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Studies Document Some Severe Outcomes After Drug-induced Liver Injury

Three recent studies conducted by NIDDK’s Drug-Induced Liver Injury Network (DILIN) have provided new insights into outcomes from this potentially severe form of liver injury, including the rate of fatal outcomes, frequency of bile duct damage and loss, and racial/ethnic disparities in disease severity. Drug-induced liver injury is a relatively rare, but potentially life-threatening type of liver disease that is a growing cause of death and of the need for liver transplantation in the United States. It can occur with use of over-the-counter or prescription drugs, as well as with herbal or dietary supplements. Diagnosis and prognosis is complicated by the varying patterns of clinical injury observed to the liver and to the ducts carrying bile away from the liver to the intestine, sometimes resulting in liver failure. The Network was formed in 2003 to understand how drugs or herbal/dietary supplements cause liver injury and to determine long-term outcomes following this injury. It includes several clinical sites, a data coordinating center, and a sample repository. Study participants are at least 2 years of age, though most are adults, of both sexes. A panel of experts reviews each case to determine whether the injury was likely caused by the drug or herbal/dietary supplement, as well as the severity of the injury.

As part of the prospective study conducted by the Network, researchers analyzed how frequently participants with drug-induced liver injury experienced what were considered “fatal outcomes”—either death or liver transplantation, without which the individual would have died—over the following 2 years. Experts reviewed the case details to assess whether the injury was a primary cause of death or life-saving transplantation, or if it was simply one contributing factor. Among their findings, they showed that fatal outcomes occurred in 9.8 percent of the study participants in the 2 years following liver injury. The liver injury was judged to directly cause the fatal outcome in 64 percent of these cases and to contribute to it in 14 percent of cases, both mostly occurring in individuals who were younger than 45 years of age or women. The investigators also tested three mathematical formulas used to predict mortality risk from liver disease based on clinical measures, such as liver enzymes, bilirubin, and creatinine. They were able to rank the relative value of these formulas, some of which proved more useful for predicting who might be at greater risk of dying after drug-induced liver injury.

Another Network-driven study focused on one particular pattern of injury from drug-induced liver injury in which the bile ducts are damaged or even lost in a condition called vanishing bile duct syndrome. They analyzed liver biopsies that had been obtained from some of the participants sometime in the decade following their injury and scored the biopsies for bile duct loss. During this time, 26 (7 percent) of the study participants who had liver biopsies showed signs of bile duct loss, from which seven individuals died and two others eventually required liver transplantation. Most of these individuals first presented with a type of clinical pattern marked by severe injury to the bile ducts and liver inflammation. The researchers identified some of the drugs or supplements most commonly associated with the bile duct injury, including specific antibiotics and herbal supplements. The degree of the bile duct loss was found to be the best predictor of poor outcomes, such as death or need for a liver transplantation. As there is currently no way to prevent or treat bile duct loss, these findings may help to identify those at risk at an earlier point in the disease process, before bile duct loss occurs, and to prompt the development of early interventions.

In a third analysis conducted by Network investigators, the focus was on defining any racial/ethnic differences in drug-induced liver injury, specifically in African Americans compared to Caucasians. The analysis was prompted by evidence from other studies of adverse drug reactions, such as the NIDDK-supported Acute Liver Failure Study Group, which found that African Americans were more at risk for acute liver failure from drugs than Caucasians. In the Network’s study, the most frequent cause of drug-induced liver injury in African Americans was a two-drug antibiotic treatment containing trimethoprim and sulfamethoxazole, while another common two-antibiotic combination (clavulanic acid/amoxicillin) was the most frequent culprit in Caucasians. African Americans typically experienced more severe liver disease after drug-induced liver injury than Caucasians, which was more likely to result in outcomes such as death or need for liver transplantation. Severe skin reactions following drug-induced liver injury were also more common in African Americans. These findings may help improve care of groups at higher risk for liver injury from certain drugs by informing health care providers’ prescription choices and monitoring of those individuals who might be at higher risk for developing severe disease.

These results represent some of the major advances coming from the DILIN’s extensive studies of how liver injury caused by drugs and herbal or dietary supplements affects the U.S. population. Each of these studies’ findings points to new research questions that need to be addressed in drug-induced liver injury, including new approaches to managing potentially fatal outcomes such as bile duct loss and understanding why groups such as African Americans suffer worse outcomes or why the injury is more often a primary cause of death in those who are younger and female. Work towards answering these questions and others will be continued by DILIN’s investigators and study participants through a 5-year extension starting in 2018.