Accepted Manuscript

Title: Antiepileptic Drugs and Liver Disease

Author: Jorge Vidaurre, Satya Gedela, Shannon Yarosz

PII: S0887-8994(17)30637-9
DOI: https://doi.org/doi:10.1016/j.pediatrneurol.2017.09.013
Reference: PNU 9234

To appear in: Pediatric Neurology

Received date: 20-6-2017

Revised date: 5-9-2017
Accepted date: 19-9-2017

Please cite this article as: Jorge Vidaurre, Satya Gedela, Shannon Yarosz, Antiepileptic Drugs
and Liver Disease, Pediatric Neurology (2017),
https://doi.org/doi:10.1016/j.pediatrneurol.2017.09.013.

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 Antiepileptic drugs and liver disease

Jorge Vidaurre, MD1, Satya Gedela, MD1, Shannon Yarosz, Pharm.D1

1
Division of Pediatric Neurology, Department of Pediatrics, Nationwide Children’s Hospital,

Columbus, Ohio

Running Title: Antiepileptic drugs and liver disease

Corresponding Author: Jorge Vidaurre, MD

700 Children’s Drive

Columbus, OH 43205

Tel: (614) 722-4730 Fax: (614) 722-4633

Jorge.Vidaurre@nationwidechildrens.org

Word count: Abstract, 229; Text: 4,292

Keywords: Antiepileptic drugs, hepatotoxicity, hepatic disease, seizures, epilepsy

The authors report no financial disclosures relevant to this work.

Page 1 of 37
Abstract

Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease.

Choosing the most appropriate antiepileptic drug (AED) 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 AEDs.

Newer AEDs with no, or 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, such as patients affected by

acute intermittent porphyria; exposure to most AEDs 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 IV preparations, are

good second line therapies after benzodiazepines fail to control seizures.

Hepatotoxicity is also a rare and unexpected side effect of AED therapy. Some drugs, such as

valproic acid, phenytoin and felbamate have a well-recognized association with liver toxicity.

Other AEDs, including phenobarbital, benzodiazepines, ethosuximide and the newer generations

of AEDs, have only rarely been linked to hepatotoxicity.

It is therefore necessary for physicians to be mindful of the pharmacokinetic profile and

hepatotoxic potential of the different AEDs available to treat patients affected by liver disease.

Introduction

Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease.

Page 2 of 37
Initiating antiepileptic therapy in this clinical scenario represents a difficult challenge, as most

medications are metabolized by the liver. Severe liver disease also affects the binding capacity of

AEDs to serum protein, increasing the risk of toxicity. Therefore, choosing the most appropriate

AED in this vulnerable population is extremely important.

Newer AEDs undergo no, or minimal, hepatic metabolism and constitute excellent therapeutic

choices. These medications have less potential for drug to drug interactions and lower protein

binding capacity. Some are available in IV formulations and can be used in emergency

situations. It is important for physicians to be familiar with these therapeutic choices and

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 which 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 for recurrent seizures or status epilepticus. There

are no current standardized guidelines to assist physicians in this situation.

Multiple randomized control studies support the use of benzodiazepines as first line treatment

for status epilepticus in general.1 The RAMPART study showed a trend in favor of intramuscular

midazolam vs intravenous lorazepam for initial seizure control (73.4% vs 63.4%)2, 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 disease3

and has fewer chances of drug interactions, making it a good choice for first line therapy (Table

Page 3 of 37
1). Benzodiazepines could potentially exacerbate any preexisting encephalopathy,4 but liver

injury is not a major concern.5 The choice of benzodiazepine should be based on availability of

the drug and presence or absence of an IV access (Figure 1).

If benzodiazepines fail to control seizures, second line agents are necessary. Commonly used

drugs for 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. 4, 6-9

Phenytoin has nonlinear kinetics and in the presence of hypoalbuminemia toxic levels can be

easily reached. 10-14

Phenobarbital is primarily metabolized in the liver and has a prolonged half-life of up to 126

hours5, which can be longer in the setting of liver disease. This could potentially complicate

encephalopathy in susceptible patients.15, 16

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 proteins1 with

fewer chances of drug to drug interactions, minimizing the risk of toxicity.

