Development and Validation of a Symptom-Based Patient-Reported Outcome Measure for MASH: The CLDQ-MASH Symptom Questionnaire (CLDQ-MASH-SQ)

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with a substantial symptom burden. However, no validated symptom-focused patient-reported outcome (PRO) instrument exists for this population. We aimed to develop and validate the MASH Symptom Questionnaire. METHODS: We analyzed MASLD subjects from the Global NASH/MASH Registry (GNR) with clinical data and completed CLDQ-MASH instruments. For the new instrument development and preliminary validation, we used CLDQ-MASH items supplemented with symptom-related items from other generic instruments (development sample: n=2,066) and expert input. A list of 50 symptom-related items was identified. After removal of redundancy, 36 items were retained and evaluated using exploratory factor analysis. Standard pipeline for validation of a PRO instrument was applied. The instrument was validated using another independent validation sample from GNR (validation sample: n=2541). RESULTS: In the development phase, 36 items were distributed in 8 symptom domains: Mental, Cognitive, Fatigue, Systemic, Abdominal, Health distress, Sleep Disturbance, and Peripheral symptoms domains. Seven of eight domains demonstrated Cronbach's alpha >0.80 (high internal consistency); the remaining Peripheral symptoms domain included diverse items. The domain scores significantly discriminated across histologic disease severity (early fibrosis vs. F2-F3 vs. cirrhosis), liver stiffness categories (<10 vs. 10-20 vs. >20 kPa) in both development and independent validation samples. The instrument discriminated well based on non-hepatic comorbidities (type 2 diabetes, hypertension, psychiatric, sleep, pruritus, clinically overt fatigue, GERD, other GI disorders). Similar strong validation properties were noted in the independent validation sample. CONCLUSION: The 36-item, 8-domain CLDQ-MASH Symptom Questionnaire (CLDQ-MASH SQ) represents the first validated, disease-specific symptom questionnaire for patients with MASH showing good psychometric properties. With further external validation, the CLDQ-MASH-SQ has the potential to serve as a standardized tool in both clinical research and routine practice to comprehensively assess disease burden and treatment response.