Should the theory of methotrexate-induced liver toxicity be abandoned?

Table 3 Stepwise algorithm for liver fibrosis risk stratification and monitoring in methotrexate-treated patients

Step	Criteria and interpretation (key thresholds)	Actions and followup
Baseline risk	Alcohol intake; metabolic risk: BMI/waist, diabetes, lipids, blood pressure. Review co-medications (polypharmacy); check ALT/AST, platelets, eGFR. Known chronic liver disease (viral hepatitis, cholestatic/autoimmune), significant alcohol use, or CKD start in a higher-risk lane	Place the patient in the appropriate risk lane before NITs
Primary triage (FIB-4)	Calculate FIB-4 for steatosis risk or unexplained enzyme elevation. Interpretation: FIB-4 < 1.3 (low risk). If age > 65: < 2.0 (low risk). FIB-4 ≥ 1.3 (or ≥ 2.0 if > 65 years) proceed to secondary assessment	Low risk: Continue MTX and risk-factor optimization; repeat FIB-4 every 2-3 years (every 1-2 years with diabetes or > 2 metabolic risk factors)
Secondary assessment	Use VCTE first (fast ≥ 3 hours; correct probe; document IQR/median). VCTE: < 8 kPa (low risk); 8-12 kPa (indeterminate); > 12 kPa (high likelihood of advanced fibrosis). Alternatives/complements: ELF (rule-out < 9.8; consider cirrhosis risk if ≥ 11.3), MRE (≥ 3.63 kPa suggests advanced fibrosis)	Repeat if suboptimal conditions; if uncertainty persists, consider hepatology consultation
Follow-up - low risk	FIB-4 < 1.3 and VCTE < 8 kPa	Continue MTX; optimize metabolic risk. Recheck FIB-4 in 1-3 years; repeat VCTE if clinical status changes
Follow-up - intermediate risk	FIB-4 ≥ 1.3 or VCTE 8-12 kPa or ELF 9.8-11.2	Continue MTX; intensify metabolic management. Repeat NITs in 6-12 months
Follow-up - high risk	VCTE > 12 kPa, or ELF ≥ 11.3, or MRE ≥ 3.63 kPa, or falling platelets	Discuss with hepatology. Consider dose reduction/alternative therapy; evaluate for portal hypertension. Initiate HCC surveillance if cirrhosis is suspected
Switch therapy despite mild fibrosis	Consider switching from MTX (or reducing dose) if either of the following occurs despite optimized metabolic care: ≥ 20% increase in VCTE/MRE with the final value in or approaching the indeterminate band (e.g., 6.5-8.0 kPa), confirmed on repeat testing in strict fasting; persistent ALT/AST elevations ≥ 2 × ULN on ≥ 2 tests ≥ 4 weeks apart without another cause	Switch or reduce MTX after risk-benefit discussion
Biopsy and referral triggers	Non-invasive tests discordant (e.g., FIB-4 high but VCTE low). Confirmed VCTE ≥ 12 kPa or ELF ≥ 11.3. New cytopenias or synthetic dysfunction; persistent clinical suspicion despite equivocal NITs	Refer to hepatology; consider liver biopsy

Vibration-controlled transient elastography quality: Interquartile range/median < 30%, ≥ 10 valid shots; correct probe (XL for high body mass index). Prefer fasting when possible; standardize timing and conditions between measurements. Interpret results with clinical context (alanine aminotransferase, platelets). BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; NIT: Non-invasive test; FIB-4: Fibrosis-4 index; MTX: Methotrexate; VCTE: Vibration-controlled transient elastography; IQR: Interquartile range; ELF: Enhanced liver fibrosis; MRE: Magnetic resonance elastography; HCC: Hepatocellular carcinoma; ULN: Upper limit of normal.