Can Keppra (levetiracetam) affect liver function in patients, particularly those with a history of liver disease?

Keppra (Levetiracetam) and Liver Function

Levetiracetam does not significantly affect liver function in most patients, including those with mild to moderate liver disease, because it undergoes minimal hepatic metabolism and is primarily eliminated unchanged by the kidneys. 1

Metabolism and Hepatic Safety Profile

• Levetiracetam is NOT dependent on liver cytochrome P450 enzymes for metabolism, with only 24% of the drug undergoing enzymatic hydrolysis of the acetamide group to form an inactive metabolite (ucb L057). 1
• 66% of the drug is excreted unchanged in the urine, making renal function—not hepatic function—the primary determinant of drug clearance. 1
• Less than 10% of levetiracetam is protein-bound, further reducing the risk of hepatic complications or drug interactions. 1

Use in Patients with Liver Disease

Mild to Moderate Hepatic Impairment (Child-Pugh A and B)

• No dose adjustment is necessary for patients with mild to moderate hepatic impairment, as pharmacokinetic studies demonstrate unchanged levetiracetam clearance in Child-Pugh class A and B cirrhosis. 1, 2
• Formal pharmacokinetic studies in patients with alcohol-induced cirrhosis showed that levetiracetam total clearance and half-life remained comparable to healthy controls in Child-Pugh A and B patients. 2

Severe Hepatic Impairment (Child-Pugh C)

• In severe hepatic impairment (Child-Pugh C), total body clearance is reduced by 50%, but this reduction is primarily due to decreased renal clearance that accompanies severe liver disease, not hepatic metabolism. 1, 2
• Patients with Child-Pugh C cirrhosis should initially receive half the commonly recommended dose due to the associated renal dysfunction. 2
• The area under the curve (AUC) increases 2.41-fold and half-life increases 2.27-fold in Child-Pugh C patients compared to controls. 2

Rare Cases of Drug-Induced Liver Injury (DILI)

Incidence and Clinical Presentation

• Levetiracetam-induced liver injury is extremely rare but has been documented in case reports and case series, ranging from asymptomatic transaminase elevation to fulminant liver failure requiring transplantation. 3, 4, 5
• The median time to onset of liver injury is 19 days (range 3-120 days) after initiating levetiracetam. 4
• 76.2% of reported cases present with fever, digestive symptoms, and skin rash, while 23.8% have only asymptomatic enzyme elevation. 4

Laboratory Findings

• Median alanine aminotransferase (ALT) levels reach 773 IU/L (range 60-4800) and aspartate aminotransferase (AST) levels reach 667.5 IU/L (range 53-10,387) in documented cases. 4
• Liver biopsy in affected patients demonstrates hepatocellular necrosis. 4
• Postmarketing surveillance has identified abnormal liver function tests, hepatic failure, hepatitis, and rare cases of fulminant liver failure. 1

Management of DILI

• Immediate discontinuation of levetiracetam is the first and most critical therapeutic measure when DILI is suspected. 3, 5
• Liver function typically returns to normal within a median of 9 days (range 2-270 days) after drug discontinuation. 4
• Immunosuppression with corticosteroids can be considered for serious cases of levetiracetam-induced liver injury. 5

Monitoring Recommendations

Routine Monitoring

• Routine liver function monitoring is not required for most patients taking levetiracetam, given the drug's minimal hepatic metabolism and excellent safety profile. 1

High-Risk Populations

• Patients receiving long-term levetiracetam therapy should consider periodic liver function monitoring, particularly if they develop symptoms suggestive of hepatotoxicity (fever, jaundice, right upper quadrant pain, nausea). 4, 5
• Monitoring serum transaminase values may be helpful in detecting early liver injury, especially during the first 3-5 months of therapy when DILI risk is highest. 4, 5

Common Pitfalls to Avoid

• Do not confuse levetiracetam with older antiepileptic drugs (such as phenytoin, carbamazepine, or valproate) that have significant hepatic metabolism and higher hepatotoxicity risk.
• Do not attribute reduced levetiracetam clearance in severe cirrhosis to hepatic dysfunction alone—the primary mechanism is impaired renal function that accompanies Child-Pugh C disease. 1, 2
• Do not overlook the possibility of DILI simply because levetiracetam has minimal hepatic metabolism—rare idiosyncratic reactions can still occur and may be life-threatening. 3, 5