The NIH Funds Network to Study Drug-induced Liver Injury (DILIN)
The National Institutes of Health (NIH) has launched a network
of five clinical centers and a data coordinating center to conduct
studies over the next three years of patients who have suffered
severe liver injury because of both prescription and "over-the-counter
medications," nutritional supplements, alternative medicines
and herbals. The DILIN centers are located in North Carolina, Indiana,
San Francisco, Michigan, and Connecticut, and will be awarded $2.25
million per year.
One objective of DILIN is to develop standardized definitions and
instruments to identify and fully characterize cases of drug-induced
liver injury. With a systematic way of classifying drug-induced
liver injury, researchers will be able to analyze the epidemiology
and clinical issues of liver injury and collect biological samples
that can be used to study the causes of liver toxicity using biochemical,
serological, and genetic testing. The DILIN is sponsored by the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), one of the institutes of the NIH.
Another objective of DILIN is to establish a registry of patients
who have experienced severe drug induced liver injury. "Part
of the difficulty in studying drug-induced liver disease is the
absence of a sufficient cohort of well-characterized patients in
whom to carry out clinical, genetic, immunological and biochemical
investigation," says Jose Serrano, M.D., Ph.D, director, NIDDKs'
Liver and Biliary Diseases Program and coordinator of the DILIN.
"DILIN will help to eliminate this barrier and advance the
understanding of drug-induced liver injury forward," he adds.
Drug-induced liver injury occurs in all age groups, but most cases
occur within the elderly population because they take more medications
than younger persons and also use multiple medications. Furthermore,
drug-induced liver injury is the most common reason why drugs are
not approved by the Food and Drug Administration (FDA) or are removed
from the market after they have been approved.
Most drugs that can cause liver injury are entirely safe for the
majority of patients taking them. The reason why some patients are
susceptible to liver injury from a drug is rarely known. "It
is likely a result of many interrelated factors that involve complex
interactions between our genes and the environment," says Jay
Hoofnagle, M.D., director, NIDDK Liver Diseases Research Branch.
"Liver injury is unpredictable and variable in clinical presentation,
making causality very tough to assess," explains Hoofnagle.
At present, DILIN has developed protocols for both retrospective
and prospective studies of drug-induced liver disease. The retrospective
study will establish a registry of patients who have taken one of
four specific drugs since 1994 and developed liver injury later.
The four drugs are isoniazid, phenytoin, valproic acid, and clavulanic
acid/amoxicillin. These drugs were chosen because they are widely
prescribed and have definite clinical presentation. A minimum of
50 cases of each form of drug-induced liver disease will be collected
along with an equal number of patients who have taken the drugs
safely (controls). The researchers will obtain clinical and DNA
information from each patient.
The prospective study will focus on enrolling patients who recently
suffered an adverse liver reaction after taking any drug or herbal
medicine. These patients will be followed over time to find out
what happens to them as a result of their injury. Patients who have
not sustained liver injury, but who have taken any of the drugs
in question, will also be enrolled in the prospective study.
"Overall, we believe that the DILIN will bring greater focus
and interest to the study of drug-induced liver injury and help
to develop better ways to prevent, detect, and treat this growing
liver problem," says Paul Watkins, M.D., chair, the DILIN Steering
Committee and principal investigator for the center in North Carolina.
The DILIN researchers have also developed diagnostic criteria and
measures for grading causality in patients with drug-induced liver
disease and will prospectively assess these instruments for sensitivity
and specificity. Patient enrollment is ongoing.
The DILIN consists of the following principal investigators and
Dr. Paul Watkins, University of North Carolina, Chapel Hill, North
Dr. Naga Chalasani, University of Indiana, Indianapolis, Indiana
Dr. Timothy Davern, University of California, San Francisco, California
Dr. Robert Fontana, University of Michigan, Ann Arbor, Michigan
Dr. Herbert Bonkovsky, University of Connecticut, Hartford, Connecticut
Dr. James Rochon, (Data Coordinating Center), Duke University,
Raleigh-Durham, North Carolina
For more information, contact Leslie Curtis or Marcia Vital at
the NIDDK Information Office (301-496-3583).
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) is a component of the National Institutes of Health (NIH),
U.S. Department of Health and Human Services (DHHS). NIDDK supports
a significant amount of the Federal Government's research on endocrine
and metabolic diseases such as diabetes and obesity, digestive diseases
such as hepatitis and inflammatory bowel disease, kidney and urologic
diseases such as kidney failure and prostate enlargement, and blood
diseases such as the anemias. The Institute carries out a large
variety of research initiatives and programs that will bring new
knowledge into proven therapies that benefit the public. Health
information and additional information about NIDDK can be found
on the NIDDK home page at: http://www.niddk.nih.gov/.