The Drug Induced Liver Injury Network (DILIN) was established in 2003 to advance understanding and research into the causes, pathogenesis, and natural history of DILI. The ongoing Retrospective study has collected 109 DNA samples from subjects with liver injury attributed to one of 8 drugs. In addition, 1215 patients with liver injuy attributed to over 100 individual drugs and herbal and dietary supplements (HDS) have been enrolled and followed for at least 6 months in the ongoing DILIN Prospective study. Manuscripts describing the presenting features and clinical outcomes in the overall cohort and with DILI attributed to specific agents have been published. Ancillary studies exploring the chemical content of implicated HDS products have been initiated. The collected DNA, lymphocytes, serum, plasma, and liver tissue have also been used to conduct informative mechanistic studies. The primary aim of the current application is to continue to recruit and enroll suspected DILI patients as early as possible after liver injury onset for collection of biological samples tobe used in genetic, immunological, transcriptomic, and proteomic studies. It is hypothesized that these studies will lead to improved biomarkers of DILI susceptibility, mechanisms, and outcomes. We also propose novel studies of liver elastography to longitudinally assess disease severity and a pilot clinical trial for patients with severe acute DILI. Recruiting and enrolling cases within 2 weeks of DILI onset at the University of Michigan will be accomplished via use of natural language processing algorithms to search inpatient and outpatient electronic medical records as well as the referral of patients from the 140 physician member Michigan Hepatotoxicity Research Network.
A second aim of this application is to continue to explore the role of host genetic variation in DILI susceptibility and outcomes using next generation sequencing techniques in high causality score cases. Exome arrays, whole genome, and whole exome sequencing are proposed to identify rare genetic polymorphisms associated with DILI susceptibility followed by expression system and pathway analysis studies.
The third aim of this application is to further develop an accurate and reliable computerized causality assessment instrument that will have improved sensitivity and specificity compared to expert opinion and other currently used methods. The coefficients for specific variables of this instrument will be developed from the DILIN database and tested and validated using future DILIN cases and other acute cases of non-DILI hepatitis.
The fourth aim of this application is to further develop the LiverTox website as a comprehensive and authoritative resource on DILI. A LiverTox Executive Committee is proposed to oversee and coordinate the development of a computerized causality assessment instrument as well as the development and maintenance of chapters on liver injury due to prescription drugs and HDS products. Finally, a LiverTox website portal is proposed to allow for the submission of bona-fide DILI cases for causality assessment and potential enrollment into future DILIN studies.

Public Health Relevance

The Michigan Hepatotoxicity Research Network proposes to improve our understanding of the causes, mechanisms, and outcomes of drug induced liver injury via the continued enrollment of adult and pediatric patients into the ongoing DILIN Prospective and Retrospective studies. The collection of early blood and urine samples from well-characterized DILI patients will allow for innovative studies of patient, drug and environmental risk factors. Further development of a computerized diagnostic instrument and expansion of the LiverTox website is also planned which will provide doctors, researchers, and the general public an authoritative and up-to-date resource that can help accelerate DILI research in the US and abroad.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK065184-11
Application #
8627692
Study Section
Special Emphasis Panel (ZDK1-GRB-N (M7))
Program Officer
Serrano, Jose
Project Start
2003-09-30
Project End
2018-06-30
Budget Start
2013-08-15
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$321,402
Indirect Cost
$132,558
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Orman, Eric S; Conjeevaram, Hari S; Vuppalanchi, Raj et al. (2011) Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 9:517-523.e3

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