Levetiracetam has shown efficacy in the treatment of status epilepticus.17-22 The lack of major

side effects, such as hypotension or cardiac arrhythmias, makes it an ideal choice for critically ill

patients.21-23 Lacosamide, a newer AED with a favorable pharmacokinetic profile has also

showed efficacy in controlling status epilepticus and constitutes a good alternative.24-26

Page 4 of 37
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 affected by liver disease may require long term AED treatment. The selection of AEDs

in this specific group deserves careful consideration.

Drug metabolism depends on the integrity of the hepatocyte, blood flow, and patency of

hepatobiliary system.5 Due to the large hepatic reserve, the liver dysfunction must be severe in

order to cause substantial alterations in drug metabolism.27 Mild to moderate liver disease may

need very minor dose adjustments, if any at all. Most AEDS are classified as “low extraction

drugs”, as they have an extraction of < 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.28

Chronic management of seizures in patients with liver disease may become a difficult task.

Accurate calculation of drug adjustments is not possible, as there is no endogenous marker to

calculate hepatic clearance. Comorbidities such as renal failure and gastrointestinal dysmotility

affect the clearance or absorption of these drugs, resulting in toxicity or failure to control

seizures.29 Individual assessment of the severity of liver involvement is important and

consultation with a gastrointestinal specialist or hepatologist may be needed.

The newer generation of AEDs offers a more favorable pharmacokinetic profile than older

anticonvulsants and constitute a better option for long term treatment.

Page 5 of 37
In general, medications with minimal or no hepatic metabolism should be 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 in different categories

from more to less suitable therapy, based on individual pharmacological characteristics and

chances of toxicity (Table 2).

First line therapy

Levetiracetam, a broad spectrum AED is an ideal first line therapy for patients with liver

disease.30 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.31 Levetiracetam has a

wide safety window with no major pharmacokinetic interactions. The dose needs no changes in

mild to moderate liver failure, but it should be decreased by half in patients with severe disease

and Child-Pugh class C (Table 3).31 Levetiracetam can effectively be utilized in patients on

venovenous hemofiltration.32

Lacosamide is metabolized by the CYP450, 2C19 system but has no major drug interactions and

the metabolites are inactive. Its protein binding capacity is less than 15% and 40% of the drug is

eliminated unchanged by the urine. Due to its linear pharmacokinetics, lacosamide constitutes as

a safe choice.15, 33

Topiramate is predominantly excreted by the kidneys as 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%.31, 34

Page 6 of 37
Gabapentin is mostly used for neuropathic pain, headaches and sleep disorders. Nevertheless,

due to his favorable pharmacokinetic profile, it’s another good alternative. It is excreted

unchanged in the urine and does not bind to serum proteins, minimizing the possibilities of drug

to drug interactions.35, 36

Pregabalin, similar to gabapentin, doesn’t bind to plasma proteins and is excreted by the

kidneys. In clinical practice, pregabalin is used mainly for treatment of neuropathic pain, but due

to its benign pharmacokinetics is a reasonable alternative in the treatment of seizures in patients

with hepatic disease.37, 38

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 expected. Monitoring levels is not

necessary. Vigabatrin irreversibly affects gamma aminobutyric acid transaminase and the

duration of pharmacological effect is independent of serum concentration. 39 Vigabatrin is a very

good choice for patients with hepatic disease, but due to concerns of peripheral vision loss and

reversible MRI abnormalities,40, 41 it can be considered a second tier drug.

Oxcarbazepine may offer an advantage over carbamazepine in patients with liver disease. The

main metabolite is a monohydroxilated derivative, which is eliminated mainly by

glucoronidation.42-44 It is a weaker enzyme inducer with linear pharmacokinetics and less

potential for drug interactions. Oxcarbazepine also has fewer chances 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.

