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Low B12 results are common . Pragmatic solutions
- john sharvill (21 August 2006)
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Over diagnosis and treatment of B12 deficiency in primary and secondary care?
- Anan Raghunath, Kathleen Howlett, Val Featherstone (24 August 2006)
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B12 deficiency; simple solution for a complicated problem
- Eddie Vos (26 August 2006)
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Two other common scenarios where the clinical picture is of utmost importance when interpreting a vitamin B-12 assay result
- Adam P Morton (30 August 2006)
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Further cases of false normal B12 assays - intrinsic factor antibody interference a possible mechanism?
- Malcolm S Hamilton, Sheena Blackmore, Anne Lee (31 August 2006)
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Author's reply
- Vinod Devalia (1 September 2006)
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Management of atypical haematological forms of vitamin B12 deficiency
- Emmanuel ANDRES (2 September 2006)
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Estimating Nutritional Status & B12 Levels
- Joseph W Arabasz MD (9 September 2006)
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john sharvill, General Practitioner Deal England
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We are doing many more bloods tests for routine disease monitoring. As a result many asymtomatic people are found with macrocytosis leading to B12 levels being checked. It is common now to find low levels. Pragmatically my practice is to start parentral repalcement therapy and measure antibodies with no further tests. The question arises though for how long to treat with (parentral) B12. Other causes of deficiency such as PPI prescribing and possibly also metformin use are also common. If antibody negative should the patient be advised to buy B12 tablets over the counter after the first few jabs and repeat the measurements in say 6 and 12 months. Guidance would be welcome. Competing interests: None declared |
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Anan Raghunath, General Practitioner Hull HU143 3PA, Kathleen Howlett, Val Featherstone
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We have through the offices of our local research network (WoReN)have just completed data collection in over 500 patients on Injectable B12 from a cross-section of UK general pratices in the North-East. We have undertaken both quantitative and qualitative research. We have only just started analysing our results. Our preliminary impressions are that intiation and long-term maintenance of parenteral B12 therapy in a significant number of patients are made on "doubtful" clincial and biochemical results. This approach appears to exist across both primary and secondary care. Qulitative data from health professionals appear to suggest significant lack of consenus and confusion around interpretation of results, intitation of therapy and route of administration (oral vs parenteral). Patients similarly and not suprisingly appear to have little understanding of their B12 therapy. We are in the process of writing up this paper which will include guidelines on an integrated approach to diagnosis and management of patients with possible B12 deficiency. Competing interests: None declared |
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Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
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Based on a price of US$660 per kg of vitamin B12 [watsonii.com product V013], 1 gram or $0.66 provides about 1 million daily required doses of 1 mcg and would be sufficient for 34 eighty year long life-times, with 1 gram arguably representing the only non-toxic true megadose of any nutrient. Conversely, $0.02 is the life-time cost for vitamin B12 for a human. Even assuming worst case scenarios or when elderly and that only 1/100th is absorbed, this likely represents a fraction of the cost of the blood analysis of the 4.25% of the patient population measured yearly, and found to contain 18% individuals 'below normal' for B12. Considering the current debate about folate fortification and its theoretical harm from masking vitamin B12 deficiency, this is a golden opportunity to fortify grain products with both vitamins with, for example, targeting B12 at 10 mcg/d. A zero cost remedy to known deficiency problems that simultaneously solves the majority of the diagnosis issues raised by Devalia. While scientists debate and before politicians act regarding food fortification, my U.S. mail-ordered 'high potency' multivitamin / mineral capsule contains 100 mcg B12 [and 800 mcg folic acid plus 6 other B- vitamins] and I have yet to see science that this amount of B12 does not eventually replete most worst case scenario patients at virtually no cost, risk or effort. The vitamin bottle has a six month supply at $0.12/day and comes without a child-proof cap; it's considered that safe! vos{at}health-heart.org Competing interests: None declared |
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Adam P Morton, Physician Mater Hospital South Brisbane Australia 4101
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Approximately 20 % of women show a physiological fall in serum vitamin B12 during pregnancy without signs of megaloblastic anaemia or a rise in homocysteine concentrations. Treatment with metformin may be associated with a fall in serum vitamin B12 and increases in homocysteine both in the short term (after 16 weeks) and up to 30 % of those on long term therapy. While individuals have been described with megaloblastic anaemia, subacute combined degeneration of the cord and memory loss in the setting of vitamin B12 deficiency and metformin therapy, with improvement following vitamin B12 replacement, the clinical significance of vitamin B12 deficiency with metformin therapy is uncertain. In about half of individuals vitamin B12 deficiency will resolve with withdrawal of the medication or calcium supplementation. Competing interests: None declared |
