Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease
- Joel M Kremer, MD
Joel M Kremer, MD
- Pfaff Family Professor and Chair in Medicine
- The Albany Medical College
- Section Editor
- Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
- Section Editor — Rheumatoid Arthritis
- Emeritus Professor of Rheumatology, Imperial College London
- Visiting Professor, Oxford University
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 folinic acid . A relationship between folate depletion and hepatic toxicity has not been established. However, supplementation with either folic acid 1 mg per day or folinic acid 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 . The enzymes may rise with each course of MTX and are also higher in patients receiving daily, as opposed to intermittent, dosing . 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 . 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 . 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).
- Rodenhuis S, Kremer JM, Bertino JR. Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate. Arthritis Rheum 1987; 30:369.
- Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol 2009; 160:622.
- van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001; 44:1515.
- Berkowitz RS, Goldstein DP, Bernstein MR. Ten year's experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986; 23:111.
- King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist 2001; 6:162.
- Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate guidelines--revised. J Am Acad Dermatol 1982; 6:145.
- Lewis JH, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. The ACG Committee on FDA-related matters. American College of Gastroenterology. Am J Gastroenterol 1988; 83:1337.
- Weinstein GD. Methotrexate. Ann Intern Med 1977; 86:199.
- Psoriasis-liver-methotrexate interactions. Arch Dermatol 1973; 108:36.
- Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics. Acta Pathol Microbiol Scand A 1977; 85:511.
- Zachariae H, Kragballe K, Søgaard H. Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102:407.
- Furst DE, Kremer JM. Methotrexate in rheumatoid arthritis. Arthritis Rheum 1988; 31:305.
- Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum 1989; 32:121.
- Kremer JM, Kaye GI, Kaye NW, et al. Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables. Arthritis Rheum 1995; 38:1194.
- Kremer JM, Furst DE, Weinblatt ME, Blotner SD. Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis. J Rheumatol 1996; 23:459.
- Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009; 61:451.
- Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010; 69:43.
- Barbero-Villares A, Mendoza Jiménez-Ridruejo J, Taxonera C, et al. Evaluation of liver fibrosis by transient elastography (Fibroscan®) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial. Scand J Gastroenterol 2012; 47:575.
- Barbero-Villares A, Mendoza J, Trapero-Marugan M, et al. Evaluation of liver fibrosis by transient elastography in methotrexate treated patients. Med Clin (Barc) 2011; 137:637.
- Laharie D, Seneschal J, Schaeverbeke T, et al. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J Hepatol 2010; 53:1035.
- Berends MA, Snoek J, de Jong EM, et al. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis. Liver Int 2007; 27:639.
- Kaplan MM, DeLellis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997; 126:682.
- Knox TA, Kaplan MM, Gelfand JA, Wolff SM. Methotrexate treatment of idiopathic granulomatous hepatitis. Ann Intern Med 1995; 122:592.
- Schmajuk G, Miao Y, Yazdany J, et al. Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record. Arthritis Care Res (Hoboken) 2014; 66:1159.
- Kremer JM, Alarcón GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994; 37:316.
- Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59:762.
- Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 1992; 35:138.
- Furst DE, Erikson N, Clute L, et al. Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol 1990; 17:1628.
- Weinblatt ME, Weissman BN, Holdsworth DE, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update. Arthritis Rheum 1992; 35:129.
- Rosenberg P, Urwitz H, Johannesson A, et al. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol 2007; 46:1111.
- Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology (Oxford) 2009; 48:1107.