Page 7 of 37
Eslicarbazepine is rapidly and extensively metabolized in the liver, but has minimal interactions

with cytochrome p450, minimizing the risk of drug to drug interactions.45-48

Zonisamide, a broad spectrum antiepileptic drug offers no significant hepatotoxicity. About

70% of the drug is cleared by the liver with 35% 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.5, 49, 50

Third line therapy

Carbamazepine, an older generation sodium channel blocker, is mainly metabolized by the

liver. Carbamazepine undergoes auto induction and may produce transient elevation of hepatic

enzymes. Due to its enzyme inducing properties, there are higher chances of drug to drug

interactions than the newer generation sodium channel blockers.51-53

Perampanel, a recently approved glutamate receptor antagonist, undergoes extensive hepatic

metabolism by CYP3A4, but appears to have minimal effect on liver function. The half-life is

prolonged in patients with mild to moderate liver disease, so slow titration is recommended.54-58

Lamotrigine is primarily metabolized to the inactive N-2 nitrogen glucuronide metabolite by the

enzyme uridine diphosphate glucuronyl transferase and it should be used with caution in

moderate to severe liver disease. Recommendations are to reduce dose by 25% in moderate to

severe liver disease without ascites and 50% in patients with severe hepatic disease and ascites.28,
59

AEDs of last resort

Page 8 of 37
Valproic acid is not recommended in patients with liver dysfunction and should be avoided to

the extent possible. Despite the lack of strong evidence, valproic acid could potentially

exacerbate hepatic disease.5 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 non-linear pharmacokinetics and frequent monitoring of blood levels is necessary

in order to avoid toxicity.60 . 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 preexisting encephalopathy.61 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 a medication used mainly in specialized centers for the treatment of patients with

Lennox Gastaut, Doose syndrome or refractory seizures.62 Felbamate is an enzyme inhibitor and

is metabolized by enzymes of the P450 system. It 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

is also metabolized by the liver by cytochrome P450 system and should not be a first line drug.63

Page 9 of 37
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 (FDA). This drug

was developed by modification on its predecessor levetiracetam. It has greater affinity towards

synaptic vesicle 2A (SV2A) and its binding capacity is low. Only 20% of the total in vivo

clearance is by the liver, so it is unlikely to be affected by significant drug interactions. Current

data is limited, but brivaracetam would likely be a safe medication for patients with liver disease.

Its clearance is reduced in patients with hepatic insufficiency and dose may need adjusting.64

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.65-67

For absence seizures in children, ethosuximide is the drug of choice.68 Due to favorable

pharmacokinetics, levetiracetam can be considered first.69 There is also data from small studies

about efficacy of zonisamide and topiramate.70

For seizures of focal onset levetiracetam continues to be an ideal choice, but virtually any first or

second line therapy can be considered, including sodium channel blockers such as lacosamide,

oxcarbazepine and eslicarbazepine71, 72

Page 10 of 37
Hepatotoxicity caused by AEDs.

Chemicals that cause liver injury are call hepatotoxins. There are more than 900 drugs, toxins

and herbs that can produce liver damage.73

In order to determine the hepatotoxic potential of a specific drug, a high number of patients need

to be exposed to the drug and the risk for hepatotoxicity is usually discovered in the

postmarketing phase.13

Drug induced liver injury (DILI) is a rare but potential side effect of AEDs. Serious liver injury

may be the cause of disapproval or removal from the market of a new compound. In patients

receiving liver transplantation in the USA between 1990 and 2002, AEDs were the third most

common cause.74

AEDs can commonly cause asymptomatic or transient elevations in the liver function test.

