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Antiepileptic Drugs and Liver Disease

      Abstract

      Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease. Choosing the most appropriate antiepileptic drug in this setting represents a difficult challenge, as most medications are metabolized by the liver. This article focuses on the acute and chronic treatment of seizures in patients with advanced liver disease and reviews the hepatotoxic potential of specific antiepileptic drugs. Newer antiepileptic drugs without, or with minimal, hepatic metabolism, such as levetiracetam, lacosamide, topiramate, gabapentin, and pregabalin should be used as first-line therapy. Medications undergoing extensive hepatic metabolism, such as valproic acid, phenytoin, and felbamate should be used as drugs of last resort. In special circumstances, as in patients affected by acute intermittent porphyria, exposure to most antiepileptic drugs could precipitate attacks. In this clinical scenario, bromides, levetiracetam, gabapentin, and vigabatrin constitute safe choices. For the treatment of status epilepticus, levetiracetam and lacosamide, available in intravenous preparations, are good second-line therapies after benzodiazepines fail to control seizures. Hepatotoxicity is also a rare and unexpected side effect of some antiepileptic drugs. Drugs such as valproic acid, phenytoin, and felbamate, have a well-recognized association with liver toxicity. Other antiepileptic drugs, including phenobarbital, benzodiazepines, ethosuximide, and the newer generations of antiepileptic drugs, have only rarely been linked to hepatotoxicity. Thus physicians should be mindful of the pharmacokinetic profile and the hepatotoxic potential of the different antiepileptic drugs available to treat patients affected by liver disease.

      Keywords

      Introduction

      Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease. Initiating antiepileptic therapy in this setting represents a difficult challenge because most medications are metabolized by the liver. Severe liver disease also affects the binding capacity of antiepileptic drugs (AEDs) to serum proteins, increasing the risk of toxicity. Therefore, choosing the most appropriate AED in this vulnerable population is extremely important.
      Newer AEDs undergo minimal or no hepatic metabolism and constitute excellent therapeutic choices. These medications have less potential for drug-to-drug interaction and lower protein-binding capacity. Some are available in intravenous (IV) formulations and can be used in emergency situations. It is important for physicians to be familiar with these therapeutic choices and to understand the pharmacodynamics and pharmacokinetics of these drugs. This article focuses on the acute and chronic treatment of seizures in patients with advance liver disease. The hepatotoxic potential of different AEDs and special conditions that may require more specific treatment, such as porphyria and Wilson disease, is also reviewed.

      Emergency treatment of seizures in patients with liver disease

      Patients affected by hepatic disease are at risk of recurrent seizures or status epilepticus. There are no standardized guidelines to assist physicians in this situation.
      Multiple randomized control studies support the use of benzodiazepines as a first-line treatment for status epilepticus in general.
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      Monotherapy or polytherapy for first-line treatment of SE?.
      The Rapid Anticonvulsant Medication Prior to Arrival Trial study showed a trend in favor of intramuscular midazolam versus IV lorazepam for initial seizure control (73.4% versus 63.4%),
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      • et al.
      Intramuscular versus intravenous therapy for prehospital status epilepticus.
      likely reflecting the speed of administration rather than the efficacy of the drug. Benzodiazepines are metabolized predominantly in the liver, and hepatic disease can alter their metabolism. Midazolam is metabolized by the cytochrome P450 system, and its clearance can be affected by hepatic dysfunction. Lorazepam metabolism is minimally affected by liver disease
      • Greenblatt D.J.
      Clinical pharmacokinetics of oxazepam and lorazepam.
      and drug interactions are less likely, making it a good choice for first-line therapy (Table 1). Benzodiazepines could potentially exacerbate associated encephalopathy,
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      Antiepileptic treatment in patients with epilepsy and other comorbidities.
      but liver injury is not a major concern.
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      • Siddiqi Z.A.
      Antiepileptic drugs and liver disease.
      The choice of benzodiazepine should be based on the availability of the drug and the presence or the absence of an IV access (Fig).
      Table 1Parenteral Benzodiazepines Used in Acute Treatment
      MedicationMetabolismHalf-Life in Healthy SubjectsOnset of ActionDuration of Action
      Diazepam has high lipid solubility, rapidly reaching the brain. However, it redistributes to peripheral tissues in 15-20 minutes, diminishing its anticonvulsant properties.
      Diazepam
      HepaticParent compound: 33-45 hours;

      Active metabolite—desmethyldiazepam: ~87 hours
      1-3 minutes15-30 minutes
      LorazepamHepaticApproximately 14 to 17.8 hoursWithin 10 minutes6-8 hours
      MidazolamHepatic1.8-6.4 hours (mean ~3 hours)3-5 minutes<2 hours
      * Diazepam has high lipid solubility, rapidly reaching the brain. However, it redistributes to peripheral tissues in 15-20 minutes, diminishing its anticonvulsant properties.
      Figure
      FigureProposed drug treatment algorithm of status epilepticus in patients with liver disease.
      If benzodiazepines fail to control seizures, second-line agents are necessary. Commonly used drugs for the treatment of status epilepticus are valproic acid, phenytoin or fosphenytoin, and phenobarbital. Nevertheless, these are not ideal choices for patients with hepatic disease.
      Valproic acid is mainly eliminated through the liver. Patients with hepatic disease could potentially shift its metabolism to alternate pathways with the production of hepatotoxic metabolites.
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      Antiepileptic treatment in patients with epilepsy and other comorbidities.
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      Valproic acid toxicity: overview and management.
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      Valproic acid hepatic fatalities. II. US experience since 1984.
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      Effect of valproic acid on hepatic function.
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      Phenytoin has nonlinear kinetics and, in the presence of hypoalbuminemia, it is easy to reach toxic levels.
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      Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite.
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      Role of cytochrome P450-mediated metabolism and identification of novel thiol-conjugated metabolites in mice with phenytoin-induced liver injury.
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      Hepatotoxicity associated with antiepileptic drugs.
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      Plasma activities of hepatic enzymes in patients on anticonvulsant therapy.
      Phenobarbital is primarily metabolized in the liver and has a prolonged half-life of up to 126 hours,
      • Ahmed S.N.
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      Antiepileptic drugs and liver disease.
      which can be longer in the setting of liver disease. The long half life could potentially complicate encephalopathy in susceptible patients.
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      • et al.
      Lacosamide as add-on treatment of focal symptomatic epilepsy in a patient with alcoholic liver cirrhosis.
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      The effect of liver disease in man on the disposition of phenobarbital.
      Newer AEDs such as levetiracetam and lacosamide constitute a more appropriate choice in this group of patients. Both medications are available in IV formulations and have less chances of exacerbating the hepatic injury. These drugs also have low or no binding to serum proteins
      • Alvarez V.
      • Rossetti A.O.
      Monotherapy or polytherapy for first-line treatment of SE?.
      with fewer chances of drug-to-drug interactions, minimizing the risk of toxicity.
      Levetiracetam has shown efficacy in the treatment of status epilepticus.
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      • Maurya P.K.
      Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study.
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      Levetiracetam for the treatment of status epilepticus.
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      • et al.
      Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam—pilot study.
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      The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.
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      • Freeman W.D.
      Safety and efficacy of levetiracetam for critically ill patients with seizures.
      • Shin H.W.
      • Davis R.
      Review of levetiracetam as a first line treatment in status epilepticus in the adult patients—what do we know so far?.
      Its lack of major side effects, such as hypotension or cardiac arrhythmias, makes it an ideal choice for critically ill patients.
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      • Divertie G.D.
      • Valentino A.K.
      • Freeman W.D.
      Safety and efficacy of levetiracetam for critically ill patients with seizures.
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      • Davis R.
      Review of levetiracetam as a first line treatment in status epilepticus in the adult patients—what do we know so far?.
      • Lyseng-Williamson K.A.
      Spotlight on levetiracetam in epilepsy.
      Lacosamide, a newer AED with a favorable pharmacokinetic profile, has also shown efficacy in controlling status epilepticus and constitutes a good alternative.
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      • et al.
      Intravenous lacosamide in refractory seizure clusters and status epilepticus: comparison of 200 and 400 mg loading doses.
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      • et al.
      Lacosamide in children with refractory status epilepticus. A multicenter Italian experience.
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      • Trinka E.
      Intravenous lacosamide in status epilepticus and seizure clusters.
      If these drugs are not available or fail to control seizures, older AEDs can be used, but close monitoring of drug levels is necessary. Phenobarbital can be an acceptable alternative, especially if the risk of sedation is not a concern.

