Primary Evaluation and Management of Statin Therapy Complications

Dean A. Seehusen, MD, MPH, FAAFP; Chad A. Asplund, MD; Dawn R. Johnson, DO; Kevin Horde, A. DO


South Med J. 2006;99(3):250-254. 

In This Article

Monitoring Transaminases

Early clinical trials on lovastatin showed frequent elevations of transaminases. High dose lovastatin has previously been shown to cause hepatitic necrosis in laboratory animals.[19] Because of concerns regarding the risk of hepatitis in humans, the Food and Drug Administration and drug manufacturers have recommended screening transaminase values before starting, at 12 weeks following initiation of therapy, at any elevation in dose, and periodically thereafter. Most physicians follow these recommendations.[15,17] In the Scandinavian Simvastatin Survival Study (S4),[10] minor elevations of ALT were almost always greater than AST and were unrelated to alkaline phosphatase or bilirubin. Therefore, some authors have recommended that monitoring ALT is all that is required for documenting possible hepatotoxicity because of the relative nonspecificity of AST levels, which can occur with either muscle or liver injury.[31]

No data to date has shown that elevated liver enzymes are predictive of liver injury or acute hepatocellular reactions with statin therapy, thus questioning the necessity of routine monitoring.[32] The presentation of early symptoms consistent with toxic effects, such as pruritus or jaundice, may be the best way to prompt further laboratory testing. In a retrospective review of over 1,000 patients, Smith et al found that routine monitoring of transaminases revealed no significantly or moderately abnormal values attributable to statins.[17] In a meta-analysis of 3 major trials of pravastatin, assessing over 112,000 person-years of exposure, only 1.4% showed significant transaminase elevations, which was the same as placebo.[7] A separate large meta-analysis, involving almost 50,000 patients from 13 clinical trials, showed that statins at low to moderate doses are not associated with a risk of significant liver abnormalities.[33]

Even in patients with elevated baseline transaminases, there is little objective evidence that statins increase the risk of significant elevations. In the Prospective Pravastatin Pooling Project, 5% of patients with baseline transaminase elevations of 1.5 to 3 times the upper limit of normal went on to have elevations of greater than 3 times the upper limit of normal. In comparison, 7.3% of similar patients on placebo developed similar elevations.[7] In a study by Chalasani, patients with a history of elevated baseline liver enzymes had a higher incidence of mild-moderate but not severe elevations in liver biochemistries. The frequency of mild-moderate or severe elevations in patients with existing elevated transaminases was not significantly different from those not prescribed a statin. This suggests that individuals with elevated baseline liver enzymes are not at higher risk for hepatotoxicity from statins.[34] Although there is no strong evidence, two areas where more frequent monitoring may be warranted are in the presence of pre-existing liver disease and in patients on multiple medications for which hepatitis is a known side effect.[35]