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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]