Hidetake Shimizu

Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury1

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially been characterized. For example, it is known that chronic ethanol ingestion increases hepatotoxicity and produces fatty liver, hepatitis and cirrhosis. However, acute ethanol consumption reduces endotoxin hepatotoxicity. It now appears that Kupffer cells participate in several aspects of these phenomena. Previously, most studies on the effects of alcohol on liver function have focused chiefly on the hepatocyte. Recently, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut‐derived endotoxins (lipopolysaccharides) via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol‐induced liver injury. Here we will review new evidence for the proposal that Kupffer cells and endotoxins play a pivotal role in hepatotoxicity following alcohol exposure, based on studies using the continuous intragastric enteral feeding model developed by Tsukamoto and French and an acute model developed by us.

Efficacy of 1 week omeprazole or lansoprazole– amoxycillin–clarithromycin therapy for Helicobacter pylori infection in the Japanese population

Background: The effectiveness of curative therapy for Helicobacter pylori may vary according to the geographic region and patient population, thus the efficacy of each treatment regimen should be determined according to the specific patient population. However, there is no literature available concerning the efficacy of 1 week omeprazole–amoxycillin–clarithromycin (OAC) regimens for the cure of H. pylori infection in Japan.

Detection of IgA, IgM, and IgG subclasses of anti-M2 antibody by immunoblotting in autoimmune cholangitis: is autoimmune cholangitis an early stage of primary biliary cirrhosis?

Abstract: Autoimmune cholangitis (AIC) has been proposed as a distinct disease entity from primary biliary cirrhosis (PBC), without antimitochondrial antibody (AMA) and anti-M2 antibody but with a high titer of antinuclear antibody (ANA) in the serum. However, negativity for AMA and anti-M2 antibody was determined by different methods in different studies. We hypothesized that anti-M2 antibody negativity in AIC resulted from methodological differences, including selection of the immunoglobulin subclass of the autoantibody. Twenty-three patients compatible with AIC whose serum tested negative for AMA and positive for ANA (≧1 : 80) were compared with 71 AMA-positive PBC patients. Laboratory findings, histology, and the pattern of anti-M2 antibody assessed by immunoblotting were compared. Alkaline phosphatase, total bilirubin, total cholesterol, and IgM values were lower in patients with AIC (P < 0.05, 0.01, respectively). Anti-smooth muscle antibody was detected more frequently in patients with AIC (P < 0.01). However, anti-M2 antibody was detected using immunoblotting not only in PBC but also in AIC cases. IgA class alone, IgM class alone, or both IgA and IgM classes of anti-M2 antibody were detected in 13%, 17%, and 22% of AIC patients, respectively, whereas they were not detected in PBC patients (P < 0.05, P < 0.01, P < 0.01). IgG class anti-M2 was detected in all patients with PBC, whereas it was detected in 48% of patients with AIC (P < 0.01). Histological evaluation showed that the early stages of disease were found more frequently in AIC (78%) than in PBC patients (39%) (P < 0.01). Anti-M2 antibody was detected by immunoblotting in all AIC patients. Hence, AIC is not a distinct disease from PBC. For diagnosing AIC and/or PBC, anti-M2 antibody should be examined by the immunoblotting assay to detect not only IgG but also IgA and IgM subclasses.

The ability of anti-carbonic anhydrase II antibody to distinguish autoimmune cholangitis from primary biliary cirrhosis in Japanese patients

Abstract: Serum antibody against carbonic anhydrase (CA) II has been described as a serological marker for distinguishing autoimmune cholangitis (AIC) from primary biliary cirrhosis (PBC). To validate this finding in a Japanese population, we evaluated sera from patients with PBC and AIC for antibody to human CA II. An enzyme-linked immunosorbent assay was employed to quantify serum antibody against CA II in patients with PBC (n = 40), AIC (n = 23), autoimmune hepatitis (n = 10), and extrahepatic obstructive jaundice (n = 10). Compared with the finding of a 4% prevalence of anti-CAII antibody in healthy subjects (n = 24), a significantly higher prevalence of anti-CA II antibody was detected in patients with PBC (35%) and AIC (30%) (P < 0.05), but not in patients with autoimmune hepatitis and patients with obstructive jaundice. No significant difference was observed between PBC and AIC patients. These results showed that AIC and PBC would be indistinguishable by anti-CA II antibody testing in Japanese patients. However, the finding of serum anti-CA II antibody in patients with PBC and AIC supports the disease concept of autoimmune exocrinopathy.

Immunoreactivity to M2 proteins in antimitochondrial antibody-negative patients with primary biliary cirrhosis.

Abstract Although antimitochondrial auto‐antibodies are characteristically present in the serum of patients with primary biliary cirrhosis (PBC), there is a discrepancy between the positivity for antimitochondrial antibody (AMA) and that for anti‐M2 auto‐antibody. In an attempt to explain the discrepancy, this study investigates the relationship between the AMA titre, determined by indirect immunofluorescence, and immunoreactivity to four inner mitochondrial membrance proteins (M2 proteins) with molecular weights of 70, 50, 47, and 40 kDa in 129 patients with PBC. Antimitochondrial antibody positivity was identified in 114 (88%) of 129 patients with clinically and histologically confirmed PBC. There were no significant differences between the AMA‐negative and AMA‐positive groups in clinical characteristics or histologically determined disease stage. Immunoblot analysis showed that all patients had anti‐M2 auto‐antibodies to one or more of the four M2 proteins. Nine (60%) of the 15 AMA‐negative patients had antibodies to only one M2 protein (either 70 or 47 kDa). In contrast, 34 (53%) of the 64 patients with high AMA titres ( 1: 320) had antibodies to all four M2 proteins. There was a significant rank correlation between the AMA titre and the number of antibodies to M2 proteins (P < 0.01). These findings indicate that the AMA titre is not influenced by the immunogenicity of M2 protein but by the number of M2 proteins that elicit an antibody response and that decreased immunoreactivity to M2 proteins may induce AMA negativity in PBC serum samples.

Integrity of myosin light chain kinase is essential for Ito cell contraction

Hepatic sinusoidal Ito cells (fat storing cells) are believed to play a regulatory role on hepatic sinusoidal blood flow through their contraction. The detailed mechanism of contraction of Ito cells, however, is still unknown. The present study was undertaken to clarify the effect of new myosin light chain kinase inhibitor, wortmannin, on Ito cell contraction. Ito cells prepared from rat liver were cultured for 4 days before the study. The contraction of Ito cells, which was monitored and analysed by time‐lapse video tape recording, was triggered by addition of endothelin‐1. Wortmannin pretreatment for 1 h inhibited endothelin‐induced Ito cell contraction dose‐dependently. Therefore, the integrity of the actomyosin system is essential for Ito cell contraction and normal sinusoidal blood flow.