Satoko Uegaki

The Clinical Significance of IgA Antimitochondrial Antibodies in Sera and Saliva in Primary Biliary Cirrhosis

Abstract:  It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA‐AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA‐AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA‐type autoantibodies in sera or saliva and progression of liver diseases. Fifty‐three patients with PBC were enrolled, and IgA‐AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuers classification consisting of four histological stages. We found IgA‐AMA, IgA‐anti‐PDC‐E2, and IgA‐anti‐E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA‐anti‐PDC‐E2 (P= 0.0124), but neither with IgA‐AMA (P= 0.1296) nor anti‐IgA‐E3BP (P= 0.5973). In saliva, detectable IgA‐AMA, IgA‐anti‐PDC‐E2, and IgA‐anti‐E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA‐anti‐PDC‐E2 was strongly associated with progression of PBC (P= 0.0002), whereas detection of IgA‐AMA and IgA‐anti‐E3BP were not associated (P= 0.2145 and P= 0.5118). The current findings suggest that the presence of IgA‐anti‐PDC‐E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA‐anti‐PDC‐E2 at early stages will be required to conclude the contribution of IgA‐anti‐PDC‐E2 to the progression of PBC.

Effect of organic anions and bile acid conjugates on biliary excretion of taurine-conjugated bile acid sulfates in the rat

Biliary organic anion excretion is mediated by an ATP-dependent primary active transporter, canalicular multispecific organic anion transporter/multidrug resistance protein 2. On the other hand, a multiplicity of canalicular organic anion transporter/multidrug resistance protein 2 has been suggested. Therefore, to examine the effect of hydrophobicity on the substrate specificity of canalicular multispecific organic anion transporter/multidrug resistance protein 2, we examined the effect of organic anions and bile acid conjugates on biliary excretion of three taurine-conjugated bile acid sulfates with different hydrophobicity, taurolithocholate-3-sulfate, taurochenodeoxycholate3-sulfate, and taurocholate-3-sulfate in rats. Biliary excretions of these bile acid conjugates were delayed in Eisai hyperbilirubinemic rats. Biliary excretion of these bile acid conjugates was inhibited by sulfobromophthalein, whereas biliary excretion and taurocholate-3-sulfate was not inhibited by phenolphthalein glucuronide. Taurolithocholate-3-sulfate and ursodeoxycholate-3-glucuronide decreased biliary excretion of taurochenodeoxycholate-3-sulfate and taurocholate-3-sulfate, but ursodeoxycholate-3,7-disulfate did not affect biliary excretion of taurochenodeoxycholate-3-sulfate and taurocholate-3-sulfate. These findings indicate that very hydrophilic organic anions are not good substrates of canalicular multispecific organic anion transporter/multidrug resistance protein 2.

Effects of bile acid conjugates on biliary excretion of estradiol-17β-glucuronide in the rat

Abstract Estradiol-17 β -glucuronide is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestasis of pregnancy. We previously reported that biliary estradiol-17 β -glucuronide excretion was delayed in Eisai hyperbililubinemic rats (EHBR) and inhibited by sulfobromophthalein whereas dibromosulfophthalein had not effect on biliary estradiol-17 β -glucuronide excretion. In the present study, we examined the effects of bile acid conjugates on biliary excretion of tracer doses of [ 3 H]estradiol-17 β -glucuronide and [ 14 C]estradiol intravenously injected to rats. Biliary excretion of estradiol-17 β -glucuronide and estradiol metabolites was significantly delayed by the infusion of taurolithocholate-3-sulfate or ursodeoxycholate-3-O-glucuronide, but not by ursodeoxycholate-3,7-disulfate. These findings indicate that estradiol-17 β -glucuronide is excreted into bile at least partially by the canalicular multispecific organic anion transporter which is common for sulfobromophthaleinglutathione and some bile acid sulfates and glucuronides.

Gene expression profiling in whole liver of bile duct ligated rats: VEGF-A expression is up-regulated in hepatocytes adjacent to the portal tracts.

Background and Aim:  It would be of clinical importance to clarify molecular mechanisms of cholangiocytes proliferation for the treatment of intractable cholestatic diseases. The aim of this study was to elucidate gene expression profiling in the whole liver of bile duct ligated (BDL) rats using microarray analysis. In addition, the localization and time course of up‐regulated expression of vascular endothelial growth factor (VEGF) was investigated.

Impaired biliary excretion of organic anions and cations in bile duct-ligated rat

Abstract The effects of bile duct ligation for 3 days on biliary excretion of organic anions and cations were studied in the rat. Biliary excretion of organic anions, sulfobromophthalein, leukotriene C 4 and pravastatin, was markedly impaired. Biliary excretion of organic cations, vinblastine and erythromycin was also markedly impaired. These findings indicate that, in the bile duct-ligated rats, various excretory pathways from the liver are damaged, at least partly due to the impairment of canalicular carriers.

Primary hepatic somatostatinoma developed in a patient with von Recklinghausen's disease

3), and even ERCP findings were significantly improved in 2 cases. Our retrospective investigation suggests that SASP is more effective to normalize hepatobiliary enzymes compared with other treatments. Interestingly, SASP was much more effective than oral 5-aminosalicylates (mesalazine, 5-ASA), which was used for IBD patients with PSC (Table 1). The mechanism of therapeutic action of SASP for PSC is not clear. One hypothesis is that SASP improves inflammation of the colonic mucosa, which then results in a decrease in translocation of bacteria and toxins into the portal tract. This hypothesis, however, is inconsistent with our observation because oral 5-ASA was ineffective. The majority of SASP passes directly into the colon and is digested by bacterial enzymes into sulfapyridine and 5ASA.4 5-ASA is antiinflammatory5,6 and is the primary therapeutic compound in SASP, whereas sulfapyridine has been said to be of no value for treatment of bowel inflammation. However, sulfapyridine is effective for rheumatoid arthritis and possesses antibacterial activity, and the action of this component might be an alternative explanation of the observed efficacy. A large randomized and controlled study is warranted to clarify the efficacy of SASP in patients with PSC.