At what level of liver function test (LFT) elevation should statins (HMG-CoA reductase inhibitors) be discontinued?

From the Guidelines

Statins should be stopped when liver function tests (LFTs) show an elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) on repeated measurements, as recommended by the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults 1. If a patient develops symptoms of liver injury (such as fatigue, loss of appetite, right upper quadrant pain, dark urine, or jaundice) along with elevated LFTs, statins should be discontinued immediately regardless of the exact level of elevation. After stopping the statin, LFTs should be monitored until they normalize. The reason for this threshold is that mild elevations in liver enzymes (less than 3 times ULN) are common with statin therapy and often transient, while elevations above this level may indicate potential liver injury. Some key points to consider when managing statin therapy in relation to LFT elevations include:

• Mild elevations in liver enzymes are common and often transient, but elevations above 3 times ULN may indicate potential liver injury.
• The decision to stop statins should be based on repeated measurements of LFTs, rather than a single elevated result.
• Symptoms of liver injury, such as fatigue, loss of appetite, right upper quadrant pain, dark urine, or jaundice, should prompt immediate discontinuation of statins, regardless of the level of LFT elevation.
• Once LFTs normalize, a different statin can be cautiously reintroduced at a lower dose with regular monitoring, as not all statins affect the liver equally.
• Medications like atorvastatin and simvastatin tend to have higher rates of liver enzyme elevations compared to pravastatin and rosuvastatin, as noted in the 2013 ACC/AHA guideline 1 and other studies 1. It's essential to weigh the cardiovascular benefits of statins against the risk of liver injury when making decisions about continuing or discontinuing therapy, considering the latest guidelines and evidence, including the 2019 consensus guidelines on detection, assessment, and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis 1.

From the FDA Drug Label

If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets ( 5.3). Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0. 7% of patients who received atorvastatin calcium in clinical trials.

Statins should be stopped if there is a serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice. Additionally, persistent elevations in serum transaminases more than 3 times the ULN should prompt consideration of discontinuation. 2 2

From the Research

Statin Use and Liver Function Test Elevations

• Patients with transaminase levels no more than three times the upper limit of normal can continue taking statins, as the elevations will often resolve spontaneously 3, 4.
• Statins are associated with elevations in aminotransferases in up to 3% of treated patients, but they rarely lead to serious drug-induced liver injury (DILI), chronic liver disease, or acute liver failure 5.
• There is no specific level of liver function test (LFT) elevation at which statins should be stopped, but rather a consideration of the overall clinical context and the presence of other risk factors for liver disease.
• In patients with elevated LFTs, statins may be continued or initiated, as they may have a beneficial therapeutic effect in treating the underlying liver disease, such as nonalcoholic fatty liver disease (NAFLD) 5.

Monitoring and Management

• Liver function tests should be monitored before starting statin therapy, 12 weeks after initiation, with any dose increase, and periodically for long-term maintenance therapy 4.
• If LFT elevations are significant or persistent, the statin dose may be reduced or an alternative statin may be considered 3.
• Clinically important drugs that interact with statins and increase the risk of adverse effects, including liver toxicity, should be avoided or used with caution 3.