Statins and its hepatic effects: Newer data, implications, and changing recommendations

Abstract

Hepatic adverse effects are one of the most commonly known adverse effects reported with statins. Frequently, fear of serious hepatic effects contributes to underutilization of statins as well as unnecessary discontinuation of its use among those indicated. There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders. Based on reviewed literature, statins appear to be associated with a very low risk of true and serious liver injury. Unprecedented fears regarding hepatic adverse effects of statins among prescribers and patients can deny patients of the significant benefits of these agents. Routine periodic monitoring of liver function does not appear to detect or prevent serious liver injury and hence may not be indicated. But the potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice. Statin use need not be avoided in patients with preexisting liver dysfunction such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, compensated cirrhosis, and compensated chronic liver disease if its use is clearly indicated. Physician's judgment based on the risk and benefit for an individual patient does matter when a strategy is chosen regarding the use of statins and monitoring patients while on statins.

HMG Co-A reductase inhibitors (Statins) are currently one of the most frequently used and largest selling prescription drugs worldwide.[1,2,3] The use of statins has increased dramatically in the recent past in view of the encouraging data from clinical studies on the beneficial effects of these agents in the primary and secondary prevention of cardiovascular disease (CVD).[4,5,6]

Even though statins are considered as safe drugs, they are not free from side effects.[7] Statin therapy is associated with greater odds of adverse events compared with placebo even though similar rates of serious adverse events were observed between statin and placebo in a meta-analysis of statin-related adverse events.[8] In real practice, increasing use and broadening indications for use of stains have led to a significant number of patients with reported/suspected adverse effects to statins being identified in health care settings.[9]

From the time statins were marketed, two adverse drug reactions (ADRs) which were of concern were the effects on the muscle as well as on the liver. Hepatic adverse effects are one of the most commonly known adverse effects reported with statins.[10,11] Hepatic effects are of concern that contributes to underutilization of statins as well as unnecessary discontinuation of its use among those indicated.[12,13] There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk and monitoring required, and safety of use in those with hepatic disorders. The aim of this narrative review is to appraise the available literature focusing on the above-mentioned aspects of statin-induced hepatic effects.

Search Strategy

Articles in the literature sources, such as PubMed and Google Scholar, were searched with the search terms of “statin and hepatic effects” as well as “statin and hepatotoxicity.”

Nature and Incidence of Hepatic Adverse Effects

A wide range of hepatic adverse effects can occur with statins. Most common is asymptomatic and usually temporary elevation of transaminases that are rarely clinically significant and usually occurs in the early stages of therapy.[14] This phenomenon is called as transaminitis as is thought to be related to alteration of hepatocyte cellular membrane with enzyme leakage rather than direct liver injury.[15,16,17] It may result from changes in the lipid component of the hepatocyte membrane, leading to an increase in its permeability with subsequent leakage of liver enzymes.[14,17,18] Apparently, this phenomenon is characteristic of all the lipid-lowering agents and may be secondary to the lipid-lowering process itself and not specific to statins.[9,19] Since most often this laboratory abnormality is not correlated with significant histopathological changes, it does not meet the criteria as a true indicator of liver injury.[20,21]

Considering the frequency of occurrence, elevated aminotransferase levels across multiple studies with various kind of statins did not exceed 3% of the studied patients.[22,23,24,25,26] Further, it was reported that only 3% of the patients with early, minor elevation in serum transaminases experience a subsequent persistent elevation of >3 times the upper limit of normal.[11,19,27,28,29,30] But, in a systematic review conducted by Kashani et al., the absolute risk of transaminase elevations was significantly higher with statin therapy compared with placebo.[31] Persistent elevation in serum transaminases requiring withdrawal or interruption of therapy occurred in approximately 0.5% of the patients receiving simvastatin.[32]

Considering the prognosis of these statin-induced elevation of liver enzymes observed, approximately, 70% of these elevations will spontaneously fall back into the normal range even as treatment continues[4,26] while, in other cases, these elevations are usually reversible with a dose reduction.[33] These elevations do not always recur if the patient resumes the statin.[24]

