Exploring psychotherapeutic issues and agents in clinical practice Psychopharmacology

What Will it Do to My liver?

W
ith a few exceptions (e.g.,
lithium, gabapentin, pre-
gabalin), most psychotro-
pic drugs are metabolized in the liver.
For this reason, many patients want to
know whether medications they take
can harm the liver and whether blood
testing is necessary. This article reviews
the effects of anticonvulsant, antide-
pressant, and antipsychotic drugs on the
n
tee
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Drug-inDuceD liver inJury

Drug-induced liver injury is the
fourth leading cause of liver damage
and the second main cause of acute
liver failure worldwide; moreover, it is
the primary cause of liver failure in the
United States (Bernal, Auzinger, Dha-
ABstrAct wan, & Wendon, 2010). Liver toxicity
Liver toxicity is the leading reason for withdrawal of marketed drugs and is a is the leading reason for withdrawal
common reason for terminating the development of new drugs. Anticonvul- of marketed drugs and is a common
sant, antidepressant, and antipsychotic drugs can be associated with signifi- reason for terminating the develop-
ment and marketing of investigational
cant liver injury or liver failure, but this is relatively rare compared to other non-
drugs. Antidepressant, antipsychotic,
psychotropic drug classes. More commonly, mild asymptomatic elevations in and anticonvulsant drugs can be as-
liver function tests are seen and these are not predictive of progression to more sociated with hepatotoxicity, but their
severe liver injury. Laboratory monitoring of liver function before and during relative risk of causing significant liver
treatment is recommended with the use of valproic acid and carbamazepine, injury or liver failure is considerably
but not for other psychotropic drugs, although regular laboratory testing is not less compared with other nonpsycho-
tropic drug classes, such as analgesic
a reliable method for detecting or preventing severe liver injury. Clinical moni-
drugs, antimicrobial agents, herbal
toring for signs and symptoms suggesting hepatotoxicity or hypersensitivity medicines, and other drugs (Bernal et
reactions that affect the liver is more important. [Journal of Psychosocial Nursing al., 2010; Reuben, Koch, Lee, & Acute
and Mental Health Services, 52(8), 23-26.] Liver Failure Study Group, 2010).

robert h. howland, MD
Journal of Psychosocial nursing • Vol. 52, no. 8, 2014 23
Psychopharmacology
Indeed, paracetamol (acetamino-
phen [Tylenol®]) is by far the most
common cause of drug-induced liver
failure, either by intentional or un-
intentional overdose. In the United
States, approximately one half of cases
of acetaminophen-associated liver
failure are due to intentional over-
dose. In addition, excessive alcohol
use is the fourth leading preventable
cause of death, accounting for approx-
imately 10% of deaths among adults,
and the two most frequent chronic
causes of alcohol-attributable death
are alcoholic liver disease and cirrho-
sis (Stahre, Roeber, Kanny, Brewer, &
Antidepressant and antipsychotic drugs are less
likely to cause significant liver injury or failure
than anticonvulsant drugs.
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ock
14 S
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erst
© 20
Zhang, 2014). Combining acetamino-
phen and alcohol is associated with an
increased risk of severe hepatotoxicity;
however, alcohol use is not clearly or
consistently identified as a risk factor
for liver injury associated with other
drugs (Björnsson, 2009).
Liver injury can be broadly classi-
fied as hepatocellular (i.e., referring to
hepatocyte involvement) or cholestatic
