Vitamin B12 deficiency commonly causes megaloblastic anaemia, chronic tiredness, loss of appetite and mood disturbance. If left untreated, serious neurological and neuropsychiatric complications occur.
Screening for Vitamin B12 deficiency in Wales: a targeted multiphasic approach.
SUMMATIVE ASSESSMENT EP 23EPIDEMIOLOGY IN PRACTICE Dr Josep Vidal-Alaball April 04
Epidemiology in Practice. Number: 21344Title:Screening for Vitamin B12 deficiency in Wales: a targeted multiphasic approach.BackgroundVitamin B12 deficiency commonly causes megaloblastic anaemia, chronic tiredness,loss of appetite and mood disturbance. If left untreated, serious neurological andneuropsychiatric complications occur. Neurological sequelae include peripheralneuropathy, paresthesias and demyelination of the corticospiral tract and dorsalcolumns (Oh and Brown, 2003). Vitamin B12 deficiency has also been linked with anincreased risk of myocardial infarction and stroke (Nygard et al., 1997).The most common cause of vitamin B12 deficiency is autoimmune perniciousanaemia where its absorption in the terminal ileum is impaired due to intrinsic factor(IF) deficiency. Other causes of IF deficiency include gastrectomy, total ilealresection and other ileal malabsorption syndromes such as Crohns disease, tropicalsprue and coeliac disease. Nutritional deficiency is rare and usually occurs only instrict vegetarians.The true prevalence of vitamin B12 deficiency in the general population is stillunknown but is common, especially amongst the elderly as his incidence appears toincrease with age. The prevalence of vitamin B12 deficiency in the elderly has varieddramatically in different studies depending on the diagnostic criteria used to definevitamin B12 deficiency. Prevalence between 1.5 and 15% have been reported (Figlinet al., 2003, van Walraven and Naylor, 1999, Pennypacker et al., 1992, Rajan et al.,2002). As well as with age, the prevalence also varies with sex and ethnic group;elderly men are more likely to have low vitamin B12 levels than elderly women andthe prevalence of vitamin B12 deficiency is higher in Europe than in USA(Pennypacker et al., 1992, Lindenbaum et al., 1994).The diagnosis of vitamin B12 deficiency can be difficult, especially among the elderlybecause the neurological manifestations of vitamin B12 deficiency overlap with othercommon conditions in the elderly such as dementia. The diagnosis of vitamin B12deficiency relays on clinical and laboratory tests. For many years the laboratory 2
Epidemiology in Practice. Number: 21344diagnosis was based on serum cobalamin levels but this had the inconvenience thatsubnormal serum cobalamin levels are not specific for vitamin B12 deficiency. In thelate 80’s two biochemical markers derived from the vitamin B12 metabolism werefound to be useful in diagnosing vitamin B12 deficiency and assessing response totreatment, the metabolites are methylmalonic acid (MMA) and total homocysteine(tHcy) (Stabler et al., 1990). Vitamin B12 deficiency is usually accompanied byelevated serum MMA and tHcy concentrations. Recently a new test that measuresholo-trancobalamin II (holo-TCII) levels has been introduced and it is though toprovide a better index of cobalamin status (Goh et al., 1991).Vitamin B12 (cobalamin) was first isolated in 1948 (Rickes et al., 1948, Smith, 1948),and is now widely used for the treatment of vitamin B12 deficiency.Screening for Vitamin B12 deficiencyThe screening programme will be targeted at 3 groups with proven increased risk ofdeveloping Vitamin B12 deficiency. These groups are: • People over 65 years • Patients who have had gastric surgery (gastrectomy, ileal resection) • Patients with ileal malabsorption syndromes (Crohn’s disease, tropical sprue, coeliac disease)Several studies have recommended screening for vitamin B12 deficiency in some ofthese groups (Green, 1996, Rajan et al., 2002, Clarke et al., 2003). I could not findstudies justifying mass screening of the whole population.As well as being a targeted screening, the vitamin B12 screening will be a multiple(or multiphasic) screening as will involve 4 different blood tests: serum cobalaminlevels, MMA, tHcy and in places available, holo-TCII. The screening will beopportunistic for people over 65 who will have the tests when they consult theirdoctor for another purpose but will be systematic for people who had gastric surgeryor have diagnosed ileal malabsorption syndromes who will be invited for a blood test. 3