The incidence of true liver injury caused by statin is noticed to be around 1%.[34] Clinically significant hepatic effects, including fulminant hepatic failure and autoimmune hepatitis, can occur with statins.[14] Even though rare, idiosyncratic liver injury associated with statins could be severe.[23,27] Based on the reports from Swedish ADRs Advisory Committee, rare but severe idiosyncratic liver injury was reported with statins which usually developed within 3–4 months after the start of therapy. A similar pattern of liver injury may be reproduced on re-exposure. It was reported that atorvastatin is mostly associated with cholestatic liver injury whereas hepatocellular injury is more common with simvastatin.[27] In the rare cases of true statin-related hepatotoxicity, no characteristic biochemical or histologic pattern of liver injury has been established and hepatocellular, cholestatic, or even mixed histologic patterns have been reported. The proposed mechanism is idiosyncratic or an immunoallergic reaction, and isolated cases of autoimmune hepatitis have been described.[14,35,36,37]

An infrequent occurrence of significant hepatic effects associated with statins was reported in a study conducted in Sultanate of Oman. Among the 927 studied patients, a significant transaminase rise was observed only in 1% of those on statins.[38] ADR reports from UK Committee on Safety of Medicines reveal that four deaths due to hepatobiliary disease in association with atorvastatin treatment have been reported over 8 years, with female gender and age over 60 years identified as the most commonly associated variables.[15] Evaluating the spectrum of statin hepatotoxicity as reported in the USA drug-induced liver injury network, variable patterns of liver injury were reported with a latency to onset ranging from 34 days to 10 years.[39]

In Iceland, it was reported that the risk of jaundice caused by statin drugs was very rare with a frequency of one in 17,434 users a year. Investigators commented that this is a higher risk than has previously been estimated and encourage alertness when managing patients with statins with regard to clinical signs of hepatitis before jaundice occurs.[40] Third National Health and Nutrition Examination Survey mortality linked files were used to assess the association between statin use and liver-related mortality. It was reported that after a decade of follow-up, there was no association between statin use and liver-related mortality. In fact, the rate of liver-related mortality was significantly lower among statin users compared to nonstatin users.[41] Analysis of cases of hepatotoxicity associated with statin use in Spanish hepatotoxicity registry revealed that statins are not a common cause of hepatotoxicity in Spain and atorvastatin seems to be the most commonly involved statin agent.[37]

United States Federal Drug Administration (US FDA) published that reporting of statin-associated serious liver injury to its adverse event reporting system database was extremely low (reporting rate of ≤2/1 million patient-years) based on a review of its postmarketing data. Even though there has been a rising use of statins, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use.[42] Only very rarely elevations in transaminase levels seen in low to moderate dosages of statins progress to liver failure.[43,44,45]

Risk Factors for Hepatic Effects

There seems to be a direct relationship between statin dose and incidence of the asymptomatic rise in transaminases with a higher incidence of transaminitis occurring with higher dose of statins.[9,46] There does not seem to be a difference in the incidence of transaminase elevations among different statins.[16] Additional contributing factors reported are preexisting hepatitis, advanced age, and chronic illness.[33,47] It was reported that serious hepatic reactions with atorvastatin tend to occur more commonly in females.[15] Other hepatotoxic substances when used concurrently, including acetaminophen, alcohol, fibrates, niacin, macrolide antibiotics, azole antifungals, cyclosporine, and calcium channel blockers, may increase the propensity of hepatotoxicity induced by statins.[18] The interactions between alcohol intake and statin treatment have been poorly studied.[9]

Impact on Clinical Practice

Many a times, concerns about adverse effects may prevent physicians from prescribing statins.[31,48] Unfounded safety concerns about hepatotoxicity are commonly identified among physicians. Many physicians are reluctant to start statins in patients with an insignificant out-of-range liver enzymes value, and this unwarranted reluctance leads to dyslipidemia and its grave consequences.[10,49] Many a times, statin agents are not prescribed or they are under prescribed in those with an indication because of fears of injury to the liver.[13] Thirty-seven percentage of respondents in a survey conducted among primary care physicians in United States to assess the impact of concern about hepatotoxicity with statins on prescribing the same had falsely elevated perceptions of statin hepatotoxicity risk. These perceptions correlated inversely with statin prescribing.[12] Fears of statin use among clinicians have been minimized by the enhanced understanding of the mechanisms behind the adverse effects of statin use.[50]

