Detection of serum nitrite and nitrate in primary biliary cirrhosis: Possible role of nitric oxide in bile duct injury

Background: The role of nitric oxide synthase (NOS) in autoimmune disease is gaining increased attention because of the relationships between NOS activity and T-lymphocyte subpopulations and, in particular, the influence of NO on cytokine production by Th1 versus Th2 cells. In addition, there is evidence that both the liver and infiltrating hepatic T cells have inducible NOS-2 activity. Methods: We studied serum levels of nitrite (NO₂ ^-) and nitrate (NO₃ ^-) in groups of patients with liver disease secondary to hepatitis B, hepatitis C, autoimmune hepatitis and primary biliary cirrhosis (PBC). Simultaneously, in a nested subpopulation, we studied the liver expression of NOS-2. Results: Interestingly, there was a significant elevation both of nitrite and of nitrate in patients with PBC but not other liver diseases. Despite such increments, there was no correlation of the levels of nitrite and nitrate with sera levels of tumor necrosis factor-α, interferon-γ, alanine aminotransferase, total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, platelet count, IgG, IgM, antimitochondrial antibodies or prothrombin time. These data were extended by demonstrating the expression of NOS-2 by immunohistochemistry in 13/14 patients with PBC, including in 9/14 patient hepatocyte populations and 4/14 bile duct cells. In contrast, NOS-2 expression was noted in hepatitis B and hepatitis C, but only found within mononuclear cells. Conclusion: Our data suggest that NO produced through NOS-2 may play a role in the pathogenesis of bile duct injury in some PBC patients.