Does methotrexate (MTX) have hepatotoxic effects?

Methotrexate Hepatotoxicity: Clinical Implications and Management

Yes, methotrexate definitively has hepatotoxic effects and requires regular monitoring, with hepatotoxicity being more common in psoriasis patients than in those with rheumatoid arthritis. 1

Mechanisms and Presentation of Hepatotoxicity

Methotrexate can cause both acute and chronic hepatotoxicity:

• Acute hepatotoxicity: Presents as transient elevations in liver enzymes (transaminases)

  • Common during treatment (90.8% of patients may experience some elevation in aminotransferases) 2
  • Usually transient and asymptomatic 3
  • Most patients (93.8%) return to normal or low-grade elevations after treatment without dose modification 2

• Chronic hepatotoxicity: Can lead to fibrosis and cirrhosis with prolonged use

  • Develops gradually over years of treatment 1
  • May not be preceded by symptoms or abnormal liver function tests, especially in psoriasis patients 3
  • Risk increases with cumulative dose, particularly after 3.5-4.0 g total exposure 1

Risk Factors for Methotrexate-Induced Hepatotoxicity

Several factors increase the risk of methotrexate hepatotoxicity:

1. Patient-related factors:

   • Obesity (BMI ≥ 40 kg/m²) 1
   • Diabetes mellitus 1
   • Hyperlipidemia 1
   • Greater than moderate alcohol consumption 1
   • Pre-existing liver disease (including hepatitis B or C) 1
   • Non-alcoholic fatty liver disease (NAFLD) 1, 4
   • Baseline liver function test abnormalities 5

2. Treatment-related factors:

   • Cumulative dose (particularly after 3.5-4.0 g) 1
   • Duration of therapy 6
   • Concomitant use of other hepatotoxic medications 1, 3
   • Lack of folic acid supplementation 1

Monitoring Recommendations

Baseline Assessment

Before starting methotrexate:

• Complete blood count (CBC)
• Liver function tests (LFTs)
• Renal function tests
• Non-invasive liver fibrosis assessment (FIB-4, Fibrosure, Fibrometer, or Hepascore) 1
• Consider hepatitis B and C screening in patients with risk factors 7

Ongoing Monitoring

For patients without risk factors for hepatotoxicity:

• Monitor LFTs every 3-6 months assuming no abnormal results 1, 7
• Repeat non-invasive blood serology annually 1

For patients with risk factors for hepatotoxicity:

• More frequent monitoring may be necessary
• Annual gastroenterology consultation and/or vibration-controlled transient elastography 1

Management of Abnormal LFTs

• Elevations < 3-fold the upper limit of normal: Repeat in 2-4 weeks 1
• Elevations ≥ 3-fold the upper limit of normal: Closely monitor, repeat in 2-4 weeks, and decrease dose as needed 1
• Persistent elevations during a 12-month period or decline in serum albumin: Consider GI consultation and/or liver biopsy 1
• Signs of stage 3 liver fibrosis: Consider switching to another agent or discontinuing therapy 1

Special Considerations

1. Psoriasis vs. Rheumatoid Arthritis:

   • Hepatotoxicity is more common in psoriasis than in rheumatoid arthritis 1
   • Psoriasis patients often have comorbid NAFLD, which can be aggravated by methotrexate 1

2. Folic Acid Supplementation:

   • Should be prescribed concurrently with methotrexate to reduce side effects, including hepatotoxicity 7
   • Typically 1-5 mg/day given daily except on the day of methotrexate 1

3. Drug Interactions:

   • NSAIDs should be used with caution as they may increase methotrexate toxicity 7, 3
   • Trimethoprim-sulfamethoxazole can increase bone marrow suppression 7
   • Other hepatotoxic agents may increase risk of liver damage 3

Recent Evidence on Cumulative Dose

Recent research challenges the traditional belief that cumulative dose is directly associated with hepatotoxicity:

• A 2021 systematic review and meta-analysis found no significant association between methotrexate cumulative dose and hepatotoxicity 8
• This suggests that regular monitoring is important regardless of cumulative dose, and that other risk factors may play a more significant role

Common Pitfalls in Managing Methotrexate Hepatotoxicity

1. Failure to identify risk factors before initiating therapy
2. Inadequate monitoring frequency, especially after dose increases
3. Overlooking drug interactions that may increase hepatotoxicity
4. Not providing folic acid supplementation
5. Continuing methotrexate despite persistent liver abnormalities
6. Performing laboratory tests immediately after methotrexate administration (can lead to transient elevations)

By following appropriate monitoring protocols and recognizing risk factors, clinicians can safely use methotrexate while minimizing the risk of serious hepatotoxicity.