Hepatotoxicity, or drug-induced liver inury (DILI), is currently the most common cause of acute liver failure in the United States and the main indication for market withdrawal of drugs. DILI thus represents a problem of enormous medical, financial, legal and regulatory importance. Although a vast number of drugs, toxins and alternative medications have the potential to cause liver injury, severe DILI is a problem of sufficient rarity that a large group of dedicated investigators working in a cooperative and coordinated effort is required to better understand the pathogenesis of DILI and develop effective prevention and treatment strategies. This proposal brings together a unique, multi-disciplinary consortium of investigators and resources, concentrated within Northern California, with a plan for a continuing participation as a Clinical Center in the Drug-Induced Liver Injury Network (DILIN). Our research plan describes, firstly, the establishment of a large multi-component Clinical Center patient database that would contribute to the DILIN. The proposed DILI patient informational database, serum, DNA and tissue bank will comprise a prospective cohort derived from several sources, each providing distinct epidemiological facets and research potential. These include the Liver Transplant Programs at UCSF, Stanford University and California Pacific Medical Center, the liver clinics and inpatient service at the Palo Alto Veterans Administration Hospital, and the HIV Clinic at San Francisco General Hospital. At each site, we have developed strategies to identify well-defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of detailed epidemiological and clinical information, as well as serum, DNA and tissue samples for biochemical, pharmacological and genetic studies. We plan to initially identify patients with potential DILI based on proposed operational diagnostic criteria and then further evaluate cases using a validated causality assessment instrument. Patients classified as having """"""""highly probable"""""""" DILI using this instrument will be followed prospectively in order to better define the natural history of DILI. Identification of such DILI-associated polymorphisms is an essential first step in the development of a rational gene-based prevention strategy. We anticipate that our Clinical Center will recruit approximately 120 cases and well-matched controls from an ethnically and racially diverse patient population to the DILIN. We have a well-organized, multi-disciplinary group of physicians, scientists, and research nurses who are dedicated to the success of this Clinical Center and the overall DILIN effort.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK065238-11
Application #
8330955
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Serrano, Jose
Project Start
2003-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$113,438
Indirect Cost
$68,299
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107
Chalasani, Naga; Reddy, K Rajender K; Fontana, Robert J et al. (2017) Idiosyncratic Drug Induced Liver Injury in African-Americans Is Associated With Greater Morbidity and Mortality Compared to Caucasians. Am J Gastroenterol 112:1382-1388
Bonkovsky, Herbert L; Kleiner, David E; Gu, Jiezhun et al. (2017) Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology 65:1267-1277
Nicoletti, Paola; Aithal, Guruprasad P; Bjornsson, Einar S et al. (2017) Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology 152:1078-1089
Hayashi, Paul H; Rockey, Don C; Fontana, Robert J et al. (2017) Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology 66:1275-1285
Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga et al. (2017) Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B?35:02 as a risk factor. J Hepatol 67:137-144
Russo, Mark W; Steuerwald, Nury; Norton, Harry J et al. (2017) Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance. Liver Int 37:757-764
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
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
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
Alqahtani, Saleh A; Kleiner, David E; Ghabril, Marwan et al. (2015) Identification and Characterization of Cefazolin-Induced Liver Injury. Clin Gastroenterol Hepatol 13:1328-1336.e2

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