Abstract
Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk for progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB) - particularly when TB <0.6 times the upper limit of normal (xULN) - is associated with improved outcomes compared to ALP reduction to <1.5 xULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC.
We compared complication-free survival in patients achieving an ALP >ULN and <1.5 xULN (adequate response) to those with an ALP <ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained.
Patients achieving normal ALP and/or TB ≤0.6 xULN demonstrated significantly improved complication-free survival compared to those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI:0.56, 2.11; p=0.001) for ALP normalization alone, 3.7 years (95% CI:3.11, 4.29; p< 0.001) for TB ≤ 0.6 xULN, and 4.51 years (95% CI:4.13, 4.88; p<0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (HR 0.34; 95% CI:0.15, 0.80; p=0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI:0.09, 0.55; p=0.001), or both (HR 0.14; 95% CI:0.05, 0.38; p<0.001). High-risk patients, defined by LSM ≥10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit.
Achieving normal ALP and TB ≤0.6xULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.