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Malcolm S Hamilton, Director UKNEQAS Haematinics Dept Haematology Good Hope NHS Trust, Rectory Rd, Sutton Coldfield, B75 7RR, Sheena Blackmore, Anne Lee
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Sir,
One of the cases in the report by Devalia is a timely reminder that current “no boil” automated cobalamin immunoassays may produce normal results in the presence of severe cobalamin deficiency. Since 2004 the external quality assessment scheme for cobalamin assays UKNEQAS Haematinics has become aware of a further eight cases of sera from patients with severe megaloblastic anaemia or subacute combined degeneration of the cord in whom current commercial assays have failed to detect cobalamin deficiency. In all eight cases intrinsic factor antibody levels were strongly positive, suggesting that intrinsic factor antibody interference may be the cause of assay failure. These cases are not just a difficulty in the selection of a cut off point for the reference range but are “false normal results” with levels well within the manufacturers normal reference range and yet severe clinical deficiency. Manufacturers’ product literature stresses that diagnosis of cobalamin deficiency should not be based on the results of a single assay and that all clinical features and other laboratory tests including intrinsic factor antibody levels should be considered. Devalia suggests heterophilic antibody interference may be relevant to the mechanism but the cases reported are more likely to be due to high titre anti-intrinsic factor antibody levels. In two patients both with megaloblastic anaemia, which subsequently responded to cobalamin treatment, the initial cobalamin assay results were normal, but the clinical features aroused suspicion that the laboratory result was incorrect. Pre treatment sera were available in both cases for further study by UKNEQAS haematinics. Both sera had high titre anti-intrinsic factor, heterophilic antibodies were not detected in one case, and the pre-treatment sera were investigated further in a round robin exercise of cobalamin assays. Table 1. Pretreatment serum cobalamin in two cases with false normal cobalamin results with current commercial assays.
The results demonstrate that only two of five methods found extremely low levels of cobalamin consistent with the clinical presentation of severe cobalamin deficiency in both cases. The Bayer centaur assay detected one of the two patient samples as low. The mechanism of assay failure is not yet clear, nor the frequency with which this may occur. The current commercial assays are competitive binding immunoassays which are no boil, and rely on alkaline hydrolysis and dithiothreitol or monothioglycerol treatment to release cobalamin from transcobalamin and other binders, and denature intrinsic factor antibody, prior to competitive binding against labelled cobalamin to assay intrinsic factor. We postulate that intrinsic factor antibody present in the patient serum at high titre fails to be denatured by the alkaline hydrolysis and dithiothreitol treatment and persists into the binding stage, resulting in assay failure. UKNEQAS Haematinics has alerted all manufacturers to this issue. Ideally assays should be tested pre-commercial release with sera which contain high titre anti-intrinsic factor antibody to ascertain whether the assays will detect low cobalamin levels in this circumstance. It is not yet clear whether some assays are more vulnerable to assay interference that others. The incidence of these”false normal” sera are rare but in our own clinical laboratory we detected four similar cases over a two year period from 12,000 cobalamin assay requests. Laboratories should not report cobalamin results in isolation from intrinsic factor antibody results or full blood count data. Clinicians are urged to be vigilant for these potentially dangerous “false normal” cobalamin results, and once suspected laboratories should store pre-treatment sera where available for repeat analysis on an alternative assay. Elevated homocysteine and methylmalonic acid levels which correct on B12 treatment, and positive anti-intrinsic factor antibody will confirm that the megaloblastic anaemia or neuropathy is indeed due to cobalamin deficiency. These cases of assay failure should be reported to the in vitro diagnostics section of Medicines and health care related products agency (MHRA) as adverse events via http://www.mhra.gov.uk. UKNEQAS Haematinics would be pleased to assist laboratories to investigate any suspected false normal sera ( email: ukneqas.haematinics.org.uk) and collect data on any further cases. A trial of therapy in suspected cobalamin therapy once serum has been stored will prevent delay in treatment and adverse clinical consequences. Malcolm.S.Hamilton
Sheena Blackmore
Anne Lee
Competing interests: None declared |
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Vinod Devalia, Consultant Haematologist Princess of Wales Hospital, Coity Road, Bridgend CF31 1RQ
