Can Donepezil Increase ALT?
Donepezil does not cause clinically significant elevations in ALT or other liver function tests in elderly patients with Alzheimer disease who have no pre-existing liver disease. 1
Evidence from Clinical Trials and Systematic Reviews
High-quality systematic reviews of randomized controlled trials in Alzheimer's disease patients found no clinically significant changes in laboratory parameters, including liver function tests, with donepezil treatment. 1
The Annals of Internal Medicine systematic review (2008) reported that donepezil was well-tolerated with adverse events primarily limited to cholinergic effects (gastrointestinal symptoms), not hepatotoxicity. 2
A pilot safety study evaluating donepezil at doses up to 20 mg/day (double the standard maximum dose) found no clinically significant changes in clinical laboratory tests, including liver enzymes. 3
Long-Term Safety Data
A 6-year longitudinal study specifically examining hepatic function in Alzheimer's patients treated with donepezil found that AST and ALT levels remained within normal reference intervals throughout the entire treatment period. 4
In this long-term study, although AST and ALT levels showed statistically significant increases compared to pretreatment baseline after 2 years of therapy, they stayed below the upper limit of normal and did not progress further at 4-year and 6-year follow-ups. 4
The increases observed were not clinically meaningful and did not require dose adjustment or discontinuation. 4
Contrast with Other Cholinesterase Inhibitors
Tacrine, an older cholinesterase inhibitor, causes hepatotoxicity in approximately 40% of patients and requires biweekly liver function monitoring, which is why it is no longer recommended as a first-line agent. 5
Donepezil was specifically developed to overcome the hepatotoxic disadvantages of tacrine and has a fundamentally different safety profile. 1
No routine laboratory monitoring of liver function is necessary with donepezil, unlike tacrine. 5
Clinical Implications
Elderly patients with Alzheimer disease and normal baseline liver function can safely initiate donepezil without concern for hepatotoxicity. 1
Routine monitoring of ALT or other liver enzymes is not indicated during donepezil therapy in patients without pre-existing liver disease. 5, 1
Donepezil can be safely administered to patients with mild-to-moderate hepatic impairment without dose modification. 6
Important Caveat
- While donepezil does not cause hepatotoxicity, galantamine (another cholinesterase inhibitor) is contraindicated in patients with hepatic impairment. 5 This distinction is important when selecting among cholinesterase inhibitors for patients with any degree of liver dysfunction.