When a statin-induced hepatic effect is suspected, the first step should be to rule out other causes or undiagnosed, nonstatin related liver disease.[9,14,51] It would be prudent to reassess before interrupting statin therapy out of fear of hepatotoxicity.[51] Concomitant use of medications known to interact with statins or that induce hepatotoxicity per se should be scrutinized before establishing a causal relationship of hepatic effects with statins.[42] Among those cases in which the transaminase elevation persists, the physician must cautiously decide the next action; whether, to reduce the dose of the statin, switch to a different statin, or discontinue statin therapy entirely based on an individual assessment of risks and benefits.[10,18,52]

It is reported that even patients overestimate the risk of liver damage from statins and many a times, patients withdraw statins without consulting physicians because of the side effects or perceived side effects mainly myopathy and hepatic effects.[10,53] It is opined that direct to consumer advertising for statins which warned about the risks of hepatotoxicity without mentioning the magnitude of risk involved might had an influence on the perception of patients regarding the hepatic effects of statins, sometimes exaggerated.[10] In a recent survey, it was observed that patient reporting of liver adverse effects with statins was not related to alanine aminotransferase (ALT) level and monitoring.[54]

Nevertheless, it is clinically wise to consider that statins do possess the risk of developing significant hepatic effects. Accordingly, this adverse effect has to be given importance before initiating statin, during patient medication counseling and follow-ups, and of course, as a differential diagnosis while a patient on statin develops hepatic effects.[38]

Monitoring of Hepatic Effects

The need of getting a baseline liver function tests (LFTs) before starting statin and routine monitoring thereafter has been recommended from the time of introduction of these agents in the market.[4,42]

The significance and utility of routine monitoring of LFTs after initiation of statins were a matter of discussion from more than a decade, and many were advocating that there is no indication for such routine monitoring.[22,23] It is reported based on evidence that one would have to monitor transaminase 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 the statistical 0.1 person who may experience liver failure.[55] The liver expert panel and US FDA stated that there is no evidence supporting the effectiveness of routine monitoring in identifying patients likely to progress to liver failure and will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy.[23,42] Since the actual risk is sufficiently low, the cost of screening, evaluation of minor test result abnormalities, and drug discontinuation could be minimized by avoiding routine monitoring.[56,57] Recent label changes for statins approved by US FDA states that “healthcare professionals should perform liver enzyme tests only before initiating statin therapy and as clinically indicated thereafter.” If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be interrupted. If an alternate etiology is not found, the statin should not be restarted.”[42] Changes in labeling based on the latest data needs to be considered while prescribing as well as advising the patients.[58]

Use of Statins in those with Preexisting Hepatic Dysfunction

A clinical dilemma most often encountered by prescribers is the use of statins in those patients with already existing baseline elevations of serum liver enzyme levels or having liver disease.[59]

Increasing incidence of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD) and hepatitis C, has contributed to this dilemma. It should be borne in mind that the presence of baseline elevations of serum liver enzyme levels is frequently secondary to associated co-morbid conditions; dyslipidemia, obesity, and diabetes mellitus which shares features of NAFLD than any actual liver dysfunction per se.[16] Patients should not be denied of the cardiovascular benefits of statin use if their elevated aminotransferase levels have no clinical relevance or are attributable to known stable chronic liver conditions.[16,60,61] Studies support that statins can generally be used safely in patients with NAFLD with appropriate monitoring.[9,16,62] According to Gillet and Norrell, presence of nonalcoholic steatohepatitis should not discourage physicians from using statins in those indicated. Fewer severe increase in transaminase levels were observed in patients using statins than in patients not using them in two retrospective studies over a period of 12 months, examining patients with mildly elevated transaminases levels.[63,64] Two small studies evaluating patients with non alcoholic steatohepatitis demonstrated some degree of improvement in liver pathology in patients receiving statins.[65,66] Statin use was associated with protection toward the full spectrum of liver damage in individuals at risk of nonalcoholic steatohepatitis in a recent multicenter study conducted in Europe.[67] In the Dallas Heart Study, in which the relationship between statin use, ALT elevations and hepatic steatosis were evaluated, it was observed that there was a lack of relationship between statin use and more severe worsening hepatic steatosis or elevated ALT values.[68]

