INTRODUCTION: Primary biliary cholangitis (PBC) is a cholestatic liver disease that results in inflammation of the intrahepatic bile duct and the portal tract. While the liver biopsy is the gold standard in relation to disease activity and fibrosis, histological findings have not been compared to serum alkaline phosphatase (ALP) changes with therapy. This is important as ALP is a well-established serum marker in the assessment of PBC. METHODS: Patients with biopsy-confirmed PBC, received a retrospective medical record review. The histological features were stratified by a GI pathologist into the following categories: 1) lymphocytic infiltration of the portal tract, 2) neutrophilic infiltration of the portal tract, 3) eosinophilic infiltration of the portal tract, 4) plasma cell infiltration of the portal tract, 4) florid duct lesions and bile duct loss, 5) bile flow obstruction, 6) inflammation of the hepatic parenchyma, and 7) hepatic necrosis. The primary endpoint was the non-reduction in ALP over the 1-year period. RESULTS: Of the 217 patients in the study, 173 (79.7%) did not have a reduction in their ALP levels over a 1 year period even though 148 of the 173 patients (85.5%) were undergoing therapy. Of the histological features analyzed in the study, lymphocytic infiltration of the portal tract was associated with the non-reduction in ALP levels (P = 0.02, OR 2.18 95%CI 1.11–4.30). However, other features including neutrophilic infiltration (P = 0.97, OR 0.98 95%CI 0.37–2.59), eosinophilic infiltration (P = 0.27, OR 1.87 95%CI 0.68–5.10), plasma cell infiltration (P = 0.27, OR 1.94 95%CI 0.71–5.28), bile duct damage (P = 0.52, OR 1.24 95%CI 0.64–2.41), hepatic inflammation (P = 0.13, OR 0.58 95%CI 0.28–1.18), and hepatic necrosis (P = 0.17, OR 1.65 95%CI 0.81–3.38) were not significantly associated with disease exacerbation that is demonstrated by the maintenance or elevation in ALP levels. In a multivariate model, the association between lymphocytic infiltration and the non-reduction in ALP remained significant (P = 0.26, aOR 2.31 95%CI 1.11–4.84), despite controlling for age (P = 0.34), gender (P = 0.49), race (P = 0.78), weight (P = 0.80), diabetes (P = 0.03), alcohol use (P = 0.998), and ursodiol therapy (P = 0.88). CONCLUSION: A lack of reduction in serum ALP correlates with disease activity and lymphocytic infiltration of the portal tract in patients with PBC. Hence, patients with these characteristics in biochemical and histological analysis would likely benefit from escalation of therapy and close surveillance.Figure 1.: Multivariate model: lymphocytic infiltration of the portal tract is an independent predictor of PBC disease activity as demonstrated by the non-reduction in the level of alkaline phosphatase.