Can statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) cause transaminitis (elevated liver enzymes)?

From the Guidelines

Yes, statins can cause transaminitis, which is an elevation in liver enzymes (specifically ALT and AST), as reported in the 2019 guideline on the management of blood cholesterol by the American College of Cardiology/American Heart Association task force on clinical practice guidelines 1. This side effect typically occurs in approximately 0.5-3% of patients taking statins, though the incidence varies by specific medication and dosage. The elevation is usually mild (less than 3 times the upper limit of normal) and often transient, occurring within the first few months of therapy. More significant elevations (greater than 3 times normal) are rare, occurring in about 1% of patients. Some key points to consider include:

• The mechanism involves direct hepatocyte injury from the medication, though the exact pathophysiology isn't fully understood.
• Despite these potential elevations, routine liver function monitoring is no longer recommended for all patients on statins unless they have pre-existing liver disease or develop symptoms suggesting hepatotoxicity.
• If significant elevations occur (greater than 3 times normal), especially with symptoms, the statin should be temporarily discontinued and liver enzymes monitored until they normalize.
• Statins are not contraindicated in patients with increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, as stated in the 2019 guideline 1. Some of the statins that may cause this effect include atorvastatin, rosuvastatin, and simvastatin. It is essential to weigh the benefits of statin therapy against the potential risks, including the risk of transaminitis, and to monitor patients accordingly. In patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge, it is reasonable to use RCT proven nonstatin therapy that is likely to provide net clinical benefit 1. Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of SAMS 1. In patients treated with statins, routine measurements of creatine kinase and transaminase levels are not useful, as stated in the 2019 guideline 1.

From the FDA Drug Label

Increases in serum transaminases have been reported with use of rosuvastatin [see Adverse Reactions (6. 1)] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to more than three times the ULN occurred in 1.1% of patients taking rosuvastatin versus 0. 5% of patients treated with placebo. Marked persistent increases of hepatic transaminases have also occurred with rosuvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8. 7)] . Consider liver enzyme testing before rosuvastatin initiation and when clinically indicated thereafter. Rosuvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue rosuvastatin.

Yes, statins can cause transaminitis (elevated liver enzymes), as evidenced by increases in serum transaminases reported with the use of rosuvastatin and simvastatin 2 3.

• The increases in serum transaminases are usually transient and resolve or improve on continued therapy or after a brief interruption in therapy.
• However, marked persistent increases of hepatic transaminases have also occurred with statin use.
• Patients with a history of liver disease or substantial alcohol consumption may be at increased risk for hepatic injury.
• Liver enzyme testing is recommended before statin initiation and when clinically indicated thereafter.

From the Research

Statins and Transaminitis

• Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been associated with elevated liver enzymes, a condition known as transaminitis 4, 5, 6, 7.
• The risk of hepatic injury caused by statins is estimated to be about 1 percent, similar to that of patients taking a placebo 5.
• Transaminitis is usually asymptomatic, reversible, and dose-related, and is the most commonly reported hepatic adverse effect of statins 6.

Incidence and Resolution of Transaminitis

• A study found that severe transaminitis deemed directly attributable to statin use occurred infrequently, in about 0.1% of patients 4.
• In most cases, transaminitis resolved upon statin discontinuation, with 16 out of 17 cases resolving after statin discontinuation in one study 4.
• Another study found that patients with transaminase levels no more than three times the upper limit of normal can continue taking statins, and often the elevations will resolve spontaneously 5.

Factors Influencing Transaminitis Risk

• Coexisting elevations of transaminase levels from nonalcoholic fatty liver disease and stable hepatitis B and C viral infections are not contraindications to statin use 5, 6.
• Drug interactions, such as those with fibrates, diltiazem, verapamil, and amiodarone, can increase the risk of adverse effects, including transaminitis 5.
• Patients with comorbid conditions, such as chronic liver disease, may require closer monitoring of liver enzymes while taking statins 6, 7.

Evaluation and Management of Transaminitis

• The initial evaluation of mildly elevated transaminase levels should include an assessment for metabolic syndrome and insulin resistance, as well as testing for common causes such as nonalcoholic fatty liver disease and hepatitis C 8.
• If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate, and if the elevation persists, hepatic ultrasonography and further testing for uncommon causes should be considered 8.
• In cases of suspected statin-induced liver injury, a complete medical history, laboratory tests, and hepatic imaging are crucial for a complete causality analysis 7.