      Long-term AED therapy in patients with hepatic disease

      Patients with liver disease may require long-term AED treatment. The selection of AEDs in these individuals deserves careful consideration. Drug metabolism depends on the integrity of the hepatocyte, the blood flow, and the patency of the hepatobiliary system.
      • Ahmed S.N.
      • Siddiqi Z.A.
      Antiepileptic drugs and liver disease.
      Because of the large hepatic reserve, the liver dysfunction must be severe to cause substantial alterations in drug metabolism.
      • Asconape J.J.
      • Penry J.K.
      Use of antiepileptic drugs in the presence of liver and kidney diseases: a review.
      Mild to moderate liver disease may need very minor dose adjustments, if any at all. Most AEDS are classified as “low extraction drugs,” because they have an extraction rate of less than 30% during the first passage through the liver. In clinical practice, treatment can be started at regular doses, but lower maintenance doses may be required.
      • Delco F.
      • Tchambaz L.
      • Schlienger R.
      • Drewe J.
      • Krahenbuhl S.
      Dose adjustment in patients with liver disease.
      Chronic management of seizures in patients with liver disease may difficult. Accurate calculation of drug adjustments may be impossible because there is no endogenous marker to calculate hepatic clearance. Comorbidities such as renal failure and gastrointestinal dysmotility may also affect the clearance or the absorption of these drugs, resulting in toxicity or failure to control seizures.
      • Borges de Lacerda G.C.
      Treating seizures in renal and hepatic failure.
      Individual assessment of the severity of liver involvement is important, and consultation with a gastrointestinal specialist or a hepatologist may be needed.
      The newer generation of AEDs offers a more favorable pharmacokinetic profile than older anticonvulsants and constitutes a better option for long-term treatment. In general, medications with minimal or no hepatic metabolism should be the first-line therapy, and drugs undergoing extensive hepatic metabolism should be avoided to the extent possible. We provide a choice of different therapeutic options. Drugs are classified from more to less suitable therapy based on individual pharmacologic characteristics and the likelihood of toxicity (Table 2).
      Table 2Pharmacologic Characteristics of Antiepileptic Drugs and Recommendations for Their Use in Patients With Hepatic Disease
      MedicationMetabolismHalf-LifeProtein BindingPotential for Drug Interactions
      Drugs with high protein-binding capacity and potential to inhibit or induce hepatic enzymes have high chances for drug-to-drug interactions.
      Recommended Monitoring in Patients With Liver Disease
      Drug level is recommended for antiepileptic drugs with a high chance of drug-to-drug interactions or toxicity, especially in patients undergoing polytherapy.
      Association With Hepatotoxicity
      Hepatotoxicity is a potential but rare side effect of antiepileptic drugs.
      Recommended Dose Changes: Mild to Moderate Hepatic DiseaseRecommended Dose Changes: Severe Hepatic Disease
      BrivaracetamHepatic (20%)~9 hours≤20%MinimalClinicalNo known associationManufacturer recommendation for patients ≥16 years of age: Child-Pugh A and B: initial: 25 mg twice daily, up to a maximum of 75 mg twice dailyManufacturer recommendation for patients ≥16 years of age: Child-Pugh C: initial: 25 mg twice daily, up to a maximum of 75 mg twice daily
      CarbamazepineHepaticChildren: 8-14 hours

      Adults: 12-17 hours
      75%-90%HighDrug levelWell establishedNSRNSR
      EslicarbazepineHepatic13-20 hours<40%MinimalClinical or consider drug levelLowNSRNSR
      EthosuximideHepaticChildren: ~30 hours

      Adults: 50-60 hours
      InsignificantIntermediateClinical or consider drug levelLowNSRNSR
      FelbamateHepatic20-23 hours22%-25%HighDrug levelWell establishedContraindicated by manufacturer recommendationContraindicated by manufacturer recommendation
      GabapentinNoneChildren: ~4.7 hours

      Adults: 5-7 hours
      <3%MinimalClinicalLowNSRNSR
      LacosamideHepatic (~60%)~13 hours<15%MinimalClinical or consider drug levelLowManufacturer recommendation for adults: maximum daily dose of 300 mg/day
      Concentration of lacosamide can increase by 50%-60% in patients with a moderate liver dysfunction.
      NSR
      LamotrigineMainly hepaticChildren: ~19 hours

      Adults: 25-33 hours
      ~55%HighDrug levelLowManufacturer recommendation:

      Mild: none

      Moderate without ascites: reduce initial, escalation, and maintenance doses by ~25%; adjust based on clinical response.

      Moderate impairment with ascites: reduce initial, escalation, and maintenance doses by ~50%; adjust based on clinical response.
      Manufacturer recommendation:

      Severe without ascites: reduce initial, escalation, and maintenance doses by ~25%; adjust based on clinical response.

      Severe impairment with ascites: reduce initial, escalation, and maintenance doses by ~50%; adjust based on clinical response.
      LevetiracetamPrimarily enzymatic hydrolysis in the bloodChildren: ~5.3-6 hours

      Adults: 6-8 hours
      <10%MinimalClinicalLowNoneDecrease dose by half
      OxcarbazepineHepaticActive metabolite: children: 4.8-9.3 hours

      Adults: ~9 hours
      Parent drug: 67% Active metabolite: 40%IntermediateClinical or consider drug levelLowNoneNSR
      PerampanelHepatic~105 hours95%-96%HighDrug levelNo known associationManufacturer recommendation:

      Child-Pugh class A: maximum daily dose: 6 mg/day

      Child-Pugh class B: maximum daily dose: 4 mg/day
      Manufacturer recommendation: Child-Pugh class C: NSR
      PhenobarbitalHepaticChildren: ~110 hours (60-180)

      Adults: ~ 79 hours (53-118)
      50%-60%HighDrug levelLowNSRNSR
      PhenytoinHepatic7-42 hours

      Half-life increases with increasing phenytoin concentrations
      ≥85%HighDrug levelWell establishedNSRNSR
      PregabalinNegligible metabolism~6.3 hours0%MinimalClinicalLowNSRNSR
      TiagabineHepaticChildren: ~5.7 hours (2-10)

      Adults: 7-9 hours
      96%HighClinical or consider drug levelNo known associationNSRNSR
      TopiramateHepatic (20%)Children: 7.7-12.8 hours

      Adults: 19-23 hours
      15%-41%
      Protein-binding capacity inversely related to plasma levels.
      MinimalClinicalLowNSRDecrease by 30%
      Valproic acidHepaticChildren: 7-13 hours

      Adults: 9-19 hours
      80%-90%HighDrug levelWell establishedNot recommended by manufacturerContraindicated by manufacturer
      VigabatrinNo significant metabolismChildren: 5.7-9.5 hours

      Adults: ~10.5 hours
      0%MinimalClinicalLowNSRNSR
      ZonisamideHepatic (70%)~69 hours40%Minimal or intermediateClinical or consider drug levelLowNSRNSR
      Abbreviation:
      NSR = No specific recommendation
      * Drug level is recommended for antiepileptic drugs with a high chance of drug-to-drug interactions or toxicity, especially in patients undergoing polytherapy.
      Protein-binding capacity inversely related to plasma levels.
      Drugs with high protein-binding capacity and potential to inhibit or induce hepatic enzymes have high chances for drug-to-drug interactions.
      § Hepatotoxicity is a potential but rare side effect of antiepileptic drugs.
      Concentration of lacosamide can increase by 50%-60% in patients with a moderate liver dysfunction.

