Mild alkaline phosphatase elevation associates with increased mortality and major adverse liver outcomes in MASLD.

BACKGROUND: Alkaline phosphatase (ALP) elevation is commonly observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but its clinical implications in MASLD are unclear. We evaluated whether longitudinal patterns of mild ALP elevation are associated with mortality and major adverse liver outcomes (MALO). METHODS: We performed a multicenter retrospective cohort study of adults with MASLD from Michigan Medicine and the Banner Health system. We included patients with MASLD defined as hepatic steatosis on imaging and at least one cardiometabolic comorbidity, with at least 1 ALP measurement within 1 year of the imaging date. Mild ALP elevation was defined as >1 to ≤1.5× the upper limit of normal and categorized as persistently normal, transiently elevated, or persistently elevated. Primary outcomes were all-cause mortality and MALO. Mortality was modeled as a Cox proportional hazards model, and MALO as Fine-Gray competing risk models. RESULTS: Among 32,753 patients, persistently elevated ALP was present in ~10% of both cohorts. After multivariable adjustment, persistently elevated ALP was associated with increased mortality and MALO in both Michigan (mortality HR 1.51, 95% CI 1.20-1.89; MALO SHR 2.45, 95% CI 1.55-3.88) and Banner (mortality HR 1.81, 95% CI 1.19-2.75; MALO SHR 2.13, 95% CI 1.55-2.94). Associations were most consistent in low-risk and intermediate-risk FIB-4 groups. Associations remained significant in sensitivity analyses excluding baseline cirrhosis and restricting to patients with at least 2 ALP measurements. CONCLUSIONS: Persistent ALP elevation was associated with increased risk of mortality and MALO in MASLD, particularly among patients with low-risk and intermediate-risk FIB-4 scores. These findings suggest that ALP may serve as a clinically meaningful biomarker in early MASLD.