Discussion
Clopidogrel is highly effective in the treatment of cardiovascular
disease, but occasional side effects, such as rash, gastrointestinal
problems and bleeding. Have been reported after its administration. In
recent years, some researchers have cited hepatotoxic side effects
related to this drug (7,8); more specifically, 20 such cases have been
reported in the literature (table 2). In most of these investigations,
the average age of the patients was approximately 68 (34-90) years and
the average time between the observation of side effects and the
initiation of clopidogrel [therapy] was 35 (3-180) days; these
figures are consistent with our findings. In the literature, the most
common pattern of liver damage was mixed (11 cases), while 5 cases
showed solely hepatocellular involvement and two displayed only
cholestatic injury (5,9,10) . Most studies have indicated the survival
of the majority of patients and improvement of lab results within 1 week
to 6 months of discontinuing the medication. In our presented case,
improvement of lab findings took 2 weeks. To our knowledge, there has
only been a single death reported due to the hepatotoxic side effects of
clopidogrel (11).
The exact cause of liver injury due to clopidogrel remains undetermined,
but two possible mechanisms consisting of a direct dose-dependent
reaction or an idiosyncratic non-dose-dependent reaction have been
suggested (12).
In our case, hepatotoxicity was observed 1 month after the initiation of
clopidogrel; he demonstrated no signs of hypersensitivity, such as rash,
arthralgia or eosinophilia and the clinical presentation pointed
[more] towards a dose-dependent reaction.
Clopidogrel is a prodrug converted to its active form, which consists of
MERCAPTO group, by various cytochromes in the liver, including CYP 4A3
and CYT P 450 (12) . These active metabolites are responsible for the
anti-platelet effects as well as the hepatotoxic effects of the
medication due to inhibition of cell glutathione. Medications that
stimulate CYP 4A3, such as rifampin, can increase the harmful effects of
clopidrogrel on the liver; moreover, one significant finding on biopsies
carried out by various investigators was that the greatest damage was
observed in zone 3 of the liver, which indicates the potential
involvement of CYT P 450 in the pathogenesis of liver injury. The
inhibition of the cytochrome P 450 isoenzyme by clopidogrel is dependent
on time, dosage and NADPH. Drugs such as captopril, hydrochlorothiazide
and allopurinol can lead to cholestasis via this pathway. By affecting
some isoenzymes in the cytochrome P 450 and CYP 4A3 pathways,
interactions between clopidrogrel and omeprazole or certain statins,
such as atorvastatin, may lead to liver damage (14).
In summary, due to the widespread use of clopidrogrel in various
diseases, it is prudent to bear in mind the less common side effects of
this medication, particularly when there is a possibility of drug
interaction.
Table 1. Patient’s lab data