Staging Liver Fibrosis by Fibroblast Activation Protein Inhibitor Positron Emission Tomography in a Human-sized Swine Model

Abstract

Rationale: Current methods of staging liver fibrosis have notable limitations. We investigated the utility of positron emission tomography (PET) in staging liver fibrosis by correlating liver uptake of ⁶⁸Ga-labeled fibroblast activation protein inhibitor (FAPI) with histology in a human-sized swine model. Methods: Five pigs underwent baseline FAPI PET/MRI and liver biopsy, followed by liver parenchymal embolization, 8 weeks of oral alcohol intake, endpoint FAPI PET/MRI, and necropsy. Regions of interest (ROIs) were drawn on baseline and endpoint PET images and standardized uptake values (SUVs) were recorded. At endpoint, liver sections corresponding to ROIs were identified and cut out. Histologic evaluation of fibrosis was performed using a modified METAVIR score for swine liver and quantitatively using collagen proportionate area (CPA). Box-and-whisker plot and linear regression were used to correlate SUV with METAVIR score and CPA, respectively. Results: Liver FAPI uptake strongly correlated with CPA (Pearson correlation coefficient, r=0.89, P<0.001). FAPI uptake was significantly and progressively higher across F2 and F3/F4 fibrosis stages, respective median SUVs [interquartile range, IQR] of 2.9 [2.7 – 3.8] and 7.6 [6.7 – 10.2] (P<0.001). There was no significant difference between FAPI uptake of baseline liver and endpoint liver sections staged as F0/F1, respective median SUVs [IQR] of 1.7 [1.3 – 2.0] and 1.7 [1.5 – 1.8] (P = 0.338). Conclusion: The strong correlation between liver FAPI uptake and the histologic stage of liver fibrosis suggests FAPI PET is a promising tool that can achieve noninvasive and accurate staging of fibrosis throughout the entire liver, pending validation in patients.