      First-line therapy

      Levetiracetam, a broad-spectrum AED, is an ideal first-line therapy for patients with liver disease.
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      • Chuang Y.C.
      Levetiracetam in the treatment of epileptic seizures after liver transplantation.
      Sixty-six percent of the drug is excreted unchanged by the kidney, 24% undergoes enzymatic hydrolysis, and less than 2% is metabolized by hepatic enzymes.
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      • Thomsen T.
      • Wittstock M.
      • Coupez R.
      • Lochs H.
      • Roots I.
      Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests.
      Levetiracetam has a wide safety window with no major pharmacokinetic interactions. The dose needs no changes in mild to moderate liver failure, but should be decreased by half in patients with severe disease and Child-Pugh class C (Table 3).
      • Brockmoller J.
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      • Wittstock M.
      • Coupez R.
      • Lochs H.
      • Roots I.
      Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests.
      Levetiracetam can effectively be utilized in patients on venovenous hemofiltration.
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      Table 3Child-Pugh Class Score Data
      Measurement1 Point2 Points3 Points
      Bilirubin (total) (mg/dL)<22-3>3
      Serum albumin (g/L)>3528-35<28
      International normalized ratio<1.71.71-2.20>2.20
      AscitesNoneMildSevere
      Hepatic encephalopathyNoneGrades I and II (or suppressed with medication)Grades III and IV (or refractory)
      Interpretation
      PointsClass1-Year Survival (%)2-Year Survival (%)
      5-6A10085
      7-9B8157
      10-15C4535
      Derived from Trey et al., 1966,
      • Trey C.
      • Burns D.G.
      • Saunders S.J.
      Treatment of hepatic coma by exchange blood transfusion.
      with reproduction permission from Wiley Global Permissions.
      Lacosamide is metabolized by the CYP450, 2C19 system but has no major drug interactions and the metabolites are inactive. The protein-binding capacity of lacosamide is less than 15%, and 40% of the drug is eliminated unchanged in the urine. Because of its linear pharmacokinetics, lacosamide constitutes a safe choice.
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      • Liguori C.
      • et al.
      Lacosamide as add-on treatment of focal symptomatic epilepsy in a patient with alcoholic liver cirrhosis.
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      Use of antiepileptic drugs in hepatic and renal disease.
      Topiramate is predominantly excreted by the kidneys as an unmetabolized drug. Only 20% of the dose is biotransformed by the liver. Topiramate is a potent anticonvulsant with a relatively low potential for drug interactions, making it a reasonable choice for patients on multiple medications. In severe liver disease, doses may need to be reduced by 30%.
      • Brockmoller J.
      • Thomsen T.
      • Wittstock M.
      • Coupez R.
      • Lochs H.
      • Roots I.
      Pharmacokinetics of levetiracetam in patients with moderate to severe liver cirrhosis (Child-Pugh classes A, B, and C): characterization by dynamic liver function tests.
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      Pharmacokinetic profile of levetiracetam: toward ideal characteristics.
      Gabapentin is mostly used for neuropathic pain, headaches, and sleep disorders. Nevertheless, because of gabapentin's favorable pharmacokinetic profile, it represents good alternative in individuals with hepatic failure. Gabapentin is excreted unchanged in the urine and does not bind to serum proteins, minimizing the possibilities of drug-to-drug interactions.
      • Calandre E.P.
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      Pharmacokinetics and metabolism of gabapentin in rat, dog and man.
      Pregabalin, similar to gabapentin, does not bind to plasma proteins and is excreted by the kidneys. In clinical practice, pregabalin is used mainly for the treatment of neuropathic pain, but because of its benign pharmacokinetics, it is a reasonable alternative in the treatment of seizures in individuals with hepatic disease.
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      • Burger P.
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      Second-line therapy

      Vigabatrin is excreted unchanged by the kidneys without undergoing hepatic metabolism and is not protein bound, so drug-to-drug interactions are not common. Monitoring levels is unnecessary. Vigabatrin irreversibly affects gamma aminobutyric acid transaminase and the duration of the pharmacologic effect is independent of its serum concentration.
      • Schechter P.J.
      Clinical pharmacology of vigabatrin.
      Vigabatrin is a very good choice for patients with hepatic disease, but because of concerns of peripheral vision loss and reversible magnetic resonance imaging abnormalities,
      • Westall C.A.
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      Vigabatrin-induced CNS changes in juvenile rats: induction, progression and recovery of myelin-related changes.
      it can be considered a second-tier drug.
      Oxcarbazepine may offer an advantage over carbamazepine in individuals with liver disease. Its main metabolite is a monohydroxilated derivative that is eliminated mainly by glucuronidation.
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      • Flesch G.
      • Dieterle W.
      Clinical pharmacology and pharmacokinetics of oxcarbazepine.
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      • Reinikainen K.J.
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      • Riekkinen P.J.
      Comparison of oxcarbazepine and carbamazepine: a double-blind study.
      Oxcarbazepine is a weaker enzyme inducer with linear pharmacokinetics and less potential for drug interaction. Oxcarbazepine also has a lower risk of hypersensitivity reactions than carbamazepine.
      Eslicarbazepine, a third-generation member of the dibenzazepines, is similar to carbamazepine and oxcarbazepine but appears to have a more favorable profile than its predecessors. Eslicarbazepine is rapidly and extensively metabolized in the liver but has minimal interactions with cytochrome p450, minimizing the risk of drug-to-drug interactions.
      • Shorvon S.D.
      • Trinka E.
      • Steinhoff B.J.
      • et al.
      Eslicarbazepine acetate: its effectiveness as adjunctive therapy in clinical trials and open studies.
      • Almeida L.
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      • Mota F.
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      Pharmacokinetics of eslicarbazepine acetate in patients with moderate hepatic impairment.
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      • Bialer M.
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      Pharmacokinetics and drug interactions of eslicarbazepine acetate.
      Zonisamide, a broad-spectrum AED, has no significant hepatotoxicity. About 70% of the drug is cleared by the liver and 35% is excreted unchanged by the kidneys. The metabolism is through cytochrome P450 without production of active metabolites. Zonisamide has linear pharmacokinetics and only 40% of the drug is protein bound, minimizing the risk of drug interactions. Despite the favorable pharmacokinetic profile, the half-life can be up to 69 hours, so close monitoring is recommended.
      • Ahmed S.N.
      • Siddiqi Z.A.
      Antiepileptic drugs and liver disease.
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      Zonisamide—a review of experience and use in partial seizures.
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      • Nair A.B.
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      Third-line therapy

      Carbamazepine, an older-generation sodium channel blocker, is mainly metabolized by the liver. Carbamazepine undergoes autoinduction and may produce transient elevation of hepatic enzymes. Because of its enzyme-inducing properties, the likelihood of drug-to-drug interactions is higher than that of the newer-generation sodium channel blockers.
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      Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine.
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      Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide. An update.
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      Induction of endogenous pathways by antiepileptics and clinical implications.
      Perampanel, a recently approved glutamate receptor antagonist, undergoes extensive hepatic metabolism by CYP3A4, but it appears to have a minimal effect on liver function. The half-life is prolonged in patients with mild to moderate liver disease, so slow titration is recommended.
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      The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist.
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      • Zhou S.
      • Ferry J.
      Absence of liver toxicity in perampanel-treated subjects: pooled results from partial seizure phase III perampanel clinical studies.
      Lamotrigine is primarily metabolized to the inactive N-2 nitrogen glucuronide metabolite by the enzyme uridine diphosphate glucuronyl transferase and should be used with caution in moderate to severe liver disease. Recommendations are to reduce the dose by 25% in moderate to severe liver disease without ascites and by 50% in patients with severe hepatic disease and ascites.
      • Delco F.
      • Tchambaz L.
      • Schlienger R.
      • Drewe J.
      • Krahenbuhl S.
      Dose adjustment in patients with liver disease.
      • Hurley S.C.
      Lamotrigine update and its use in mood disorders.

      AEDs of last resort

      Valproic acid is not recommended in individuals with liver dysfunction and should be avoided to the extent possible. Although the evidence is not strong, valproic acid could potentially exacerbate hepatic disease.
      • Ahmed S.N.
      • Siddiqi Z.A.
      Antiepileptic drugs and liver disease.
      Its binding to serum proteins is 90% and the unbound fraction increases with chronic liver disease. This could lead to toxicity and increase the chances of drug-to-drug interactions.
      Phenytoin is metabolized by the cytochrome P450 and has been associated with hepatotoxicity. Phenytoin has nonlinear pharmacokinetics and frequent monitoring of blood levels is necessary to avoid toxicity.
      • Dreifuss F.E.
      • Langer D.H.
      Hepatic considerations in the use of antiepileptic drugs.
      This is a special concern for patients with hypoalbuminemia.
      Phenobarbital is metabolized by the liver, mostly by CTP2C9. It has a prolonged half-life and could exacerbate a pre-existing encephalopathy.
      • Pacifici G.M.
      Clinical pharmacology of phenobarbital in neonates: effects, metabolism and pharmacokinetics.
      Phenobarbital also has the potential for drug-to-drug interactions. On the other hand, phenobarbital is a cheap medication, available worldwide and has rarely been linked to hepatotoxicity. These characteristics could make it a reasonable choice when newer AEDs are not available.
      Felbamate is used mainly in specialized centers for the treatment of patients with Lennox-Gastaut-Doose syndrome or refractory seizures.
      • Burdette D.E.
      • Sackellares J.C.
      Felbamate pharmacology and use in epilepsy.
      Felbamate is an enzyme inhibitor and is metabolized by enzymes of the P450 system. Felbamate has potential for liver toxicity and significant drug interactions.