Elevation in gamma-glutamyl transferase is observed in up to 75-95% of patients exposed to

enzyme inducers, such as carbamazepine, and phenobarbital.53

Zimmerman in 1960 showed that an increase in alanine transferase ≥3 the upper limit of normal

(x ULN) and total bilirubin level ≥2 × ULN (especially in the presence of jaundice) may lead to a

mortality rate of 10-50%.75

In 2011, the new consensus criteria defined DILI as:

(1) Increase in alanine transferase ≥3 x ULN and total bilirubin levels ≥2 × ULN;

(2) increase in alanine transferase level ≥5 × ULN;

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(3) increase in alkaline phosphatase level ≥2 × ULN (especially when associated to elevations in

γ-glutamyl transpeptidase).76

These values are useful in clinical practice, as it’s difficult to predict the occurrence of DILI,

before the clinical course becomes irreversible. The mechanism of liver injury caused by AEDS

is heterogeneous. Hypersensitivity features are found in 70% of cases of DILI related to

phenytoin, but only 30% of cases 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 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.77 The

mechanism of injury is unclear, but it may be related to interference with mitochondrial beta

oxidation of fatty acids.78 An inherited or acquired impairment in beta -oxidation of valproate

may contribute to the liver toxicity.79 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.80 More severe reactions are rare, occurring in about 1 per 15,000 exposures.7, 81

These severe reactions are usually observed in the first three months of treatment.82, 83 In cases of

significant elevation of hepatic enzymes of more than 3 x ULN, valproic acid should be

discontinued.

Clinical symptoms of hepatotoxicity are nausea, vomiting, increase in seizures, jaundice and

fatigue, but signs of hypersensitivity are usually lacking.73 There are clear risk factors identified

in valproic acid associated hepatotoxicity. These include younger age

Page 12 of 37
and polytherapy (Table 4). Additional risk factors include developmental delay, metabolic

disorders, febrile illness and status epilepticus.84, 85

Patients bearing mutations within the mitochondrial DNA replicase, polymerase gamma encoded

by the POLG gene, responsible for the Alpers-Huttenlocher syndrome are at high risk of liver

failure from valproic acid exposure. Testing for POLG mutations may be necessary in children

with refractory seizures and developmental regression before use of valproic acid.86, 87 Despite

available testing, the diagnosis of POLG related disorders remains challenging. The degree of

involvement can be milder and there is a high degree of phenotypic variation.88-91

Valproic acid has also been associated with Reye-like syndrome, which manifests with lethargy,

fever, vomiting and microvesicular steatosis on liver biopsy.92

Asymptomatic hyperammonemia is a common abnormality observed during valproate therapy

and it doesn’t require discontinuation of the drug.93, 94 Valproic acid hyperamonemic

encephalopathy is a more serious condition. Symptoms consist of progressive confusional state

which can lead to coma and death.95, 96 Hepatic enzymes may be normal, but glutamine in CSF

can be high.97 Concomitant use of AEDS, especially topiramate can increase risk of developing

this complication.98

Phenytoin

Phenytoin is an aromatic anticonvulsant with enzyme inducing properties. Its association with

hepatotoxicity is also well recognized.77 Phenytoin produces transient and asymptomatic increase

in ALT in 25% of patients.99 Severe liver injury is part of an idiosyncratic reaction, occurring in

genetically predisposed patients.100 Hepatotoxicity occurs with a frequency of 1 per 10,000 to 1

per 50,000 exposures.101 The incidence is higher in blacks. Children appear to be less

Page 13 of 37
susceptible.102 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.103 These

metabolites may trigger an oxidative injury with a secondary immune mediated response. The

majority of cases are associated with hypersensitivity reactions.104 Fever is observed in 75% of

cases, rash in 62% and eosinophilia in 89%.102 Pathological studies show variable types of

injury, including granuloma formation, cholestatic, cytotoxic or mixed pattern. The cytotoxic

pattern is the most common and the mortality rate after severe liver involvement is 13%.102, 103

Carbamazepine

Carbamazepine is another aromatic drug which 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 exposed

to the drug.105 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.106

Carbamazepine can also produce intermediate arene oxides, but unlike phenytoin, only 30-40%

of cases are linked to hypersensitivity reactions. Once hepatotoxicity has developed, the

mortality rate is about 25%.60 Liver biopsies show inflammatory reactions, cholestasis or

hepatocellular injury with hepatic necrosis observed in lethal cases.103 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.107, 108

