DILIN's Prospective Study

Liver injury due to prescription and non-prescription medication use is a medical, scientific
and public health problem of increasing frequency and importance in the United States.
Indeed, drug-induced liver injury (DILI) is the most important reason for non-approval,
withdrawal, limitation in use and clinical monitoring by the Food and Drug Administration
(FDA). However, detection of signals for liver injury frequently relies upon the reporting of
cases by practitioners to health authorities in post-marketing surveillance. Under-reporting
of cases, lack of mandatory reporting systems, and difficulties in establishing a diagnosis
make the current system sub-optimal. Moreover, with the growing use of complementary and
alternative medications (CAM), there have also been increasing reports of liver toxicity due
to various non-prescription herbal, dietary and food additive supplements. Because the
manufacturing, dispensing and testing of these products is not regulated, the hepatotoxic
potential of these formulations is poorly characterized or completely unknown.

The DILIN Prospective Study is a multi-centered epidemiological study designed to gather
clinical information and biological specimens on cases of suspected liver injury due to drugs
and CAM. The goals of this study are to develop a database of recent DILI cases, identify the
clinical, environmental and genetic risk factors that predict DILI, develop standardized
instruments and terminology and perform careful longitudinal follow-up of DILI subjects.
Biological samples collected will be used in future studies of the mechanisms and genetics of
DILI.

Patients who are referred to one of the DILIN clinical sites and who, in the opinion of
gastroenterologist/hepatologist, experienced a drug-induced liver injury are enrolled.
Detailed clinical data and biological specimens are collected. Clinical data will be reviewed
by the DILIN Causality Committee and the final determination on whether the subject qualifies
as a bona fide DILI case is made by consensus opinion. DILI cases (only) are followed for at
least 6 months to derive the longitudinal profile of drug-and CAM-induced liver injury.
Detailed clinical data including liver elastography (FibroScans) and biological specimens are
collected. Patients who satisfy the definition of chronic DILI will be evaluated with
additional FibroScans at 12, 24, 36 and 48 months thereafter.

Inclusion Criteria:

- Age > 2 years at enrollment into the study.

- Evidence of liver injury that is known or suspected to be related to consumption of a
drug or CAM product in the 6-month period prior to enrollment.

- Written Informed consent from the patient or the patient's legal guardian.

- Documented clinically important DILI, defined as any of the following:

1. ALT or AST >5 x ULN or A P'ase >2 x ULN confirmed on at least 2 consecutive blood
draws in patients with previously normal values.

2. If baseline (BL) ALT, AST or A P'ase are known to be elevated, then ALT or AST >5
x BL or A P'ase >2 x BL on at least 2 consecutive blood draws. "Baseline" is
defined as the average of at least 2 measurements performed during the 12-month
period prior to starting the DILI medication.

3. Any elevation of ALT, A P'ase, or AST, associated with (a) increased total
bilirubin [ ≥ 2.5 mg/dL], in absence of prior diagnosis of liver disease,
Gilbert's syndrome, or evidence of hemolysis or (b) coagulopathy with INR > 1.5
in absence of coumadin therapy or known vitamin K deficiency.

Exclusion Criteria:

Patients with any of the following will not be eligible for participation:

- Competing cause of acute liver injury such as hepatic ischemia that is felt by the
investigator to be the primary reason for observed liver injury and supported by
laboratory tests, serologies, liver biopsy, or radiology.

- Known, pre-existing autoimmune hepatitis, primary biliary cirrhosis, primary
sclerosing cholangitis, or other chronic biliary tract disease which may confound the
ability to make a diagnosis of DILI.

- Acetaminophen hepatotoxicity.

- Liver/bone marrow transplant prior to the development of drug- or CAM-induced liver
injury.