Radiation-induced changes in hepatocyte-specific Gd-EOB-DTPA enhanced MRI: potential mechanism

Liver irradiation leads to a decreased uptake of a hepatobiliary directed MRI contrast agent (Gd-EOB-DTPA) as shown in studies performed 1-6 months after proton therapy, stereotactic ablative body radiation therapy and brachytherapy. Therefore, Gd-EOB-DTPA enhanced MRI could potentially be used for in vivo verification of the delivered dose distribution. Achieving this would be highly desirable, especially for particle therapy, where the accuracy and precision of the spatial dose deposition is affected by uncertainties of the range of particles in patients. However, the empirically detected effect needs to be understood before it can be used as a surrogate imaging biomarker for in vivo treatment verification or even liver functionality. Here, we propose a model of the underlying molecular mechanism of this phenomenon and discuss its implications for radiation therapy. We model the multi-step process starting from the immediate response after liver irradiation to the delayed/subsequent signal decrease in Gd-EOB-DTPA enhanced MRI. The model is based on both: (a) Evidence from different previously published reports and (b) a detailed evaluation of intra-hepatic signaling using a pathway analysis to identify potential pathways that are critical in this process. The proposed model provides mechanistic understanding of the reduced signal intensity in Gd-EOB-DTPA enhanced MRI occurring in irradiated liver. We think that establishing this comprehensive model will be of great interest for the field of radiation oncology and can trigger further research. For example, measuring the expression of involved cytokines and specific transport proteins in blood samples and biopsy derived tissue samples and correlating the results with MRI imaging could give important information and may even explain inter-patient variations in MRI signal decrease.