migration to provide the “retro‐adrenal” diaphragm is a process quite different from the common dogma. It is likely that the sheet‐like loose mesenchymal tissue becomes the caudal part of the pleural cavity through a process involving cell death. Anat Rec, 2011.