This proposal addresses the topic Hepatitis in areas of encouragement: (1) development of strategies for reliable, non-invasive, early detection of hepatitis-related liver disease and hepatocellular carcinoma (HCC) and (2) research on strategies to promote reversal of liver fibrosis and/or assess the associated clinical and pathological outcomes.
Unmet Needs: Hepatitis causes chronic liver damage via inflammation and subsequent cellular injury and fibrosis. Without treatment, eventual cirrhosis development can accelerate to hepatocellular dysfunction, hepatic insufficiency, cirrhosis, and HCC resulting in hospitalization, healthcare cost, and death. Hepatitis, a major Military Health System (MHS) concern, is a US and worldwide public health problem. The 12th leading cause of death in the US, it generates an economic burden estimated at $13 billion annually. Timely hepatitis identification and monitoring allows for early intervention to avoid progression to end-stage liver disease or death. Needle liver biopsy, as hepatology foundations were built upon, is long considered the gold standard for diagnosing liver disease severity by the presence and pattern of specific histological abnormalities. It is also an expensive diagnostic test and invasive with possible complications. Sampling error and a subjective scoring system further affects liver biopsy accuracy. These liver biopsy limitations as bedrock for liver disease diagnosis created the impetus to translate basic research into improved therapeutics and management of hepatitis. The prolonged natural Hepatitis C virus (HCV) history and lack of accurate noninvasive liver injury assessment also act as critical barriers to a translational study design.
Impact: In developing necessary technologies and confirming diagnostic and prognostic performance through pilot patient studies, our solutions accelerate the use of liver and spleen magnetic resonance elastography (MRE) as a practical tool for monitoring chronic liver disease (CLD) progression and advancing basic imaging science. This proposal success establishes noninvasive imaging biomarkers critically important to understand and monitor progression from inactive chronic hepatitis infection to active HCV with increasing inflammation, fibrosis accumulation, cirrhosis, and HCC occurrence with high risks of microvascular invasion. The rigorously validated MRE biomarkers will have a dual-use opportunity for federal and civilian applications in drug evaluation, disease monitoring, and assessing therapy response.
The proposed project's major goal develops advanced noninvasive liver MRE imaging technology to accurately detect and monitor HCV activity, injury, and progression. Liver MRE technical development has promise for: (1) early detection and monitoring hepatitis-related liver diseases, such as early onset of inflammation before fibrosis; (2) timely monitoring of inflammation and fibrosis for accurate evaluation of treatment efficacy; (3) understanding the natural history of hepatitis progression and changes in MRE parameters from inactive chronic infection to active hepatitis; (4) establishing MRE parameters for the initiation and duration of viral hepatitis treatment; and (5) early identification of HCC involvement, differentiation and risks of microvascular invasion. Our proposed advanced liver MRE will be a practical imaging tool for qualitatively and quantitatively assessing the mechanical properties of the liver and tumors, and detecting or characterizing important diffuse and focal liver disease processes, providing capabilities unavailable with other imaging techniques.
Our central hypothesis and final product is the development of advanced multifrequency 3D liver MRE acquisition and inversion methods with improved and new mechanical parameters, including shear attenuation, volumetric strain, and slip interface imaging (SII). These quantitative imaging biomarkers will more fully characterize the pathophysiologic state of viral hepatitis during the long CLD progression period. Rigorous evaluations and preliminary translational validations of these new biomarkers will be conducted in both cross-sectional and longitudinal clinical studies in patients with HCV infection or HCC. In this proposal, we will investigate (1) MRE-assessed mechanical properties to assess hepatitis activity in HCV and (2) MRE-assessed capsule integrity and intratumoral pressure for assessing HCC differentiation and prognostic risks of microvascular invasion.
|Effective start/end date||1/1/18 → …|
- Congressionally Directed Medical Research Programs: $2,970,690.00