A wide variety of prescription and nonprescription medications and nutritional supplements are at the root of drug-induced liver injury in the United States.
Moreover, combinations of potentially hepatotoxic agents, rather than single agents, account for at least 20% of cases reported to the Drug-Induced Liver Injury Network (DILIN), a registry of clinically significant cases and a repository of biological specimens established in 2003. The registry is run cooperatively by the National Institutes of Health and five academic clinical centers.
That percentage is much higher than was reported in a recent European study, and it may reflect greater use of medications in the U.S. population, Dr. Naga Chalasani and his colleagues reported (J. Gastro. 2008 December [Epub doi:10.1053/j.gastro.2008.09.011]).
Dr. Chalsani, professor of medicine at Indiana University, Indianapolis, and his associates described the cases and short-term outcomes of the first 300 subjects reported to this registry and enrolled in an ongoing prospective study. The researchers hope the registry and study will furnish data for further research on the etiology and prevention of drug-induced liver injury.
The 300 subjects were enrolled in 2004–2007. Of the group, 93% were adults, including 18% who were older than 65 years. The severity of liver damage was judged to be mild in 27%, moderate in 19%, moderate requiring hospitalization in 33%, severe in 15%, and severe requiring transplant or precipitating death in 6%.
Single prescription medication was the likely cause of the liver injury in 73% of the cases. Multiple prescription medications or a combination of prescription medicine and dietary supplements were the cause in 18%. Single or multiple dietary supplements were the cause in the remaining 9%.
Dietary supplements that caused liver injury included those taken to build muscle, lose weight, cure insomnia, prevent colds, boost energy, and control menopausal symptoms. Many patients were using multiple dietary supplements and, even when a single dietary supplement caused the liver damage, it often contained multiple herbal or nutritional components.
Among prescription medicines, antimicrobials (including antibacterials, antivirals, and antifungals) were the most frequent offenders, causing liver damage in over 45% of cases. This finding is in accord with the results of previous studies.
The reason why antimicrobials have such a propensity to cause liver damage is not yet known. It may be related to the generally high usage of antimicrobials in the U.S. population, or it may be that patients' underlying infection and inflammation confer increased susceptibility to liver injury, Dr. Chalsani and his associates said.
CNS agents such as antiepileptics, antidepressants, and antipsychotics were the likely cause of liver damage in 15% of cases, immunomodulatory agents were the likely cause in 5%, analgesics in 5%, antineoplastic drugs in 4%, antihypertensives in 5%, and lipid-lowering agents in 3%.
The most common single prescription drugs that caused liver injury in registry patients were amoxicillin/clavulanate (23 cases), nitrofurantoin (13 cases), isoniazid (13 cases), and trimethoprim-sulfa-methoxazole (13 cases).
This observational study did provide information “of practical relevance in monitoring and counseling patients with drug-induced liver injury,” the investigators noted.
First, serum bilirubin reached its peak an average of 1 week after diagnosis, regardless of the patient's age, the pattern of liver injury, or the causative agent. In patients who developed jaundice, the condition took nearly a month on average to resolve; jaundice took even longer to resolve in elderly patients and in those whose liver injury was caused by dietary supplements rather than by medications.
Second, diabetes was a strong independent risk factor for severe drug-induced liver injury. Diabetes has not been considered as a possible confounding factor in previous studies of drug-induced liver injury, Dr. Chalsani and his associates said.
Third, acute hepatitis C infection should be thoroughly ruled out before attributing a case of acute liver injury to acute drug exposure. Several patients in this series had liver damage thought to be unrelated to acute hepatitis C because they initially tested negative for the virus and reported no risk factors. However, they later seroconverted.
“As better diagnostic tests become available for specific causes of acute liver injury, more cases of suspected drug-induced liver injury may be found to have other etiologies,” the investigators noted.
The DILIN and this study were supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Chalsani is a paid consultant to Takeda Pharmaceuticals, AtheroGenics Inc., Advanced Life Sciences, Kari Bio, Metabasis, Pfizer Inc., and Eli Lilly & Co. He received grant support from Debiovision Inc. and Sanofi-Aventis. On his behalf, Indiana University has initiated contract negotiations with Gilead Sciences Inc. and Pfizer for conducting clinical trials unrelated to drug-induced liver injury. In addition, Dr. Chalsani has served as a defendant's expert witness for a product liability litigation involving suspected drug-induced liver injury.