(i.e., referring to bile flow), but these
pathological changes can be mixed.
“Liver function tests” is a catch-all
phrase for laboratory determinations
of various chemical products, enzymes,
and proteins relevant to the liver that
can be measured in serum. The enzymes
alanine transaminase (ALT), aspartate
transaminase (AST), gamma-glutamyl
24
transferase (GGT), and alkaline phos-
phatase (ALP), as well as the hemoglo-
bin breakdown product bilirubin, are
most commonly used as markers of liver
injury. Mild or transient elevation of
liver enzymes (i.e., less than three times
the upper laboratory limit of normal
[ULN] for ALT or less than two times
the ULN for ALP) occurs much more
commonly with the use of antidepres-
sant, antipsychotic, or anticonvulsant
drugs than severe hepatotoxicity (Au &
Pockros, 2013; U.S. National Library of
Medicine, 2014; Voican, Corruble, Na-
veau, & Perlemuter, 2014).
l
Sel
ot4
Anticonvulsant Drugs and
the Liver
Phenytoin (Dilantin®), which
is not typically used in psychiatry,
is more likely to be associated with
liver failure in adults compared with
other anticonvulsant drugs, such as
valproic acid (Depakote®), carba-
mazepine (Tegretol®), lamotrigine
(Lamictal®), topiramate (Topamax®),
and gabapentin (Neurontin®), which
are used in psychiatric practice (Min-
dikoglu, Magder, & Regev, 2009; Reu-
ben et al., 2010). Severe hepatotoxic-
ity (including liver failure) associated
with valproic acid and carbamazepine
occurs primarily in pediatric popula-
tions, often when used together with
multiple anticonvulsant drugs (Au
& Pockros, 2013; Mindikoglu et al.,
2009). Antidepressant and antipsy-
chotic drugs are less likely to cause
significant liver injury or failure than
anticonvulsant drugs.
With the use of valproic acid, tran-
sient elevations in ALT and AST
occur in 10% to 15% of patients,
as well as increased bilirubin in up
to 44% of patients (Au & Pockros,
2013). Elevations of GGT and ALP
are less common. Severe hepatotox-
icity is rare, idiosyncratic, unpredict-
able, and generally unrelated to dose.
Should patients stop taking valproic
acid if their liver function tests are ab-
normally elevated? The recommenda-
tion is that patients can continue to
take the drug if their levels are not ex-
cessively elevated (i.e., less than three
times the ULN for ALT or AST; less
than two times the ULN for ALP; less
than two times the ULN for biliru-
bin). Clinical monitoring (i.e., assess-
ing for fatigue, poor appetite, abdomi-
nal pain, nausea, vomiting, dark urine,
jaundice) and laboratory monitoring
should be conducted during follow up.
Ammonia is a breakdown product of
proteins and is converted to urea in
the liver. Valproic acid can inhibit this
conversion, resulting in elevated am-
monia levels that can sometimes cause
confusion or hepatic encephalopa-
thy (i.e., a more severe delirium-like
state). Monitoring ammonia levels is
not routinely necessary, but it should
be done if confusion develops. Ammo-
nia levels will drop and confusion will
resolve by stopping valproic acid.
Asymptomatic elevations of liver
function tests (most commonly GGT)
occur in up to 60% of patients tak-
ing carbamazepine (Au & Pockros,
2013). Similar to valproic acid, car-
bamazepine can be continued with
clinical and laboratory monitoring as
long as the elevations are not exces-
sive. Severe hepatotoxicity is unpre-
dictable, idiosyncratic, and uncom-
mon. Hypersensitivity (i.e., allergic)
reactions to carbamazepine, which
are characterized by skin rash, fevers,
eosinophilia, and (rarely) the Stevens-
Johnson syndrome, can also involve
the liver in approximately 10% of pa-
Copyright © SLACK Incorporated

