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| Journal of the New Zealand Medical Association,
28-January-2005, Vol 118 No 1208
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Hyponatraemia, fever, vomiting, severe abdominal pain, and
weight loss associated with omeprazole
Barry Colls, Oliver Menzies
The management of upper gastrointestinal disease has been
revolutionised since the introduction of proton pump inhibitors (PPIs). This is
reflected in their sales figures in first world countries.
Canada and the USA account for nearly one half of the
world’s total drug sales of PPIs; esomeprazole generated worldwide sales
of US$3.8 billion in 2003,1second only to
atorvastatin. In New Zealand in 2003, anti-ulcerant drugs were the largest
expenditure in the Pharmaceutical Schedule, and account for more than $NZ50
million annually; omeprazole accounted for the vast majority of this
expenditure.2
In addition to being effective, PPIs are relatively free of
significant adverse effects (AEs). The commonest AEs that have been reported are
gastrointestinal;3 of these, nausea and
abdominal pain are two of the most frequently recorded.
Fever4 and
hyponatraemia3,5 have rarely been reported
(although not in combination), and neither of these have been reported in
association with gastrointestinal AEs.
The current case report concerns a patient in whom
hyponatraemia, fever, vomiting, severe abdominal pain, and striking weight loss
were seen together and considered to be due to omeprazole.
Case reportA 60-year-old Caucasian female was
admitted to hospital on 29 December 2003 complaining of nausea, vomiting,
anorexia, severe abdominal pain, and significant weight loss. Her past medical
history included a long standing non-toxic nodular goitre, type 1 diabetes
mellitus diagnosed 4 months earlier, and hypertension. Her medication included
insulin penmix 30 (24 units mane and 10
units at dinner time), cilazapril (1 mg
mane), and omeprazole (40 mg
mane). The omeprazole had been started
4 months previously because of a presumed Mallory-Weiss oesophageal tear.
Physical examination revealed a miserable, wasted, febrile
lady with a multinodular goitre and slight hirsutism. There was generalised
abdominal tenderness but no other abnormalities were noted.
She was comprehensively investigated. Gastroscopy was
normal. All radiology scans, including CT (abdomen, chest) and MRI (head), were
unhelpful—although her multinodular goitre and an incidental uterine
fibroid were noted. A thyroid fine needle biopsy and duodenal biopsy were also
unhelpful. Midstream urine and blood cultures were negative. The haematology
tests were normal. Her blood sugars were compatible with reasonably controlled
diabetes and her other biochemistry was normal with the exception of a low serum
sodium—ranging between 129 and 134 mmol/L. Endocrine tests, including
thyroid pituitary and adrenal functions were all normal. She continued to lose
weight, reaching a nadir of 44.6 kg—a weight loss of 14.4 kg.
Omeprazole was discontinued on 21 January 2004 and her fever
ceased within 3 days. The nausea, vomiting, and abdominal pain resolved over 1
week. Her serum sodium remained in the low 130 mmol/L range for a few days and
then normalised. Her appetite returned and she gained weight—by 24 March
2004, she had reached 56.8 kilograms and was feeling well.
DiscussionPrior to the commencement of
omeprazole, this patient weighed 59 kilograms and was eating normally without
nausea, vomiting, or abdominal pain. It is known that she was afebrile and
eunatraemic before omeprazole was instituted. Her gastrointestinal symptoms
developed a few weeks after the institution of omeprazole and progressively
worsened over the next 4 months. Fever and hyponatraemia were noted.
Omeprazole was continued for approximately 3 weeks, and then
stopped because of the possibility that it was related to her symptomatology. As
discussed in the case report, the gastrointestinal symptoms and the fever and
hyponatraemia ceased shortly after the cessation of omeprazole.
The temporal relationship between the cessation of PPIs and
her general improvement was striking. A challenge would have been interesting
and informative, but it was felt that it would be inappropriate in view of the
life-threatening nature of the adverse effects.
All of the symptoms and signs noticed in this case have been
previously reported as AEs of omeprazole, but there is no report of them all
occurring in a single patient. Some of these adverse effects are rare. Fever,
for example, has only been reported four times in the New Zealand Centre for
Adverse Reactions Monitoring (CARM)
database.6
A Medline search (with keywords ‘omeprazole’ and
‘fever’) found only two articles in
English,4,7 which mention fever, but only in
the context of omeprazole causing acute interstitial nephritis. Also, in the
case reported by Landray et al, pyrexia, anaemia, and acute renal failure were
present—but gastrointestinal symptoms or hyponatraemia did not
feature.4
Hyponatraemia has been reported on at least eight
occasions5,8 and there are three cases reported
in the CARM database.6 Interestingly, Rosholm
et al noted in a population study that omeprazole usage was associated with a
lower median serum sodium concentration (difference 3 mmol/L), although they
felt that this was not clinically
relevant.9
The question arises whether this lady’s adverse events
were due to idiosyncrasy or prolonged exposure to a higher dose range of
omeprazole. Another possibility is that she may have been a poor metaboliser of
the drug. It is known that omeprazole is extensively metabolised in the liver by
the cytochromes P450 enzyme system, the major part of the metabolism being
dependent on the polymorphically expressed specific isoform
CYP2C19.
People with two copies of the gene coding for this enzyme
are known as homozygous extensive metabolisers; those with one copy,
heterozygous extensive metabolisers; and those with no copies (approximately
2%–6% of the Caucasian population10),
poor metabolisers. In poor metabolisers, levels of omeprazole in the blood can
be much higher than in the other two genotypes, and poor metabolisers can have
up to 10 times the AUC (area under the curve) compared with homozygous extensive
metabolisers.
Such a mechanism might explain our patient’s adverse
reaction. There are several gene mutations that may render one or more of the
CYP2C19 genes inactive—or cause
decreased, altered, or absent gene products. Two of the most common mutations
(accounting for 95% of cases) are known as
CYP2C19*2 and
CYP2C19*3. These mutations were tested
for in our patient, and found not to be present. This does not definitely
exclude her being a poor metaboliser, as she may have been a poor metaboliser
due to a much rarer mutation—but with no
CYP2C19 mutations found, this patient
is likely to be an extensive metaboliser.
Whatever the mechanism (idiosyncrasy is perhaps the most
likely), this patient appeared to have had a life-threatening complex of signs
and symptoms (fever, hyponatraemia, vomiting, weight loss, and abdominal pain)
associated with exposure to omeprazole—a combination of adverse effects
not hitherto reported in association with this drug.
Author information:
Barry M Colls, General Physician; Oliver H Menzies, Medical Registrar,
Department of General Medicine, Christchurch Hospital, Christchurch
Correspondence: Prof
B M Colls, Department of Medicine, Christchurch School of Medicine and Health
Sciences, PO Box 4345, Christchurch. Fax: (03) 364 0935; email: rowena.fisher@chmeds.ac.nz
References:
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