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Hamilton et al further highlight the fact that the problem of a ‘false-normal’ serum B12 assay truly exists, and suggest that this may be due to the presence of a high titre anti-intrinsic factor antibody interfering with the assay. Further studies would help in confirming this possibility. However, it remains unclear whether the magnitude of the problem is ‘rare’, given the fact that literally hundreds of thousands of assays are done globally and clinical information on patients with ‘normal’ B12 levels is unavailable. Laboratories providing serum B12 assays need to be aware of possible technical problems resulting in ‘false -normal’ results, and data collected centrally (i.e. MHRA) of such cases will help to clarify the magnitude any reasons for it. Sharvill raises the question of how long should one treat a patient empirically if the anti-intrinsic actor antibody is negative. My pragmatic practice is to give an initial treatment of five injections (1mg/ml) of hydroxycobalamin and then to measure serum B12 at six monthly intervals, without any further treatment, for two years. If the serum B12 remains well within the reference range without any clinical problems, I suggest a further check in a year’s time and then no further monitoring or treatment if stable. It will be interesting to see what recommendations are proposed by Raghunath and colleagues. Morton describes other scenarios where a low serum B12 level may have uncertain clinical significance, which again emphasises the importance of a very thorough clinical evaluation in the context of the laboratory result. Vos’s suggestion of empirical oral B12 supplementation has to be taken with caution since it may not contain adequate amounts of B12 for an individual with pernicious anaemia 1. Reference 1 Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood 2004; 103: 2863. Competing interests: None declared |
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Emmanuel ANDRES, Professor of Internal Medicine Department of Internal Medicine B, University Hospital, 1 place de l'Hôpital, 67091 STRASBOURG, F
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Dear Sir, We have read with interest the paper entitled “Diagnosing vitamin B12 deficiency on the basis of serum B12 assay” from the last BMJ issue (1). We have been aware that the paper has stirred some anxiety among British colleges. To our opinion, we feel that "dysmyelopoietic appearance" might be a greater problem than neurological lesions nowadays, especially in countries in which homocysteine is not a routine test. In fact there is a possible risk to confuse “atypical forms” of vitamin B12 (cobalamin) deficiency with dysmyelopoetic stages, especially in elderly patients. In our experience (of more than 300 patients with documented cobalamin deficiency), this risk exists in at least 20% of the patient (2,3). Thus to exclude this possibility of confusion, we usually propose a "traitement d'épreuve" (exclusion therapy) with oral cobalamin therapy (1000 µg per day of oral cyanocobalamin for at least 7 days). In fact, in several studies, we have reported that one week of oral vitamin B12 therapy may be effective to improve or cure cobalamin deficiency (4-6). The readers of the BMJ may find several informations in a practical review of cobalamin deficiency management we have recently published in the CAMJ (7). Professor Emmanuel ANDRES
1. Devalia V. Diagnosing vitamin B-12 deficiency on the basis of serum B12 assay. BMJ 2006; 333: 385-386. 2. Andrès E, Affenberger S, Vinzio S, Kurtz JE, Noel E, Kaltenbach G et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med 2005; 118: 1154-1159. 3. Andrès E, Affenberger S, Zimmer J, Vinzio S, Grosu D, Pistol G et al. Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency. Clin Lab Haem 2006; 28: 50-56. 4. Kaltenbach G, Noblet-Dick M, Andrès E, Barnier-Figue G, Noel E, Vogel T et al. Réponse précoce au traitement oral par vitamine B12 chez des sujets âgés hypovitaminiques. Ann Med Interne (Paris) 2003; 154: 91-95. 5. Andrès E, Kaltenbach G, Noblet-Dick M, Noel E, Perrin AE, Vinzio S et al. Hematological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in elderly patients. J Nutr Health Aging 2006; 10: 3-6. 6. Andrès E, Kaltenbach G, Noel E, Noblet-Dick M, Perrin AE, Vogel T et al. Efficacy of short-term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food-cobalamin malabsorption. A study of 30 patients. Clin Lab Haem 2003; 25: 161-166. 7. Andrès E, Loukili NH, Noel E, Kaltenbach G, Ben Abdelgheni M, Perrin AE et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CAMJ 2004; 171: 251-260. Competing interests: None declared |
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Joseph W Arabasz MD, Physician Denver, Colorado 80206 USA
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Congratulations on Authoring and
Publishing such an excellent Article regarding the inaccuracies of
Vitamine B12 serum levels. Dr William Osler, the Father of Internal
Medicine, The Art of Medicine perspective fortunately allowed Dr Devalia to
arrive at the correct choice for treating the Patients' anemia with a
Vitamine B-12 Supplement, when their clinical conditions didn't seem to be
as life threatening as the "normal" B12 levels indicated.
It is unfortunate that some individuals, on this side of the Pond,
measure solely a B-12 level when attempting to evaluate the entire
Nutritional Status of a Patient. In my opinion, if you want to measure a
Thiamine or Niacin serum level, or their metabolites, then that is the
entity that has to be sent to the Lab, not a B-12 measurement which is
then used to erroneously relate, or extrapolate, to other Vitamine levels.
This is how, in my opinion, other medical misadventures could be
initiated.
Your Article is excellent food for thought, keep up the good work.
Cordially,
Joseph W Arabasz MD PC
Past Division Chairman, Anesthesiology, Cook County Hospital, Chicago,
Illinois
Past Chairman, Respiratory Therapy, Cook County Hospital, Chicago,
Illinois
Diplomate ABA
Mensa
Sigma Xi, The Professional International Science Research Society
Competing interests:
None declared |
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