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Therapeutics Today
March 2015
Number 3
For personal use only. Not to be reproduced without permission of the editor.
Vitamin B12 Deficiency. Vitamin (Vit) B12 is essential for normal cell
metabolism, therefore a deficiency may lead to disruption of DNA and cell
metabolism with serious clinical consequences. A recent article reviewed the
causes, clinical features and management of Vit B12 deficiency (BMJ 2014;
349: g5226). The prevalence of Vit B12 deficiency in the Western world is
estimated to be around 6% in people <60 years rising to 20% in those >60
years. In developing countries the prevalence is much higher. Foods
containing Vit B12 are derived only from animals (meat, fish and dairy). The typical Western diet
contains 5 to 30 micrograms of Vit B12 per day of which 1 to 5 microgram is absorbed.
Recommended daily intakes range from 1 to 2.4 microgram per day. Because body storage is
relatively high (1 to 5mg), deficiency from diminished intake or absorption may not manifest itself for
many years after the depletion of stores. Common causes of Vit B12 deficiency include impaired
gastric absorption (due to pernicious anaemia, partial / total gastrectomy, Zollinger-Ellison syndrome),
impaired intestinal absorption (such as ileal resection or diseases like Crohn’s disease, pancreatic
insufficiency, parasites), decreased intake (malnutrition, reduced intake of animal products / vegan
diet), increased requirements (haemolysis, HIV), or rarely inherited disorders. Certain drugs (such
as alcohol, PPIs, H2 receptor antagonists, metformin, slow release potassium preparations, and
colestyramine) have also been reported to cause Vit B12 deficiency. Deficiency is most likely to
occur during periods of increased Vit B12 requirement (e.g. growth periods during childhood and
adolescence or pregnancy) or due to reduced nutrition (e.g. older people, those on vegan or
vegetarian diet). Clinical features of Vit B12 deficiency are heterogeneous because of its effects on
multiple systems. Mild deficiency presents as fatigue and anaemia (with blood tests suggestive of Vit
B12 deficiency) but no neurological features. Moderate deficiency may include glossitis, distal sensory
impairment in addition to macrocytic anaemia. Severe deficiency may show bone marrow
suppression, neurological symptoms (sensory loss, motor disturbances, abnormal balance and
reflexes, cognitive impairment and memory loss) with a risk of cardio-myopathy. Diagnosis is based
on the clinical symptoms, anaemia (mean cell volume >100fl) and history of GI disease / dietary and
drug history. It is important to note that the clinical features may manifest without anaemia,
therefore if the clinical presentation suggests Vit B12 deficiency, patients should be treated
without delay to avoid neurological impairment. Management involves identifying and treating the
cause (if possible) and Vit B12 therapy. In the absence of obvious reduced intake or GI disease,
measurement of intrinsic factor and anti-parietal cell antibodies to rule out pernicious anaemia should
be considered. Hydroxocobalamin 1mg (parenteral Vit B12) is administered on alternate days for two
weeks (should be started immediately if neurological deficit). Folic acid 5mg daily should be started
after Vit B12 therapy and the patient should be monitored for hypokalaemia which may occur with Vit
B12 treatment. Lifelong therapy (every 2 / 3 months depending on presence / absence of neurological
deficits) may be required for those with irreversible causes of low Vit B12 or where diet is likely to
remain a poor source. For temporary causes, such as pregnancy, the treatment can be reviewed
when the patient is fully replete and the causative agent removed. Specialist referral may be needed
as follows: early neurology referral for those with neurological deficits; haematology referral if the
diagnosis is uncertain or if the macrocytic anaemia doesn’t respond to treatment; GI referral if there is
a suspected GI cause (e.g. gastric malignancy, possible malabsorption or inflammatory disease).
Do oral bisphosphonates reduce risk of postmenopausal
endometrial cancer? Bisphosphonates (BisP) are widely used for the
prevention and treatment of osteoporosis. Some studies have shown an inverse
association between the use of certain BisP and breast cancer risk. Since
hormonally-mediated endometrial cancer shares many risk factors with breast
cancer, a recent study evaluated the potential effect of BisP on endometrial
cancer risk (JCO 2015; 10.1200/JCO/2014.58.6842). A total of 89,918 women enrolled in the Women’s
Health Initiative (WHI) were included in this analysis; 44% had been enrolled in at least one of the WHI
randomised trials (RCTs), 56% were in the observational WHI (WHI-O) cohort. Information on
medication use, (including oral BisP) was collected at baseline and at 1, 3 and 6 years (RCT group) and
at baseline and 1 and 3 years for the WHI-O group. Results showed only 2% of the study population
were taking BisP at baseline but this increased to 10% by year 6; alendronate accounted for 90% of the
reported usage. BisP users were slightly older, more highly educated, less likely to be current smokers
and leaner than non-users. There was no difference in hormone replacement therapy (HRT) use
between the study groups at baseline; 19% of non-BisP users versus 11% of BisP users came from the
RCT / WHI-O groups respectively but treatment and placebo arms were well-balanced between users
and non-users. During study follow-up, 1,123 women were diagnosed with incident endometrial
cancer (1,070 non-users; 53 users), which represents a statistically significant 20% risk
reduction. BisP usage was inversely associated with age-adjusted endometrial cancer risk and the
association was largely unchanged when adjusted for other potential confounders (including baseline 5year hip fracture risk, BMI, ethnicity, smoking status, prior use of oral contraceptives or HRT, parity and
mammography results). The authors note that since the study was observational, confounding might be
present which could interfere with the truthfulness of the results. However, their full-adjustment process
should have accounted for possible confounding and in particular the possibility that BisP users might
represent a group of patients with low endogenous oestrogen, who are at lower risk of endometrial
cancer anyway. They conclude that the results suggest a modest inverse association between BisP use
and endometrial cancer risk which is consistent with the inverse association seen with BisP use and
breast cancer risk.
New Guidance on Drug Allergy! The diagnosis of drug allergy can be
challenging – it is estimated that about half a million people admitted to NHS
hospitals each year in England and Wales have a diagnostic label of “drug
allergy”, most commonly penicillin allergy, but only <10% are thought to be truly
allergic to penicillin (BMJ 2014; 349: g4852). The UK National Institute for
Health and Care Excellence (NICE) recently published a guideline on drug
allergy. NICE defines drug allergy as “any reaction caused by a drug with clinical features compatible
with an immunological mechanism”. Guidance pathways are provided on assessing whether drug
allergy has occurred (e.g. immediate versus non-immediate reactions and systemic versus non-systemic
involvement); the importance of documenting the event (e.g. generic AND proprietary drug name,
number of doses taken, route administered, exact details of reaction and condition being treated,
possible need for avoidance of drug/drug class in the future); and updating the patient records and
informing all healthcare professionals involved in the patient’s management. As well as stopping the
suspect drug and treating the symptoms as appropriate (send severe reactions to hospital),
personalised information and advice on the allergic reaction should be provided to the patient
(and family) as soon as possible after the event. Specific advice is provided on how to handle potential
drug allergy for NSAIDs (including OTC usage) and beta-lactam antibiotics and when to seek specialist
input. The guideline and its various pathways are available at: www.nice.org.uk/guidance/cg183.
Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the
time of issue. References are available on request. This newsletter is produced by the National Medicines Information Centre, St. James’s
Hospital (SJH) Dublin 8 and Dept of Therapeutics Trinity College, Trinity Centre, SJH. Tel: Direct Line (01) 473 0589 or 1850 727 727
Fax: (01) 473 0596 Email: [email protected]