      Others

      Tiagabine is not a widely used medication. There is no clear association with hepatotoxicity, but it is metabolized by the liver by the cytochrome P450 system and should not be a first-line drug.
      • Brodie M.J.
      Tiagabine pharmacology in profile.
      Ethosuximide is the drug of choice for absence seizures and can be used for specific epilepsy syndromes. About 80% of the drug undergoes hepatic metabolism and 20% is excreted unchanged. Close monitoring is advised when used in a patient with hepatic impairment.
      Brivaracetam was recently approved by the Food and Drug Administration. This drug was developed by modification of its predecessor levetiracetam. Brivaracetam has greater affinity toward synaptic vesicle 2A, and its binding capacity is low. Only 20% of the drug is cleared by the liver, so it is unlikely to exhibit drug interactions. Current data are limited, but brivaracetam would likely be a safe medication for individuals with liver disease. Its clearance is reduced in patients with hepatic insufficiency, so the dose may need adjusting.
      • von Rosenstiel P.
      Brivaracetam (UCB 34714).
      In addition to individual pharmacokinetic properties of the different AEDs, other variables must be considered when selecting therapy in patients affected by liver disease. These variables include formulations and cost of medications, associated comorbid conditions, and seizure type. First- or second-line agents are effective in treating multiple seizure types.
      For generalized convulsive seizures, including myoclonus and generalized tonic-clonic seizures, broad-spectrum drugs, such as levetiracetam, topiramate, or zonisamide, are good choices.
      • Beydoun A.
      • D'Souza J.
      Treatment of idiopathic generalized epilepsy—a review of the evidence.
      • Coppola G.
      • Piccorossi A.
      • Operto F.F.
      • Verrotti A.
      Anticonvulsant drugs for generalized tonic-clonic epilepsy.
      • Mantoan L.
      • Walker M.
      Treatment options in juvenile myoclonic epilepsy.
      For absence seizures in children, ethosuximide is the drug of choice.
      • Glauser T.A.
      • Cnaan A.
      • Shinnar S.
      • et al.
      Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months.
      Because of favorable pharmacokinetics, levetiracetam can be considered first.
      • Hughes J.R.
      Absence seizures: a review of recent reports with new concepts.
      There are also data from small studies about the efficacy of zonisamide and topiramate.
      • Velizarova R.
      • Crespel A.
      • Genton P.
      • Serafini A.
      • Gelisse P.
      Zonisamide for refractory juvenile absence epilepsy.
      For focal-onset seizures, levetiracetam is an ideal choice, but virtually any first- or second-line therapy can be considered, including sodium channel blockers such as lacosamide, oxcarbazepine, and eslicarbazepine.
      • Bauer S.
      • Willems L.M.
      • Paule E.
      • et al.
      The efficacy of lacosamide as monotherapy and adjunctive therapy in focal epilepsy and its use in status epilepticus: clinical trial evidence and experience.
      • Coppola G.
      • Iapadre G.
      • Operto F.F.
      • Verrotti A.
      New developments in the management of partial-onset epilepsy: role of brivaracetam.

      Hepatotoxicity caused by AEDs

      There are more than 900 drugs, toxins, and herbs that are known to be hepatotoxic.
      • Pandit A.
      • Sachdeva T.
      • Bafna P.
      Drug-induced hepatotoxicity: a review.
      A drug's hepatotoxicity may not become apparent until after a large number of patients have taken it, so the risk of hepatotoxicity is usually discovered in the postmarketing phase.
      • Bjornsson E.
      Hepatotoxicity associated with antiepileptic drugs.
      Drug-induced liver injury is a rare side effect of AEDs. Serious liver injury may result in failure to approve a drug or in its removal from the market after approval. In patients undergoing liver transplantation in the United States between 1990 and 2002, AEDs were the third most common cause.
      • Russo M.W.
      • Galanko J.A.
      • Shrestha R.
      • Fried M.W.
      • Watkins P.
      Liver transplantation for acute liver failure from drug induced liver injury in the United States.
      AEDs commonly cause asymptomatic or transient enzyme elevations. Elevation of the gamma-glutamyl transferase level occurs in up to 75% to 95% of patients exposed to enzyme inducing agents such as carbamazepine and phenobarbital.
      • Strolin Benedetti M.
      • Ruty B.
      • Baltes E.
      Induction of endogenous pathways by antiepileptics and clinical implications.
      Zimmerman in 1960 showed that an increase in the alanine aminotransferase (ALT) level of ≥3 times the upper limit of normal, and a total bilirubin level of ≥2 times the upper limits of normal (especially in the presence of jaundice) is associated with a mortality rate of 10% to 50%.
      • Bjornsson E.
      • Olsson R.
      Outcome and prognostic markers in severe drug-induced liver disease.
      In 2011, the new consensus criteria defined drug-induced liver injury as:
      • (1)
        an increase in the ALT level of ≥3 times the upper limits of normal and total bilirubin levels of ≥2 times the upper limits of normal,
      • (2)
        an increase in the ALT level of ≥5 times the upper limits of normal, and
      • (3)
        an increase in the alkaline phosphatase level of ≥2 times the upper limits of normal (especially when associated with elevations in γ-glutamyl transpeptidase).
        • Robles-Diaz M.
        • Lucena M.I.
        • Kaplowitz N.
        • et al.
        Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.
      These values are useful in clinical practice because it is difficult to predict the occurrence of drug-induced liver injury before the clinical course becomes irreversible. The mechanism of hepatic injury caused by AEDS is heterogeneous. Hypersensitivity features are found in 70% of the individuals with hepatic injury related to phenytoin, but only 30% of cases were associated with carbamazepine. Hypersensitivity is usually not observed in valproic acid. The hepatotoxic potential between different AEDs is also variable and a detailed analysis is presented later in this article.

      AEDs with well-recognized hepatotoxicity

      Valproic acid

      The hepatotoxic potential of valproic acid is well recognized. Valproic acid is the third most common cause of drug-induced liver fatalities reported by the World Health Organization.
      • Bjornsson E.
      • Olsson R.
      Suspected drug-induced liver fatalities reported to the WHO database.
      The mechanism of injury is unclear, but it may be related to interference with the mitochondrial beta oxidation of fatty acids.
      • Coulter D.L.
      Carnitine, valproate, and toxicity.
      An inherited or acquired impairment in beta-oxidation of valproate may contribute to the liver toxicity.
      • Siemes H.
      • Nau H.
      • Schultze K.
      • et al.
      Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity.
      Hepatic injury can be of different types, the most common type being asymptomatic elevation of liver function tests, which does not require discontinuation of the drug.
      • Powell-Jackson P.R.
      • Tredger J.M.
      • Williams R.
      Hepatotoxicity to sodium valproate: a review.
      More severe reactions are rare, occurring in about 1 per 15,000 exposures.
      • Dreifuss F.E.
      • Langer D.H.
      • Moline K.A.
      • Maxwell J.E.
      Valproic acid hepatic fatalities. II. US experience since 1984.
      • Koenig S.A.
      • Buesing D.
      • Longin E.
      • et al.
      Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003.
      These severe reactions are usually observed during the first three months of treatment.
      • Suchy F.J.
      • Balistreri W.F.
      • Buchino J.J.
      • et al.
      Acute hepatic failure associated with the use of sodium valproate.
      • Caparros-Lefebvre D.
      • Lecomte-Houcke M.
      • Pruvot F.R.
      • Declerck N.
      • Paris J.C.
      • Petit H.
      Unusual electronmicroscopic changes in valproate-associated liver failure.
      In individuals whose hepatic enzymes increase to more than three times the upper normal range, valproic acid should be discontinued.
      Clinical symptoms of hepatotoxicity are nausea, vomiting, an increase in seizures, jaundice, and fatigue, but signs of hypersensitivity are usually lacking.
      • Pandit A.
      • Sachdeva T.
      • Bafna P.
      Drug-induced hepatotoxicity: a review.
      There are clear risk factors for valproic acid-associated hepatotoxicity. These risk factors include younger age and polytherapy (Table 4). Additional risk factors include developmental delay, metabolic disorders, febrile illness, and status epilepticus.
      • Dreifuss F.E.
      • Santilli N.
      • Langer D.H.
      • Sweeney K.P.
      • Moline K.A.
      • Menander K.B.
      Valproic acid hepatic fatalities: a retrospective review.
      • Bryant 3rd, A.E.
      • Dreifuss F.E.
      Valproic acid hepatic fatalities. III. U.S. experience since 1986.
      Table 4Calculated Risk of Hepatotoxicity for Specific Antiepileptic Drugs
      MedicationCalculated RiskIdentified or Potential Risk Factors
      CarbamazepineRareChildren undergoing polytherapy
      Felbamate1 per 26,000-1 per 34,000Female gender