Epidemiology in Practice. Number: 21344I have used the Criteria for Instituting a Screening Programme described byWilson & Jungner in 1968 (Beaglehole et al., 1993, pp 93-95) to justifyimplementing screening for vitamin B12 deficiency. Meeting these criteria is regardedas essential before a screening programme is implemented:Disease1. Serious. Vitamin B12 deficiency can lead to serious diseases and complications if not detected early. Although the anaemia caused by vitamin B12 deficiency is reversible with treatment, early detection is important as cognitive decline associated with vitamin B12 deficiency may not be reversible (Rajan et al., 2002).2. High prevalence of preclinical stage. Although there is some controversy around the true prevalence of vitamin B12 deficiency, there is a general consensus about the higher prevalence amongst the 3 groups this screening is targeting (Rajan et al., 2002, Thompson and Freeman, 1990, Green, 1996).3. Natural history understood. For many years we have known the effects that vitamin B12 deficiency produces. We also know well the benefits and the costs of the treatment.4. Long period between first signs and overt disease. We do not have a long time once the first clinical signs of the disease occur and the disease is overt but in this screening we are not screening for clinical signs, we will screen for laboratory changes and these are detected much earlier than the clinical signs.Diagnostic test1. Sensitive and specific. In the past, vitamin B12 deficiency was diagnosed by measuring the serum vitamin B12 level. This test is easy and readily available but has problems of sensitivity and specificity (Green, 1996). Bad sensitivity and specificity leads to poor positive and negative predictive values. Low serum vitamin B12 levels not always indicate vitamin B12 deficiency and normal serum vitamin B12 can not exclude deficiency. In one study true vitamin B12 deficiency was present in only 88% of 94 elderly people with low serum vitamin B12 levels (Metz et al., 1996). To overcome this problem the screening programme is going to increase sensitivity and specificity by checking 2 metabolites involved in vitamin B12 metabolism: MMA and tHcy. It is important to check this 2 metabolites in 4
Epidemiology in Practice. Number: 21344 conjunction with serum vitamin B12 as metabolites levels may be elevated in other disorders (e.g. renal failure, hypothyroidism). When available the screening will include measurements of holo-TCII in order to increase sensibility even more. As vitamin B12 deficiency can lead to serious diseases, the screening programme is aiming to have very high sensitivity, even if this implies having some false positives.2. Simple and cheap. Screening for vitamin B12 deficiency is simple if we use the 4 diagnostic tests. Serum vitamin B12 levels, MMA and tHcy are easy and cheap to measure in hospital laboratories although tHcy requires the blood sample to arrive in the laboratory between 2 hours after being taken, this means that unless quick transport is guaranteed from the Primary Care setting the patient will have to go to the hospital to have the blood taken. Holo-TCII is a novel technique currently being piloted in some Hospitals, including the University Hospital of Wales in Cardiff. It is not widely available at the moment but in a few years may be available in smaller hospitals.3. Safe and acceptable. The diagnostic test is very safe and acceptable as it just involves a blood sample being taken.4. Reliable. The objective of combining 3 and possible 4 blood tests is to increase the reliability of the diagnostic test, obtaining consistent results. The test will consistently categorize people into groups with or without disease.Treatment1. Facilities are adequate. Doctors in hospitals and Primary Care centres have been treating people with vitamin B12 deficiency for many years, facilities for this are adequate.2. Effective, acceptable and safe treatment available. Most vitamin B12 deficient individuals in the UK and other countries are treated with parenteral vitamin B12. It is a very effective, acceptable and safe treatment. Side effects are very rare (Green, 1996). Several studies have demonstrated that vitamin B12 could also be given orally (Kuzminski et al., 1998, Bolaman et al., 2003) although this is not current practice in UK. The oral route could be very convenient in patients that take anticoagulants to whom an injection could be dangerous. 5
