Koshi Shimanaka

Histochemical Study of Hyaluronate in Alcoholic Liver Disease

Recently, it has been reported that serum hyaluronate (hyaluronic acid; HA) concentrations increase in various liver diseases, especially in alcoholic liver disease (ALD), and serum HA concentration has been used as a marker for hepatic fibrosis. However, it is unknown whether hepatic HA contents in ALD increase by alcohol or not. In this study, we histochemically stained HA in liver biopsy specimens obtained from ALD patients while actively drinking and after abstinence to clarify the effects of alcohol on hepatic HA contents. Liver biopsy specimens were obtained from 13 patients with ALD and 10 patients with non-ALD. In ALD patients, liver biopsy was performed twice within 3 days, and 4 to 8 weeks after abstinence when serum levels of AST and ALT normalized. HA in biopsy specimens was stained histochemically with biotinylated HA binding protein. Staining intensity of HA in liver tissue was also determined by computer-assisted imaging analyzer. HA staining was clearly observed in sinusoidal wall and fibrous regions around the portal tract and central vein in liver diseases. HA staining intensities in patients actively drinking with ALD increased markedly, compared with those in patients with non-ALD, and these intensities decreased with abstinence. These results clearly suggest that hepatic HA contents in ALD may be increased by alcohol in addition to hepatic fibrosis, and, therefore, increased HA deposition in the liver may be reversible by abstinence of alcohol.

Clinicopathological study of chronic hepatitis induced by alcohol with or without hepatitis G virus

The concept of chronic hepatitis induced by alcohol (AL-CH) has not been widely accepted, because AL-CH may be due to non-A-E hepatitis virus in heavy drinkers. Recently, hepatitis G virus (HGV) was identified as a positive-strand RNA virus related to members of the Flaviviridae family. In this study, we determined serum HGV in patients with AL-CH and analyzed the clinicopathological changes after abstinence to evaluate whether AL-CH is caused by alcohol or not. Serum samples were obtained from 16 patients with AL-CH who had neither hepatitis B nor C virus. The diagnosis was confirmed histologically. In eight patients, liver biopsy was performed twice, within 3 days and 4 to 8 weeks after abstinence. The NS3 region of the HGV genome was detected using an reverse transcriptase-polymerase chain reaction method. Serum levels of AST, ALT and -γ-glutamyltranspeptidase were measured once a week sequentially after admission. Serum HGV-RNA was detected in only one patient with AL-CH (6.3%). In all patients, including one patient with HGV, serum levels of AST, ALT and γ-glutamyltranspeptidase clearly decreased to normal levels after abstinence. Inflammatory activity in the periportal area of patients with actively drinking decreased or disappeared after abstinence for 4 to 8 weeks. These results suggest that HGV may not play an important role for development of AL-CH, and that AL-CH may be caused by alcohol itself, although a more larger number of patients with AL-CH are needed to obtain definitive conclusions.

Effects of ethanol and its metabolites on collagen synthesis by cultured rat liver cells

Abstract The effects of ethanol and its metabolites on collagen synthesis in cultured rat Ito cells and hepatocytes were studied. In cultured Ito cells, collagen synthetic ability reached peak values after incubation for 24 h and after 8 h in cultured hepatocytes. The distribution patterns of 14C‐activity in each collagen fraction were quite different between the two cell types. About 80% of the activity was found in the degraded collagen fraction in the cultured hepatocytes, indicating a rapid turn‐over of collagen protein in this cell type. In the Ito cells, the activity in the intact collagen was about 50%. Ethanol and its metabolites added to the incubation medium did not stimulate collagen synthesis in either cell type; rather, they inhibited it. Collagen metabolism in the cells to which ethanol or its metabolites had been added was slower than in the control medium. These results indicate that the pathogenesis of alcoholic liver fibrosis is not simple and that interaction or modulation of cell function in different types of cells should be considered when examining the mechanisms of fibrogenesis in alcoholic liver fibrosis.

Effects of a new orally active dopamine prodrug, docarpamine, on refractory ascites: a pilot study

OBJECTIVE:Refractory ascites is a debilitating condition in patients with cirrhosis. Recently, docarpamine, an orally active dopamine prodrug, was reported to increase renal blood flow, glomerular filtration, and sodium excretion. This suggests docarpamine may be useful for the treatment of refractory ascites.METHODS:In this study, we investigated docarpamine metabolism in cirrhotic patients and its effect on refractory ascites.RESULTS:Blood samples were obtained from seven cirrhotic patients and six healthy subjects after administration of 750 mg docarpamine, and plasma levels of free dopamine were measured. In healthy subjects, maximum plasma concentration (Cmax), time taken to reach Cmax (Tmax), elimination half-life (T1/2), and area under the plasma concentration-time curve (AUC) of plasma free dopamine were 76.8 ± 24.1 ng/ml, 1.3 ± 0.2 h, 0.8 ± 0.1 h, and 97.5 ± 21.1 ng · h /ml, respectively. In patients with cirrhosis, Cmax (53.1 ± 24.9 ng/ml), T1/2 (0.8 ± 0.1 h), and AUC (100.6 ± 45.6 ng · h /ml) were no different from healthy subjects when comparing each parameter, whereas Tmax (2.7 ± 0.2) was significantly longer than that of healthy subjects. We treated 10 cirrhotic patients with refractory ascites with docarpamine or placebo and the same dose of diuretics used before hospitalization. After 8 wk of docarpamine treatment, ascites disappeared completely in three of the five patients and decreased in the remainder. However, in five patients treated with placebo, ascites was not changed or increased. Side effects were not observed in any case.CONCLUSIONS:Docarpamine was found to metabolize in cirrhotic patients as well as in normal subjects and may be an effective treatment for refractory ascites.