Methotrexate: does it harm the liver?

Methotrexate was first developed in 1940s by Yellapragada Subbarao. In 1947, Dr. Sydney Faber & colleagues found that Methotrexate could induce remission in children with leukemias. In 1953, it was approved by FDA as an oncology drug. It was later studied for non-cancer indications including psoriasis & rheumatoid arthritis.

Attention was first drawn to Methotrexate related liver side effects in the late 1960s, when isolated cases of Methotrexate induced liver toxicity in psoriasis patients were reported. Studies conducted to look into this matter showed that psoriasis patients on Methotrexate indeed have varying degrees of liver fibrosis.

The next logical step from the scientific community was to confirm whether Methotrexate was responsible for the liver fibrosis. Liver fibrosis can be only be confirmed by a liver biopsy. Hence, studies were conducted with a liver biopsy before & after starting Methotrexate to confirm the cause & effect relationship. A few facts emerged from these studies – 1) many psoriasis patients (as many as 50%) had liver fibrosis even before starting Methotrexate; alcohol being the main causative factor. 2) methotrexate was given on a daily basis in those days & this was found to increase the chances of liver toxicity four fold as compared to weekly doses. 3) Risk factors contributing to liver toxicity were identified as alcohol consumption, diabetes, obesity & preexisting liver disease. 4) No consensus was reached regarding Methotrexate as the cause of liver fibrosis since different studies came up with contrasting results.

Similar studies were conducted in Rheumatoid arthritis (RA) patients. These studies revealed that- 1) Liver fibrosis (baseline biopsies) is much less common in RA patients as compared to those with psoriasis. 2) Liver toxicity with Methotrexate is much less common in RA as compared to psoriasis. 3) Folate & hydroxychloroquine reduce the risk of Methotrexate induced liver side effects. 4) A few studies showed that Methotrexate induced liver fibrosis/ cirrhosis occurred only in the presence of other risk factors mentioned above. Alcohol was the main risk factor.

Thus, these studies added three main safety features to Methotrexate therapy: Weekly doses (in contrast to daily Methotrexate in the past), folate supplementation & avoiding alcohol. They also cleared the air about severe liver toxicity with Methotrexate.

Pincus & colleagues studied 248 RA patients treated with Methotrexate over 13 years. This amounted to 1007 person years (Person years is the product of the number of years times the number of members. 1007 would mean approximately 100 patients taking methotrextae for 10 years.) of Methotrexate exposure. The incidence of severe liver enzyme abnormalities was only 0.9 per 100 years. A similar study by Kramer & colleagues showed that severe ALT elevation was found in 6% & did not require withdrawal of Methotrexate. Paget & colleagues found a rate of 3.4% abnormal liver function tests in 182 patients. Salliot C & colleagues studied 88 available studies of Methotrexate in RA & concluded that transient elevation of liver enzymes with Methotrexate is seen in about 20.2% patients. This number definitely looks bigger but it is worthwhile to note that folate was not given to patients in many of the included studies.

Walker A M & colleagues also studied methotrexate liver toxicity & found that severe liver toxicity is rare. The study concluded that on an average, one case of serious liver disease is seen per 1000 patients treated for 5 years.

The incidence of liver enzyme abnormalities observed with methotrexate are much lower than that listed for Rofecoxib, celecoxib & other NSAIDs. Pincus & colleagues thus concluded that low dose weekly Methotrexate with folate supplementation is safe (probably even safer than the NSAIDs). In fact, the side effects of untreated RA are substantially greater than the observed side effects of Methotrexate.

Thus, Methotrexate does have the potential to affect the liver; however, with weekly doses, folate supplementation the risk is substantially reduced. Regular clinical monitoring, & that of liver enzyme make it a safe drug to use. Side effects of untreated RA are many times bigger that the liver toxicity risk associated with Methotrexate.

· Y Yazici, T Sokka, H Kautiainen, C Swearingen, I Kulman, T Pincus Long term safety of methotrexate in routine clinical Care : discontinuation is unusual and rarely the result of laboratory abnormalities. Annals of Rheumatic Disease 2005;64:207-211

· Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines? Journal of Rheumatol 2002;29:1586–9.

· Bridges SL, Alarcon GS, Koopman WJ. Methotrexate-induced liver abnormalities in rheumatoid arthritis. Journal of Rheumatol 1989;16:1180–3.

· Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. American Journal of Medicine 1988;85:771–4.

· Cartwright VW, Michaud K, Choi HK, Wolfe F. Methotrexate, laboratory testing and risk of serious illness: analyses in 20 000 patients. Arthritis Rheumatism 2003;48:S428.

· C Salliot, D Van der Heijde Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research Annals Rheumatic Diseases 2009;68:1100-1104

· Walker Am, Funch D, Dreyer NA et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for Rheumatoid Arthritis. Arthritis Rheumatism 1987; 36:186-95.


18 Responses to Methotrexate: does it harm the liver?

  1. Nagesh Wagholikar says:

    Thanks for posting. It is more than a year now, my wife is taking MTX and no side effects on liver are observed. Quite happy ! There is occassional flareup in RA acivity, but your emergency action plan helps dowsing the fire before it sperds and becomes uncontrollable. Thanks a lot. Article taken for translation.


  2. rachel says:

    informative post. but included only liver side effects.
    nausea and weakness the next day bother much more.
    but doctors doesnt bother.n such feeling induces depreeion n all..
    hope u dicuss that along with some effective remedies besides folic acid in ur next post….


  3. Shuvra Dey says:

    We develop so many preconceived notions regarding medicines and their side effects.It’s very helpful for patients to make them knowledgeable about these issues.Thanks for all your endeavour.


  4. Purba says:

    Again a very good post. Your posts keep us aware of the disease as well as the medicines. Thank you Doctor.:)

    Doctor, I am taking the medicines regularly and I am quite fine now. But still I would like to know a certain thing. Is there anything else exists that can help us to deal with RA along with taking medicines? For example, as we know fenugreek seeds(methi) are good for people who are suffering from Diabetes, is anything of this kind available for RA? or does any proper diet or something else help us to deal with RA better along with the medicines. So that in the long run it will be helpful for us.


  5. Narayan says:

    I am suffering from rheumatoid since 5 years; have been on methotrextate for 2 years. I did have a rise in the liver enzymes last year. I did not have any symptoms but it was detected incidentally on the routine blood reports I do for methotrexate.

    The SGOT, SGPT had risen to 90 & 105. However, my Doc stopped methotrexate for some time & the liver enzymes settled. Presently I’m back on methotrexate & without any problems. It is a wonderful drug & my rheumatoid is well controlled; thanks to methotrexate.


    • Yes, Mr. Narayan.

      Your liver enzymes will be monitored on a regular basis once you are on methotrexate. American College of Rheumatology has elaborate guidelines for monitoring to avoid methotrexate side effects.

      It is a very effective medicine; of course, with all the precautions in place.


  6. Jolie says:

    I respect your work , thanks for all the useful articles .


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  9. Chelsea says:

    Excellent post Dr. Akerkar,
    I too once had quite elevated liver enzymes that took 7 months to come back down to normal. We did not stop the mtx, but did reduce the dose for a while – and changed some other medications that might have been contributing to it in combination with the mtx. It may have been at that time that we added PRESCRIPTION STRENGTH FOLIC ACID. I think I’d only been taking over-the-counter folic acid until that point.

    That was years ago. Recently, we increased my methotrexate dose up to 25 mgs, orally. However, I was told to split that dose and take half of it on Mondays, and half on Fridays. I need to remember to ask what level my liver enzymes are at now, to see how they compare to past levels. I’ve also added Tylenol Arthritis to my mix, though trying to take that less often. Plaquenil was added last year, so perhaps that will help to counteract liver enzymes a bit.

    I must say, the new increased and split dose regimine of MTX, in conjunction with the Plaquenil has worked so much better than any of my past treatments. It has even helped with pain in joints that apparently only have Osteo Arthritis. I haven’t figured that one out yet, but will gladly accept it! I have however developed an unrelenting itchy and spreading rash that did coincide with the start of the increased, split dose regimine of the methotrexate. It remains to be seen if that is the cause, and the cause may never be found. It is as best as I can tell at this point an Erythema Annulare Centrifugum (EAC) type rash. I would appreciate hearing from anyone else who may have had a similar type reaction.


  10. nageshaw says:

    My wife is doing fine with possibly lowest dose of MTX. And so far no side effects are seen. All the reports are norma. No nautia no vomitting. Every thing is fine. Thank you Doctor !


  11. Good post…

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