Epidemiology in Practice. Number: 21344Implementation of the screening programmeOne of the main problems I will encounter when implementing the screeningprogramme is that no consensus exists about the best way to diagnose vitamin B12deficiency (Hvas et al., 2003). With new tests available consensus is needed on thecut-offs of MMA and tHcy to apply to define vitamin B12 deficiency (Clarke et al.,2003). I will overcome this problem by organizing an International Conference onvitamin B12 screening. The conference will invite world experts on the field with asole agenda of achieving consensus on the diagnosis and treatment of vitamin B12.It is very important that there is an evidence-based prescribing of vitamin B12 as thescreening programme could generate excessive prescribing. Archie Cochrane,working in South Wales, was one of the first to identify that there was inappropriate,excessive prescription of vitamin B12 (Cochrane and Moore, 1971). Despite the factthat excessive prescribing does not constitute a direct risk for patients because thekidneys will excrete excessive vitamin B12, financially over treatment could drainscarce resources from the NHS. Treatment protocols will be also agreed in theInternational Conference.Although it is not the main objective of the screening programme, the programme willincrease awareness about vitamin B12 deficiency amongst the medical profession.This could lead to a reduction of inappropriate prescribing of vitamin B12 in patientsalready using vitamin B12 replacement.It is important that at risk groups are screened for the first time. For people over 65the screening could take place at the same time as other blood tests (e.g. lipids,glucose) or during the visit to their GP for the Flu jab. People from the other 2 groupshave bloods taken very regularly to check for signs of anaemia or deterioration oftheir condition, the screening for vitamin B12 could be done during those visits.Patients not requiring regular blood test will need to be contacted to invite them to thescreening programme. According to the initial results, patients will need either yearlyscreening or less regular follow up. A computer programme can easily tract thispatients and ensure they are invited for regular blood tests. 6
Epidemiology in Practice. Number: 21344The screening programme will be piloted in the city of Cardiff for 18 months, if it issuccessful, it will be introduced to the whole Wales.ReferencesBeaglehole, R., Bonita, R. and Kjellstrom, T. (1993) Basic Epidemiology, World Health Organization, Geneva.Bolaman, Z., Kadikoylu, G., Yukselen, V., Yavasoglu, I., Barutca, S. and Senturk, T. (2003) Oral Versus Intramuscular Cobalamin Treatment in Megaloblastic Anemia: A Single-Center, Prospective, Randomized, Open-Label Study, Clinical Therapeutics, 25, 3124-34.Clarke, C., Refsum, H., Birks, J., Evans, J. G., Johnston, C., Sherliker, P., Ueland, P. M., Schneede, J., McPartlin, J., Nexo, E. and Scott, J. M. (2003) Screening for vitamin B-12 and folate deficiency in older persons, Am J Clin Nutr., 77, 1241-7.Cochrane, A. and Moore, F. (1971) Expected and observed values for the prescription of Vitamin B12 in England and Wales, British Journal of Preventative and Social Medicine, 25, 147-151.Figlin, E., Chetrit, A., Shahar, A., Shpilberg, O., Zivelin, A., Rosenberg, N., Brok- Simoni, F., Gadoth, N., Sela, B.