Fibrosis is the final common pathway to organ failure in many chronic diseases, and it leads to over $142 billion in annual medical costs in the United States. Intestinal fibrosis is the primary reason for surgical intervention in Crohn's disease (CD) which is required in more than two-thirds of patients. Despite this huge impact of fibrosis in CD, we are unable to noninvasively detect or measure intestinal fibrosis in CD. Our recent preliminary data suggest that novel methods of nonlinear ultrasound stiffness imaging (USI) can accurately detect fibrosis in the intestine. The long-term objective of this research program is to develop and test novel methods of measurement of intestinal fibrosis in Crohn's disease to determine prognosis and guide medical and surgical therapy. We propose to evaluate the accuracy of two novel ultrasound methods for measuring intestinal fibrosis in CD. Our preliminary data show that two nonlinear forms of USI (quasi-static strain imaging [QSSI] and shear wave elasticity imaging [SWEI]) can accurately differentiate inflamed from fibrotic intestine. The central hypothesis of this proposal is that accurate measurement of intestinal fibrosis in Crohn's disease will guide therapy and predict future clinical outcomes based on two observations. First, our preliminary data demonstrate that nonlinear QSSI and SWEI methods detect and quantitatively measure fibrosis of the rodent intestine, with bowel wall strain and shear wave speed, respectively, serving as surrogate radiologic biomarkers. Second, while inflammation clearly initiates fibrosis, three observations have challenged the paradigm that inflammation is required to perpetuate fibrosis: published data demonstrates that anti- inflammatory biologic therapy has not changed surgery rates in CD; our in vivo studies which demonstrate that fibrosis autopropagates despite the eradication of inflammation; and our in vitro studies which demonstrate that tissue stiffness in the absence of inflammation can activate fibrogenesis. Our results suggest that bowel wall strain and shear wave speed measurements can help distinguish strictures destined to require surgery from those strictures likely to respond to medical therapy, even when inflammation is present. This application aims: (1) to test the accuracy of nonlinear QSSI and SWEI in a rat model of intestinal fibrosis used in preclinical therapeutic studies; (2) to test the accuracy of nonlinear QSSI and SWEI in a cross- sectional human cohort by comparing these USI measures to the histopathology of resected bowel specimens; and (3) to test the predictive accuracy of the nonlinear USI methods in a prospective human longitudinal cohort by determining whether USI measurements predict clinical outcomes in patients with CD. The proposed studies will directly impact patient care throughout the United States, and by demonstrating the effectiveness of novel forms of ultrasound in the measurement of fibrosis, spur further innovation and application of ultrasound to clinical care in other chroni, fibrotic disease states.

Public Health Relevance

This project addresses the challenge of developing imaging biomarkers to non-invasively measure fibrosis in human organs without exposing patients to radiation. The proposed studies will directly impact the care of pediatric and adult patients with Crohn's disease throughout the United States. Furthermore, by demonstrating the effectiveness of novel forms of nonlinear ultrasound stiffness imaging in detecting, measuring, and monitoring organ fibrosis, this project will have a broad impact in a range of chronic fibrotic disease states beyond inflammatory bowel disease and will enable future development and testing of antifibrotic therapies in many fibrotic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Hamilton, Frank A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Limsrivilai, Julajak; Rao, Krishna; Stidham, Ryan W et al. (2018) Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection. Dig Dis Sci 63:1801-1810
Dillman, Jonathan R; Dehkordy, Soudabeh Fazeli; Smith, Ethan A et al. (2017) Defining the ultrasound longitudinal natural history of newly diagnosed pediatric small bowel Crohn disease treated with infliximab and infliximab-azathioprine combination therapy. Pediatr Radiol 47:924-934
Dillman, Jonathan R; Heider, Amer; Bilhartz, Jacob L et al. (2015) Ultrasound shear wave speed measurements correlate with liver fibrosis in children. Pediatr Radiol 45:1480-8
Dillman, Jonathan R; Chen, Shigao; Davenport, Matthew S et al. (2015) Superficial ultrasound shear wave speed measurements in soft and hard elasticity phantoms: repeatability and reproducibility using two ultrasound systems. Pediatr Radiol 45:376-85
Dillman, Jonathan R; Stidham, Ryan W; Higgins, Peter D R et al. (2014) Ultrasound shear wave elastography helps discriminate low-grade from high-grade bowel wall fibrosis in ex vivo human intestinal specimens. J Ultrasound Med 33:2115-23