Statins and elevated liver tests: What’s the fuss?
Even when liver function tests are moderately elevated, statins are safe for most patients
A retrospective review over a 5-year period of 23,000 patients receiving statins in a large health maintenance organization found that only 17 (0.1%) patients had severe elevations of ALT (defined as >10 times the ULN). Of those 17 patients, 13 cases were associated with drug-drug interactions, and all but 1 resolved with discontinuation of the statin.8
What to monitor, how often
Product labeling for all statins advises measurement of transaminases (AST as well as ALT), although some liver experts would recommend ALT alone. ALT is found primarily in the liver, while AST is also found in muscle (cardiac and skeletal), kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes. AST is, therefore, less specific for hepatic damage than ALT.
Routine monitoring of other liver function tests that measure the liver’s transport ability (eg, bilirubin, alkaline phosphate) or synthetic ability (eg, albumin, prothrombin time) will increase the likelihood of false-positive results and increase expense; they should not be done.
The 2002 American Gastroenterological Association guidelines recommend that for any hepatotoxic drug, if the ALT and/or AST elevations are <5 times the ULN, the drug should be stopped and the enzymes rechecked after an appropriate interval before pursuing a more extensive evaluation for liver disease.9
The FDA labeling information for all statins recommends liver function testing before putting a patient on a statin, 12 weeks after initiation, at any dose increase, and “periodically” for long-term maintenance therapy (TABLE 1).10 These recommendations are based on expert opinion only, because most data suggest that significant liver damage from statins is very rare and that routine monitoring of liver enzymes is not necessary.
The ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins agrees with the FDA, although it specifies “periodically” to mean annually.11
TABLE 1
When to monitor liver function in patients taking statins10,11
| WHEN TO CHECK ALT/AST | WHAT TO DO |
|---|---|
| Initiation of treatment or increase in dose | Begin/increase dose of statin if ALT and AST are <3 times the ULN |
| 12 weeks after initiation of statin therapy | Discontinue the statin (or lower the dose) if ALT or AST are >3 times the ULN |
| Long-term (annually or “periodically”) | |
| ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. | |
It’s difficult to predict hepatic effects
Individual statins vary as to potency, efficacy, metabolism, and drug interactions. However, the exact mechanism of how statins cause elevations of ALT and AST is unknown, making it difficult to predict the hepatic effects of an individual statin based on its characteristics.
One analysis of multiple clinical trials concluded that overall statin toxicity (muscle, liver, etc.) was not directly related to the degree of lowering LDL cholesterol; instead, it correlated with the dose of the statin.12 As seen in TABLE 2, statins have variable drug-drug interactions based on their metabolism by the cytochrome P450 system. Drugs that increase the level of a statin in the blood may potentially increase the risk for toxicity and may warrant more cautious monitoring of liver enzymes, but are not necessarily contraindications to statin therapy.
Cyclosporine, macrolide antibiotics, azole antifungal agents, and other cytochrome P450 inhibitors (TABLE 2) are among the relative contraindications to the use of statins, more for concerns about myopathy than hepatoxicity.1 If these medications are used with a statin, consider more frequent monitoring of transaminases.
TABLE 2
Statin snapshot: LDL reductions to expect, interactions to avoid
| LOVASTATIN (MEVACOR, GENERICS) | PRAVASTATIN (PRAVACHOL, GENERICS) | SIMVASTATIN (ZOCOR, GENERICS) | FLUVASTATIN (LESCOL, GENERICS) | ATORVASTATIN (LIPITOR) | ROSUVASTATIN (CRESTOR) | |
|---|---|---|---|---|---|---|
| Usual daily dose | 20 to 80 mg | 40 to 80 mg | 10 to 80 mg | 20 to 80 mg | 10 to 80 mg | 10 to 40 mg |
| LDL reduction | 27% to 42% | 34% to 37% | 30% to 47% | 22% to 35% | 39% to 60% | 52% to 63% |
| % protein binding | >95% | 50% | 95% | 98% | >98% | 88% |
| Cytochrome P450 metabolism | 3A4* | None | 3A4* | 2C9 (75%)† 2C8 (5%) 3A4 (20%) | 3A4* | Limited 2C9 (10%) |
| * Drugs that may significantly increase statin levels via competitive metabolism or inhibition of CYP3A4 enzymes include macrolide antibiotics, HIV protease inhibitors, azole antifungal agents, calcium channel blockers, fluoxetine, cimetidine, cyclosporine, and omeprazole. Grapefruit juice may also have this effect. | ||||||
| † Drugs that may significantly increase statin levels via interference with CYP2C9 enzymes include phenytoin, glyburide, cimetidine, omeprazole, diclofenac, and cyclosporine. | ||||||
| Source: Physicians’ Desk Reference. 2008. 62nd ed. Montvale, NJ: Thomson PDR; 2008. | ||||||
Discontinue the statin?
ACC/AHA/NHLBI recommendations indicate that you should discontinue (or lower the dose of) statin therapy if the ALT or AST are above 3 times the ULN on 2 consecutive occasions.11 When elevations of ALT or AST are <3 times the ULN, consider the following:
