Liver & intrahepatic bile ducts

Drug / toxin induced hepatitis

Methotrexate


Editorial Board Member: Catherine E. Hagen, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Maryam Aghighi, M.D.
Raul S. Gonzalez, M.D.

Topic Completed: 28 January 2021

Minor changes: 28 January 2021

Copyright: 2019-2021, PathologyOutlines.com, Inc.

PubMed Search: Methotrexate[TI] liver[TIAB] review[PT]

Maryam Aghighi, M.D.
Raul S. Gonzalez, M.D.
Page views in 2020: 234
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Cite this page: Aghighi M, Gonzalez RS. Methotrexate. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverdrugtoxinmethotrexate.html. Accessed September 21st, 2021.
Definition / general
  • Methotrexate in liver can cause reactive changes, steatosis or fibrosis and rarely lymphoma
  • Duration and dosage of methotrexate impact the risk of liver damage
  • Methotrexate is an immunosuppressant medication, mainly used for treatment of cancer and autoimmune diseases
Essential features
  • Methotrexate is an antimetabolite and antifolate
  • Mild elevation in liver enzymes, fibrosis and cirrhosis may be observed due to extended usage of methotrexate
  • Roenigk classification is used to grade liver biopsies
Terminology
  • Methotrexate induced liver fibrosis
ICD coding
  • ICD-10: K71.9 - Toxic liver disease, unspecified
Epidemiology
  • Methotrexate is the first line therapy for treatment of rheumatoid arthritis worldwide
  • Incidence rate of liver enzymes elevation in patients with low dose methotrexate therapy is 13 per 100 patient years
  • 20% of patients with low dose methotrexate therapy have elevation in liver enzymes during average of 4.6 years of therapy (PLoS One 2018;13:e0203084)
Sites
  • Liver
Pathophysiology
  • Methotrexate is an antimetabolite and antifolate (World J Hepatol 2017;9:1092)
    • Prevents synthesis of tetrahydrofolate in cells by inhibiting dihydrofolate reductase enzyme
    • Presence of folic acid is essential for synthesis of nucleosides
    • Therefore, methotrexate hinders synthesis of DNA and RNA, resulting in cell cycle arrest in liver
  • Methotrexate inhibits an enzyme causing an increase in extracellular adenosine, which promotes liver fibrosis (Psoriasis (Auckl) 2018;8:21)
  • In rheumatoid arthritis, methotrexate causes adenosine accumulation by changing purine metabolism (Joint Bone Spine 2019;86:301)
Clinical features
  • Clinically, patients may be asymptomatic or present with jaundice, hepatomegaly or constitutional symptoms including weight change and fever
  • Symptoms may present after months to years of using methotrexate
  • Elevation in liver enzymes may occur due to high dosage of intravenous methotrexate
  • Mild elevation in liver enzymes, fibrosis and cirrhosis may be observed due to extended usage of methotrexate (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Accessed 8 December 2020])
Diagnosis
Laboratory
  • Normal or elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in patients with methotrexate therapy
Radiology description
Prognostic factors
  • Risk of liver damage is associated with the dosage and duration of methotrexate therapy
  • Risk of liver damage is intensified by obesity or alcohol usage
  • Roenigk classification is used to grade liver biopsies (World J Hepatol 2017;9:1092)
  • Patients are advised to stop the medication if their liver shows Roenigk stage IIIB (advanced fibrosis) or Roenigk stage IV (cirrhosis) disease; for Roenigk stage IIIA, repeat of biopsy is advised in 6 months (PLoS One 2018;13:e0203084)
Case reports
  • 56 year old woman with rheumatoid arthritis and methotrexate treatment developed primary hepatic lymphoma (Intern Med 2015;54:401)
  • 64 year old man with rheumatoid arthritis and methotrexate treatment developed primary hepatic lymphoma (Biomark Res 2015;3:10)
  • 82 year old man with rheumatoid arthritis and methotrexate treatment developed lymphoproliferative disorders in liver, spleen and lung (J Med Case Rep 2019;13:196)
  • 88 year old woman with rheumatoid arthritis under methotrexate therapy for 6 years developed hepatosplenic Hodgkin lymphoma after methotrexate withdrawal (Mod Rheumatol 2017;27:372)
Treatment
Microscopic (histologic) description
  • Mainly macrovesicular steatosis but sometimes microvesicular
  • Reactive changes, such as hyperchromasia and anisocytosis of hepatocyte nuclei or patchy hepatocyte necrosis
  • Portal inflammation
  • Periportal fibrosis to central bridging or pericellular fibrosis
  • Roenigk classification has 4 grades: grade I (normal to mild fatty changes), grade II (moderate to severe fatty changes), grade IIIA - B (mild to severe periportal fibrosis) and grade IV (cirrhosis) (Arch Dermatol 2007;143:1515)
  • Rarely, lymphoproliferative disorders such as primary hepatic lymphoma has been reported after using methotrexate in autoimmune disease patients (Biomark Res 2015;3:10)
Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Macrovesicular steatosis

Liver fibrosis

Positive stains
  • Trichrome stain shows an increase in portal, periportal or bridging fibrosis in methotrexate toxicity
Sample pathology report
  • Liver, biopsy:
    • Macrovesicular steatosis with periportal and bridging fibrosis (see comment)
    • Comment: Macrovesicular steatosis involves approximately 50% of the hepatocytes. A trichrome stain demonstrates periportal and bridging fibrosis. The differential diagnosis includes alcoholic hepatitis, nonalcoholic steatohepatitis or drug induced liver injury (the patient's history of methotrexate use is noted).
Differential diagnosis
Board review style question #1
Methotrexate injury in the liver is graded using the Roenigk classification. Which of the following grades indicates methotrexate use should be stopped?

  1. Stage I
  2. Stage II
  3. Stage IIIA
  4. Stage IIIB
Board review style answer #1
D. Stage IIIB

Comment Here

Reference: Methotrexate
Board review style question #2

Liver injury secondary to methotrexate use usually causes which of the following findings?

  1. Cholestatic hepatitis
  2. Macrovesicular steatosis
  3. Sinusoidal dilation
  4. Zonal hepatocyte necrosis
Board review style answer #2
B. Macrovesicular steatosis

Comment Here

Reference: Methotrexate
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