Withholding Statins in Patients with Underlying Liver Disease: Wise or Unwise?

The “statins,” or hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors, are extremely popular and successful drugs for the treatment of hypercholesterolemia. One of the side effects of statin therapy that has received a great deal of clinical attention is liver toxicity. Although aminotransferase elevations have been observed in up to 2% of users, however, statins are rarely associated with clinically significant liver injury. As testimony to this, an electronic search of PubMed, the US National Library of Medicine online citation database, identified only 40 cases of statin liver toxicity from 26 publications despite the fact that more than 142 million prescriptions were written in 2008 (1). Only a handful of cases of acute liver failure have been reported, and causality has often proved difficult to establish. Most patients who develop statin hepatotoxicity have been in the sixth or seventh decade, presumably reflecting the demographics of patients who are prescribed these drugs. The duration of therapy before the development of hepatotoxicity has been variable, ranging from 5 days to 4 years. However, hepatotoxicity most frequently occurs within the first 12 weeks of therapy. While statins are not closely related structurally, prior exposure to either the same statin or another statin has been reported in 20% of cases. Data from clinical trials suggest that hepatotoxicity is dose related. Liver histology usually shows hepatocellular inflammation, but eosinophils, the biologic hallmark of drug hepatotoxicity, are frequently absent. The chronic use of these agents has thus far not been linked to cirrhosis. Being a hepatologist, I frequently encounter cases where statin therapy has been discontinued due to detection of mild serum aminotransferase elevations, even when the biochemical abnormalities existed prior to the start of therapy. Also, I see several cases yearly where the primary provider has been unwilling to initiate statin therapy until the opinion of a hepatologist was rendered. This degree of concern presumably reflects the great frequency with which these drugs are used as well as the general need for long-term therapy. Simply stated, however, the existing clinical data do not support the need for such an ultraconservative approach in patients with mild serum aminotransferase abnormalities. In two large retrospective cohort studies using the same database, patients with nonalcoholic fatty liver and abnormal liver biochemistries at baseline did not demonstrate any greater evidence of increased frequency of bilirubin elevation or marked serum aminotransferase elevations after 6 to 12 months of treatment when compared with treated patients with normal baseline liver tests (2). Even more compelling data can be found in a retrospective study in which the safety of lovastatin was documented in a managed care cohort of more than 93,000 patients with underlying chronic liver disease (3). Findings from the Dallas Heart Study also have shown that chronic statin use is not associated with a higher frequency of hepatic steatosis or serum alanine transaminase (ALT) abnormalities in patients with preexisting hepatic steatosis (4). In the current issue of Baylor University Medical Center Proceedings, Stroup and Harris, from Oklahoma State University Center for Health Sciences, have reviewed their experience in patients with combined HIV/hepatitis C virus infection (5). Their patients lacked other causes of liver disease. Of 60 such patients, only 5 were receiving statin therapy. None of these patients had any evidence of worsening liver tests during statin therapy. While the authors admit that this is a small sample size, the data are perfectly consistent with the large studies cited above in patients with other forms of liver disease. According to the manufacturers' recommendations, periodic liver function monitoring is needed during statin therapy. It should be noted, however, that there is no consensus on how this can be best applied in clinical practice, nor is it likely to be cost effective. It has been estimated that one would have to monitor aminotransferase levels in 100,000 patients each year for an average of 3 years to detect 110 patients who have consecutive elevations in ALT in order to identify one person who may experience liver failure, assuming that statins cause liver failure in the first place (6). Experience has shown that regular liver test monitoring is not very effective in identifying individuals who are at risk for serious idiosyncratic drug reactions (7). They point out that such was the case with triglitazone, a drug for diabetes that was taken off the market after several cases of acute liver failure were reported, despite the issuance of multiple warning letters from the US Food and Drug Administration recommending routine ALT monitoring. Further lack of consensus about routine aminotransferase screening comes from a panel of liver experts who concluded that liver enzymes need not be monitored routinely in patients receiving long-term statin therapy (8). The panel made this recommendation after consideration that any benefit from screening would be more than offset by the tendency of physicians to alter or discontinue statin therapy when minor abnormalities in serum aminotransferase levels were appreciated, thereby placing patients at increased risk for cardiovascular events. We are in the midst of an epidemic of obesity and nonalcoholic fatty liver disease. As this is rapidly becoming the most common form of chronic liver disease in the US population and statins are used so frequently, the clinical convergence of the need for lipid-lowering therapy and fatty liver disease is quite common. Population-based studies have taught us that obese patients with fatty liver and elevated serum ALT levels may have an 8-fold increased risk of cardiovascular mortality (9). These statistics have recently led the National Lipid Association Task Force to conclude that chronic liver disease, including compensated cirrhosis, is not a contraindication to statin therapy and statins can be safely prescribed to patients with nonalcoholic fatty liver (8). Based on expert opinion, the panel further recommended that these drugs not be used in patients with decompensated cirrhosis and acute liver failure. It is also recommended that statin therapy not be reinitiated whenever its role in previous significant liver injury cannot be excluded with certainty. Should this be the case, alternative agents to the use of statins for hypercholesterolemia are recommended. Ironically, several of these alternative agents are associated with clinically apparent hepatotoxicity as well (10). Maybe, it is just time for us to remember that more than nearly 1,000 drugs have been linked to abnormalities of liver function tests, the vast majority of which are only mild in nature. Furthermore, abnormalities in serum aminotransferase levels cannot be used to accurately predict liver disease in these patients and may in some instances resolve with continued use of the same agent. While it is always good to keep an eye open for drug-related hepatotoxicity, blind refusal to use statin therapy in patients with mild abnormalities of liver chemistries, particularly when patients have cardiovascular risk factors, is certainly not wise. How does the old expression go? “It is like throwing the baby out with the bath water. ”