15 The study has since expanded to include eight clinical sites. Network investigators were charged with identifying and enrolling persons who developed DILI, carefully phenotyping the clinical condition, and collecting appropriate biological samples. Details concerning the planning, initial study design, study outcomes, eligibility criteria, and conduct of the study have been reported,14 and the clinical features of the first 300 patients enrolled have been summarized.16 The study protocols were approved

by the institutional review boards at all participating institutions and were registered at ClinicalTrials.gov. In brief, enrollees in the prospective study were persons receiving single

or multiple drugs, herbals, or other over-the-counter www.selleckchem.com/products/GDC-0980-RG7422.html products identified to have biochemically defined liver dysfunction, provided that they could be evaluated within 6 months of onset of the liver disease.14 Biochemical this website criteria for enrollment included (1) two consecutive serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values > 5 times the upper limit of normal (ULN) or > 5 times the baseline abnormal value, (2) two consecutive serum alkaline phosphatase (AP) values greater than twice the ULN or twice the baseline abnormal value, or (3) an otherwise unexplained total serum bilirubin Ketotifen value > 2.5 mg/dL or an international normalized ratio (INR) > 1.5 on two consecutive occasions. Symptoms or signs of liver injury were not required. Exclusion criteria were liver injury due to acetaminophen, preexisting autoimmune hepatitis or sclerosing cholangitis, and previous receipt of

a bone marrow or liver transplant. Persons were not excluded for preexisting chronic hepatitis B or C or human immunodeficiency virus infection, provided that baseline laboratory test results were available. Sequential steps in causality assessment are outlined in Fig. 1. Complete clinical data, including serial laboratory test results together with the local ULN values, were extracted from the clinical records and entered into a 65-page case report form (CRF). To exclude conditions that can mimic drug-induced liver disease, the patients and their medical records were screened for previous liver disease, alcohol use, serological and virological evidence of hepatitis A, B, or C infection, autoantibodies, ceruloplasmin, alpha-1-antitrypsin, ferritin, and iron; additionally, results of imaging studies were reviewed. Patients who had not been fully evaluated when they were first identified underwent testing for any missing laboratory data at enrollment. Liver biopsy was not required for adjudication purposes, but if it was performed as part of routine clinical care, the results were collected and made available to reviewers.