Statin Hepatotoxicity: Is it a Real Concern?

Statins are the most effective and widely used drugs for treating dyslipidemia, a major risk factor for coronary heart disease. These are one of the safest hypolipidemic drugs but many patients are advised to discontinue statins for the fear of hepatotoxicity. Despite a lack of evidence that statins cause liver diseases, many physicians are reluctant to start statins in patients with an out-of-range liver enzymes value and this reluctance to initiate or interrupt the therapy with statins leads to dyslipidemia and its grave consequences. Further, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver function tests.

INTRODUCTION

Hyperlipidemia is a major cause of coronary heart disease (CHD) and associated conditions. It is estimated that an average of 11.5 years of life are lost as a consequence of having CHD.[1] Statins, the most efficacious hypolipidemic drugs, not only prevent grave consequences of dyslipidemia but also have various beneficial pleiotropic effects.[2] More than 2 decades of statin use has saved innumerable lives but a few post marketing surveillance studies have revealed statin associated elevations in hepatic aminotransferases. However, most hepatologists no longer consider statins to have any significant hepatotoxicity. The elevated aminotransferases are only dose related, mild and unrelated to LDL levels.[34] Hence, it would be prudent to think twice before interrupting statin therapy out of fear of hepatotoxicity.

History

The National Institute of Health Guidelines after Fogarty conference in 1978, decreed that alanine aminotransferase (ALT) value more than three times the upper level of normal (ULN) was “markedly abnormal” and should be used as an indicator for drug-induced liver injury. Not a shred of proof was offered for this recommendation. This arbitrary measure became a standard for monitoring drugs in clinical trials.[5] In the 1980s, trials of statins were just getting started. Since then, statins have been observed to cause mild ALT elevations in 10% of recipients, and in 1-3% of patients, the elevations are more than three times the ULN.[6] ALT testing is not specific to the liver; it was first discovered as a marker for acute myocardial infarction in 1955 by Arthur Karmen.[7] ALT is only one of the parameters for drug related hepatotoxicity, because Hy's rule states that serum bilirubin 2 times ULN, with all other causes of liver dysfunction excluded, indicates drug related hepatotoxicity.

The truth

Although elevations in ALT or aspartate aminotransferase (AST) less than 3 times ULN may occur during statin therapy, such elevations are usually transient, asymptomatic and do not require interruption of therapy. In placebo-controlled outcome trials (as reported in 2003), where 10-40 mg doses of simvastatin, lovastatin, fluvastatin, atorvastatin, and pravastatin were compared with placebo, the incidence of ALT elevation >3 times ULN was found to be 1.3% with test drugs and 1.1% with placebo with no case of liver failure,[8] whereas four large trials of statins have shown no difference in the frequency or degree of deranged liver function tests (LFT) between treatment and placebo groups (involving greater than 48,000 patients). Interestingly, out-of-range values, which do occur with statin use, eventually return to normal even if the same statin is continued.[9] Although serious hepatotoxicity is rare, a few cases of liver failure associated with statin use have been reported to the FDA between 1987 and 2000, the rate of about one case per million person-years of use,[810] but the occurrence of acute liver failure (ALF) thought to be caused by statins is well below what is now understood as the background rate of idiopathic ALF in the general population.[9] One estimate determined the idiopathic ALF rate to be from 0.5 to 1.0 case per million, and the incidence of possible statin-induced ALF to be 0.2 cases per million in United States.[11] No consistent liver biopsy picture from possible statin-related drug injury has emerged, and there are no reports of chronic carriers of drug-induced liver damage from statins.[9] Thus, an increased ALT in this situation should not be considered pathology and also, that statins are involved in ALF because of background noise. Madhoun and Bader (2010) have shown statins to be safe even in Hepatitis C patients,[12] and interestingly, Bader and colleagues (2008) have shown fluvastatin to have anti-HCV activity in chronic carriers of HCV in whom treatment with peginterferon/ribavirin had failed.[13] Abraldes and colleagues (2009) have successfully investigated simvastatin as an agent to treat portal hypertension.[14] Moreover, there are some reports showing an additional benefit of statins in reducing cardiovascular events in patients with abnormal liver-function tests.[121315]

According to the United States Food and Drug Administration (USFDA), a base line LFT may be done before starting statins and that is even not necessary for asymptomatic patients without a history of liver disease using lovastatin. However, these guidelines may seem to be optional as there is no evidence that monitoring reduces the rate of hepatotoxicity.[11]

Non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, muscle relaxants, numerous other over-the-counter (OTC) medications, alcohol consumption, and intercurrent illness are other frequent causes of elevated aminotransferases, which have to be taken into account before blaming statins. In addition there are reports which suggest that 20% of high ALT patients are due to fatty liver and non-alcoholic steatohepatitis (NASH).[16] Interestingly, ALT status has improved or normalized after starting statins in fatty liver or NASH patients. Although decompensated cirrhosis, acute liver failure and worsening obstructive biliary disease remain contraindications for statin therapy; low doses of statins can be used with careful monitoring in compensated cirrhosis, chronic liver disease and partial obstructive biliary disease.[10] Statins can be used safely in patients with either non-alcoholic fatty liver disease or NASH and even, mild to moderate alcohol consumption (up to 1–2 drinks/d) is not a contraindication for their use.[17] Large trials support statin therapy in patients with cardiac, kidney, or liver transplants.[17]

Most physicians know that statins cause hepatotoxicity because the package inserts contain warnings about this problem. The USFDA is no longer concerned about package insert stating statins causing hepatotoxicity. According to FDA regulations, only the manufacturer can request a label change and the FDA can then consent to the change; the agency cannot unilaterally delete language on a package insert. These types of rules and regulations are not just harming the patients who are in need of the drugs but keep physicians in a dilemma.

In those who need statins for their hypercholesterolemia, statins may be the most life-preserving therapy in the entire pharmacopoeia. In large 5-10 year trials, statins prevent about 30% to 40% of major cardiovascular events when compared to placebo.[1] In other words, the number needed to treat (NNT) is 3. If statins cause serious liver disease, it may be on the order of 1 in a million. The number needed to harm (NNH) is 1 million. Estimates of patients who fail to receive statins out of fear of hepatotoxicity range from 10-30%. Thus, the disproportionate anxiety over this possible though remote toxic effect, denies several thousand of patients with fatal cardiovascular disorders, the well documented benefits of statins. So, it is advisable to set a very high bar to establish the possibility of liver injury, since failure to do good is unjustifiable vis-a-vis harming a much larger group of patients. Hence, it would be prudent to think twice before interrupting statin therapy out of fear of hepatotoxicity.