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DILIN Overview

DILIN Network

There is a critical need to develop an improved means of detecting, defining, and studying drug- and CAM-induced liver injury (or simply, "DILI") in the United States. Establishing a diagnosis of DILI is difficult due to the presence of other potential causes of liver injury, and the injury itself can range from mild and transient to severe and protracted leading to acute liver failure. To stimulate and facilitate research, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has established the Drug-Induced Liver Injury Network (DILIN). The mandate of this network is to develop standardized procedures to identify and fully characterize bona fide cases of drug- and CAM-induced liver injury, and to conduct controlled, clinical studies, which will include extensive collection of data, serum, DNA, and tissue specimens.

We need your help with recruitment for these studies. Every patient is important, and if you have patients who are eligible to participate, we very much want to hear from you.

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Drug-Induced Liver Injury in the United States

Liver injury due to prescription and nonprescription medications is a growing medical, scientific, and public health problem in the United States. Drug-induced liver injury (DILI) is the single most common reason for Food and Drug Administration regulatory actions concerning drugs, including failure to gain approval for marketing, removal from the marketplace, and restriction of prescribing indications. Worldwide, the estimated global annual incidence rate of DILI is 13.9-24.0 per 100,000 inhabitants, and DILI accounts for an estimated 3%-9% of all adverse drug reactions reported to health authorities.^1-3

At the same time, the use of complementary and alternative medicines (CAM) has been increasing in Western countries, and there are numerous reports of hepatotoxicity from CAM products in both animal models as well as in humans.⁴ Examples of CAM products that have a well-established potential to cause liver injury include pyrrolizidine alkaloids (Comfrey), chaparral leaf, germander, pennyroyal (squawmint oil), mistletoe, kava, and weight-loss preparations containing usnic acid.⁵

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DILIN's Research Goals

The research goals of DILIN are the following:

• Create a registry of carefully documented DILI cases and corresponding controls
• Identify clinical, immunological, and environmental risk factors for drug- and CAM-mediated hepatotoxicity
• Create a bank of biological specimens consisting of DNA, plasma, and immortalized lymphocytes to facilitate detailed genetic analyses
• Characterize the natural history of drug- and CAM-induced DILI for at least six months following enrollment
• Develop the capability to recontact these individuals over an extended period of time so that additional studies exploring DILI mechanisms can be performed

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The Studies

Two studies are being initiated by the network. In the "Retrospective Study," the implicated drugs are restricted to isoniazid, phenytoin, combination clavulanic acid/amoxicillin, and valproic acid. These drugs were chosen because they are frequently administered to patients not receiving other hepatotoxic drugs, making it easier to establish causality. Patients must be alive, and the date of onset of the DILI episode must be on or after January 1, 1994.

In the "Prospective Study," all incident cases of drug- and CAM-induced liver injury are being considered. Initial presentation to a healthcare professional must be within the previous six months. A detailed medication history of the implicated DILI drug together with all prescription, OTC, and herbal medications is being recorded. Liver and serological tests are being performed to characterize the injury and to exclude competing causes of liver injury. A blood sample is also being drawn for plasma storage and DNA isolation. These cases will be followed longitudinally to characterize the long-term effects of the DILI episode.

For both studies, documented, clinically significant DILI must be recorded in the patient's medical charts so that a causal determination can be made. Patients will be excluded if they are unwilling or unable to provide a blood sample or participate in the genetics component. Children under two years of age at the time of enrollment are excluded due to blood-volume requirements.

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Importance of Controls

Although we have focused on DILI cases, controls are vital to the success of these studies. A control is an individual similar to the case, who took the implicated medication yet did not experience a liver injury. By comparing the clinical and genetic characteristics of cases and controls, we will be able to determine which factors facilitate liver injuries. Recruiting controls may be even more difficult because they are less "invested" in the study. DILIN will need your help in identifying these individuals, too.

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How to Participate?

The best way to stay informed is continue to check in at this web site. You can chart our progress with the two studies. You can also monitor our efforts to develop terminology and standardized definitions for DILI, and to develop causality assessment instruments that are sensitive, specific, and reproducible. This Web site will be in the forefront for staying current on all the issues surrounding drug- and CAM-induced liver injury.

Please contact one the five DILIN clinical sites you have patients who are eligible to participate in either study.

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References:

1. Aithal GP, et al. Br Med J 1999; 319: 1541-5.
2. Friis H, Andreasen PB. J Intern Med 1992; 232: 133-138.
3. Dossing M, Anderson PB. Scan J Gastroenterol 1982: 17, 205-211.
4. Zimmerman HJ. Hepatotoxicity: the Adverse Effects of Drugs and other Chemicals on the Liver, 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 1999, pp. 731.
5. Favreau JT, et al. Ann Intern Med 2002, 136:590-5.

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