      Polytherapy
      Phenytoin1 per 10,000-1 per 50,000Black ethnicity

      Children less susceptible
      Valproic acidMonotherapy

      Adults: 1 per 45,000

      Children <2 years: 1 per 7,000

      Polytherapy

      Adults: 1 per 12,000

      Children <2 years: 1 per 500-600
      Polymerase gamma 1 (POLG1) mutations

      Younger age

      Polytherapy

      Developmental delay

      Metabolic disorders

      Febrile illness

      Status epilepticus
      The POLG gene codes for the mitochondrial DNA replicase, polymerase gamma, and is responsible for the Alpers-Huttenlocher syndrome. Individuals with these mutations are at high risk for liver failure due to valproic acid exposure. Pre-treatment testing for POLG mutations may be useful in some children with refractory seizures and developmental regression.
      • Stewart J.D.
      • Horvath R.
      • Baruffini E.
      • et al.
      Polymerase gamma gene POLG determines the risk of sodium valproate-induced liver toxicity.
      • Rust R.S.
      Alpers-Huttenlocher syndrome: origins of clinicopathologic recognition.
      Despite available testing, the diagnosis of POLG-related disorders remains challenging. The clinical manifestations can be mild and there is wide phenotypic variation.
      • Stumpf J.D.
      • Saneto R.P.
      • Copeland W.C.
      Clinical and molecular features of POLG-related mitochondrial disease.
      • Burusnukul P.
      • de los Reyes E.C.
      Phenotypic variations in 3 children with POLG1 mutations.
      • Rajakulendran S.
      • Pitceathly R.D.
      • Taanman J.W.
      • et al.
      A clinical, neuropathological and genetic study of homozygous A467T POLG-related mitochondrial disease.
      • Da Pozzo P.
      • Cardaioli E.
      • Rubegni A.
      • et al.
      Novel POLG mutations and variable clinical phenotypes in 13 Italian patients.
      Valproic acid has also been associated with a Reye-like syndrome, which manifests with lethargy, fever, vomiting, and microvesicular steatosis on liver biopsy.
      • Gerber N.
      • Dickinson R.G.
      • Harland R.C.
      • et al.
      Reye-like syndrome associated with valproic acid therapy.
      Asymptomatic hyperammonemia is common during valproate therapy and does not require discontinuation of the drug.
      • Murphy J.V.
      • Marquardt K.
      Asymptomatic hyperammonemia in patients receiving valproic acid.
      • Nicolai J.
      • Carr R.B.
      The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?.
      Valproic acid hyperammonemic encephalopathy is a more serious condition. Symptoms consist of a progressive confusional state, which can lead to coma and death.
      • Gerstner T.
      • Buesing D.
      • Longin E.
      • et al.
      Valproic acid induced encephalopathy—19 new cases in Germany from 1994 to 2003—a side effect associated to VPA-therapy not only in young children.
      • Kifune A.
      • Kubota F.
      • Shibata N.
      • Akata T.
      • Kikuchi S.
      Valproic acid-induced hyperammonemic encephalopathy with triphasic waves.
      Hepatic enzymes may be normal, but glutamine in cerebrospinal fluid can be high.
      • Vossler D.G.
      • Wilensky A.J.
      • Cawthon D.F.
      • et al.
      Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy.
      Concomitant use of AEDS, especially topiramate, can increase the risk of developing this complication.
      • Blackford M.G.
      • Do S.T.
      • Enlow T.C.
      • Reed M.D.
      Valproic acid and topiramate induced hyperammonemic encephalopathy in a patient with normal serum carnitine.

      Phenytoin

      Phenytoin is an aromatic anticonvulsant with enzyme-inducing properties. Its association with hepatotoxicity is also well documented.
      • Bjornsson E.
      • Olsson R.
      Suspected drug-induced liver fatalities reported to the WHO database.
      Phenytoin induces a transient and asymptomatic increase in the ALT in a quarter of the patients who take it.
      • Wall M.
      • Baird-Lambert J.
      • Buchanan N.
      • Farrell G.
      Liver function tests in persons receiving anticonvulsant medications.
      Severe liver injury is part of an idiosyncratic reaction, occurring in genetically predisposed patients.
      • Spielberg S.P.
      • Gordon G.B.
      • Blake D.A.
      • Goldstein D.A.
      • Herlong H.F.
      Predisposition to phenytoin hepatotoxicity assessed in vitro.
      Hepatotoxicity occurs with a frequency of 1 per 10,000 to 1 per 50,000 exposures.
      • Farrell G.C.
      Drug-Induced Liver Disease.
      The incidence is higher in blacks. Children appear to be less susceptible.
      • Mullick F.G.
      • Ishak K.G.
      Hepatic injury associated with diphenylhydantoin therapy. A clinicopathologic study of 20 cases.
      Liver toxicity usually occurs during the first six weeks of treatment and is likely related to the production of arene oxide and cathecol metabolites in liver microsomes.
      • Bjornsson E.
      • Kalaitzakis E.
      • Olsson R.
      The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury.
      These metabolites may trigger an oxidative injury with a secondary immune-mediated response. The majority of cases are associated with hypersensitivity reactions.
      • Sasaki E.
      • Matsuo K.
      • Iida A.
      • et al.
      A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.
      Fever is observed in 75% of these patients, rash in 62%, and eosinophilia in 89%.
      • Mullick F.G.
      • Ishak K.G.
      Hepatic injury associated with diphenylhydantoin therapy. A clinicopathologic study of 20 cases.
      Pathologic studies show variable types of injury, including granuloma formation and a cholestatic, cytotoxic, or mixed pattern. The cytotoxic pattern is the most common, and the mortality rate after severe liver involvement is 13%.
      • Mullick F.G.
      • Ishak K.G.
      Hepatic injury associated with diphenylhydantoin therapy. A clinicopathologic study of 20 cases.
      • Bjornsson E.
      • Kalaitzakis E.
      • Olsson R.
      The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury.

      Carbamazepine

      Carbamazepine is another aromatic drug that is metabolized by epoxidation and hydroxylation and is a well-established cause of hepatotoxicity. Carbamazepine induces its own metabolism and produces a transient, asymptomatic elevation in hepatic enzymes in 10% of patients who take it.
      • Pellock J.M.
      Carbamazepine side effects in children and adults.
      Severe hepatotoxicity is rare, unpredictable, not dose dependent, and can occur in the first 12 months of therapy. The likelihood of hepatic death appears higher in children, especially when exposed to multiple AEDs.
      • Kalapos M.P.
      Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation.
      Carbamazepine can also produce intermediate arene oxides, but unlike phenytoin, only 30% to 40% of cases are linked to hypersensitivity reactions. Once hepatotoxicity has developed, the mortality rate is about 25%.
      • Dreifuss F.E.
      • Langer D.H.
      Hepatic considerations in the use of antiepileptic drugs.
      Liver biopsies show inflammatory reactions, cholestasis, or hepatocellular injury with hepatic necrosis observed in lethal cases.
      • Bjornsson E.
      • Kalaitzakis E.
      • Olsson R.
      The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury.
      Other types of liver injury include granulomatous hepatitis and ductopenia, a rare condition with loss of small bile ducts and jaundice, also associated with valproic acid and lamotrigine exposure.
      • Gokce S.
      • Durmaz O.
      • Celtik C.
      • Aydogan A.
      • Gulluoglu M.
      • Sokucu S.
      Valproic acid-associated vanishing bile duct syndrome.
      • Bhayana H.
      • Appasani S.
      • Thapa B.R.
      • Das A.
      • Singh K.
      Lamotrigine-induced vanishing bile duct syndrome in a child.

