Background: The success of liver transplantation with good short-term and long-term survival rates has resulted in its widespread use for treatment of many patients with end-stage liver disease. The current 1-year, 5-year and 10-year survival rates are 84%, 68% and 54%, respectively. According to the American Liver Foundation, more than 6,000 liver transplants are performed each year in the United States. The most common complication in the early post-transplant period is acute cellular rejection (ACR), occurring in 20-40% of patients. Diagnosis of ACR by serum biomarkers is not specific and confirmation requires a liver biopsy, which is invasive and may cause hemorrhage and mortality. In addition, needle liver biopsy samples only about 1/50,000 of the liver and is limited by sampling variability and inter-observer variation in histological interpretation. At the Mayo Clinic, patients receive a liver biopsy on day 7 post-transplant if serum liver enzymes remain elevated. Approximately 60% of biopsied patients have ACR and are treated with additional immunosuppression, followed by a second biopsy on day 14 to evaluate treatment response. A noninvasive biomarker of ACR with high sensitivity and specificity may provide a better alternative to biopsy to reduce complications and facilitate more frequent follow-up and monitoring of the allograft. Our Goal is develop ultrasound-based methods to quantify mechanical properties of the liver for the purpose of noninvasive ACR diagnosis. The field of ultrasound elastography has developed various techniques to measure mechanical properties of the liver, most of which ignore tissue viscosity. All biological tissues are inherently viscoelastic and ignoring the viscous component not only biases the estimates of elasticity but also fails to report a potentially important tissue parameter. Disregarding tissue viscosity also masks potentially complex pathophysiological changes that manifest in structural changes affecting both elasticity and viscosity by grouping the two terms under the elasticity parameter. The omission of tissue viscosity largely stems from the inability to make stable measurements of shear wave attenuation. Several techniques have proposed model-based methods to estimate tissue viscosity by assuming a fixed relationship between wave velocity and attenuation without any knowledge of tissue attenuation. Because it is difficult to measure tissue attenuation in vivo, these models cannot be verified. Thus, the only appropriate approach for true measurements of tissue viscoelasticity requires independent measurements of wave velocity and attenuation. Attenuation Measuring Ultrasound Shearwave Elastography (AMUSE) is a method developed by our group that measures shear wave velocity and attenuation at multiple frequencies independently to provide true model-free characterization of tissue mechanical properties and is the first and only method of its kind. AMUSE is a post-processing method and is compatible with the current ultrasound shear wave elastography system worldwide. Method: We will use acoustic radiation force to generate waves in the transplanted liver and then measure the wave propagation with high frame rate ultrasound imaging. We will analyze the resulting wave motion data and evaluate the shear wave velocity and attenuation at multiple frequencies and compare the results with clinical findings of presence of acute cellular rejection. Approach: To achieve these important goals we will conduct a program with the following two coordinated Specific Aims: 1) To compare ultrasound measurements of shear wave velocity and attenuation in post-transplant liver patients to clinical diagnosis, 2) To study changes in mechanical properties of transplanted livers with acute cellular rejection due to medications and treatment.
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