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Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease

Joel M Kremer, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


The most common side effects associated with the use of methotrexate (MTX) in doses commonly used to treat rheumatic diseases (particularly rheumatoid arthritis [RA]) are not life-threatening. However, some complications, particularly hepatic toxicity, can be quite serious. Fortunately, careful and appropriate patient monitoring can minimize the risk and can allow MTX to remain an important drug in the treatment of rheumatic diseases. (See "Major side effects of low-dose methotrexate" and "Methotrexate-induced lung injury".)


Methotrexate (MTX) can induce a variety of histologic changes including steatosis, stellate (Ito) cell hypertrophy, anisonucleosis (nuclei of varying sizes), and hepatic fibrosis (picture 1). The mechanism by which MTX adversely affects the liver is unclear. Hepatic folate stores are depleted by MTX in the doses used in rheumatoid arthritis (RA), and these stores can be repleted by short-term administration of oral leucovorin (folinic acid) [1]. A relationship between folate depletion and hepatic toxicity has not been established. However, supplementation with either folic acid 1 mg per day or leucovorin 2.5 mg per week is associated with a reduced incidence of serum transaminase elevation [2,3]. Thus, folate supplementation may help prevent hepatotoxicity in patients taking MTX but does not substitute for ongoing monitoring and appropriate MTX dose adjustments if transaminase elevation occurs.

Use of MTX for neoplastic diseases has been associated with abnormalities of liver biochemical tests. The reported incidence of MTX-induced increases in serum alanine aminotransferase (ALT) is approximately 14 percent, while the incidence of increases into the abnormal range of aspartate aminotransferase (AST) is 8 percent [4]. The enzymes may rise with each course of MTX and are also higher in patients receiving daily, as opposed to intermittent, dosing [5]. The abnormal liver enzymes usually resolve within a month of discontinuation of the drug. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Methotrexate'.)

Most of our understanding of the hepatotoxic potential of MTX comes from its use in nonmalignant disease, such as psoriasis and RA. MTX hepatotoxicity in patients with psoriasis appears to increase with the total cumulative dose [6]. Cirrhosis and fibrosis occur more than twice as frequently in patients receiving daily MTX therapy when compared with those receiving intermittent dosing [7,8].

Early studies from the dermatology literature described severe liver disease, including cirrhosis, in patients with psoriasis who were treated with MTX [9-11]. The authors of these studies also noted an inability of liver function testing to predict actual liver toxicity. Thus, in the past, the dermatology community recommended monitoring for liver disease by liver biopsy performed after a total cumulative dose of 1.5 g of MTX and again after each additional 1 g cumulative dose [6]. Potential limitations of the studies on which the past recommendations were based included the performance of blood sampling only on the day of the liver biopsy and the lack of control for exposure to other hepatotoxins (such as alcohol and arsenic).

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Literature review current through: Nov 2017. | This topic last updated: Nov 16, 2017.
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