      Felbamate

      Felbamate was synthetized in 1950 while in search of new anxiolytic substances. The antiepileptic properties of felbamate were discovered some 30 years later and approved by the Food and Drug Administration in 1993. Felbamate was the first new AED after the approval of valproic acid in 1978. This drug was widely used until the reports of aplastic anemia and liver failure in the postmarketing phase. Subsequent analysis showed that the risk of liver failure is between 1:26,000 and 1:34,000 (which may be lower than the risk of valproic acid-associated hepatotoxicity). The risk factors associated with hepatic failure are less defined. Female gender and polytherapy could increase this risk.
      • Pellock J.M.
      Felbamate in epilepsy therapy: evaluating the risks.
      The mean time of presentation is between six and 12 months of therapy. Liver failure can occur without warning and can be fulminant. Patients should be taught to recognize the clinical symptoms. Felbamate should be discontinued with aspartate aminotransferase-alanine transferase elevations of twice the upper limits of normal.
      • Pellock J.M.
      • Faught E.
      • Leppik I.E.
      • Shinnar S.
      • Zupanc M.L.
      Felbamate: consensus of current clinical experience.

      AEDS with low or unclear hepatotoxic potential

      Oxcarbazepine

      Oxcarbazepine is a newer-generation sodium channel blocker. Hepatotoxicity is extremely rare in individuals taking oxcarbazepine. Most cases occurred with previous exposure to another AED or in the setting of elevated liver enzymes. There are isolated reports of anticonvulsant hypersensitivity syndrome and hepatitis.
      • Planjar-Prvan M.
      • Bielen A.
      • Sruk A.
      • Marusic M.
      • Bielen I.
      Acute oxcarbazepine-induced hepatotoxicity in a patient susceptible to developing drug-induced liver injury.
      • Chait Mermelstein A.
      • Mermelstein J.
      • Adam T.
      • Brody B.D.
      • Dubin M.J.
      Oxcarbazepine-induced liver injury after sensitization by valproic acid: a case report.
      • Bosdure E.
      • Cano A.
      • Roquelaure B.
      • et al.
      Oxcarbazepine and DRESS syndrome: a paediatric cause of acute liver failure.

      Topiramate

      Topiramate can produce hyperammonemia when combined with valproic acid, but hepatotoxicity when used as monotherapy is very rare. There are a few reports of severe hepatotoxicity, including one individual who was also receiving carbamazepine who required a liver transplant.
      • Bjoro K.
      • Gjerstad L.
      • Bentdal O.
      • Osnes S.
      • Schrumpf E.
      Topiramate and fulminant liver failure.
      • Tsien M.Z.
      • Cordova J.
      • Qadir A.
      • Zhao L.
      • Hart J.
      • Azzam R.
      Topiramate-induced acute liver failure in a pediatric patient: a case report and review of literature.

      Phenobarbital

      Phenobarbital is one of the oldest aromatic AEDs, available since 1911. Despite its extensive use, phenobarbital has only been associated with hepatotoxicity in rare instances. Phenobarbital can produce elevation in liver enzymes, and has been occasionally linked to hypersensitivity reactions, hepatitis, and acute liver failure.
      • Li A.M.
      • Nelson E.A.
      • Hon E.K.
      • et al.
      Hepatic failure in a child with anti-epileptic hypersensitivity syndrome.
      • Roberts E.A.
      • Spielberg S.P.
      • Goldbach M.
      • Phillips M.J.
      Phenobarbital hepatotoxicity in an 8-month-old infant.
      • Di Mizio G.
      • Gambardella A.
      • Labate A.
      • Perna A.
      • Ricci P.
      • Quattrone A.
      Hepatonecrosis and cholangitis related to long-term phenobarbital therapy: an autopsy report of two patients.
      Oxidative stress in the hepatic mitochondria may be one of the mechanisms leading to hepatic injury.
      • Santos N.A.
      • Medina W.S.
      • Martins N.M.
      • Rodrigues M.A.
      • Curti C.
      • Santos A.C.
      Involvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs.

      Lamotrigine

      Lamotrigine is an effective and relatively safe medication. Rare examples of severe hepatotoxicity have been reported. The liver dysfunction can be reversible upon drug discontinuation. Lamotrigine is an aromatic drug and can produce liver toxicity as part of a general hypersensitivity reaction. Patients with comorbid conditions, such as status epilepticus and those undergoing polytherapy (especially with valproate or carbamazepine), are more susceptible to hepatotoxicity.
      • Fayad M.
      • Choueiri R.
      • Mikati M.
      Potential hepatotoxicity of lamotrigine.
      • Im S.G.
      • Yoo S.H.
      • Park Y.M.
      • et al.
      Liver dysfunction induced by systemic hypersensitivity reaction to lamotrigine: case report.
      • Mecarelli O.
      • Pulitano P.
      • Mingoia M.
      • et al.
      Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (MARS).

      Levetiracetam

      Levetiracetam does not interact with the cytochrome P450 system and is the drug of first choice for patients with liver disease. Nevertheless, there are rare reports of hepatotoxicity, ranging from elevations of liver enzymes to severe hepatotoxicity or liver failure. The physiopathology of liver toxicity is poorly understood.
      • Broli M.
      • Provini F.
      • Naldi I.
      • et al.
      Unexpected gamma glutamyltransferase rise increase during levetiracetam monotherapy.
      • Syed A.A.
      • Adams C.D.
      Acute liver failure following levetiracetam therapy for seizure prophylaxis in traumatic brain injury.
      • Tan T.C.
      • de Boer B.W.
      • Mitchell A.
      • et al.
      Levetiracetam as a possible cause of fulminant liver failure.
      • Skopp G.
      • Schmitt H.P.
      • Pedal I.
      Fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus.
      • Selvaraj V.
      • Madabushi J.S.
      • Gunasekar P.
      • Singh S.P.
      Levetiracetam associated acute hepatic failure requiring liver transplantation: case report.

      Lacosamide

      Lacosamide is a new-generation AED. Forty percent of it is excreted unchanged in the urine. Part of the drug is metabolized by the liver and there are only rare reports of hepatic enzyme elevation and liver toxicity.
      • Sunwoo J.S.
      • Byun J.I.
      • Lee S.K.
      A case of lacosamide-induced hepatotoxicity.
      • Gutierrez-Grobe Y.
      • Bahena-Gonzalez J.A.
      • Herrera-Gomar M.
      • Mendoza-Diaz P.
      • Garcia-Lopez S.
      • Gonzalez-Chon O.
      Acute liver failure associated with levetiracetam and lacosamide combination treatment for unspecified epileptic disorder.
      • Ben-Menachem E.
      • Biton V.
      • Jatuzis D.
      • Abou-Khalil B.
      • Doty P.
      • Rudd G.D.
      Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures.

      Zonisamide

      Zonisamide has been rarely linked to hepatotoxicity. There are a few reports of liver toxicity and “vanishing bile duct syndrome.” Patients with chronic cirrhosis may be at risk.
      • Vuppalanchi R.
      • Chalasani N.
      • Saxena R.
      Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide.
      • Coelho R.
      • Rodrigues S.
      • Gaspar R.
      • Silva R.
      • Lopes J.
      • Macedo G.
      Zonisamide-induced acute-on-chronic liver failure: first report.

      Ethosuximide

      Evidence linking ethosuximide to hepatotoxity is limited to only a few reports, mainly related to its use in combination with other drugs, usually valproic acid.
      • Conilleau V.
      • Dompmartin A.
      • Verneuil L.
      • Michel M.
      • Leroy D.
      Hypersensitivity syndrome due to 2 anticonvulsant drugs.
      • Coulter D.L.
      Ethosuximide-induced liver dysfunction.

      Benzodiazepines

      Despite the widespread use of benzodiazepines, liver toxicity in association with their use is extremely rare.
      • Dossing M.
      • Andreasen P.B.
      Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs.
      • Cunningham M.L.
      Acute hepatic necrosis following treatment with amitriptyline and diazepam.
      • Stacher G.
      Intrahepatic cholestasis following combined diazepam-barbiturate therapy in patients with tetanus.

      Gabapentin

      Gabapentin has no appreciable liver metabolism and there are only rare case reports about possible hepatotoxicity. Some of these reports describe patients taking multiple drugs, so the association remains unclear.
      • Richardson C.E.
      • Williams D.W.
      • Kingham J.G.
      Gabapentin induced cholestasis.
      • Bureau C.
      • Poirson H.
      • Peron J.M.
      • Vinel J.P.
      Gabapentin-induced acute hepatitis.
      • Lasso-de-la-Vega M.C.
      • Zapater P.
      • Such J.
      • Perez-Mateo M.
      • Horga J.F.
      Gabapentin-associated hepatotoxicity.
      • Ragucci M.V.
      • Cohen J.M.
      Gabapentin-induced hypersensitivity syndrome.