Felbamate

Page 14 of 37
Felbamate was synthetized in 1950, while exploring anxiolytic substances. Its antiepileptic

properties were discovered 30 years later and approved by the FDA 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 post marketing phase. Subsequent analysis

showed that the risk of liver failure is between 1:26,000 to 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.109 The mean

time of presentation is between 6- 12 months of therapy. Liver failure can occur without warning

and be fulminant. Patients should be advised about recognition of clinical symptoms. Felbamate

should be discontinued with aspartate aminotransferase – alanine transferase elevations of ≥2 ×

ULN.110

AEDS with low or unclear hepatotoxic potential

Oxcarbazepine

Oxcarbazepine is a newer generation sodium channel blocker. Unlike carbamazepine its older

relative, the association with hepatotoxicity is rare. 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.111-113

Topiramate

Topiramate can produce hyperamonemia when combined with valproic, but hepatotoxicity when

used in monotherapy is very rare. There are few reports of severe hepatotoxicity including one

case leading to liver transplant in a patient also receiving carbamazepine.114, 115

Phenobarbital

Page 15 of 37
Phenobarbital is one of the oldest aromatic AEDs, available since 1911. Despite its extensive

use, phenobarbital has only been associated to hepatotoxicity in rare instances. Phenobarbital can

produce elevation in liver enzymes, and it has been occasionally linked to hypersensitivity

reactions, hepatitis and acute liver failure.116-118 Oxidative stress in the hepatic mitochondria may

be one of the mechanisms of hepatic injury.119

Lamotrigine

Lamotrigine is an effective and relatively safe medication. Rare cases 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

receiving polytherapy (especially valproate and carbamazepine) are more susceptible to

hepatotoxicity.120-122

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 unknown.123-127

Lacosamide

Lacosamide is a new generation AED, which is 40% excreted unchanged by the urine. Part of the

drug is metabolized by the liver and there are only rare reports of hepatic enzymes elevation and

liver toxicity.128-130

Page 16 of 37
Zonisamide

Zonisamide, a second generation medication 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.131, 132

Ethosuximide

Evidence linking Ethosuximide to hepatotoxity is lacking with exception of few reports, mainly

related to its use in combination with other drugs, usually valproic acid .133, 134

Benzodiazepines

Despite the wide use of benzodiazepines, an association with liver toxicity is not strong and

extremely rare.135-137

Gabapentin

Gabapentin has no appreciably liver metabolism and there are only rare individual case reports

about possible hepatotoxicity. Some of these cases include patients taking multiple drugs and the

association remains unclear.138-141

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 2 weeks of treatment.

Cholestatic and hepatocellular patterns of injury have been described.142-145

Vigabatrin

Page 17 of 37
 Vigabatrin is a drug which lacks hepatic metabolism and hepatotoxicity has rarely been

reported.146, 147

Eslicarbazepine

Eslicarbazepine is a drug related to oxcarbazepine and there are only isolated reports about liver

injury , usually with rapid recovery after drug discontinuation.148

AEDs with no known association with hepatotoxicity

Drugs such as tiagabine, perampanel and brevaracetam have not yet been linked to liver

toxicity.58

Despite the available information, most cases of hepatoxicity associated with AEDs are

unexpected and difficult to predict. An increase in liver function tests of 2-3 folds from baseline

warrant enhanced vigilance. Once laboratory values surpass this range or the diagnosis of DILI

has been made, prompt discontinuation of the drug should follow. Other specific treatment

modalities have shown some benefit (Table 5).122, 147, 149-156 Liver transplantation is the treatment

of choice for end stage hepatic damage

AED therapy in special circumstances

Acute porphyria

The acute porphyrias are a group of rare inherited disorders of haem 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

multiple drugs. Symptoms usually consist of abdominal pain, symmetric motor neuropathy,

Page 18 of 37
confusion and seizures. During a crisis there is elevation of the porphyrins precursors δ-

aminolevulinic acid (ALA) and porphobilinogen (PBG).157

The prevalence of seizures in patients with acute intermittent porphyria is about 3.7%, but this

number can increase to. 5.1 % in patients who already presented with acute attacks.158 Selecting

the most appropriate AED remains problematic, as most anticonvulsants are porphorygenic.

Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital can precipitate attacks,

likely by an increase in catabolism of hydroxymethylbilane synthetase and uroporphyrinogen

decarboxylase, affecting haem synthesis.159, 160

Other AEDS including lamotrigine, valproic, primidone, tiagabine, ethosuximide, topiramate,

methsuximide, trimethadione and felbamate have been associated with clinical worsening or

demonstrated porphyrin accumulation in chick embryo liver cells.161-168

Bromides have been historically the drug of choice until new AEDs with more favorable kinetics

appeared in the 1990s (Table 6).169-172 AEDs such as levetiracetam and gabapentin with

negligible hepatic metabolism should be first line treatment. Vigabatrin lacks hepatic metabolism

and constitutes a safe option, but has the potential of causing visual field defects.159, 167

Oxcarbazepine with low hepatic induction of microsomal enzymes has been tried successfully.173

Carbamazepine, a drug with porphorygenic potential has been used in isolated cases and it can be

an alternative when no other options are available, especially in patients with normal ALA and

PBG levels.174

For acute treatment, benzodiazepines are good therapeutic choices. Clonazepam have been tried

safely, but at higher doses could exacerbate symptoms.160, 161, 175 Levetiracetam is available in IV

preparations and is another good alternative for emergency situations.

If general anesthesia is needed midazolam and propofol are probably safe medications.176

Page 19 of 37
Wilson’s disease

Wilson’s disease is a rare autosomal disorder of altered copper transport by loss of function of

the ATP7B copper – binding protein, resulting in accumulation of copper in multiple organs.

Laboratory testing shows low ceruloplasmin and increase in 24 hour urine copper assay.177

Hepatic and neurological involvement are prominent features. Hepatic involvement can vary

from elevation of liver enzymes to hepatic failure or cirrhosis

Neurological symptoms consist of movement disorder and cognitive deterioration, but seizures

can be observed in about 5.5 % of patients before initiation of therapy and in 2.8 % during de-

coppering treatment.178 Seizures can be focal or generalized and can present as status epilepticus.

Good seizure control is achieved in most patients and only a small proportion may become

refractory.178, 179 Multiple AEDS, including phenytoin, valproic acid , benzodiazepines and

carbamazepine have been used successfully; however newer AEDs with less hepatic metabolism

should be favored, especially if the hepatic function is severely compromised. It is important to

supplement with pyridoxine during penicillamine therapy, as pyridoxine deficiency can cause

seizures during the chelation treatment.180

Conclusion

Hepatic disease and seizures may coexist and the use of anticonvulsant therapy is indicated.

Selecting the most appropriate AED therapy remains challenging. The goal of therapy is to

maximize efficacy and 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 lower risk of toxicity offer

good therapeutic choices for this subset of patients. . These medications are also ideal first line

Page 20 of 37
treatment for patients affected by rare conditions, like porphyria or Wilson’s disease with severe

hepatic involvement. 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 but

potential side effect of AEDs and identification of high risk populations is important to prevent

liver injury.

It is therefore necessary for clinicians to be aware of the different therapeutic options available

for the treatment of seizures in patients with liver disease and recognize the hepatotoxic potential

of the different AEDs.

Page 21 of 37
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Figure 1

Page 30 of 37
Table 1: Parenteral benzodiazepines used in acute treatment

Medication Metabolism Half-life in Heathy Subjects Onset of Action Duration of

Action
*Diazepam Hepatic Parent compound: 33 to 45 hours; 1 to 3 minutes 15-30 minutes
Active metabolite-
Desmethyldiazepam: ~87 hours

Lorazepam Hepatic Approximately 14 to 17.8 hours Within 10 minutes 6-8 hours

Midazolam Hepatic 1.8 to 6.4 hours (mean ~3 hours) 3 to 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.