-A. and Seligsohn, U. (2003) High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel, British Journal of Haematology, 123, 696-701.Goh, Y. T., Jacobsen, D. W. and Green, R. (1991) Diagnosis of functional cobalamin deficiency; utility of transcobalamin-bound vitamin B12 determination in conjunction with total serum homocysteine and methylmalonic acid, Blood, 78, 100a.Green, R. (1996) Screening for vitamin B12 Deficiency: Caveat Emptor, Ann Intern Med, 124, 509-11.Hvas, A. M., Juul, S., Nexo, E. and Ellegaard, J. (2003) Vitamin B-12 treatment has limited effect on health-related quality of life among individuals with elevated plasma methylmalonic acid: a randomized placebo-controlled study, Journal of Internal Medicine, 253, 146-52.Kuzminski, A. M., Del Giacco, E. J., Allen, R. H., Stabler, S. P. and Lindenbaum, J. (1998) Effective treatment of cobalamin deficiency with oral cobalamin, Blood., 92, 1191-8.Lindenbaum, J., Rosenberg, I. H., Wilson, P. W., Stabler, S. P. and Allen, R. H. (1994) Prevalence of cobalamin deficiency in the Framingham elderly population, American Journal of Clinical Nutrition, 60, 2-11.Metz, J., Bell, A., Flicker, L., Bottiglieri, T., Ibrahim, J., Seal, E. C., Schultz, D., Savioa, D. and Mcgrath, K. M. (1996) The significance of subnormal serum vitamin B12 concentrations in the elderly a case study. Journal of the American Geriatrics Society, 44, 1355-41.Nygard, O., Nordrehaug, J. E., Refsum, H., Ueland, P. M., Farstad, M. and Vollset, S. E. (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease, N Engl J Med, 337, 230-6. 7
Epidemiology in Practice. Number: 21344Oh, R. C. and Brown, D. L. (2003) Vitamin B12 Deficiency, American Family Physician, 67, 979-86.Pennypacker, L. C., Allen, R. H., Kelly, J. P., Matthews, L. M., Grigsby, J. and Kaye, K. (1992) High prevalence of cobalamin deficiency in elderly outpatients, Journal of the American Geriatrics Society, 40, 1197-204.Rajan, S., Wallace, J. I., Beresford, S. A., Brodkin, K. I., Allen, R. A. and Stabler, S. P. (2002) Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake, Journal of the American Geriatrics Society, 50, 624-30.Rickes, E., Brink, N., Koniuszy, F., Wood, T. and Folkers, K. (1948) Crystalline vitamin B12, Science, 107, 396.Smith, E. (1948) Purification of anti-pernicious anaemia factor from liver, Nature, 161, 638.Stabler, S. P., Aleen, R. H., Savage, D. G. and Lindenbaum, J. (1990) Clinical spectrum and diagnosis of cobalamin deficiency, Blood, 79, 871-81.Thompson, W. G. and Freeman, M. L. (1990) Vitamin B12 and geriatrics: unanswered questions, Acta Haematologica, 84, 108.van Walraven, C. and Naylor, C. (1999) Use of vitamin B12 injections among elderly patients by primary care practitioners in Ontario, Canadian Medical Association Journal, 161, 146-9.Vidal-Alaball, J., Butler, C., Hood, K., Cannings, R., McCaddon, A. and Papaioannau, A. (2004) Oral vitamin B12 versus parenteral vitamin B12 for vitamin B12 deficiency. (Protocol for a Cochrane Review), John Wiley & Sons, Ltd., Chichester, UK. Word count: 2335 (including 21 references) 8
Epidemiology in Practice. Number: 21344Reflective statementI am part of a multi-disciplinary and cross-professional research group developing andimplementing research into related aspects of vitamin B12 that range from molecularfunction through to replacement therapy in pragmatic health care settings. I aminvolved in a systematic review on the use of oral vitamin B12 deficiency. Myprincipal role has been the day to day running of the study, coordinating andmanaging a group of researchers. I registered a title with the Cochrane Endocrine andMetabolic Group and together with the group of researchers, I wrote the protocol,which has been published in the Cochrane Library of Systematic Reviews (Vidal-Alaball et al., 2004).During my literature review I identified the possibility of implementing a screeningprogramme to detect vitamin B12 deficiency amongst 3 groups with proven increasedrisk of developing vitamin B12 deficiency: people over 65 years, patients who havehad gastric surgery (gastrectomy, ileal resection) and patients with ileal malabsorptionsyndromes (Crohn’s disease, tropical sprue, coeliac disease). As far as I am aware atthe moment there is not such a programme anywhere in the world. This assignmenthas provided me the incentive and the opportunity to look at the aspects ofimplementing this programme. I am planning to do further research on the subject andI will try to publish my results in a scientific publication. 9