Background/Purpose: Methotrexate (MTX) is widely used in rheumatologic disease but carries hepatotoxic risk. Standard monitoring relies on measurement of alanine and aspartate aminotransferase (ALT and AST), though their variability limits specificity. The FIB-4, a composite fibrosis index that combines biochemical values (platelet count, ALT, and AST) and age, may offer a more stable marker of hepatic injury. Our objective was to evaluate the utility of ALT, AST, and FIB-4 in monitoring MTX-related hepatotoxicity and to characterize provider management of transaminitis.

Methods: We retrospectively analyzed 43 patients followed at the Louis Stokes Cleveland Veterans Affairs Medical Center Rheumatology Clinic, treated with MTX for rheumatologic disease, and with AST/ALT >2× upper limit of normal (ULN) during this treatment. Interventions and clinical data—including FIB-4 scores, cumulative MTX exposure, and risk factors (non-alcoholic fatty liver disease (NAFLD), body mass index (BMI) statin use, diabetes, hyperlipidemia, hypertension)—were analyzed. Discriminative performance for MTX dose changes in relation to AST/ALT/Fib4 change was assessed using area under the ROC curve (AUC).

Results: MTX was held or reduced in 60% of cases (with the median delay between first AST/ALT elevation and MTX dose change: 4.2 months). Responses included early (less than 3 months) repeat of LFTs (37%), liver imaging (12%), and no action (19%). FIB-4 showed modest discrimination for MTX associated change in laboratory parameters (AUC 0.64), slightly outperforming ALT (0.62) and AST (0.57); a composite score incorporating all three yielded a higher AUC of 0.66. None reached statistical significance. Cumulative MTX dose did not differ significantly between patients with persistent vs. non-persistent transaminitis (mean 48,650 mg vs. 55,307 mg; p=0.34). No demographic or clinical variable—including NAFLD, BMI, or statin use—was independently associated with AST, ALT or FIB-4 change.

Conclusion: Provider responses to MTX-induced transaminitis were inconsistent and often delayed beyond 3 months. A composite of FIB-4, ALT, and AST showed the highest discriminative value for guiding MTX modification. Neither traditional metabolic risk factors nor cumulative methotrexate dose were predictive of hepatotoxicity in this cohort. FIB-4 may offer a more consistent signal for MTX hepatotoxicity monitoring compared to AST/ALT, though this requires additional analysis in a larger cohort.

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/utility-of-alt-ast-and-fibrosis-4-index-fib-4-score-in-monitoring-methotrexate-hepatotoxicity-in-rheumatologic-disease-a-retrospective-analysis/