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Table 2: Pharmacological characteristics of antiepileptic drugs and recommendations for their use in patients with hepatic disease
Medication Metabolism Half-Life Protein Potential for Recommended Association Recommended Dose Recommended Dose
Binding Drug Monitoring in with Changes: Mild to Moderate Changes: Severe Hepatic
Interactions‡ Patients with Liver Hepatotoxicity║ Hepatic Disease Disease
Disease*
Brivaracetam Hepatic (20 ~ 9 hours ≤ 20% Minimal Clinical No known Manufacturer Manufacturer
%) association recommendation for patients recommendation for
≥ 16 years of age: Child patients ≥ 16 years of age:
Pugh A/B: Initial: 25 mg Child Pugh C: Initial: 25
twice daily, up to a mg twice daily, up to a
maximum of 75 mg twice maximum of 75 mg twice
daily daily
Carbamazepine Hepatic Children: 8-14 hours 75-90% High Drug Level Well established NSR NSR
Adults: 12-17 hours
Eslicarbazepine Hepatic 13-20 hours < 40% Minimal Clinical/Consider Low NSR NSR
Drug Level
Ethosuximide Hepatic Children: ~30 hours Insignificant Intermediate Clinical/ Consider Low NSR NSR
Adults: 50-60 hours Drug Level
Felbamate Hepatic 20-23 hours 22-25% High Drug Level Well established Contraindicated by Contraindicated by
manufacturer manufacturer
recommendation recommendation
Gabapentin None Children: ~4.7 hours < 3% Minimal Clinical Low NSR NSR
Adults: 5-7 hours
Lacosamide Hepatic ~13 hours < 15% Minimal Clinical/Consider Low Manufacturer NSR
(~60%) Drug Level recommendation for adults:
Maximum daily dose of 300
mg/day ¥
Lamotrigine Mainly hepatic Children: ~19 hours ~ 55% High Drug Level Low Manufacturer Manufacturer
Adults: 25-33 hours recommendation: recommendation: Severe
Mild: None without ascites: Reduce
Moderate without ascites: initial, escalation, and
Reduce initial, escalation, maintenance doses by
and maintenance doses by ~25%. Adjust based on
~25%. Adjust based on clinical response.
clinical response. Severe impairment with
Moderate impairment with ascites: Reduce initial,
ascites: Reduce initial, escalation, and
escalation, and maintenance maintenance doses by
doses by ~50%. Adjust based ~50%. Adjust based on
on clinical response. clinical response.
Levetiracetam Primarily Children:~5.3-6 < 10% Minimal Clinical Low None Decrease dose by half
enzymatic hours Adults:
hydrolysis in 6-8 hours
the blood

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Oxcarbazepine Hepatic Active metabolite: Parent drug: Intermediate Clinical/Consider Low None NSR
Children: 4.8 to 9.3 67% Drug Level
hours Active
Adults: ~9 hours metabolite:
40%
Perampanel Hepatic ~105 hours 95-96% High Drug Level No known Manufacturer Manufacturer
association recommendation: recommendation: Child-
Child-Pugh class A: Pugh class C: NSR
Maximum daily dose: 6
mg/day Child-
Pugh class B: Maximum
daily dose: 4 mg/day
Phenobarbital Hepatic Children: ~110 hours 50-60% High Drug Level Low NSR NSR
(60-180)
Adults: ~79 hours
(53-118)
Phenytoin Hepatic 7-42 hours ≥85% High Drug Level Well established NSR NSR
Half-life increases
with increasing
phenytoin
concentrations
Pregabalin Negligible ~6.3 hours 0% Minimal Clinical Low NSR NSR
metabolism
Tiagabine Hepatic Children: ~5.7 hours 96% High Clinical/Consider No known NSR NSR
(2-10) Drug Level association
Adults: 7-9 hours
Topiramate Hepatic (20 Children: 7.7-12.8 15-41% † Minimal Clinical Low NSR Decrease by 30%
%) hours Adults:
19-23 hours
Valproic Acid Hepatic Children: 7-13 hours 80% - 90% High Drug Level Well established Not recommended by Contraindicated by
Adults: 9-19 hours manufacturer manufacturer
Vigabatrin No significant Children: 5.7-9.5 0% Minimal Clinical Low NSR NSR
metabolism hours
Adults:~10.5 hours
Zonisamide Hepatic (70%) ~69 hours 40% Minimal/ Clinical/Consider Low NSR NSR
Intermediate Drug Level
* Drug level is recommended for AEDs with high chance of drug-drug interactions or toxicity. Especially patients with polytherapy
† Protein binding capacity inversely related to plasma levels
‡ Drugs with high protein binding capacity and/or potential to inhibit or induce hepatic enzymes have high chances for drug-drug interaction
║Hepatotoxicity is a potential but rare side effect of AEDs
¥ Concentration of lacosamide can increase by 50-60% in patients with moderate liver dysfunction.
NSR=No specific recommendation

