The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia and are generally well tolerated. Mild elevations in serum aminotransferases arise in up to 3% of treated patients, but clinically apparent drug-induced liver injury is rare. The aim of this study is to report the presenting features and outcomes of 22 patients with clinically apparent liver injury due to statins. Among 1,188 cases of drug-induced liver injury enrolled between 2004 and 2012 in a prospective registry by the U.S. Drug Induced Liver Injury Network, 22 were attributed to a statin. All patients were evaluated in a standard fashion and followed for at least 6 months after onset. The median age was 60 years (range 41-80), and 15 (68%) were female. The latency to onset of liver injury ranged from 34 days to 10 years (median = 155 days). Median peak levels were alanine aminotransferase 892 U/L, alkaline phosphatase 358 U/L, and total bilirubin 6.1 mg/dL. Nine patients presented with cholestatic hepatitis and 12 patients presented with hepatocellular injury, of which six had an autoimmune phenotype. Nine patients were hospitalized, four developed evidence of hepatic failure, and one died. All commonly used statins were implicated. Four patients developed chronic liver injury, of which three had an autoimmune phenotype of liver injury. Conclusion: Drug-induced liver injury from statins is rare and characterized by variable patterns of injury, a range of latencies to onset, autoimmune features in some cases, and persistent or chronic injury in 18% of patients, most of whom have an autoimmune phenotype. (Hepatology 2014;60:679–686)
The HMG-CoA reductase inhibitors (statins) are among the most frequently prescribed medications worldwide, with over 143 million prescriptions annually dispensed in the United States alone. Statins reduce cardiovascular morbidity and mortality in high-risk patients with hyperlipidemia.[2, 3] They are also generally well tolerated, although dose-dependent adverse events, including myositis and myalgias, develop in 10% to 15% of patients. In addition, up to 3% of patients develop mild serum aminotransferase elevations within the first year of therapy, but these elevations are rarely associated with symptoms and often resolve even with continued treatment.[4, 5]
Clinically apparent drug-induced liver injury attributed to statins has been reported but appears to be rare. A systematic review of the literature published in 2009 identified only 40 cases of statin hepatotoxicity, mostly from single case reports and no case series with more than four patients. The U.S. Acute Liver Failure Study Group reported six cases of acute liver failure attributed to statins among a total 131 cases of acute liver failure due to drugs other than acetaminophen over a 10-year period. In a 2-year, population-based study from Iceland only three cases of liver injury from statins were identified. In an analysis of 12 years of adverse drug reaction reports to a Swedish registry, 73 cases of liver injury attributed to statins were identified, 34% of which were jaundiced and 4% fatal. Although there is substantial literature on statin-induced liver injury, the systematic evaluation and exclusion of other liver diseases, details on dose and duration of therapy, and long-term follow-up on recovery are lacking.
The U.S. Drug Induced Liver Injury Network (DILIN) is an ongoing multicenter, prospective study of the etiologies and outcomes of liver injury due to drugs, herbal medications, or dietary supplements in the United States. In addition to carefully characterizing the presenting clinical features of liver injury due to medications, DILIN collects biological samples for mechanistic studies of pathogenesis.[10, 11] The current study provides detailed information on the presentation and course of 22 cases of statin-induced liver injury which underwent expert adjudication and standardized collection of clinical data, laboratory tests, and, when available, liver biopsy findings.
The statins were originally thought to have a high potential for causing drug-induced liver injury. When first approved for use in the U.S., routine monitoring of serum enzyme levels at monthly intervals was recommended. Subsequently, however, the frequency of serum aminotransferase elevations during long-term use of statins was found to be only slightly greater than occurs with placebo treatments, and these abnormalities rarely resulted in clinically apparent liver injury. In this prospective study of drug-induced liver injury in the U.S., statins were initially implicated in 61 cases, but careful adjudication found only 22 (36%) could be considered convincing (more than 50% likelihood). All of the major statins were implicated at rates similar to their relative use in the U.S. Perhaps the most striking finding in this study is the lack of a single distinctive phenotype of liver injury cause by statins. Both mild and severe, short and long latency, and very cholestatic and very hepatocellular cases were found and the clinical features did not correlate with type of statin or conventional clinical demographics of patients. As with many other drugs, hepatocellular injury was more common among younger patients, but there was considerable overlap. Time to onset, severity, and outcome did not seem to correlate with any clinical phenotype or specific implicated statin. For unclear reasons histology did not correlate with biochemical classification; however, the timing of the biopsy was often late in the course, whereas the biochemical classification was usually based on the laboratory findings at onset, and in addition many subjects did not have a biopsy.
