Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy

Background: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 ± 0.25 g (n = 20) and 3 ± 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. Conclusions: Immunohistochemical quantification of matrix proteins and collagens type 111 and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.