The effect of ursodeoxycholic acid (UDCA) treatment for more than one year on chronic hepatitis in regard to responder and non-responder and influence of UDCA administration on serum bile acid metabolism were studied. All of non-responders (16 patients) were hepatitis B or C patients, and seven of fifteen responders were negative for hepatitis B and C virus marker and could be considered autoimmune hepatitis. These patients got drastic improvement of liver function test, anti-nuclear antibody in five patients and anti-smooth muscle antibody in three patients were decreased. Although HAI scores for liver pathology before UDCA treatment were not different between responders and non-responders, the intralobular necrosis was improved in responders after UDCA treatment. Concerning serum bile acid analysis, total bile acid and UDCA concentration in responders were lower than non-responders. Percentage of iso-ursodeoxycholic acid in responders was significantly higher than non-responders. These results suggest the effectiveness of UDCA therapy on autoimmune hepatitis.
: The chemokines play roles in the development of immune mediated liver diseases. In this study, we investigate the involvement of macrophage inflammatory protein-1alpha (MIP-1alpha), one of the CC chemokines in concanavalin A (Con A)-induced liver injury in mice.: Liver injury was induced by intravenous injection of Con A. Anti-mouse MIP-1alpha antibody, recombinant murine-MIP-1alpha and gadolinium chloride (GdCl(3)) were administrated prior to Con A injection. Plasma alanine aminotransferase (ALT), MIP-1alpha, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) levels were determined and histological assessment of the liver was performed.: Plasma MIP-1alpha level was elevated after Con A injection. The elevated plasma ALT level, mortality rate and histological change after Con A injection were inhibited by anti-MIP-1alpha antibody pretreatment. The elevated plasma ALT level after Con A injection was further enhanced by recombinant murine-MIP-1alpha. The elevated plasma TNF-alpha and IFN-gamma levels after Con A injection were inhibited by anti-MIP-1alpha antibody, and enhanced by recombinant murine-MIP-1alpha. GdCl(3) pretreatment inhibited the elevated plasma MIP-1alpha and ALT levels.: These findings suggest that MIP-1alpha is produced from Kupffer cells after Con A injection, and this CC chemokine plays a crucial role in Con A-induced liver injury through induction of proinflammatory cytokines.
Effect of ursodeoxycholic acid (600 mg/day 12 weeks) on liver function tests and bile acid metabolism were investigated in 6 patients with compensatory liver cirrhosis (CLC) and 6 with chronic active hepatitis (CAH). Serial determination of serum GOT, GPT and gamma-GTP after the initiation of UDCA revealed significant reduction in mean levels of these enzymes after 4 weeks, and further improvement was observed at the end of the 12-weeks treatment regimen (CLC: 79.3%, 81.1%, 51.5% of initial values, respectively, CAH: 61.2%, 59.3%, 42.8%). On the other hand, after UDCA administration, serum total bile acid increased and UDCA became the predominant bile acid in CLC and CAH patients. Other endogenous bile acids decreased in both groups, but reduction rate of serum chenodeoxycholic acid level in CLC was smaller than that in CAH group (CLC: 86.1% of initial values, respectively, CAH: 54.2%). During UDCA treatment, apparent side effect was not observed. We suggest that UDCA administration might constitute effective treatment for compensatory liver cirrhosis as well as chronic hepatitis.
Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl 4 )-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl 4 . Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl 4 were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl 4 -induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl 4 -induced acute liver injury. The aggravating effect of central CRF on CCl 4 -induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways.
