Hepatotoxicity Associated with Anti-Epileptic

Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug

PHENYTOIN

• most common causes of clinically apparent drug induced liver disease and acute liver failure.
• The typical case arises after 2 to 8 weeks of therapy with initial onset of fever, rash, facial edema and lymphadenopathy, followed in a few days by jaundice and dark urine
• In most cases due to hypersensitivity reaction

CARBAMAZEPINE

• Carbamazepine hepatotoxicity occurs in the setting of anticonvulsant hypersensitivity syndrome in about half of cases with onset of fever, followed by rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia or atypical lymphocytosis, 1 to 8 weeks after starting therapy
• In most cases due to hypersensitivity reaction

VALPROATE

• Valproate has been rarely associated with anticonvulsant hypersensitivity syndrome and generally is a safe alternative
•  5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug
• Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate – hyperammonemia, acute hepatocellular injury with jaundice and Reye-like syndrome.
• Young age (<2 years), presence of other neurological conditions and concurrent use of other anticonvulsants appear to be important risk factors for acute liver failure due to valproate

LAMOTRIGNINE

• less than 1% of subjects develop elevations in serum aminotransferase levels
•  typically short, ranging from one to several weeks.  Presenting symptoms are a diffuse maculopapular rash, followed in a few days by high fever, nausea and vomiting.  The rash can develop into a systemic hypersensitivity reaction and multiorgan failure or be associated with jaundice and hepatitis

LEVETIRACETAM

• rare instances of serum enzyme elevations and occasional cases of clinically apparent liver injury
• time to onset of liver injury after starting levetiracetam has ranged from 1week to 5 months and the usual pattern of injury has been hepatocellular
• Immunoallergic features and autoantibodies were rare

CLONAZEPAM, DIAZEPAM

• rarely associated with serum ALT elevations, and clinically apparent liver injury from clonazepam is extremely rare.

PHENOBARBITONE

• Clinically apparent hepatotoxicity from phenobarbital is rare but can be abrupt in onset, severe and even fatal
• typically occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia occurring 1 week to several months after starting therapy

 REFERENCES

1.    http://livertox.nih.gov/AnticonvulsantDrugs.htm
2.    www.uptodate.com
3.    http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.2008.01009.x/abstract
4.    http://www.seizure-journal.com/article/S1059-1311(06)00002-1/pdf