We undertook a dose-response study in Wistar rats to develop an animal model for methotrexate hepatotoxicity. Rats were given oral methotrexate in 300, 200, 150 and 100 pg/kg/day doses for variable lengths of time. The 300 pg/kg/day dose produced systemic toxicity; the animals needed to be killed early, and hepatotoxicity was not observed. The lower doses of methotrexate were tolerated for longer durations and were associated with hepatotoxicity in five of the five rats receiving 200 pg/kg/day, four of the five rats receiving 150 pg/kg/day and five of the five rats on 100 pg/kg/day. Within each treatment group the liver injury ranged in severity from focal necrosis of some zone 3 hepatocytes to confluent necrosis of zone 3. All five rats that received 100 pg/kg/day methotrexate for 6 wk showed continuing liver injury in the form of focal necrosis, cell lysis and enlarged Kupffer cells. In addition, three of the rats showed evidence of early hepatic fibrosis. We believe that this is the first experimental model in which oral methotrexate administration has been associated with hepatotoxicity. Further development of this model should provide valuable insights into the pathogenesis of methotrexate hepatotoxicity. (HEPATOLOGY 1991; 14:906-910.)
The place of methotrexate (MTX) in the treatment of progressive rheumatoid arthritis is well established (1-3); however, the role of MTX in liver injury seen in patients with rheumatoid arthritis remains controversial (4). No doubt exists that a number of rheumatoid patients have some liver injury before commencing MTX (5-8). However, studies of serial liver biopsy specimens by a number of groups including our own have demonstrated mild but progressive liver injury occurring in association with MTX treatment (6,8,9), whereas other studies have concluded that "MTX exerts a minor and clinically unimportant hepatotoxic effect during two to