      Pregabalin

      Pregabalin does not inhibit or induce liver enzymes. Despite its favorable pharmacokinetics, there are few reports about potential liver toxicity, with onset in the first two weeks of treatment. Cholestatic and hepatocellular patterns of injury have been described.
      • Sendra J.M.
      • Junyent T.T.
      • Pellicer M.J.
      Pregabalin-induced hepatotoxicity.
      • Dogan S.
      • Ozberk S.
      • Yurci A.
      Pregabalin-induced hepatotoxicity.
      • Crespo Perez L.
      • Moreira Vicente V.
      • Manzano Fernandez R.
      • Garcia Aguilera X.A.
      Cholestasis associated with pregabalin treatment.
      • Bamanikar A.
      • Dhobale S.
      • Lokwani S.
      Pregabalin hypersensitivity in a patient treated for postherpetic neuralgia.

      Vigabatrin

      Vigabatrin is a drug that lacks hepatic metabolism and hepatotoxicity has rarely been reported.
      • Locher C.
      • Zafrani E.S.
      • Dhumeaux D.
      • Mallat A.
      Vigabatrin-induced cytolytic hepatitis.
      • Kellermann K.
      • Soditt V.
      • Rambeck B.
      • Klinge O.
      Fatal hepatotoxicity in a child treated with vigabatrin.

      Eslicarbazepine

      Eslicarbazepine is related to oxcarbazepine, and there are only isolated reports about liver injury, usually with rapid recovery after drug discontinuation.
      • Massot A.
      • Gimenez-Arnau A.
      Cutaneous adverse drug reaction type erythema multiforme major induced by eslicarbazepine.

      AEDs with no known hepatotoxicity

      Drugs such as tiagabine, perampanel, and brevaracetam have not yet been linked to liver toxicity.
      • Laurenza A.
      • Yang H.
      • Williams B.
      • Zhou S.
      • Ferry J.
      Absence of liver toxicity in perampanel-treated subjects: pooled results from partial seizure phase III perampanel clinical studies.

      Potential treatments

      Despite the available information, hepatoxicity associated with AEDs is usually unexpected and difficult to predict. An increase in liver function tests of two- to threefold from baseline warrants enhanced vigilance. Once laboratory values surpass this range or the diagnosis of drug-induced liver injury has been made, the drug should be promptly discontinued. Other specific treatment modalities have shown some benefit (Table 5).
      • Mecarelli O.
      • Pulitano P.
      • Mingoia M.
      • et al.
      Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (MARS).
      • Kellermann K.
      • Soditt V.
      • Rambeck B.
      • Klinge O.
      Fatal hepatotoxicity in a child treated with vigabatrin.
      • Perrott J.
      • Murphy N.G.
      • Zed P.J.
      L-Carnitine for acute valproic acid overdose: a systematic review of published cases.
      • Russell S.
      Carnitine as an antidote for acute valproate toxicity in children.
      • Chan Y.C.
      • Tse M.L.
      • Lau F.L.
      Two cases of valproic acid poisoning treated with L-carnitine.
      • Lheureux P.E.
      • Hantson P.
      Carnitine in the treatment of valproic acid-induced toxicity.
      • Tsai M.F.
      • Chen C.Y.
      Valproate-induced hyperammonemic encephalopathy treated by hemodialysis.
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      • Sen S.
      • Ratnaraj N.
      • Davies N.A.
      • et al.
      Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS).
      • Squires R.H.
      • Dhawan A.
      • Alonso E.
      • et al.
      Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.
      Liver transplantation is the treatment of choice for end-stage hepatic damage.
      Table 5Treatment Modalities Used in Cases of Hepatotoxicity Associated With Specific Antiepileptic Drugs
      MedicationTreatmentNotes
      Valproic acidl-CarnitineDoses of 100 mg/kg followed intravenous doses of 50 mg/kg every 8 hours, to a maximum of 3 g per dose.
      • Perrott J.
      • Murphy N.G.
      • Zed P.J.
      L-Carnitine for acute valproic acid overdose: a systematic review of published cases.
      • Russell S.
      Carnitine as an antidote for acute valproate toxicity in children.
      • Chan Y.C.
      • Tse M.L.
      • Lau F.L.
      Two cases of valproic acid poisoning treated with L-carnitine.
      • Lheureux P.E.
      • Hantson P.
      Carnitine in the treatment of valproic acid-induced toxicity.
      Hemodialysis, sodium benzoate phenyl acetateUsed for progressive neurological deterioration or ammonia levels greater than 680 µg/dL (400 µmol/L).
      • Tsai M.F.
      • Chen C.Y.
      Valproate-induced hyperammonemic encephalopathy treated by hemodialysis.
      CarbamazepineN-Acetylcystein
      N-Acetylcysteine and antidote for acetaminophen drug-induced liver injury has recently shown benefits for adult patients with nonacetaminophen drug-induced liver injury, including cases of carbamazepine and phenytoin hepatotoxicity. On the contrary, N-acetylcysteine was of no benefit in young children with nonacetaminophen acute liver failure.
      Doses used are 150 mg/kg/hour over 1 hour, followed by 12.5 mg/kg/hour for 4 hours, then continuous infusions of 6.25 mg/kg/hour for the remaining 67 hours.
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      SteroidsHypersensitivity reactions
      PhenytoinN-AcetylcysteineDoses used are 150 mg/kg/hour over 1 hour, followed by 12.5 mg/kg/hour for 4 hours, then continuous infusions of 6.25 mg/kg/hour for the remaining 67 hours.
      • Lee W.M.
      • Hynan L.S.
      • Rossaro L.
      • et al.
      Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
      MARS deviceUsed to remove molecules that are highly protein bound
      • Mecarelli O.
      • Pulitano P.
      • Mingoia M.
      • et al.
      Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (MARS).
      • Sen S.
      • Ratnaraj N.
      • Davies N.A.
      • et al.
      Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS).
      SteroidsHypersensitivity reactions
      LamotrigineMARS deviceUsed to remove molecules that are highly protein bound
      • Mecarelli O.
      • Pulitano P.
      • Mingoia M.
      • et al.
      Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (MARS).
      • Kellermann K.
      • Soditt V.
      • Rambeck B.
      • Klinge O.
      Fatal hepatotoxicity in a child treated with vigabatrin.
      SteroidsHypersensitivity reactions
      Abbreviation:
      MARS = Molecular adsorbents recirculating system
      * N-Acetylcysteine and antidote for acetaminophen drug-induced liver injury has recently shown benefits for adult patients with nonacetaminophen drug-induced liver injury, including cases of carbamazepine and phenytoin hepatotoxicity. On the contrary, N-acetylcysteine was of no benefit in young children with nonacetaminophen acute liver failure.

