TRANSFORMING GROWTH FACTOR-BETA-1 AND FACTOR-ALPHA IN CHRONIC LIVER-DISEASE - EFFECTS OF INTERFERON ALFA THERAPY

Background. Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation of unknown pathogenesis. Transforming growth factor (TGF) beta-1 induces the production of extracellular matrix proteins by liver cells and has been implicated in the pathogenesis of hepatic fibrosis in laboratory animals. TGF-alpha is a hepatocyte mitogen that participates in liver regeneration. Methods. Using Northern blot analysis, we studied the expression of TGF-beta-1 messenger RNA (mRNA) in liver specimens from 42 patients with chronic hepatitis and cirrhosis and 12 subjects with either normal or fatty livers. The results were correlated with measurements of procollagen Type I mRNA in liver tissue, procollagen Type III peptide in serum, and the degree of histologic injury. We also investigated whether TGF-alpha mRNA would be detectable in biopsy specimens of livers with proliferative activity. Results. TGF-beta-1 mRNA expression correlated closely with the expression of procollagen Type I mRNA (r = 0.94) and serum procollagen Type III peptide (r = 0.89) and with the histologic activity index (r = 0.73). All patients with increased fibrogenic activity (serum procollagen Type III peptide level, > 11.9-mu-g per liter) had increased levels of TGF-beta-1 mRNA (2 to 14 times the levels in the control group or in patients with normal fibrogenic activity), and both TGF-alpha and H3 histone (a marker of DNA synthesis) mRNAs were detectable in patients with regenerative nodules. Six of eight patients with hepatitis C treated with interferon alfa for one year had sustained clinical responses with normalization of serum procollagen Type III peptide and aminotransferase activity. All these patients had normal levels of TGF-beta-1 mRNA in liver specimens obtained at the end of the year. Conclusions. TGF-beta-1 may have an important role in the pathogenesis of fibrosis in patients with chronic liver disease, and TGF-alpha expression may be associated with liver regeneration in these patients.