tients. Carbamazepine should be dis-
continued when clinical evidence of
hypersensitivity exists.
Elevations of liver function tests are
uncommon with the use of lamotrigine,
occurring in less than 1% of patients,
and severe hepatotoxicity is rare (Au
& Pockros, 2013). Similar to carbam-
azepine, hypersensitivity reactions to
lamotrigine can sometimes involve the
liver. To avoid hypersensitivity reac-
tions, the recommended use of lamotrig-
ine includes low starting doses and a
slow upward dose titration schedule.
Less than 1% of patients develop
elevations in liver enzymes during
long-term topiramate therapy, and sig-
nificant hepatotoxicity is rare and usu-
ally seen in patients taking multiple
anticonvulsant drugs (U.S. National
Library of Medicine, 2014). Gabapen-
tin is not metabolized by the liver and
is not associated with an increased fre-
quency of liver enzyme elevations or
liver toxicity (U.S. National Library
of Medicine, 2014). Rare case reports
of gabapentin-associated liver injury
have been published, but the causal
relationship cannot be established be-
cause of other concurrent medications
and/or medical conditions (U.S. Na-
tional Library of Medicine, 2014).
Antidepressant drugs and
the liver
Antidepressant drugs have been
associated with mild asymptomatic
elevations of liver enzymes in up to
10% of patients (U.S. National Li-
brary of Medicine, 2014; Voican et al.,
2014). Severe hepatotoxicity and liver
failure can occur with any antidepres-
sant drug, but it is rare, idiosyncratic,
unpredictable, and generally unrelated
to dose. Compared with anticonvul-
sant and other nonpsychotropic drugs,
antidepressant drugs are less likely to
cause significant liver injury or failure.
Among different antidepressant drugs,
whether certain drugs are more likely
to be associated with significant liver
injury cannot be definitively estab-
lished because their relative frequency
Journal of Psychosocial Nursing • Vol. 52, No. 8, 2014
of use, the reasons for their use, and
the types of patients for whom they
are used often differ. In addition, limi-
tations in the methodology of stud-
ies that investigate this issue and the
well-known problems in establishing
causality based on case reports make it
difficult to determine the relative risk
of liver injury across different antide-
pressant drugs.
However, despite the uncertainty,
nefazodone (Serzone®) and duloxetine
(Cymbalta®) have been singled out for
their potential hepatotoxicity. The
product label for nefazodone includes
a black-box warning stating that cases
of life-threatening hepatic failure
have been described. The warning
also recommends that nefazodone
should not be used in patients with
pre-existing liver disease or increased
liver enzymes; however, the statement
acknowledges that no evidence ex-
ists that these patient characteristics
increase the likelihood of developing
nefazodone-associated liver failure.
The product label for duloxetine has a
general precaution statement indicat-
ing that hepatotoxicity, including hep-
atitis, jaundice, elevated transaminase
levels, and fatal liver failure, has been
reported. Some of these reports have
been in the context of patients who
have concurrent chronic liver disease,
cirrhosis, or heavy alcohol use. The pre-
caution recommends that duloxetine
should ordinarily not be prescribed for
patients with substantial alcohol use or
evidence of chronic liver disease.
Laboratory monitoring of liver
function tests before and during treat-
ment with antidepressant drugs is not
generally recommended because doing
so has not been shown to increase the
likelihood of detecting or preventing
significant liver injury or failure. Pa-
tients taking antidepressant drugs who
have abnormally elevated liver func-
tion tests can continue to take them as
long as their levels are not excessively
elevated (following similar guidelines
and monitoring as previously de-
scribed for valproic acid).
Psychopharmacology
Antipsychotic drugs and
the liver
With the exception of chlorproma-
zine (Thorazine®), which has been as-
sociated with cholestatic liver injury
(Björnsson & Jonasson, 2013), typi-
cal (i.e., first generation) and atypical
(i.e., second generation) antipsychotic
drugs are rarely associated with severe
liver injury. During the 1960s and
early 1970s, chlorpromazine was one
of the most common causes of drug-in-
duced liver disease (U.S. National Li-
brary of Medicine, 2014). Cholestatic
hepatitis is characterized by promi-
nent elevations of ALP and bilirubin,
with symptoms that include nausea,
fatigue, pruritus, dark urine, and jaun-
dice. Chlorpromazine is classified as
a phenothiazine drug; although other
phenothiazine antipsychotic drugs can
cause cholestatic hepatitis, this condi-
tion occurs much less frequently than
with chlorpromazine. Similar to anti-
depressant drugs, antipsychotic medi-
cations can be associated with mild
asymptomatic elevated levels of liver
enzymes, which do not predict a pro-
gression to severe liver injury.
Conclusion
Anticonvulsant, antidepressant,
and antipsychotic drugs can be asso-
ciated with significant liver injury or
failure, but it is relatively rare. More
commonly, mild asymptomatic eleva-
tions in liver function tests are seen,
and these elevations are not predic-
tive of progression to more severe
liver injury. Laboratory monitoring of
liver function before and during treat-
ment is recommended with the use
of valproic acid and carbamazepine,
but not for other psychotropic drugs.
However, regular laboratory testing
is not a reliable method for detecting
or preventing severe liver injury. Ab-
normal liver function can be associ-
ated with other comorbid conditions
or concurrent medications. In addition,
increased liver enzyme tests have been
demonstrated in healthy patients taking
placebo in clinical trials (Rosenzweig,
25
Psychopharmacology
Miget, & Brohier, 1999) and in healthy
placebo-treated patients in clinical trials
who are hospitalized (Narjes & Nehmiz,
2000). Therefore, interpretation of liver
function tests is not always straightfor-
ward. Clinical monitoring for signs and
symptoms suggesting hepatotoxicity or
hypersensitivity reactions is more im-
portant. Nurses should be familiar with
these signs and symptoms, and they
should educate patients and families
about them as well, encouraging them
to call between appointments should
they notice any changes. Nurses should
also routinely counsel patients about
their use of acetaminophen and alco-
hol, as these are much more likely to
adversely affect liver function and cause
severe liver injury or liver failure.
References
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liver injury from antiepileptic drugs. Clinics
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cld.2013.07.011
Bernal, W., Auzinger, G., Dhawan, A., & Wen-
26
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Dr. Howland is Associate Professor of Psychi-
atry, University of Pittsburgh School of Medicine,
Western Psychiatric Institute and Clinic, Pitts-
burgh, Pennsylvania.
The author has disclosed no potential
conflicts of interest, financial or otherwise.
Address correspondence to Robert H. Howland,
MD, Associate Professor of Psychiatry, University of
Pittsburgh School of Medicine, Western Psychiatric
Institute and Clinic, 3811 O’Hara Street, Pittsburgh,
PA 15213; e-mail: HowlandRH@upmc.edu.
Posted: August 6, 2013
doi:10.3928/02793695-20140722-01
Copyright © SLACK Incorporated