Statins - Induced Transaminitis

Introduction 

• The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated (transient) in the absence of proven hepatotoxicity and commonly occurs in the first 12 weeks of therapy.  
• This class effect is usually asymptomatic, reversible, and dose-related.
• 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.

Effects of Statins on The Liver

• Statins exert a potent inhibition of hepatic 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which accounts for the reduction in LDL cholesterol observed with these drugs.
• Although the underlying mechanism remains unclear, hepatotoxicity may result from changes in the lipid components of the hepatocyte membrane, leading to an increase in its permeability with a subsequent “leakage” of liver enzymes.
• This is supported by the observation that elevations in aminotransferase levels.

Incidence of Elevation of Liver Enzymes During Statin Treatment

• The incidence of elevated aminotransferase levels with different types of statins generally did not exceed 3% of the studied patients' sample. 
• There seems to be a direct relationship between the statin dose and the incidence of transaminitis. 
• The reported average incidence of elevations in serum aminotransferase levels to >3x ULN was < 1% in patients receiving low to moderate doses.
• Similarly, the incidence of transaminitis increases up to 2% to 3% in those receiving high doses of statins.
• The incidence of transaminase elevations is similar among all statins, despite their different pharmacokinetic characteristics
• Most cases of transaminitis exhibit spontaneous improvement without the need for drug discontinuation, probably a result of the development of adaptation or tolerance.

Management and Monitoring

Algorithm for Management of Abnormal Liver Enzymes Before and During Statin Treatment

Statins in Preexisting Liver Dysfunction

• US FDA continues to recommend that statins be contraindicated in patients with chronic liver disease; however, several authors have recommended starting low-dose statin treatment (because of the possible greater incidence of liver enzyme elevations with higher doses) and having levels rechecked 2 weeks later.
• LFT monitoring should be performed every month for the first 3 to 4 months and 4 times a year thereafter.
•   If the levels of transaminases increase to > 3X baseline values, discontinuation of the drug should be considered.
• Clinical correlation with worsening of underlying disease, as well as exclusion of alcohol abuse and drug interactions, should be done before attempting permanent discontinuation of the drug. 
• Once levels return to baseline, rechallenge can be considered. 

Conclusion

• The latest 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.”
• 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.
• Statin use need not be avoided in patients with preexisting liver dysfunction if its use is clearly indicated.
• However, as reported in literature, potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice

References 

1. Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD, and Eugene R. Schiff, MD. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clinic Proceedings 2010 Apr; 85(4): 349–356.
2. Jimmy Jose. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharm Bioallied Sci. 2016 Jan-Mar; 8(1): 23–28.
3. Edward Onusko MD. Statins and elevated liver tests: What’s the fuss?.J Fam Pract 2008 July;57(7):449-452.
4. US Food and Drug Administration (FDA) PhRMA/FDA/ASSLD drug induced hepatotoxicity white paper post marketing considerations: November 2000.
5. US Department of Health and Human Services. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Guidance for industry: drug-induced liver injury: premarketing clinical evaluation Published July 2009