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Prospective Study

Executive Summary

Background and Rationale: 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 common reason for nonapproval, 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. Underreporting 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.

As a result, there is a great need to develop an improved means of detecting, defining, and studying DILI in the United States. The DILIN prospective study is a multicenter 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 include the earlier recognition of DILI, especially due to newer drugs, development of standardized instruments and terminology to help identify cases of DILI, investigating clinical and genetic risk factors that predict DILI, and performing a careful longitudinal follow-up of DILI subjects. The biological samples collected will be used in future studies of the mechanisms and genetics of DILI.

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Specific Aims and Objectives: The primary objective of this study is to prospectively identify bona fide cases of liver injury due to drugs and complementary and alternative medications within 6 months of presentation. Secondary objectives include collecting clinical data and biological specimens including blood, DNA, urine, and liver tissue from affected patients and matched controls for future mechanistic and genetic studies. We will also investigate the clinical, immunological, and environmental risk factors of drug-mediated hepatotoxicity by comparing DILI cases to matched controls with a similar drug exposure history but no evidence of clinically significant liver injury. The natural history of drug- and CAM-induced DILI will be tracked for at least 6 months following enrollment, with longer follow-up for those in whom there is evidence of chronic liver injury at 6 months. We will also develop and test causality assessment instruments for drug and CAM-induced liver injury that are sensitive, specific, and reproducible.

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Basic Study Design: The DILIN Prospective Study is a multi-center, prospective, epidemiological study. Patients who are referred to one of the DILIN clinical sites and who, in the opinion of a gastroenterologist / hepatologist, experienced a drug-induced liver injury will be enrolled. Detailed clinical data and biological specimens will be collected. Clinical data will be reviewed by the DILIN Causality Committee, and it will make the final determination of whether the subject qualifies as a bona fide DILI case. Up to three matched controls will be individually matched to each index case. They will be matched by age, duration of exposure to the implicated medication, and from the same clinical site. DILI cases (only) will be followed for at least 6 months to derive the longitudinal profile of drug- and CAM-induced liver injury. Detailed clinical data and biological specimens will be collected at this time point. Patients who satisfy the definition of chronic DILI will be evaluated at 12 months and yearly thereafter.

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Study Populations: Consecutive patients who are referred to one of the DILIN clinical sites and appear to have suffered a drug-induced liver injury will be considered for inclusion in the study. Subjects must be > 2 years at the time of enrollment; have 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; and, have documented clinically important DILI defined in terms of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (Alk Phos). Subjects will be excluded if there is acetaminophen hepatotoxicity, a competing cause of acute liver injury, or liver transplant prior to the development of drug- or CAM-induced liver injury.

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Data Collection Protocol: The "baseline" visit is the date of the first in-person visit by the participant to the DILIN clinical site. A number of evaluations will be performed at that time including a detailed medication history of the implicated DILI drug plus any drugs from the same class of medications; the dose, duration, and indication for all medications including prescription, OTC and herbal medications taken within 8 weeks of presentation; medical history; family history of drug allergies/ hepatotoxicity to the implicated drug or its class of drugs, and so on. Serological tests will be performed to exclude competing causes of acute liver disease; additionally, a complete blood count, kidney and liver function tests, total cholesterol, triglycerides, and a urinalysis will be performed. A blood sample will be drawn for DNA isolation, plasma, PBMC cryopreservation and serum storage. A voided urine sample will be collected, aliquoted into cryovials at the clinical site and frozen.

If the subject had not been previously imaged, a screening liver ultrasound will be obtained. A liver biopsy may be obtained for clinical purposes in cases of diagnostic uncertainty or for prognostic purposes. For example, if a patient fails to have improvement in liver biochemistries within 1 month of stopping the suspect drug or if there is a clinical suspicion of autoimmune hepatitis a liver biopsy may be recommended for diagnostic purposes.

A subset of these tests appropriate for control subjects will be performed. Follow-up evaluations will only be undertaken for DILI cases, and a subset of the tests will be repeated then. In patients with suspected chronic DILI (based on laboratory, clinical or imaging criteria), a liver biopsy will be recommended for clinical purposes at 12-month visit according to the local standard of care. A schedule of evaluations is provided.

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Statistical Considerations: Power calculations were performed using the technique of Dupont and assuming matching with three controls per case. This procedure is based on McNemar's test for matched case-control studies. As discussed below, to provide some protection against type-I error, α = 0.01 was used in these calculations. With 15 cases and 3:1 matching of controls to each case, only very strong risk factors for DILI can be detected with reasonable power. With 60 cases and 3:1 matching, an OR of approximately 3.50 or higher can be detected with adequate power.

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Study Administration: The administrative and funding mechanism used to undertake this project is an NIH "Cooperative Agreement", which is an assistance mechanism. Under the cooperative agreement, the NIDDK assists, supports, and/or stimulates and is substantially involved with investigators in conducting the study by facilitating performance of the effort in a "partner" role. The Steering Committee is the main governing body of the project. It is composed of the Principal Investigators of the clinical centers, the Principal Investigator of the Data Coordinating Center, and the NIDDK Project Scientist. The clinical centers, the Data Coordinating Center and the NIDDK each have one vote on the Steering Committee. All decisions are determined by majority vote. In addition, a number of subcommittees have been established and report to the main Steering Committee.

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