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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: The problems of establishing causality

Leonard B. Seeff, MD 
Liver Disease Research Branch, NIDDK,
National Institutes of Health
The problems of establishing causality [PDF]

It is well-known that adverse reactions to drugs, whether conventional or of herbal origin, can mimic virtually all forms of liver disease, with a spectrum that ranges from a wide array of hepatocellular injury, through cholestatic liver disease, granulomatous liver disease, various forms of vascular disease and a panoply of neoplasms. Unfortunately, there is no specific diagnostic biomarker for drug-induced liver injury which, if one actually existed, may well vary according to the class of implicated drug. Accordingly, with the present state of the art, drug-induced liver injury (DILI) is a diagnosis of exclusion when there is a temporal relationship between the initiation of drug treatment and the development of biochemical evidence of liver injury. Ideally then, in the clinical setting of detected liver dysfunction, DILI must always be considered when all other potential causes of liver injury in a person receiving a drug are considered and excluded. Such critical supporting information is, however, often not available, but it is imperative that it be acquired to establish the possibility of DILI.

The liver dysfunction signal traditionally used is that of a raised ALT value. But this enzyme is a non-specific marker that does not necessarily represent liver injury. Indeed, raised ALT values in this setting more frequently do not indicate liver injury, as evidenced by the fact that, in many if not most instances, they return to normal despite continued use of the drug, a situation referred to as “adaptation”. It is only when these values are associated with symptoms of severe fatigue or right upper quadrant discomfort, or when they are accompanied by features of coagulopathy or hyperbilirubinemia (so-called Hy’s rule) that they represent true, potentially lethal liver disease. The distinction between adaptation and true toxicity is obviously of critical importance but can be difficult to make, and will ultimately require identification of a more specific signal to ensure continued use of a critical drug that may be withdrawn for unwarranted concern of hepatotoxicity. In the meantime, the distinction must depend on close clinical observation and repetitive testing of liver chemistries.
Also confounding the issue of causality is the difficulty in identifying the culprit when many drugs are being received, such as is commonly the case in persons being treated for neoplastic disease or for AIDS. How does one select the responsible drug among many, and could injury be the consequence of drug interactions? The traditional approach has been to withdraw drugs selectively based on assumptions, but this may not always be possible. Depending on past experiences of drugs known to have a profile of toxicity is not always helpful, particularly when a new drug enters the market.
Thus various instruments have been created to help with causality analysis that includes the Roussel Uclaf Causality Assessment Method (RUCAM) and the M & V Clinical Scale, the former believed to be superior to the latter. Though commonly employed by industry and clinical researchers, the non-user friendly RUCAM is rarely utilized by practicing clinicians and, moreover, is an unwieldy instrument. Instructions for use of RUCAM and possible modifications to the questionnaire might improve its utility. Perhaps the most accepted diagnostic approach at present is the use of expert opinion, especially through a team approach, but this, too, is subject to individual bias and uncertainty. Ultimately, diagnostic verisimilitude may come from pharmacogenetics, proteomics, or metabolomics.

Biographical Sketch

Born in South Africa, Dr. Seeff graduated from the Medical School of the University of the Witwatersrand, Johannesburg, in 1961. He came to the United States in late 1964 to work with Dr. Hyman J. Zimmerman, then Chief of the Department of Medicine, Mount Sinai Hospital, Chicago, Illinois and Chairman of the Department of Medicine, Mount Sinai Medical School. Dr. Zimmerman, one of the founders of the discipline of Hepatology, was a revered teacher, mentor, administrator and clinical researcher, and also this country’s leading expert in the area of hepatotoxicity.

In 1965, he moved with Dr. Zimmerman to Washington DC to complete his training in Internal Medicine at the VA Medical Center and to pursue a career in Hepatology. While there, he initiated what was to be the first of four large-scale VA Cooperative studies related to viral hepatitis, types B and what was then called, non-A, non-B. In 1968, he moved again with Dr. Zimmerman to the VA Medical Center, Boston, Massachusetts, where he assumed the position of Chief of Liver Disease and continued overseeing the Cooperative Studies. In 1971, he returned to the VA Medical Center in Washington DC as Assistant Chief of Medicine for a period of 8 years. During this time, continuing as the PI for the 4 Cooperative Studies, he extended his interest in research in viral hepatitis and established a research hepatitis testing laboratory. In 1979, he was appointed Chief of Gastroenterology, Hepatology and Nutrition at that hospital, a position he held until 1998. During this time, he established a GI/Hepatology training program that involved Georgetown University and the GI Section of the National Institutes of Health. He became Professor of Medicine at Georgetown University in 1984. During this period, Dr. Seeff continued to study viral hepatitis, conducting a number of long-term natural history studies of both hepatitis B and C. These studies were funded by the VA, the National Cancer Institute, the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases. He also worked with Dr. Zimmerman on issues of hepatotoxicity. He is a long-standing member of the American Association for the Study of Liver Diseases, serving on several committees, and was Councilor-at-Large from 1997-2000. He is the senior author of the AASLD Guidelines on Treatment of Hepatitis C and participated in writing AASLD Guidelines regarding laboratory tests to screen, diagnose and monitor liver disease.

In 1998, he moved to the National Institute of Diabetes and Digestive and Kidney Diseases, NIH in the position of Senior Scientist for Hepatitis Research, a position he still holds, now in the Liver Disease Research Branch. This position has involved developing and overseeing numerous clinical research trials and networks, organizing several workshops (Complementary and Alternative Medicine for Chronic Liver Disease, the 1997 and 2002 Consensus Development Conference on Hepatitis C, Hepatitis C and Renal Disease, Hepatitis C in Incarcerated Persons, Hepatocellular Carcinoma, etc.), and coordinating activities related to hepatitis among several Government Agencies (NIH, VA, Centers for Disease Control, Department of Defense, Bureau of Prisons). Currently, he is deeply involved with a number of NIDDK-supported multicenter trials including the Drug-Induced Liver Injury Network (DILIN) Study.