Norihito Watanabe

Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background

BackgroundThe aim of this investigation was to elucidate the time-course of changes in the prevalence of fatty liver, and to analyze its clinical backgrounds over the previous 12-year period.MethodsThirty-nine thousand one hundred and fifty-one individuals who visited the Tokai University Hospital Health Checkup Center from 1989 to 2000 were examined for the presence of fatty liver, and their clinical backgrounds were analyzed.ResultsIn 1989, the prevalence of fatty liver was 12.6%, and it rose gradually thereafter, reaching 30.3% in 1998, corresponding to a 2.4-fold increase over the prevalence rate in 1989. The average prevalence was about twice as high in males (26.0%) as in females (12.7%). The prevalence was uniformly high in males in all ages, while the prevalence in females tended to rise gradually with age. Body mass index (BMI) was found to be the variable most closely related to the onset of fatty liver. On the other hand, nonobese individuals with a BMI of less than 25 kg/m2 accounted for approximately half of all the patients with fatty liver, and this proportion remained almost unchanged during the 12-year survey period. It was therefore difficult to simply attribute the increase in the prevalence of fatty liver to the increased prevalence of obesity. In the 35 519 repeat examinees (repeaters), it was found that 5088 individuals (14.3%) developed fatty liver, and fatty liver resolved in 1248 individuals (3.5%). As fatty liver developed, the BMI increased by 1.0 ± 1.3 kg/m2. As fatty liver disappeared, the BMI decreased by 1.0 ± 1.5 kg/m2.ConclusionsThese results suggest that the absolute value of the BMI, as well as the relative changes in the BMI in each individual, may be related to the onset of fatty liver.

Transcatheter arterial chemoembolization plus radiofrequency ablation therapy for early stage hepatocellular carcinoma: comparison with surgical resection.

Radiofrequency ablation (RFA) is becoming a well‐known local therapy for hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) is expected to enhance the effects of subsequent RFA by reducing arterial blood flow. However, the long‐term efficacy of this combined therapy has not been elucidated. In this study, the survival rates of patients who received TACE combined with RFA (TACE + RFA) were compared with those of patients treated surgically.

Current status of ectopic varices in Japan: Results of a survey by the Japan Society for Portal Hypertension

Aim:  The Clinical Research Committee of the Japan Society for Portal Hypertension has conducted a nationwide questionnaire survey to clarify the current status of ectopic varices in Japan.

Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis.

Aim:  We examined the clinical and pathological features of drug‐induced acute intrahepatic cholestasis (AIC) to elucidate the pathogenesis of prolonged cases.

Altered expression of a putative progenitor cell marker DCAMKL1 in the rat gastric mucosa in regeneration, metaplasia and dysplasia

BackgroundDoublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) is a candidate marker for progenitor cells in the gastrointestinal mucosa. Lineage cells in the gastric mucosa are derived from progenitor cells, but this process can be altered after injury. Therefore, we explored DCAMKL1 expression under pathological conditions.MethodsAn immunohistochemical analysis was performed in rat stomach with acute superficial injury, chronic ulcer, intestinal metaplasia and dysplasia.ResultsDCAMKL1 was exclusively expressed in immature quiescent cells in the isthmus of normal fundic glands, where putative progenitor cells are thought to reside. DCAMKL1-positive cells and proliferating cells shed into the lumen after superficial injury and re-appeared during the regenerative process, mainly in the superficial mucosa. In the marginal mucosa around the active ulcer, parietal and chief cells diminished, foveolar hyperplasia was evident, and trefoil factor family 2 (TFF2)/spasmolytic polypeptide-expressing metaplasia (SPEM) emerged at the gland base. DCAMKL1 cells re-emerged in the deep mucosa juxtaposed with SPEM and proliferating cells. In the healing ulcer, the TFF2 cell population expanded and seemed to redifferentiate to chief cells, while proliferating cells and DCAMKL1 cells appeared above and below the TFF2 cells to promote healing. SPEM appeared and PCNA cells increased in the intestinalized mucosa, and DCAMKL1 was expressed in the proximity of the PCNA cells in the deep mucosa. DCAMKL1, PCNA and TFF2 were expressed in different dysplastic cells lining dilated glands near SPEM.ConclusionThe ultrastructural appearance of DCAMKL1-positive cells and the expression patterns of DCAMKL1 in normal and pathological states indicate that the cells belong to a progenitor cell population. DCAMKL1 expression is closely associated with TFF2/SPEM cells after injury. DCAMKL1 cells repopulate close to proliferating, hyperplastic, metaplastic and dysplastic cells, and the progenitor zone shifts according to the pathological circumstances.

Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma.

Localization of P-glycoprotein (P-gp) and p53 was immunohistochemically examined in 41 patients with hepatocellular carcinoma (HCC) in order to determine the relationship between the expression of P-gp and p53 and the degree of histological differentiation or cell proliferation in HCC. P-gp showed different patterns of expression between cancerous and cirrhotic liver hepatocytes, and the expression in cancerous tissue also varied according to the degree of histological differentiation. In cirrhotic liver hepatocytes, expression of P-gp was found on bile canalicular membranes. In the case of cancerous tissue, P-gp was localized on the canalicular membranes in well-differentiated HCC showing a trabecular pattern, as recognized cirrhotic liver hepatocytes. In moderately differentiated HCC showing pseudo-glandular patterns, predominant expression of P-gp was found on the luminal side of cell membranes of the glandular ducts. The P-gp expression rate was 87.5% in well-differentiated HCC, 84% in moderately differentiated HCC, and 37.5% in poorly differentiated HCC, indicating a marked decrease with decreasing degree of differentiation. On the other hand, the rate of mutation of p53, a tumor suppressor gene, was 12.5% in well-differentiated HCC, 52.0% in moderately differentiated HCC, and 85.5% in poorly differentiated HCC, showing a significant increase with decreasing degree of differentiation (P<0.005). The labeling index (LI) of proliferating cell nuclear antigen (PCNA) tended to increase with the progression of chronic liver disease, with a markedly high value of 24.0+/-1.5% in cases of HCC. The PCNA LI was 15.6+/-11.9% in well-differentiated HCC, 23.1+/-15.1% in moderately differentiated HCC, and 50.1+/-13.3% in poorly differentiated HCC, which indicated a significantly increase in poorly differentiated HCC (P<0.001). Thus, it became apparent that abnormal expressions of P-gp and p53 and the cell proliferation in HCC vary according to the degree of histological differentiation of the malignancy. This suggests that more effective chemotherapy for HCC can be potentially developed by considering the pattern and level of expression of P-gp as a mechanism of drug resistance and the extent of histological differentiation.

Balloon-occluded transarterial chemoembolization using a 1.8-French tip coaxial microballoon catheter for hepatocellular carcinoma: technical and safety considerations.

Abstract Objective: To evaluate the technical feasibility and safety considerations of balloon-occluded transarterial chemoembolization (B-TACE) using a newly developed 1.8-French (Fr) tip microballoon catheter for hepatocellular carcinoma (HCC). Material and methods: Between February 2013 and May 2013, 31 patients (20 males, 11 females; age range 56–85 years) underwent B-TACE using a 1.8-Fr tip microballoon catheter for unresectable HCC. The technical success rate, procedural complications, and adverse events of B-TACE were retrospectively investigated. Results: A total of 31 patients were subjected to 70 sessions of B-TACE using a 1.8-Fr tip microballoon catheter. The level of B-TACE was sub-subsegmental in 11, subsegmental in 35, segmental in 14, lobar in five, and right inferior phrenic artery in five sessions. The overall technical success rate was 99% (69 out of 70 sessions). As procedural complications, rupturing of the microballoon (n = 3) and aneurysmal dilatation at the site of balloon occlusion (n = 2) were encountered. There were no significant differences in any parameters between blood biochemical examination before and between two to four weeks after the procedure. Conclusion: A 1.8-Fr tip microballoon catheter enables selective catheterization in patients with HCC and B-TACE using the 1.8-Fr tip microballoon catheter is a safe procedure.

