Are patients with elevated liver tests at increased risk of drug-induced liver injury?
Article Outline
The oft-cited warning that drugs known to produce hepatic injury should not be given to patients with liver disease has little foundation in fact.- Hy Zimmerman1
When acetaminophen is excluded, most severe drug-induced liver injury (DILI) is idiosyncratic. This means the drug in question is entirely safe to the liver in most patients. The most severe form of idiosyncratic DILI is hepatocellular jaundice, which typically occurs in much less than 1 per 1000 treated patients and is not caused by overdose. Drugs capable of causing idiosyncratic hepatocellular jaundice almost always are associated with frequent minor and asymptomatic serum aminotransferase elevations, exceeding 3 times the upper limits of normal (ULN) in up to 15% of treated patients. These laboratory abnormalities are believed to reflect true liver injury but often reverse even if drug therapy is continued. The basis for this adaptation is not known, as is why some patients do not adapt and develop progressive liver injury. The object of routine liver chemistry monitoring is to detect and remove from therapy the subpopulation of patients susceptible to alanine aminotransferase elevations. This population is assumed to contain the much smaller subset of individuals who are actually susceptible to progressive injury from the drug.
Caution should be used when administering a drug capable of causing severe idiosyncratic DILI to patients with preexisting liver disease. If such patients have significant loss of liver function before the onset of toxicity, as would be the case with advanced cirrhosis, the outcome of having a severe DILI event may be worse. In addition, liver-chemistry monitoring may be more difficult to interpret in the presence of underlying liver disease. For example, if advanced cirrhosis is present, the severity of liver injury may be underestimated by the height of the serum ALT measurements.
An additional reason for concern would be if patients with underlying liver injury were inherently more susceptible to idiosyncratic DILI. The traditional wisdom among hepatologists has been that this is not the case. This opinion has been largely based on the belief that the critical factors that determine susceptibility are genetic in origin. Because idiosyncratic DILI is generally considered to be dose independent, reduced clearance of a potentially hepatotoxic drug because of advanced cirrhosis may not be relevant.
However, is the risk of developing idiosyncratic DILI really the same in patients with and without preexisting liver disease? Some recent studies have suggested that the conventional wisdom may be wrong, at least in certain patient populations.2, 3, 4, 5, 6, 7, 8, 9 However, the design of these studies may not have included the appropriate control group for comparison of risk. The controls in these studies were patients who did not have underlying liver disease but were treated with the drug of interest. For example, in one study, patients with chronic hepatitis B and active viral replication treated with isoniazid were compared with inactive carriers of the hepatitis B virus treated with isoniazid.3 The patients with active viral replication were more likely to discontinue isoniazid because increases in liver tests were generally attributed to the drug. The authors concluded that patients with active replication are at increased risk of isoniazid hepatotoxicity compared with inactive carriers. However, an important control group that was missing from this study was patients with chronic hepatitis B and active replication who were not treated with isoniazid. This control group would account for fluctuations in aminotransferase levels that occur in patients with active hepatitis B that may otherwise be attributed to the drug.
Data have also been presented that suggest there is an increased risk of DILI caused by certain drugs in patients infected with human immunodeficiency virus who also have chronic hepatitis B or chronic hepatitis C infection.6, 7, 8, 9 However, these studies have not examined patients with human immunodeficiency virus and chronic viral hepatitis who are not treated with the suspected drug. Therefore, it is possible that the increased frequency of liver chemistry elevations were caused by the underlying liver disease and not the drug.
