LiverTox: An online information resource and a site for case report submission on drug‐induced liver injury

Watch a video presentation of this article

Watch the interview with the author

Answer questions and earn CME

Abbreviations

DILI

Drug‐Induced Liver Injury

DILIN

Drug‐Induced Liver Injury Network

NIDDK

National Institute of Diabetes and Digestive and Kidney Diseases

NLM

National Library of Medicine; RUCAM, Roussel‐Uclaf Causality Assessment Method

Drug‐induced liver injury (DILI) is an infrequent cause of liver disease in the general population and accounts for < 1% of hospitalized patients presenting with jaundice.1, 2 Nonetheless, DILI is a leading reason for regulatory actions involving investigational and approved medications and is also a leading cause of acute liver failure in the United States.3, 4 Implicated drugs include not only prescription medications but also herbal products and over‐the‐counter dietary supplements and medications. It is noteworthy that since inception of the Drug‐Induced Liver Injury Network (DILIN) by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2003, the number of enrolled cases of herbal and dietary supplements‐induced liver injury have steadily increased, representing the second most commonly recorded class of hepatotoxicity‐causing products in DILIN. The low incidence of DILI, coupled with the limited knowledge of the biochemical mechanism(s) or pathways responsible for this “idiosyncratic” adverse event, make it difficult to identify high‐risk patients.5

Furthermore, preclinical testing does not always provide a reliable assessment of the hepatotoxic risk of new medications; and because DILI is a rare event, premarketing clinical studies usually conducted in highly selected populations over a relatively short period of time also may not detect a potential for liver injury. Therefore, the hepatotoxicity of a specific medication often becomes apparent only after regulatory approval—and when the drug is used by large numbers of unselected patients in the general population.

Finally, because the biochemical, clinical, and histological features of DILI mimic most other known forms of acute and chronic liver injury, and there is no objective gold standard for diagnosing DILI, its identification largely relies on excluding other more common causes of liver injury and having a “compatible” time of onset and evolution.

To keep track of which drugs cause liver injury—and what pattern is typical of which agent—is challenging even for the most dedicated subspecialist in the area. Furthermore, the literature on DILI is large and dispersed to publications in a great many disciplines, including hepatology, gastroenterology, pharmacology, internal medicine, pediatrics, and surgery. Publications on DILI appear in many journals, in multiple languages, and often as short reports or letters to the editor for which validity is difficult to assess. For this reason, it is a challenge to keep abreast of the literature on drug‐induced liver injury, and literature searches for specific medications are often incomplete. DILI is also a challenging area of research in that most cases are unpredictable, idiosyncratic, and rare; thus, it is difficult to study. As a consequence, there have been few advances in the understanding, control, or prevention of DILI in the last 50 years.

As a part of a long‐term initiative in promoting basic and clinical research on DILI, the Liver Disease Research Branch of the NIDDK—in collaboration with the National Library of Medicine (NLM) and the DILIN—has created the LiverTox website (www.livertox.nih.gov) (Fig. 1) to provide up‐to‐date, comprehensive clinical information on DILI for both the general physician, the subspecialist, and the public.

Figure 1.

Main web page of LiverTox.

The website is particularly designed for use by physicians and health care professionals who might rarely see patients with drug‐induced liver injury, including general practitioners and subspecialists in all areas of medicine. The website will also be helpful to hepatologists and experts in hepatotoxicity by providing a complete and accurate summary of information about the clinical features of liver injury for each medication, along with a complete and annotated list of references. Finally, LiverTox will be helpful to patients seeking information on liver injury due to drugs.

LiverTox consists of three major components: 1) an introductory and background section, 2) drug‐specific hepatotoxicity report, and 3) data field‐driven section that allows for submission and assessment of cases.

Introductory and Background Section

The introductory and background section includes an overview and detailed discussion on DILI (epidemiology, natural history, diagnosis, pathogenesis, and management). The section provides a description of the principal clinical and histologic patterns of liver injury, standardized definitions of terms used, and discussion of methods to diagnose and judge severity and causality in DILI. This section also includes information on commonly used causality assessment instruments, providing discussion on their strength/weakness, completion instructions, and it offers a formatted document of the instrument, which can be printed to be filled manually.

Drug Specific Hepatotoxicity Report

The bulk of the LiverTox website consists of individual records on 700 different medications, dietary supplements, and herbal supplements, representing the most commonly used medications in the United States (prescription and nonprescription, and whether or not they cause liver injury). The specific agents are searchable using both generic and trade names. The agents discussed include all of the major known causes of DILI. Each drug record is a concise summary about the drug class, mechanism of action, indications, dose regimens, frequency of use, and common side effects. This introduction is followed by a concise description of the hepatotoxicity associated with the agent, including its frequency, clinical patterns, and course—as well as a brief overview of the known or suspected mechanisms of injury. A final paragraph summarizes the prognosis and outcome of liver injury from the agent and gives a brief discussion of management.

This overview is followed by one to four actual case reports taken from the published literature or from DILIN. The drug record also includes chemical information with the drug structure and specific Internet links to the approved product labeling (Fig. 2).

Figure 2.

Drug label, structure information, and annotated literature.

Each drug record concludes with a comprehensive list of scientific articles and publications on hepatotoxicity of the medication prepared by the NLM and annotated by NIDDK staff, as well as a drug‐specific updated reference links to PubMed, ClinicalTrial.gov, and Toxline (Fig. 3).

Figure 3.

Drug‐specific updated reference links to PubMed, ClinicalTrial.gov, and Toxline.

Case Submission and Assessment

The final component of LiverTox allows clinicians to submit a case report. Submission of a case requires registration and assignment of a password (Fig. 4). The submission uses a highly structured method with cues to enter the specific information necessary to fully assess the liver injury and judge severity and causality.

Figure 4.

Case submission and assessment.

The LiverTox website then produces a computer‐generated case report that contains the history, a table of serial laboratory results, a graphic display of the course of the injury, and calculations on: latency, time to recovery, severity, causality (RUCAM score), and data completeness. The submitted cases will be maintained in a searchable database available to the registrants for analysis. This database will provide a means of monitoring the frequency and secular trends in the incidence of DILI and permits analysis of clinical features and outcomes of the submitted cases.

The site can also generate, on demand, a liver‐related adverse event report to include the case in the official Food and Drug Administration's Adverse Event Reporting System.

The creators of LiverTox hope that the website will become a reliable source of information on DILI and a widely used tool for improving its diagnosis, management, prevention, and treatment.

LiverTox is a work in progress; and new drug records, references, and information will continually be added in the years ahead. Comments about the accuracy and completeness of LiverTox and suggestions for improvement are welcomed.