ABSTRACT
In vitro, inhibition of the synthesis of guanosine monophosphate (GMP) by various drugs such as ribavirin, acyclovir, azathioprine, and mycophenolic acid leads to the formation of subcellular structures in cultured cells. Autoantibodies targeting these cellular structures can be detected as "rods and rings" (RR) patterns by immunofluorescence. In vivo, autoantibodies to RR have been almost exclusively associated with hepatitis C virus patients treated with pegylated interferon-α and ribavirin. However, longitudinal data for other patient groups are scarce. Here, we reviewed 276 sequential immunofluorescence results from 127 patients with autoimmune hepatitis for the presence of RR patterns. Of 102 patients exposed to drugs known to induce RR in vitro, two patients under long-term azathioprine therapy were positive for this pattern. This is the first report of anti-RR in patients with autoimmune hepatitis and in patients treated with azathioprine.
Subject(s)
Autoantibodies/blood , Autoantigens/drug effects , Azathioprine/adverse effects , Hepatitis, Autoimmune/drug therapy , Immunosuppressive Agents/adverse effects , Adolescent , Adult , Aged , Autoantibodies/immunology , Autoantigens/immunology , Azathioprine/administration & dosage , Child , Drug Monitoring , Female , Guanosine Monophosphate/biosynthesis , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/immunology , Humans , IMP Dehydrogenase/antagonists & inhibitors , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Young AdultABSTRACT
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated during hepatic fibrogenesis and considered to promote fibrosis in the injured liver by inhibition of matrix metalloproteases (MMP) and degradation of extracellular matrix. Moreover, TIMP-1 displays anti-apoptotic properties, in patients with hepatocellular carcinoma (HCC) TIMP-1 serum levels are elevated and high TIMP-1 expression levels in HCC are associated with a poor prognosis. Therefore, TIMP-1 could functionally link fibrogenesis and carcinogenesis in the liver. The aim of our study was to characterize the role of TIMP-1 in hepatic fibrogenesis and carcinogenesis. Experimental hepatic fibrogenesis as well as diethylnitrosamine (DEN) -induced hepatocarcinogenesis were studied in TIMP-1-deficient mice and wild type littermates. Hepatic TIMP-1 expression was upregulated following induction of liver fibrosis by bile duct ligation (BDL) or by carbon tetrachloride (CCl4). Unexpectedly, in comparison to wild type littermates, TIMP-1-deficient mice were not protected from liver fibrosis induced by BDL or CCl4. TIMP-1 expression was significantly higher in HCC nodules than in surrounding liver tissue. However, experimental hepatic carcinogenesis was similar in TIMP-1-deficient mice and wild type littermates following DEN-treatment or combined treatment with DEN and CCl4. Therefore we concluded that TIMP-1 is not essential for hepatic fibrogenesis and carcinogenesis in mice.