Another important consideration is the definition of DILI. Typically studies have defined drug-induced liver injury in terms of -fold increase in aminotransferases or total bilirubin above the upper limit of normal.2, 3, 5, 7 This practice biases the study against those with preexisting liver disease because these patients will generally have higher baseline liver chemistry values; lesser degrees of injury may cause the chemistry values to exceed standardized levels. In patients with liver disease, it makes more sense to define events in terms of fold increase relative to the patients’ baseline rather than the ULN, although few studies have done this.6, 10
In the study appearing in this issue of Gastroenterology, Chalasani et al.11 investigate the incidence of liver injury in patients with preexisting liver chemistry abnormalities by using a powerful medical electronic database that captures demographic, clinical, laboratory, and prescription data on patients from 3 hospitals and 30 clinics in the Indianapolis area. A specific strength of this database is the ability to link medical and laboratory information to pharmacy data. Atorvastatin, simvastatin, pravastatin, and fluvostatin were the statins included on the formularies and therefore the only statins studied. Serious hepatotoxicity was defined as elevations in aminotransferase levels greater than 10-fold the ULN in patients without a history of elevated liver tests or greater than 10-fold from baseline in patients with a history of elevated liver tests. A bilirubin level >3 mg/dL was considered serious hepatotoxicity regardless of baseline value.
When the investigators compared the incidence of statin-associated abnormal liver chemistries in the patients with preexisting liver disease with the corresponding incidence in patients with normal baseline liver chemistries, preexisting liver disease appeared to engender an increased risk. If this were the extent of the study, it would have been concluded that preexisting liver disease does, in fact, increase the risk of liver injury from statins. However, when compared with the group of patients with preexisting liver disease who did not receive statins, there was no difference in the incidence of hepatotoxicity. The importance of using a control group with liver disease was further highlighted when the authors examined patients with chronic hepatitis C who were not receiving statins. These patients showed a significantly higher rate of moderate or severe elevations in liver tests compared with the group receiving statins without elevated baseline liver tests. Had these patients infected with hepatitis C virus been treated with statins, the elevations may have been attributed to statins if the control group were only non-hepatitis C virus infected patients treated with statins.
There are several additional aspects of this study that deserve comment. First, patients with known hepatitis B or C and patients with history of alcohol abuse were excluded from the study. This was presumably done to focus on fatty liver disease, which is probably particularly common in patients prescribed lipid-lowering drugs. The results may therefore not be applicable to other liver diseases. A second issue is that there were relatively few patients who developed severe liver injury, limiting the statistical power of conclusions concerning this most important endpoint. Also, retrospective studies such as these are subject to “confounding by contraindication,” meaning that physicians may have chosen not to administer statins to some in the control liver-disease population because of potentially relevant characteristics of those patients. In addition, the results could be confounded if treatment with statins (or drugs associated with statin treatment) improves fatty liver. This could result in generally lower aminotransferases in the treated patients but would probably not affect the incidence of severe DILI. Finally, findings with statins are unlikely to be generalized to other drug classes. Statins appear to very rarely cause serious liver injury.12 Indeed, an argument has been made that the few instances of acute liver failure reported in association with statin therapy may be unrelated to statins and reflect the expected incidence of acute liver failure of unknown cause.13
It would obviously be desirable for physicians to be able to identify patients susceptible to severe DILI from a drug without having to prescribe it. This will not be possible until the relevant mechanisms, and the genetic and environmental factors that can influence these mechanisms, are defined. Progress in this area has been hindered by the lack of an organized mechanism to collect data on patients with DILI, and a systematic means to collect blood and other tissues from these patients for analysis. To address this critical need, The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health has recently sponsored a cooperative agreement (UO1) to create a Drug Induced Liver Injury Network (DILIN). DILIN consists of University of Michigan (principal investigator, Robert Fontana); Indiana University (principal investigator, Naga Chalasani); University of Connecticut (principal investigator, Herbert Bonkovsky), University of California, San Francisco (principal investigator, Timothy Davern); University of North Carolina (principal investigator, Paul Watkins); and Duke University (Data Coordinating Center; principal investigator, Jim Rochon). This network will begin this summer to create a registry and obtain tissues and genomic DNA from patients who have sustained severe idiosyncratic liver injury caused by isoniazid, phenytoin, valproic acid, and combination amoxicillin/clavulanate. In addition, the network will commence a second study that will prospectively enroll patients who have sustained DILI caused by any medications. The establishment of this network should greatly speed progress in DILI research.
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PII: S0016-5085(04)00483-4
doi:10.1053/j.gastro.2004.03.030
© 2004 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.
