Can Keppra (levetiracetam) cause hepatotoxicity?

Levetiracetam and Hepatotoxicity

Levetiracetam (Keppra) is generally considered to have minimal risk of hepatotoxicity compared to other antiepileptic drugs, as it undergoes minimal hepatic metabolism and is primarily excreted unchanged by the kidneys. 1

Pharmacokinetic Profile and Liver Metabolism

Levetiracetam has a favorable pharmacokinetic profile that makes it particularly suitable for patients with liver disease:

• Less than 10% is protein-bound in plasma
• Minimal hepatic metabolism (not processed through cytochrome P450 system)
• Approximately 66% is excreted unchanged in urine
• No clinically significant drug interactions with other medications through hepatic enzyme systems 1

Evidence of Hepatic Safety

The FDA drug label for levetiracetam specifically states:

• "There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients"
• "Lesser LFT abnormalities were similar in drug and placebo-treated patients in controlled trials (1.4%)"
• "No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment" 1

Rare Cases of Hepatotoxicity

Despite its generally favorable hepatic safety profile, there have been rare case reports of levetiracetam-associated liver injury:

• A 2021 review found that drug-induced liver injury (DILI) from levetiracetam can occur within days to up to five months after initiation of therapy 2
• A 2023 case report described drug-induced autoimmune hepatitis secondary to levetiracetam 3
• A 2006 case report described a patient on both carbamazepine and levetiracetam who developed fulminant hepatic failure, though the authors suggested carbamazepine was more likely responsible 4

Oxidative Stress Considerations

A 2019 study in epileptic children found that those treated with levetiracetam showed elevated levels of malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OHdG), suggesting potential oxidative damage. This was observed for the first time in childhood epilepsies, though the clinical significance remains unclear 5.

Recommendations for Clinical Practice

Based on the available evidence:

1. Levetiracetam is preferred over other antiepileptic drugs in patients with liver disease due to its minimal hepatic metabolism 6

2. Routine liver function monitoring is not mandated for patients on levetiracetam without pre-existing liver disease, as hepatotoxicity is rare 1

3. For patients with pre-existing liver disease:

   • Consider periodic liver function tests
   • No dosage adjustment is typically required for hepatic impairment alone
   • Monitor for signs of liver injury (jaundice, right upper quadrant pain, fatigue, nausea)

4. If signs of liver injury develop:

   • Discontinue levetiracetam as the first therapeutic measure
   • Consider immunosuppression with corticosteroids in severe cases 2

Comparison with Other Antiepileptic Drugs

Levetiracetam has a more favorable hepatic safety profile compared to many other antiepileptic drugs:

• Valproic acid has well-recognized hepatotoxicity (2% incidence) 7
• Phenytoin has known association with liver toxicity 6
• Carbamazepine can cause hepatotoxicity, particularly with long-term use 4

For patients with advanced liver disease requiring seizure control, levetiracetam is considered a first-line therapy along with other newer antiepileptic drugs with minimal hepatic metabolism (lacosamide, topiramate, gabapentin, and pregabalin) 6.