BACKGROUND: Serum alkaline phosphatase (ALP) is a commonly obtained laboratory test, but its diagnostic specificity is limited because it is found in multiple tissues. We investigated patients with isolated, elevated, ALP levels without an obvious etiology at presentation to determine the frequency of different causes of an isolated elevated ALP. METHODS: This was a retrospective, cohort study of adults (age >
18 years old) from January 1st, 2013, to June 30th, 2020 in both the in- and outpatient setting at the Medical University of South Carolina. 260 patients with an isolated, elevated ALP of unknown etiology (patients with known biliary obstruction, underlying parenchymal liver disease, or pregnancy were excluded) were included. A secondary outcome was mean survival time from the ALP result. RESULTS: The most common cause of ALP elevation was due to underlying malignancy (147, 57 %), with 61 patients having infiltrative intrahepatic malignancy, 52 patients having bony metastasis, and 34 patients having both hepatic and bone metastasis. Bone disease (75, 29 %), unsuspected parenchymal liver disease (18, 7 %), non-malignant infiltrative liver disease (7, 2 %), and other disorders (13, 5 %) accounted for the remainder of the cohort. Notably, 123 of 260 (47 %) patients died within an average of 58 months after identification of isolated, elevated ALP. CONCLUSIONS: An isolated, elevated ALP of unclear etiology is associated with several very specific and important disorders, in particular metastatic intrahepatic malignancy - and is uncommonly associated with primary parenchymal liver disease. Providers should be aware of the potential clinical significance of an elevated ALP.