Page 33 of 37
Table 3: Child-Pugh Class Scores
Data derived from Trey, Burns, and Saunders, 1966, with reproduction permission from Wiley Global Permissions.

Measurement 1 Point 2 Points 3 Points

Bilirubin (total) mg/dL <2 2-3 >3
Serum albumin g/L >35 28-35 <28
INR <1.7 1.71-2.20 >2.20
Ascites None Mild Severe
Hepatic None Grade I-II (or Grade III-IV (or
encephalopathy suppressed with refractory)
medication)

Interpretation

Points Class One year survival Two year survival

5-6 A 100% 85%
7-9 B 81% 57%
10-15 C 45% 35%

Page 34 of 37
Table 4: Calculated risk of hepatotoxicity for specific antiepileptic drugs

Medication Calculated risk Identified or potential risk factors

Carbamazepine Rare Children with polytherapy

Felbamate 1 per 26,000 to 1 per 34,000 Female gender

Polytherapy

Phenytoin 1 per 10,000 to 1 per 50,000 Black ethnicity

Children less susceptible

Valproic Acid Monotherapy Polymerase gamma 1 (POLG1) mutations

Adults: 1 per 45,000 Younger Age
Children < 2 years: 1 per 7,000 Polytherapy
Developmental delay
Polytherapy Metabolic disorders
Adults: 1 per 12,000 Febrile illness
Children < 2 years: 1 per 500-600 Status epilepticus

Page 35 of 37
Table 5: Treatment modalities used in cases of hepatotoxicity associated with specific AEDs

Medication Treatment Notes

Valproic acid L-carnitine Doses of 100 mg/kg followed intravenous doses of
50 mg/kg every 8 hours, to a maximum of 3 grams
per dose.149-152
Hemodialysis, Used for progressive neurological deterioration or
Sodium benzoate ammonia levels greater than 680 μg/dL (400
phenyl acetate μmol/L).153
Carbamazepine N- acetylcysteine * Doses used are 150 mg/kg/hour over one 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.154
Steroids Hypersensitivity reactions
Phenytoin N- acetylcysteine Doses used are 150 mg/kg/hour over one 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.154
Molecular adsorbents Used to remove molecules that are highly protein
recirculating system bound.122, 155
device (MARS)
Steroids Hypersensitivity reactions

Lamotrigine Molecular adsorbents Used to remove molecules that are highly protein
recirculating system bound.122, 147
device (MARS)
Steroids Hypersensitivity reactions

* N- acetylcysteine and antidote for acetaminophen DILI has recently showed benefit for adult
patients with non-acetaminophen DILI, including cases of carbamazepine and phenytoin
hepatotoxicity. On the contrary, N- acetylcysteine was of no benefit in young children with non-
acetaminophen acute liver failure.

Page 36 of 37
Table 6: Potassium Bromide* dosing and potential side effects

Initial dose Maintenance dose Half-life Common side Rare side effects
effects
30 30-80 mg/kg/day Children: 6-8 Drowsiness Bromism
mg/kg/day Increase by 10 days Gastrointestinal (Psychiatric
mg/kg/day every 2 Adults: 8-14 Acneiform symptoms,
weeks days eruption nausea, vomiting,
Concentration rash)172 †
impairment
Behavioral171
*Other formulations (ammonium bromide/potassium bromide/sodium bromide) exist and may
have different dosing regimens; †An incidence of 1 in 1,000,000 has been estimated

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