Molecular MR Imaging of Hepatic Fibrogenesis

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Project Summary Nonalcoholic fatty liver disease (NAFLD) is the most prominent cause of liver disease, with 20-30% of adults in the western world now estimated to have NAFLD. In NAFLD, hepatocytes accumulate excess fat (steatosis), which is benign and reversible. However up to 30% of patients with NAFLD will develop non-alcoholic steatohepatitis (NASH) which is characterized by steatosis, inflammation, and scarring (fibrosis). Patients with only steatosis have good long-term prognosis, with no increased liver related morbidity or mortality, but those with NASH have increased risk of cirrhosis, hepatocellular carcinoma and mortality. NASH is expected to soon be the leading indication of liver transplantation. The financial burden of NAFLD/NASH is currently estimated to cost >$100 billion in the USA alone. There is an urgent need to identify NAFLD patients who are at risk of developing NASH and cirrhosis so as to better manage patient healthcare through improved lifestyle, exercise and diet. In addition, a large number of new therapies have entered clinical trials and effective diagnostics are needed to better stratify patients into these trials and to accurately monitor response to therapy. Fibrosis stage, and not steatosis nor inflammation, is the only feature of disease associated with worse outcomes in NASH. Besides biopsy we lack good tools to noninvasively detect liver fibrosis, stage fibrosis, or monitor response to treatment. Elastography methods are not sensitive to early changes in disease. Serum biomarkers and biomarker panels to identify NASH and/or liver fibrosis, are also limited and lack accuracy for staging. None of these techniques has the accuracy to monitor treatment. An accurate, safe method to diagnose and monitor NASH and associated fibrosis is of utmost importance in both clinical practice and clinical research. We recently demonstrated in animal models that we could quantify fibrogenesis (active disease) noninvasively using a molecular magnetic resonance (MR) probe, Gd-Hyd, that targets extracellular allysine, a chemical modification of oxidized collagen, present only during active fibrogenesis. We showed that Gd-Hyd imaging could detect fibrogenesis, monitor treatment response and could distinguish active fibrogenesis from stable scar in models of lung and liver fibrosis. The overall goal of this project is to improve on this prototype to develop an optimized fibrogenesis MR probe for robust, quantification of liver fibrogenesis in patients.