      AED therapy in special circumstances

      Acute porphyria

      Acute porphyrias are a group of rare inherited disorders of heme synthesis. Acute intermittent porphyria is the most common of the hepatic porphyrias and is caused by a deficiency of hydroxymethylbilane synthase involved in heme synthesis. Most affected individuals remain asymptomatic, but acute attacks can suddenly be precipitated by exposure to numerous drugs. Symptoms can include abdominal pain, symmetric motor neuropathy, confusion, and seizures. During a crisis, the porphyrin precursors δ-aminolevulinic acid and porphobilinogen are elevated.
      • Pischik E.
      • Kauppinen R.
      An update of clinical management of acute intermittent porphyria.
      The prevalence of seizures in individuals with acute intermittent porphyria is about 3.7%, but this number increases to 5.1% in individuals who have already experienced acute attacks.
      • Bylesjo I.
      • Forsgren L.
      • Lithner F.
      • Boman K.
      Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria.
      Selecting the most appropriate AED for these patients is problematic because most anticonvulsants are porphyrogenic.
      Enzyme inducing agents such as carbamazepine, phenytoin, and phenobarbital, can precipitate attacks, likely via an increase in catabolism of hydroxymethylbilane synthetase and uroporphyrinogen decarboxylase, affecting heme synthesis.
      • Solinas C.
      • Vajda F.J.
      Epilepsy and porphyria: new perspectives.
      • Bonkowsky H.L.
      • Sinclair P.R.
      • Emery S.
      • Sinclair J.F.
      Seizure management in acute hepatic porphyria: risks of valproate and clonazepam.
      Other AEDS, including lamotrigine, valproic acid, primidone, tiagabine, ethosuximide, topiramate, methsuximide, trimethadione, and felbamate, have been associated with clinical worsening of porphyria or have demonstrated porphyrin accumulation in chick embryo liver cells.
      • Larson A.W.
      • Wasserstrom W.R.
      • Felsher B.F.
      • Chih J.C.
      Posttraumatic epilepsy and acute intermittent porphyria: effects of phenytoin, carbamazepine, and clonazepam.
      • Doss M.
      • Schafer H.J.
      Carbamazepine-induced acute porphyria syndrome.
      • Rideout J.M.
      • Wright D.J.
      • Lim C.K.
      • Rinsler M.G.
      • Peters T.J.
      Carbamazepine-induced non-hereditary acute porphyria.
      • Yalouris A.G.
      • Lyberatos C.
      • Chikrigi H.
      • et al.
      Effect of starvation and phenobarbital on the activity of liver uroporphyrinogen synthetase.
      • Reynolds Jr, N.C.
      • Miska R.M.
      Safety of anticonvulsants in hepatic porphyrias.
      • Granick S.
      The induction in vitro of the synthesis of delta-aminolevulinic acid synthetase in chemical porphyria: a response to certain drugs, sex hormones, and foreign chemicals.
      • Hahn M.
      • Gildemeister O.S.
      • Krauss G.L.
      • et al.
      Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.
      • Krijt J.
      • Krijtova H.
      • Sanitrak J.
      Effect of tiagabine and topiramate on porphyrin metabolism in an in vivo model of porphyria.
      Bromides were used as first-line therapy for porphyria until new AEDs with more favorable kinetics appeared in the 1990s (Table 6).
      • Thadani H.
      • Deacon A.
      • Peters T.
      Diagnosis and management of porphyria.
      • Magnussen C.R.
      • Doherty J.M.
      • Hess R.A.
      • Tschudy D.P.
      Grand mal seizures and acute intermittent porphyria. The problem of differential diagnosis and treatment.
      • Lotte J.
      • Haberlandt E.
      • Neubauer B.
      • Staudt M.
      • Kluger G.J.
      Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome.
      • Bowers Jr, G.N.
      • Onoroski M.
      Hyperchloremia and the incidence of bromism in 1990.
      AEDs such as levetiracetam and gabapentin, with negligible hepatic metabolism, should be the first-line treatment. Vigabatrin lacks hepatic metabolism and constitutes a safe option, but has the potential of causing visual field defects.
      • Solinas C.
      • Vajda F.J.
      Epilepsy and porphyria: new perspectives.
      • Hahn M.
      • Gildemeister O.S.
      • Krauss G.L.
      • et al.
      Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.
      Table 6Potassium Bromide
      Other formulations (ammonium bromide, potassium bromide, and sodium bromide) exist and may have different dosing regimens.
      Dosing and Potential Side Effects
      Initial DoseMaintenance DoseHalf-LifeCommon Side EffectsRare Side Effects
      30 mg/kg/day30 to 80 mg/kg/day

      Increase by 10 mg/kg/day every 2 weeks
      Children: 6-8 days

      Adults: 8-14 days
      Drowsiness

      Gastrointestinal

      Acneiform eruption

      Concentration impairment

      Behavioral
      • Thadani H.
      • Deacon A.
      • Peters T.
      Diagnosis and management of porphyria.
      Bromism (psychiatric symptoms, nausea, vomiting, and rash)
      • Magnussen C.R.
      • Doherty J.M.
      • Hess R.A.
      • Tschudy D.P.
      Grand mal seizures and acute intermittent porphyria. The problem of differential diagnosis and treatment.
      ,
      An incidence of 1 in 1,000,000 has been estimated.
      * Other formulations (ammonium bromide, potassium bromide, and sodium bromide) exist and may have different dosing regimens.
      An incidence of 1 in 1,000,000 has been estimated.
      Oxcarbazepine, with its low hepatic induction of microsomal enzymes, has been tried successfully.
      • Gaida-Hommernick B.
      • Rieck K.
      • Runge U.
      Oxcarbazepine in focal epilepsy and hepatic porphyria: a case report.
      Carbamazepine, a drug with porphyrogenic potential, has been used in isolated individuals and can be an alternative when no other options are available, especially in patients with normal δ-aminolevulinic acid and porphobilinogen levels.
      • Sykes R.M.
      Acute intermittent porphyria, seizures, and antiepileptic drugs: a report on a 3-year-old Nigerian boy.
      For acute treatment, benzodiazepines are good therapeutic choices. Clonazepam has been tried safely but could exacerbate symptoms at higher doses.
      • Bonkowsky H.L.
      • Sinclair P.R.
      • Emery S.
      • Sinclair J.F.
      Seizure management in acute hepatic porphyria: risks of valproate and clonazepam.
      • Larson A.W.
      • Wasserstrom W.R.
      • Felsher B.F.
      • Chih J.C.
      Posttraumatic epilepsy and acute intermittent porphyria: effects of phenytoin, carbamazepine, and clonazepam.
      • Suzuki A.
      • Aso K.
      • Ariyoshi C.
      • Ishimaru M.
      Acute intermittent porphyria and epilepsy: safety of clonazepam.
      Levetiracetam can be administered intravenously and is another good option in emergency situations.
      If general anesthesia is needed, midazolam and propofol are probably safe medications.
      • Gorchein A.
      Drug treatment in acute porphyria.

      Wilson disease

      Wilson disease is a rare autosomal disorder of copper transport resulting from loss of function of the ATP7B copper-binding protein, resulting in the accumulation of copper in multiple organs. Laboratory testing shows low ceruloplasmin and an increase in 24-hour urine copper assay.
      • Hedera P.
      Update on the clinical management of Wilson's disease.
      Hepatic involvement can vary from an elevation of liver enzymes to a hepatic failure or cirrhosis. Neurological manifestations most often include movement disorders and cognitive deterioration, but seizures occur in about 5.5% of patients before the initiation of chelation therapy and in 2.8% of patients undergoing treatment.
      • Prashanth L.K.
      • Sinha S.
      • Taly A.B.
      • Mahadevan A.
      • Vasudev M.K.
      • Shankar S.K.
      Spectrum of epilepsy in Wilson's disease with electroencephalographic, MR imaging and pathological correlates.
      Seizures can be focal or generalized and can present as status epilepticus. Good seizure control is achieved in most patients and only a small number become refractory.
      • Prashanth L.K.
      • Sinha S.
      • Taly A.B.
      • Mahadevan A.
      • Vasudev M.K.
      • Shankar S.K.
      Spectrum of epilepsy in Wilson's disease with electroencephalographic, MR imaging and pathological correlates.
      • Dening T.R.
      • Berrios G.E.
      • Walshe J.M.
      Wilson's disease and epilepsy.
      Multiple AEDS, including phenytoin, valproic acid, benzodiazepines, and carbamazepine, have been used successfully; however, newer AEDs with less hepatic metabolism should be favored, especially when the hepatic function is severely compromised. It is important to supplement with pyridoxine during penicillamine therapy because pyridoxine deficiency can cause seizures during the chelation treatment.
      • Turk-Boru U.
      • Kocer A.
      • Alp R.
      • Gumus M.
      Status epilepticus in a case with Wilson's disease during D-penicillamine treatment.

      Conclusion

      Hepatic disease and seizures often coexist, and the use of anticonvulsant therapy is indicated in these individuals. Selecting the most appropriate AED therapy for individuals with hepatic disease remains challenging. The goal of therapy is to maximize efficacy and to minimize toxicity. The ideal AED should have good efficacy, minimal or no hepatic metabolism, and no significant binding to serum proteins.
      Newer AEDs with a more favorable pharmacokinetic profile and with a lower risk of toxicity offer good therapeutic choices for patients with hepatic dysfunction. These medications are also the ideal first-line treatment for patients affected by rare conditions that lead to liver dysfunction, such as porphyria or Wilson disease. Some of these drugs, such as levetiracetam and lacosamide, are available in IV preparations and can be used in emergency situations. Hepatotoxicity is also a rare complication of AEDs, and identification of high-risk populations may reduce the likelihood of liver injury. Clinicians should be aware of the different therapeutic options available for the treatment of seizures in patients with liver disease and recognize the hepatotoxic potential of different AEDs.

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