This application is submitted in response to RFA DK-13-003 which solicits applications from qualified investigators for the continuation of the Drug Induced Liver Injury Network (DILIN). Indiana University is one of the five founding clinical centers and has robustly participated in all DILIN operations since its inception. We propose the following specific aims to meet the goals of this RFA.
Specific Aim # 1: To enroll large number of eligible adults with suspected DILI into ongoing DILIN studies. We propose to collect prospective cases of suspected DILI from multiple sources in Central Indiana, each providing distinctive epidemiological facets and research potential.
Specific Aim # 2: To enroll significant number of eligible children with suspected DILI into ongoing DILIN studies. We propose to include Cincinnati Children's Hospital as a satellite site to significantly increase the number of children enrolled into ongoing DILIN studies.
Specific Aim # 3: The DILI is currently a diagnosis of exclusion and it can be a challenging diagnosis to make. We propose to conduct two ancillary studies in order to develop tests that facilitate the diagnosis of DILI: (i) we will conduct a discovery proteomic study of individuals with acute liver injury due to DILI and non-DILI etiologies enrolled within two weeks of liver injury onset to identify biomarkers specific for acut liver injury due to DILI;(ii) DILI can sometime mimic autoimmune hepatitis and it is difficult to distinguish it from de novo autoimmune hepatitis. To address this clinical conundrum, we will conduct a preliminary study for autoantibody profiling using an auto-antigen array assay among individuals with (i) acute DILI with autoimmune hepatitis-like features, (ii) acute DILI without autoimmune hepatitis features, and (iii) acute autoimmune hepatitis without precedent medication exposure.
Specific Aim # 4: DILI carries considerable mortality and morbidity but there is no treatment available other than withdrawing the offending agent. In order to address this unmet therapeutic need, we propose to conduct a randomized, double-blind, placebo-controlled pilot study of budesonide in individuals with well characterized hepatocellular DILI meeting predefined eligibility criteria. Our hypothesis is that oral budesonide, a steroid with hig glucocorticoid activity and substantial first pass elimination, attenuates liver injury and improve outcomes of patients with hepatocellular DILI.

Public Health Relevance

Drug induced liver injury (DILI) is a rare but serious problem that can lead to liver failure, transplantation, death, or chronic liver disease. Drug induced liver injury network (DILIN) was set up by the National Institutes of Health in 2003 to facilitate clinical, mechanistic and therapeutic research related to DILI. Indiana University is proposing several novel specific aims to promote DILIN during the next funding period.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK065211-11
Application #
8626897
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
2013-09-03
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$284,969
Indirect Cost
$120,245
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
French, Joshua B; Bonacini, Maurizio; Ghabril, Marwan et al. (2016) Hepatotoxicity Associated with the Use of Anti-TNF-α Agents. Drug Saf 39:199-208
Schmeltzer, Paul A; Kosinski, Andrzej S; Kleiner, David E et al. (2016) Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 36:603-9
Heidemann, Lauren A; Navarro, Victor J; Ahmad, Jawad et al. (2016) Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series. Dig Dis Sci 61:2741-8
Bohm, Matt; Vuppalanchi, Raj; Chalasani, Naga et al. (2016) Febuxostat-induced acute liver injury. Hepatology 63:1047-9
Zheng, Elizabeth X; Rossi, Simona; Fontana, Robert J et al. (2016) Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK(®) Weight Loss Products: Results from the DILIN Prospective Study. Drug Saf 39:749-54
Vuppalanchi, Raj; Navarro, Victor; Vega, Maricruz et al. (2015) Herbal dietary supplement associated hepatotoxicity: an upcoming workshop and need for research. Gastroenterology 148:480-2
Chalasani, Naga; Bonkovsky, Herbert L; Fontana, Robert et al. (2015) Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 148:1340-52.e7
Hayashi, Paul H; Barnhart, Huiman X; Fontana, Robert J et al. (2015) Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the Drug-Induced Liver Injury Network (DILIN). Liver Int 35:1623-32
Hayashi, Paul H; Fontana, Robert J; Chalasani, Naga P et al. (2015) Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity. Clin Gastroenterol Hepatol 13:1676-82.e1
Martinez, Melissa A; Vuppalanchi, Raj; Fontana, Robert J et al. (2015) Clinical and histologic features of azithromycin-induced liver injury. Clin Gastroenterol Hepatol 13:369-376.e3

Showing the most recent 10 out of 46 publications