PROJECT SUMMARY/ABSTRACT Alcoholic hepatitis (AH) is a major cause of morbidity and mortality due to a lack of effective treatments. There is an unmet need for reliable noninvasive diagnosis, prognosis, and disease monitoring surrogate markers in AH patients, who often have challenging clinical diagnoses and high risks of complications with invasive liver biopsy. The overall goals of this proposal are to perform both preclinical (phase UH2) and clinical (phase UH3) studies to evaluate multiple magnetic resonance elastography (MRE) biomarkers to assess AH disease severity and monitor treatment responses. Our central hypothesis is that a multiparametric liver MRE, called a hepatogram, can provide accurate parameters for assessing AH disease progression and regression, including changes in steatosis, inflammation, and fibrosis. We believe that AH disease severity and treatment responses can be quantified when the hepatogram is integrated into a composite metric that can serve as a “virtual biopsy,” providing a reliable noninvasive surrogate for assessing AH disease severity. In phase UH2 (years 1-2; Aim 1), we will advance MRE technology to validate the relationships between each imaging parameter and the corresponding histologic feature in mice administered ethanol (EtOH). A statistical model will expand the use of these imaging biomarkers to an all-in-one diagnostic or prognostic score for AH. Recombinant IL-22, an agent that ameliorates hepatic steatosis and inflammation in mouse models will be used to promote disease regression. We will test the ability of MRE in a longitudinal study for assessing AH severity and evaluate changes of each parameter for indicating both disease progression and regression in AH mouse models with placebo or IL-22 treatment. In phase UH3 (years 3-5; Aim 2), we will verify MRE reliability for assessing AH disease severity and treatment responses in patients with AH. Predicated on the upcoming translational patient-oriented studies (RFA AA-18-002 and RFA AA-18-005) in the AlcHepNet at Mayo Clinic, we will perform a baseline MRE in patients who have had liver biopsies as part of their clinical care. We will verify the reliability of each imaging surrogate from MRE for correlation with histology features (steatosis, inflammation, and fibrosis). Additionally, a statistical model of this all-in-one “virtual biopsy” will be verified. We will also perform baseline, 30-, and 90-day follow-up hepatograms in the placebo and IL-22 cohorts from patients enrolled in a Mayo treatment trial of IL-22 (in response to RFA AA-18-005). This will allow us to evaluate MRE parameter changes in AH progression and regression respectively by correlating changes in MRE with changes in Model of End Stage Liver Disease (MELD) scores. In summary, successful verification of this novel MRE based biomarker in the proposed preclinical and clinical studies would have tremendous applications for assessing AH disease severity and response to therapy.

PROJECT NARRATIVE This research will develop and explore hepatic magnetic resonance imaging in patients with alcoholic hepatitis. The success of this proposed study will advance our understanding and ability to diagnose and monitor this disease.