Differentiation of Heterogeneous Mouse Liver from HCC by Hyperpolarized 13C Magnetic Resonance

Abstract

The clinical characterization of small hepatocellular carcinoma (HCC) lesions in the liver and differentiation from heterogeneous inflammatory or fibrotic background is important for early detection and treatment. Metabolic monitoring of hyperpolarized 13C-labeled substrates has been suggested as a new avenue for diagnostic magnetic resonance. The metabolism of hyperpolarized [1-13C]pyruvate was monitored in mouse precision-cut liver slices (PCLS) of aged MDR2-KO mice, which served as a model for heterogeneous liver and HCC that develops similarly to the human disease. The relative in-cell activities of lactate dehydrogenase (LDH) to alanine transaminase (ALT) were found to be 0.40 ± 0.06 (n = 3) in healthy livers (from healthy mice), 0.90 ± 0.27 (n = 3) in heterogeneously inflamed liver, and 1.84 ± 0.46 (n = 3) in HCC. Thus, the in-cell LDH/ALT activities ratio was found to correlate with the progression of the disease. The results suggest that the LDH/ALT activities ratio may be useful in the assessment of liver disease. Because the technology used here is translational to both small liver samples that may be obtained from image-guided biopsy (i.e., ex vivo investigation) and to the intact liver (i.e., in a non-invasive MRI scan), these results may provide a path for differentiating heterogeneous liver from HCC in human subjects.

Curbing action potential generation or ATP-synthase leads to a decrease in in-cell pyruvate dehydrogenase activity in rat cerebrum slices

“…For [ 13 C]bicarbonate acquisition, the pulse was centered 214 Hz down-field of the [ 13 C]bicarbonate frequency (161 ppm). The same acquisition strategy was previously applied for studies on other perfused tissue slices [5][6][7] . Hyperpolarized [1- 13 C] pyruvate experienced a flip angle of 1.07° and 4.5° in the respective selective excitations of [1-13 C]lactate and [ 13 C]bicarbonate acquisitions.…”

“…To ensure appropriate referencing, we selected a temporal window at which the [1-13 C]pyruvate concentration was constant (and known). In this way, the production of [1-13 C]lactate and [ 13 C]bicarbonate could be expressed in nmol/s as previously described [5][6][7] and explained in detail below. The [1- 13 C]pyruvate concentration in the NMR tube first increased during the wash-in phase, then reached a plateau at a maximal concentration of 14 mM for at least 1 min, then decreased-during the wash-out phase.…”

“…In the latter study, the sensitivity of detecting carbon-13 labeled metabolites was increased through hyperpolarization by a few orders of magnitude using the dissolution dynamic nuclear polarization (dDNP) technology 3 . In recent years, dDNP has been used to drastically improve the temporal and spatial resolution in comparison to thermal equilibrium nuclear magnetic resonance (NMR) spectroscopy in multiple preparations [4][5][6][7][8] . Hyperpolarized [1- 13 C]pyruvate is the benchmark metabolite used across different experimental dDNP designs including pioneering clinical studies on brain cancer imaging [9][10][11] .…”

“…13 C]lactate and [ 13 C]bicarbonate, θpro is the flip angle of the product (90°), and θpyr is the flip angle of [1-13 C]pyruvate (1.07° on [1-13 C]lactate acquisitions and 4.5° on [ 13 C]bicarbonate acquisitions), S pro (t) is the signal of [1-13 C]lactate or [ 13 C]bicarbonate at each time point, and S pyr (t) is the[1][2][3][4][5][6][7][8][9][10][11][12][13] …”