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

Table 2 Non-invasive monitoring: How to deal with common pitfalls

Tool/scenario	Common pitfalls	What to do (mitigation)	When to escalate
Transient elastography/shearwave elastography	False-highs with acute inflammation, cholestasis, or postprandial state; obesity/central adiposity lowers reliability; device/probe cut-off variability; suboptimal IQR/median	Repeat in fasting state; use correct probe (XL if BMI/skin-capsule distance warrants); ensure quality metrics (e.g., IQR/median ≤ 30%, ≥ 10 valid shots); standardize device/protocol; interpret with ALT, platelets, clinical context	If kPa remains high on repeat under proper conditions and discordant with labs/clinical picture - consider turnover panel or specialist review
Serum scores (FIB-4, APRI, ELF, PIIINP)	Age-dependence; low PPV for moderate fibrosis in low-prevalence settings; systemic inflammation elevates components and may over-call risk	Use rule-out/rule-in bands; re-test when disease activity is quiescent; combine with elastography for concordance	Concordant high risk across two modalities or rising trend despite risk optimization, escalate work-up or therapy discussion
Discordance management	Enzymes high but TE low; TE high with normal labs	Consider MASLD activity, extrahepatic drivers, transient flares. Confirm fasting/probe; repeat TE; consider turnover markers before biopsy	Persisting discordance after optimized repeats, and where biopsy would change management
Follow-up cadence/interpretation	Over-reliance on single thresholds during changing clinical status	Prefer trendbased interpretation (bi-directional movement over time) with standardized timing/conditions	Escalate if sustained upward trends in TE and/or serum scores occur despite riskfactor optimization

Quality criteria for transient elastography commonly include interquartile range/median ≤ 30% and ≥ 10 valid measurements; thresholds vary by device/probe and clinical context. IQR: Interquartile range; BMI: Body mass index; ALT: Alanine aminotransferase; FIB-4: Fibrosis-4 index; APRI: Aspartate aminotransferase/platelet ratio index; ELF: Enhanced liver fibrosis test; PIIINP: Procollagen III aminoterminal propeptide; PPV: Positive predictive value; TE: Transient elastography; MASLD: Metabolic dysfunction-associated steatotic liver disease.