This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Background and Rationale: Drug induced liver injury (DILI) is the single most common reason for regulatory actions concerning drugs, including failure to gain approval for marketing, removal from the market place, and restriction of prescribing indications. DILI is also a significant cause of morbidity and mortality in many patient populations. To stimulate and facilitate research into DILI, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) has recently established the Drug-Induced Liver Injury Network (DILIN). One of the initial projects to be conducted by the network is to retrospectively establish a nationwide registry of patients who have suffered severe idiosyncratic liver injury associated with drugs (ILIAD), and to collect, immortalize and store serum, Deoxyribonucleic acid (DNA), and lymphocytes from these patients (hereafter referred to as the 'ILIAD protocol'). This ILIAD protocol will serve as a resource for subsequent mechanistic investigations of the basis for susceptibility to severe idiosyncratic DILI.
Specific Aims and Objectives: The primary goal of the ILIAD protocol is to create: (a) a clinical database consisting of individuals who have experienced severe DILI caused by four specific drugs, and the relevant clinical data concerning the episode of DILI; and, (b) to create a bank of biological specimens obtained from these individuals. Corresponding information from control subjects will also be collected. These biological specimens will be DNA, plasma, and immortalized lymphocytes. Immortalized lymphocytes will provide unlimited amounts of genomic DNA for study as well as living immune cells for phenotyping studies. A secondary goal of the ILIAD protocol is to maintain a registry of cases in the ILIAD database so that they may be recontacted in the future. It is expected that this will facilitate additional studies exploring the mechanisms of DILI. Targeted Drugs: The initial drugs to be targeted in the ILIAD protocol are isoniazid (INH), phenytoin, clavulanic acid / amoxicillin (Augmentin and valproic acid. For INH, phenytoin, or clavulanic acid / amoxicillin, severe liver injury is defined as a documented serum total bilirubin > 2.5 mg/dl; for valproic acid, the criteria are compatible symptomatic clinical presentation that is severe enough to prompt hospitalization and evidence of liver dysfunction International normalized ratio (INR) > 1.5 or Alanine transaminase (ALT) > 3 X Upper Limit of Normal (ULN), and/or characteristic liver biopsy). The target drugs were chosen because they cause severe DILI at a high rate compared with other drugs, making our target enrollment for each drug (n = 50-100) attainable. In addition, these drugs are frequently administered to reasonably healthy patients not concurrently receiving other drugs more likely to be hepatotoxic, facilitating causation assessment. Basic Study Design: The five DILIN clinical centers will identify and contact patients at their own and affiliated institutions who may have suffered a liver injury due to one of the targeted drugs. They will also contact gastroenterologists, hepatologists, and other health care professionals most likely to have treated DILI cases. In the latter case, an information packet will be sent by the treating physician to the potential subject, and interested subjects will be requested to contact one of the five clinical sites. In either case, the subject will be given a brief description of the study's purpose and procedures, and when further interest in the study is expressed, s/he will be mailed provided with an information packet including the informed consent document, The Health Insurance Portability and Accountability Act (HIPAA) authorization and release of medical record forms. Once these documents have been received reviewed by the subject, study staff will contact the potential subject by telephone a second time. This follow-up contact will either occur by telephone or in person at the subject's convenience. Informed consent will be obtained, and if this occurs over the telephone, it will be witnessed by a third party on the line. Then, requisite information will be collected using a telephone or personal interview format. Prior to ending this phone call the end of the second contact, the subject will be asked to sign the consent, HIPAA authorization, and release of medical information forms and return provide them to the DILIN clinical site. Arrangements for blood drawing will be made. The blood sample will be shipped to the Rutgers University Cell and DNA Repository (RUCDR) where DNA will be extracted and lymphocytes will be immortalized. DNA, plasma and immortalized lymphocytes will be frozen and stored for future studies. Once the signed documents have been received, medical records and charts will also be retrieved from the appropriate health care provider(s). Detailed clinical information concerning the DILI event will be abstracted from the charts and entered onto case report forms. This information will then be reviewed by the DILIN Causality Committee, and it will make the final determination on whether the patient was a true DILI case.
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