ARTICLE
Auteur(s) : Glen Jickling, Angela Heino, S Nizam Ahmed
University of Alberta Hospital, Alberta, Canada
Article reçu le 7 Janvier 2009, accepté le 24 Septembre 2009
Acetaminophen is a commonly used medication that is generally
well tolerated. Problems relating to toxicity usually arise only in
acute overdose of greater than seven grams or in chronic use of
more than four grams per day. We report a case of hepatic and renal
failure from a therapeutic dose of acetaminophen in a patient on
carbamazepine. This patient raises concern that carbamazepine may
predispose to acetaminophen induced toxicity and hepatic failure in
some patients.
Case study
A 34-year-old man with complex partial seizures controlled for
eleven years on carbamazepine 1,600 mg per day and clobazam
10 mg per day. He also had Crohn’s disease treated with
mesalazine 4 g per day. Two weeks prior to presentation, he
developed musculoskeletal lower back pain. He started an analgesia
containing acetaminophen and methocarbamol. For twelve days he
received 2,000 mg of acetaminophen and 800 mg of
methocarbamol. He developed abdominal pain that radiated into both
flanks and was associated with a sense of unsteadiness. He
increased his does of analgesia to 2,500 mg of acetaminophen
and 800 mg of methocarbamol.
On presentation he complained of diplopia, gait instability and
anuria. On examination his bowel sounds were reduced and he had
diffuse abdominal tenderness, with no rebound tenderness. No
costovertebral angle tenderness was present. On neurological
examination his extraocular movements were full with bilateral gaze
evoked nystagmus. The remainder of his cranial nerve, motor, reflex
and sensory examination was unremarkable. He had a postural tremor
and mild dysmetria in both upper and lower extremities. His gait
was slightly broad based.
Routine labs identified an alanine aminotransferase (ALT) of
9,101 U/L and aspartate aminotransferase (AST) of
10,274 U/L. His PT INR was 2.2 and his albumin was
34 g/L. His creatinine was elevated at 592 umol/L with a
urea level of 17.3 mmol/L. A serum acetaminophen level
was 77 umol/L and carbamazepine level was 87 umol/L.
Viral hepatitis serology for B and C was negative, as was a work up
for autoimmune diseases including normal anti-DS-DNA, ANA,
complement levels, anti-GBM and ANCA. An abdominal ultrasound
showed a diffusely echogenic liver, with no evidence of biliary
ductal dilation or stones. Liver biopsy was not performed.
A renal biopsy showed interstitial nephritis.
The patient was treated with IV fluids, N-acetylcysteine
protocol and a course of prednisone. He was restarted on
carbamazepine two days after admission and tolerated the medication
well. His AST and ALT gradually normalized (figure 1). The patient was
discharged home three weeks after admission and has remained
medically stable for over two years.
Discussion
Acute hepatic failure is most commonly caused by acetaminophen
toxicity. Other etiologies include idiosyncratic drug reactions
(such as with carbamazepine, phenytoin and valproate), viral
hepatitis, autoimmune hepatitis, liver hypoperfusion, Wilson’s
disease, pregnancy and malignancy. In our patient, acetaminophen
was suspected to be responsible for the development of liver
failure. Other etiologies were considered less likely given his
history, negative viral hepatitis serology, negative autoimmune
workup and normal ceruloplasmin and 24-hour urine copper. Our
patient was also on a number of medications that were considered a
less likely cause. Carbamazepine can cause acute liver failure,
however our patient had been on a stable dose for eleven years
without complication. Clobazam and methocarbamol were also being
taken by our patient, however neither medication induces or
inhibits hepatic enzymes, and neither have reported cases of liver
failure on medline (Ahmed and Siddiqi, 2006). Mesalazine can rarely
cause hepatitis (3 per million) which could be an alternative
explanation for the development of our patients liver failure.
However since he had tolerated the medication well for over
2 years without a change in dose, we believe it a less likely
etiology (Ransford and Langman, 2002).