A striking feature of some cases of statin-induced liver injury was the prolonged latency. Indeed, 5 of the 22 patients had been taking the agent for a year or more before onset of acute injury. This prolonged time to onset is unusual, in that most cases of drug-induced liver injury present within 6 months. Furthermore, drugs typically associated with a long latency (nitrofurantoin, minocycline, or methyldopa) usually present with a chronic hepatitis-like syndrome rather than an acute hepatocellular or cholestatic hepatitis. Prolonged latency was seen with most of the types of statins (atorvastatin, simvastatin, fluvastatin, rosuvastatin) presenting with both hepatocellular and cholestatic patterns of liver injury. Although cases with long latency are unusual, we systematically excluded other causes of liver disease and liver test elevations resolved with discontinuation of the statin. Cases of long latency to onset of liver injury from statins have been described before, but many case series lack any instances with a latency of above a year, perhaps because such cases are excluded or considered less than probably related.[6, 9]
A proportion of subjects with statin-associated liver injury developed features of autoimmune hepatitis, with ANA or SMA positivity, raised serum immunoglobulin levels, and/or autoimmune hepatitis-like histology. All cases had a hepatocellular pattern of injury and a high proportion received systemic corticosteroid therapy. Importantly, two of the six cases appeared to have self-sustained autoimmune hepatitis with persistently elevated serum enzymes that required immunosuppressive therapy when last seen, more than 6 months after initial onset. This pattern differs from the autoimmune hepatitis-like injury that is associated with minocycline and nitrofurantoin, which typically resolves after the drug is discontinued, and in which immunosuppressive therapy can ultimately be stopped. One interpretation of these findings is that the liver injury was coincidental and unrelated to the statin use, which might not be unexpected given the frequency of long-term statin use in the general population. On the other hand, many of these cases did resolve once statins were discontinued and those that required long-term immunosuppressive therapy improved to a certain extent upon stopping the drug. Another interpretation is that statins may trigger autoimmune hepatitis in a susceptible patient, which may become self-sustaining, if the statin was not stopped promptly or the injury was particularly severe. Similar cases of self-sustained autoimmune hepatitis seemingly triggered by statin exposure have been reported.[15, 16] Importantly, among the cases with hepatocellular injury without serum autoantibodies in the current series, none developed chronic injury. Thus, the presence of autoantibodies in patients with drug-induced liver from statins may identify those at increased risk for chronic injury. Although the clinical importance of chronic injury from drugs is unknown, it seems prudent to recommend that such subjects continue to be followed for additional evidence of chronic liver disease.
While four of the 22 cases of statin-induced liver injury were considered severe and one patient died, the liver injury was largely mild-to-moderate in severity and self-limited in course. The one patient who died had preexisting alcoholic cirrhosis and esophageal varices and the other three cases that were scored as severe had a transient prolongation of the prothrombin time (INR >1.5) only, without hepatic encephalopathy, ascites, or fluid overload. The fatal case was adjudicated as probable because the underlying alcoholic liver disease was thought to have contributed to his death. Thus, statin-induced liver injury is usually mild-to-moderate in severity and fairly rapidly reversed in most cases once the agent is stopped.
The current results could not address the question of whether there is crossreactivity among the different statins in susceptibility to liver injury. One patient was restarted on the same statin and rapidly redeveloped acute injury. Four patients had received another statin previously without hepatic injury, but none of the 22 patients in this series was switched to another statin and monitored. In this regard, previous studies have presented conflicting results, with most instances not redeveloping hepatic injury when another statin was started.[9, 17-21] However, because rare instances of recurrence of hepatotoxicity after switching to another statin have been reported, switching should be done with caution and with careful monitoring.[6, 22]
In summary, the current case series suggests that clinically apparent liver injury from the statins is likely a class effect and can arise many months and sometimes years after initiation. Statin-induced liver injury has variable clinical presentations including distinctly cholestatic, markedly hepatocellular, and even autoimmune hepatitis-like phenotypic manifestations. Liver injury from statins is rare, usually mild-to-moderate in severity, and rapidly reversed upon stopping, although cases with an autoimmune phenotype of liver injury were more likely to develop evidence of chronic injury. Based on these data, prospective monitoring for drug-induced liver injury from statins is not warranted, but patients who develop a liver injury with an autoimmune phenotype should be closely monitored and evaluated for immunosuppressive therapy if liver tests fail to improve.
Author Contributions: Mark W. Russo, M.D., is a DILIN investigator who enrolled patients, developed the concept and design for this study, participated in its analysis, and wrote the first draft of the article and participated in further editing. Jay H. Hoofnagle, M.D., is an employee of NIDDK with responsibility for oversight of the DILIN network and participated in the design and analysis of the study and in editing drafts. Jiezhun Gu, Ph.D., is a biostatistician with the Data Coordinating Center for DILIN who was primarily responsible for the statistical analysis and verification of data of the study and participated in editing drafts of the article. Robert J. Fontana, M.D., is a DILIN investigator who enrolled patients and contributed to the study development design and writing of the article. Huiman Barnhart, Ph.D., is a biostatistician with the Data Coordinating Center for DILIN who was primarily responsible for the statistical analysis and verification of data of the study and participated in editing drafts of the article. David E. Kleiner, M.D., Ph.D., is an employee of NIDDK and participated in the design and analysis of the study, pathology section, and in editing drafts. Naga Chalasani, M.D., is a DILIN investigator and contributed to the study development and design. Herbert L. Bonkovsky, M.D., is a DILIN investigator and contributed to the study development design and writing of the article.