It is interesting to note that some studies demonstrated that in fact, statin treatment may improve liver enzyme levels as well as hepatic steatosis.[21,69] Based on a recent systematic review by Eslami et al., to consider the beneficial and harmful effects of statins in patients with NAFLD and nonalcoholic steatohepatitis, it was reported that it seems possible that statins may improve serum aminotransferase levels as well as ultrasound finding. However, the authors suggested that more studies are required before it could be considered as a treatment for the same.[70] The use of statins in patients with primary biliary cirrhosis was reported to be safe in those who might benefit from their use.[59]

Clinicians are often reluctant to prescribe statins in patients with hepatitis C because of their uncertainty whether benefit outweigh the risks. It was reported that there is no higher risk of alterations in liver biochemistry values in patients with hepatitis C virus (HCV) infection when they use statins.[16,71,72] A beneficial effect of the use of statins among patients infected with HCV includes sustained viral remission rate as reported by Bader et al.[73,74] Statins was reported to be a potential assist for hard-to-treat genotype 1 patients with hepatitis C-related chronic liver disease.[75] Among patients with HCV who are at risk for coronary heart disease and do not have significantly elevated serum transaminase levels at baseline, statin therapy should be considered.[76] Based on Taiwanese National Health Insurance Database, the association between statin use and risk of hospitalization for acute hepatitis in patients with hepatitis B virus (HBV) infection was studied. It was reported based on the 127,672 HBV-infected patients who had used statins, statin use may not be associated with acute hepatitis regardless of dose or drug class of statins.[77] It is reported that statins appear to be safe in patients with chronic hepatitis B and C. However, caution to be exercised as statins pharmacokinetics and metabolism may be altered with abnormally high serum levels in those patients with more extensive hepatic impairment.[16]

Among patients with cholestatic liver disease, patients with CVD or intermediate to high risk of CVD events need not be denied statins and can be used with careful monitoring.[9] It was reported that in patients with cirrhosis, statin therapy is not associated with increased mortality and may delay decompensation.[78] In a retrospective review of liver transplant patients, to assess the incidence of adverse effects with statins, a low incidence of adverse events was reported with no incidence of severe complications, and no alterations in LFTs.[79] A population-based case–control study in Taiwan suggested that statin use may reduce the risk of liver cancer.[80]

The use of statins in patients with acute viral or alcohol - associated liver disease, as well as in patients with advanced liver disease is not recommended as the primary goal during acute injury is to avoid any potential risk of further liver injury until the patient has totally recovered.[23] In patients with severely decompensated chronic liver disease, drug metabolism may be impaired even though statins appears to be safe in patients with compensated liver disease.[31] Compensated cirrhosis and chronic liver disease should not be considered as contraindications to statin therapy and should be used safety in patients with NAFLD.[23,75,76]

Conclusions

Reviewed data indicate or support the recommendation from US FDA that “all currently marketed statins appear to be associated with a very low risk of serious liver injury.” Asymptomatic and usually transient elevation of aminotransferases often observed affect the adequate use of these agents among those indicated. Unprecedented fears regarding the hepatic adverse effects of statins among prescribers and patients can deny patients of the significant benefits of these agents. Alterations in liver enzymes often result in discontinuation/interruption of the statin therapy. Clinicians should not withhold statin therapy for patients whose transaminase elevations have no clinical relevance or are attributable to known stable chronic conditions. Evaluating other causes for alteration in LFTs should be made before establishing a causal relationship with a statin agent. Cardiovascular benefits of statins generally outweigh noncardiovascular harms including the hepatic adverse effects. Routine periodic monitoring of LFTs does not appear to detect or prevent serious liver injury in association with statins and hence may not be indicated. However, as reported in literature, potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice. Statin use need not be avoided in patients with preexisting liver dysfunction as NAFLD, nonalcoholic steato hepatitis, compensated cirrhosis, and compensated chronic liver disease if its use is clearly indicated. Evidence from literature and clinical studies can provide only guidance; physician's judgment based on the risk and benefit for an individual patient does matter when a strategy is chosen regarding the use of statins and monitoring patients while on statins.

Financial support and sponsorship

I would like to acknowledge The Research Council (TRC) Oman for approving and funding the project ‘ORG/HSS/11/008’ which has been of assistance in conducting a study on statin induced hepatic effects in Oman as well as preparing this review article in the respective field of research.

Conflicts of interest

There are no conflicts of interest.