Drug-Induced Liver Injury (DILN)Network Retrospective

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 and 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 any drugs
(ILIAD) and HDS agents, and to collect, immortalize and store serum, 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.

The network will initially identify people who have developed DILI onset beyond 6 months of
enrollment due to all drugs or HDS/CAM cases that did not meet the entrance criteria for the
Prospective study.

The specific aims are as follows:

1. Establish and maintain a clinical database of these people that contains relevant
clinical data.

2. Establish a bank of biological specimens (serum, DNA, and immortalized lymphocytes)
prepared from cases and control in the clinical database.

3. Maintain a registry including yearly updated contact information of the subjects
enrolled in the clinical database so that it is possible to recontact these individuals
at a later date to offer participation in studies which are not part of the current
proposal.

Inclusion Criteria:

Screening Criteria

To be included in the ILIAD registry, the following criteria must be satisfied:

- The treating gastroenterologist / hepatologist or health care professional must
believe that the subject suffered drug-induced liver injury;

- The subject must be alive and the date of onset of the qualifying DILI episode must
have occurred on or after January 1, 1994;

- Evidence of injury that is known or suspected to be related to consumption of a drug
or HDS/CAM product

- The subject is taking only one of these drugs or HDS agent(s) in the period leading up
to the onset of the qualifying DILI episode;

- Have clinically important DILI defined in terms of serum aspartate aminotransferase
(AST), alanine aminotransferase (ALT), and alkaline phosphatase (Alk Phos).

- Sufficient documentation of the event for the Causality Committee to make a
determination.

Exclusion Criteria:

Subjects will be excluded according to the following criteria:

- are not willing to have medical information and blood samples taken;

- are unable to adequately give informed consent to participate in the study including
the blood draw for the genetic component;

- age < 2 years old at the time of study enrollment (due to blood volume requirements).

- Have a competing cause of liver injury such as hepatic ischemia that the investigator
felt to be the primary reason for the observed liver injury. Known, pre-existing
autoimmune hepatitis; primary biliary cirrhosis, primary sclerosing cholangitis, or
other chronic biliary tract disease. Subjects are excluded due to acetaminophen
hepatoxicity or liver transplant or allogeneic bone marrow transplant prior to
development of drug-CAM induced liver injury.