The mechanism by which carbamazepine may predispose to
acetaminophen toxicity can be understood by assessment of the
metabolism of these medications. Acetaminophen is metabolised in
the liver via conjugation. When this conjugation pathway becomes
saturated, acetaminophen is metabolized by the cytochrome
p450 enzymes CYP2E1 and CYP1A2. This pathway produces a
toxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI), which
normally is conjugated with glutathione and renally excreted. When
the glucoronidation capacity is exceeded, NAPQI accumulates and
covalently binds to hepatic proteins leading to hepatocellular
necrosis and apoptosis. This most commonly occurs in acute
acetaminophen overdose of greater than seven grams or when the
maximum daily dose of four grams per day is exceeded for an extend
period of time. Though our patient was taking 2.5 g of
acetaminophen per day, he had an elevated serum acetaminophen level
at 77 umol/L and was also taking carbamazepine. Carbamazepine
is an antiepileptic medication that induces the p450 enzyme
CYP3A4, which also is involved in the metabolism of acetaminophen
to NAPQI, though a lesser extent than CYP2E1 and
CYP1A2 (Kostrubsky et al., 1997). The induction of
CYP3A4 by carbamazepine thus can lead to an increase in NAPQI
and subsequent liver damage.
Two case reports also suggest that carbamazepine reduces the
dose of acetaminophen required to induce hepatocellular damage. An
80 year old female on carbamazepine developed liver
dysfunction after receiving four grams of daily acetaminophen for
18 days (Parikh et al., 2004). She subsequently improved
with N-acetylcysteine (NAC) and cessation of acetaminophen use.
A 17 year old female with anorexia and a mood disorder
treated with carbamazepine, developed acute hepatic failure with a
7.5 grams overdose of acetaminophen (Young and Mazure, 1998).
Despite this low dose of acetaminophen and the use of NAC, the
patient required a liver transplant. Though these two case reports
are confounded by age and anorexia respectively, there is a
suggestion carbamazepine may lower the required acetaminophen dose
to induce liver failure. It is also possible that these few case
reports represent patients with a genetic mutation in the metabolic
pathways of acetaminophen when combined with carbamazepine.
A retrospective study showed that carbamazepine is associated
with worse outcomes in patients who develop liver failure from
acetaminophen overdose, suggesting that carbamazepine may
potentiate the hepatotoxic effects of acetaminophen (Bray
et al., 1992).
Other medications and conditions have been also been associated
with an increased risk of hepatotoxicity from acetaminophen (table 1). Phenytoin induces the
p450 enzymes CYP3A4 and CYP2C but not CYP2E1 or
CYP1A2. Like carbamazepine, the induction of CYP3A4 by phenytoin
may lead to increased production of NAPQI from acetaminophen.
Several case reports have also been described of liver failure
related to low dose acetaminophen in patients on phenytoin (Suchin
et al., 2005).
Our patient also developed acute renal failure with the biopsy
showing interstitial nephritis. Medications are a cause of
interstitial nephritis, and both acetaminophen and carbamazepine
are among the medications associated with this immune reaction to
the kidneys (Eijgenraam et al., 1997). The management of acute
interstitial nephritis warrants cessation of offending medication,
and initiation of brief course of corticosteroids (John and
Herzenberg, 2009). In the presented case, the patient had been on
carbamazepine for eleven years without complication, and therefore
the treating physicians suspected acetaminophen as the primary
culprit responsible for the interstitial nephritis. Carbamazepine
was restarted during admission with no recurrent hepatic or renal
problem. If an anti-epileptic medication is considered as a cause
of interstitial nephritis alternative agents that could be
initiated include benzodiazepines, gabapentin and levetiracetam.
Phenytoin, lamotrigne and valproate should be avoided, as each has
been associated with the development of interstitial nephritis
(John and Herzenberg, 2009; Monckeberg et al., 2004).
This case raises caution regarding the daily use of
acetaminophen in patients on carbamazepine, though it should be
emphasised that further study is required before any
recommendations can be made. Consideration however could be given
to a dose reduction of acetaminophen, and patient education
alerting them to early signs of liver dysfunction, such as nausea,
vomiting, icterus and anorexia. The role of frequent liver function
monitoring is uncertain, however we suggest at a minimum obtaining
liver function testing when patients report such symptoms
consistent with possible liver dysfunction.
Table 1 Medications and conditions associated with an
increased risk of acetaminophen induced hepatotoxicity.
|
Medication/condition
|
Mechanism of action
|
|
Smoking Isoniazide, chronic ethanol use Carbamazepine,
phenytoin
|
p450 CYP1A2 enzyme induction p450 CYP2E1 enzyme induction p450
CYP3A4 enzyme induction
|
|
Infants Chronic ethanol use AIDS Malnutrition
|
Low Glutathione
|
|
Verapamil
|
P-glycoprotein efflux pump inhibitor
|
Disclosure
None of the authors has any conflict of interest to disclose.
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