Drug Induced Liver Injury DILI - Mechanisms and Liability

Because most medications are metabolized in the liver, Drug Induced Liver Injury (DILI) is frequently the main toxicity of many drugs on the market. Medications can induce DILI either by predictable mechanisms (i.e., acetaminophen) or their toxicity is unpredictable (idiosyncratic DILI). Acetaminophen (Tylenol and similar products) is the main cause of Acute Liver Failure (ALF) in the USA.

The reasons for poor outcomes, such as death or liver transplantation, in acetaminophen ALF are: i] delays in initiating treatment with Mucomyst; ii] incorrect use Mucomyst in either dosage or duration of treatment; iii] use of sedatives and /or narcotics when patients with ALF experience irritability, anxiety, pain or insomnia, which often accelerates the development of coma in ALF; and iv] delays in transferring the patient for Liver Transplantation. Physicians and RNs in Hospitals not familiar with the diagnosis and treatment of acetaminophen ALF or other causes of ALF may be responsible for the progression of the disease. A rapid diagnosis of ALF allows implementation of appropriate management. The liability of the Pharmaceutical Companies is often limited to the inadequate labeling and warning box; this may change since the FDA has considered ‘forcing’ correction of labeling deficiencies.

Medications that induce idiosyncratic DILI are many and the patient’s susceptibility cannot be anticipated. The Hospital liability is similar to that of acetaminophen-induced DILI if the patient presents with ALF. The Pharmaceutical Companies are often found to be liable if the pre-clinical research or the pre-marketing clinical studies shows evidences of a ‘signal’ liver injury that is similar to that observed in the cohort afflicted with the DILI (and ALF). The main issues are related to interpretation of that data including: i] cell toxicity in culture systems and the specificity and relatedness to the human DILI; ii] pharmacokinetics and liver toxicity in animals; iii] evidences of liver injury in clinical studies – even at a relatively low level- ; and iv] evidences of drug-drug or drug-disease interactions that could or should have been inferred.

Although valuable to the medical and scientific community, neither the Med-Watch Reports to the FDA nor the published case reports provide statistical support for the causal association between a medication and ALF. In addition, and except in rare instances (e.g., rechallenge), presumed idiosyncratic DILI cannot be attributed unequivocally to any drug. As evidence of the diagnostic uncertainties, in the United States, the cases of acute liver failure of undetermined causes (17%) exceed those attributed as probable to all medications combined (13%), excluding acetaminophen. Acetaminophen- induced ALF is not associated with chronic liver injury; patients that survive recover completely. In contrast, it has been postulated that liver fibrosis and cancer may result from the liver toxicity in some cases of idiosyncratic DILI. These presumed chronic complications would constitute an extraordinary medical burden to patients treated with that medication. Because these alleged long-term complications of some DILI have significant medical, social, legal, and financial repercussions, is necessary to evaluate the scientific merits of the proposed mechanisms.

About the Expert who prepared the article:

The Gastroenterologist -Liver Expert who wrote this article is a Professor of Medicine and Biomedical Sciences Program and a Full Member of the Comprehensive Cancer Center at the University of California, San Diego. He was a Resident and a Fellow in the Yale University Program and an Expert at the National Institutes of Health. He is Board Certified in both Internal Medicine and Gastroenterology with specific training in Liver Diseases and a former Chairman of the National Research Committee of the American Association for the Study of Liver Diseases.

This Expert has been a Medical and/or Scientific Advisor to the FDA, the National Institutes of Health, the European Union, WHO, Pfizer, Abbott, Wyeth, Eli Lily among others. He has been the main Expert in large class action litigations for Pfizer and Exxon Mobil as well as in individual malpractice cases. The post-hoc feedback from Jurors and Arbitrators has been outstanding.

In addition to clinical and clinical research expertise, this Expert has extensive expertise in basic sciences and pharmacokinetics, valuable assets to assess some medical malpractice cases. The Expert’s research has been founded continuously for 25 years by the NIH and the VA, and received the coveted MERIT Award from the NIH, the Hans Popper Award from the International Society for the Study of Liver Diseases, and the University of California Chancellor’s Award.

He has authored numerous publications, chaired many medical meetings and executed the development of many medical conferences.

This medical malpractice article was written by an expert witness working with American Medical Experts, LLC (AME). AME is the nation’s leading source of medical experts for case review and testimony; AME also offers the lowest flat rate fees on Complete Case Reviews ($695) and Expert Witness Reports ($995). For more information, call 888-678-EXPERTS (888-678-3973) or visit AmericanMedicalExperts.com.