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Introduction: Malnutrition can lead to liver inflammation resembled as non-alcoholic steatohepatitis (NASH) which often develops into fibrosis and hepatocellular carcinoma (HCC). Early detection of metabolic NASH can identify this transition and reverse the pathological onset in real-time. This study compares for the first time the application of metabolic hyperpolarized 1-13C-pyruvate using dissolution dynamic nuclear polarization (dDNP) and parahydrogen-induced polarization (PHIP) in MRSI offering a non-invasive and cost-effective tool for tracking longitudinal NASH progression to HCC.
Methods: C57BL/6J mice were fed with western diet (WD) or choline-deficient high-fat diet (CD-HFD) up to 15 months. MRI scans were performed on a 7T scanner (BioSpec/ ClinScan, Bruker). 13C NMR spectra (bandwidth: 3019.32 Hz; 1024 points, flip angle: 10°/5°) acquired with a liver-centered offset using a single pulse sequence, and with CSIs (128 pts; 3-sec temporal resolution; FA = 10°; FOV = 24× 24 mm²; 3 mm slice thickness). Hyperpolarized [1-13C]pyruvate was generated by a clinical SpinLab polarizer (dDNP, GE Healthcare) or a custom-built PHIP polarizer1. Data were processed and analyzed using TopSpin and self-developed Python software. Histopathology (H&E), immunohistochemistry (IHC), and 1H NMR spectroscopy (600 MHz) were performed for ex-vivo correlation. All data are presented as mean ± SD.
Results/Discussion: Both the WD and CD-HFD increased body and liver weights in the experimental groups, with histopathology confirming a NASH phenotype. 13C MRSI revealed effective differentiation of NASH and healthy control by detecting metabolites, 13C-lactate, and 13C-alanine with both dDNP and PHIP (Fig 1). In NASH, reduced lactate-to-pyruvate ratios (p=0.0018 for DNP, 0.0129 for PHIP) and alanine-to-pyruvate ratios (p=0.0304) suggested altered metabolism. After 6 months, both modified diets showed increased bicarbonate levels, indicating increased oxidative phosphorylation, gluconeogenesis, and anaplerotic conversion. Immunofluorescence showed decreased LDH-B, increased MCTs expression and NMR confirmed lower lactate levels in CD-HFD tissue at 12 months, supporting the in vivo results and suggesting an anabolic metabolism in advanced NASH before progression to cirrhosis or HCC (Fig. 2). This transition is disrupted once HCC develops at 15 months, with the upregulated anaerobic glycolysis.
Conclusion: This study demonstrate the use of hyperpolarized 13C MRSI to detect metabolism in NASH non-invasively, with implications for earlier diagnosis towards the HCC onset. While dDNP provides robust accuracy, PHIP offers a cost-effective alternative for detecting metabolites, enhancing diagnostic precision. These findings show potential for targeted and accessible monitoring of NASH and HCC towards more personalized diagnostics.