An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae: implications for endothelin-1 in hepatic microcirculation

BackgroundSinusoidal endothelial fenestrae (SEF) regulate the sinusoidal circulation by altering their diameter and number. This study documented the effects of endothelin (ET) receptor antagonists on SEF and hepatic microcirculation.MethodsThe portal pressure and hepatic tissue blood flow were measured with a hydromanometer and a laser Doppler blood flow meter, respectively. BQ-123 (ETA receptor antagonist) or BQ-788 (ETB receptor antagonist) was continuously infused into normal rats at the rate of 10 nmol/min for 10 min. The sinusoids were observed at 60 min after the infusion by scanning electron microscopy. The localization of ET-1 and ETA and ETB receptors was examined by the indirect immunoperoxidase method.ResultsWhen BQ-123 was infused, the portal pressure gradually decreased with time, and it showed a significant reduction compared with the control groups. On the other hand, a decrease in portal pressure was not evident in the BQ-788-infused groups. Hepatic tissue blood flow was maintained at the value prior to the infusion in both groups. BQ-123 also caused a marked dilatation of the SEF. The diameters of the SEF after BQ-123 infusion were almost three times those of normal SEF. ET-1 was evenly present along the sinusoidal walls, and the reaction products of the ETA receptors were recognized along the portal vein and in the sinusoidal cells, that is, the hepatic stellate cells and endothelial cells.ConclusionsAction of ET-1 via the ETA receptors may regulate the size of SEF in addition to hepatic microcirculation.

Serum concentrations of soluble HLA-class I and CD8 forms in patients with viral hepatic disorders

Soluble HLA-class I and CD8 molecules were determined by sandwich ELISA in patients with viral-induced hepatic disorders. As a whole, the patients with hepatic disorders (acute hepatitis: AH; chronic hepatitis: CH; liver cirrhosis: LC; hepatocellular carcinoma: HCC) showed higher sHLA-class I and sCD8 levels than normal controls (P<0.001). AH patients had the highest sHLA-class I levels (mean, 3513±2112ng/ml), followed by CH (2896±1290ng/ml), LC (2293±1266ng/ml), and HCC (2221±1212ng/ml) sCD8 levels were highest in AH, followed by HCC, LC, and CH, in that order. Among histologically defined C virus-positive patients, sHLA-I levels were higher in those with chronic active hepatitis (CAH) 2A (3802±1124ng/ml) than in those with chronic persistent hepatitis (CPH; 2200±711ng/ml;P<0.01), the levels then decreased as the disease progressed (CAH2B, 3564±1783ng/ml, LC, 2376±1265ng/ml). In contrast, sCD8 values showed little difference among the disorders. sHLA-class I levels showed a positive correlation with sCD8 values both in whole patients and in patients with AH (P<0.01), but no correlation was shown, in any patients, with biochemical parameters such as GPT and GOT. These findings, taken together, suggest that hepatic destruction is not the only cause of sHLA-class I production, but that sHLA-class I levels, together with sCD8 levels, may reflect immunological activity in hepatic disorders.

Serum soluble HLA-DR antigens in autoimmune hepatitis.

To investigate the significance of HLA-class II, especially DR antigens, in autoimmune hepatitis (AIH), the serum concentrations of soluble HLA-DR antigen (sDR) were measured in 16 patients with AIH. The expression of HLA-DR antigens in the liver tissues of AIH patients was also studied by immunohistochemistry. AIH at diagnosis showed markedly higher serum sDR levels than controls, in which the liver tissues exhibited positive staining of HLA-DR antigens. Seven patients received corticosteroid therapy, in whom the serum sHLA-DR concentration was reduced dramatically from activated to remission stage. In sequentially follow-up cases, sDR correlated well with the disease activity, and also with the change of surface DR expression in the liver. A single major band with a molecular size of 60 kDa was detected, both in patients sera and in normal control sera, by Western blotting. In conclusions, serum sHLA-DR level could be a marker reflecting immunological activity of the disease.