Vitamin B12 deficiency
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5226 (Published 04 September 2014) Cite this as: BMJ 2014;349:g5226
All rapid responses
Dr Hunt and her colleagues are to be congratulated on their appraisal of the current shortcomings on the diagnostic tests associated with Pernicious Anaemia and Vitamin B12 Deficiency.
I would like to point out the following in relation to the diagnostic procedures:
1. There is no reliable test for diagnosing Autoimmune Atrophic Gastritis. The British Society for Standards in Haematology state that anti-parietal cell antibodies test cannot be used to give a diagnosis and that if the patient tests Negative for Intrinsic Factor Antibodies then he or she can still be diagnosed with Pernicious Anaemia - ABNegPA.
This means that a great many patients are either wrongly diagnosed or given no explanation for their low B12 status. A recent survey of UK members of the PA Society show that common misdiagnosis include Anxiety, Depression, CFS/ME, IBS, MS, Menopause and Hypochondria. 14% of members of the charity waited over ten years for a correct diagnosis, 21% waited up to two years for a diagnosis and 19% up to five years.
2. Receiving adequate treatment is a major source of frustration for members. When asked if they were satisfied with their treatment 64% replied 'no', 28% replied 'yes' and 8% didn't reply. Many of the 28% who were satisfied with their treatment were self treating using cobalamin from various sources. 5% of members use Methylcobalamin which is not licensed in the UK. There are several doctors who are members of the society who self-inject much more frequently than every three months.
3. While some patients see their symptoms of B12 Deficiency disappear once treatment has begun a great many remain symptomatic to various degrees with those experiencing the worst effects of the condition facing career ending decisions, relationship breakdowns and an end to any meaningful social life.
The Pernicious Anaemia Society was established to provide newly diagnosed patients, and their families, a plain English explanation of their condition. It has unwittingly uncovered serious issues with the way in which the condition is both diagnosed and treated. Hopefully this paper will go some way to raising awareness of current shortcomings in these two areas.
See:
Hooper, Hudson, Porter, McCaddon; Patients Journeys; Diagnosis and Treatment of Pernicious Anaemia: British Journal of Nursing, 2014, Vol 23, No 7
Competing interests: Chairman and founder of The Pernicious Anaemia Society
Dear A A Hunt
As your research has clearly highlighted the multiple issues associated with identifying a deficiency via the serum b12 test, it is hoped that the HoloTC and MMA are consider by clinicians more often when confronted with patients displaying functional indicators of deficiency. It is also hoped that they do not rely on one test only to achieve a diagnosis.
Unfortunately the BNF and BSCH guidelines relative to dosage remain unsupported by any research or documented evidence relative to establishing if the regimen is adequate particularly in respect of reversing neurological damage. This would perhaps be an appropriate time for clinicians to be allowed the opportunity to report back remaining or reccuring symptoms to the authorities concerned to enable them to assess the situation with some level of accuracy and advance the issues your work has highlighted. It is of little benefit to patients if your work enables them to achieve a diagnosis and then the injuries remain unacknowledged or undertreated.
Identifying damage caused, as it would seem with all things related to b12 deficiency, is something not easily established (1) and it would appear to necessitate the expertise of those involved in the field of neurology and demyelinating illnesses in particular.
The issue of harm occurring from more frequent dosage would seem to be an area which requires little consideration relative to the serious neurological injury resulting if too little is given, as any excess b12 is excreted in the urine.
Competing interests: In December 2016 Mike Newman and Karen Thompson wrote Vitamin B12 Deficiency and Chronic Illness, published by CreateSpace Independent Publishing Platform. [Response modified on 4 July 2017 by Sharon Davies, The BMJ]
In response to Dr Vos' comments I would refer him to articles on Rhodanese (Thiosulphate Sulphur Transferase) deficiency, which is an important means of metabolising cyanide (1,2). Dr Vos is correct that many foods contain cyanide; congenital deficiency, probably in mitochondria and not a cell's nucleus, leads to Leber's Optic atrophy due to the gradual damage from cyanide in food. A second means of cyanide metabolism involves di-cysteine. This explains why in populations where there is severe protein deficiency and a high intake of cyanide (such as Cassava root) blindness is much more common. In fact you really need to have a low B12 level as well since hydroxocobalamin will combine with cyanide when there is an plenty around, also removing this neurotoxin. In the developed world protein deficiency with inadequate B12 intake will be extremely rare; in the developing world unfortunately this is sometimes not so.
It is also true that there is further metabolism of hydroxocobalamin to give the active coenzymes in at least two chemical reactions; my apologies to Dr Rietsema for somewhat oversimplifying the chemistry to avoid making the issue sound very complex. Likewise I did not mention that other toxins such as alcohol and smoking (smoke contains other toxins as well as cyanide) seem to be additive, so that lower doses of cyanide will still give neural damage.
As far as the amount is concerned we must remember that when treating B12 deficiency we give large amounts of the vitamin, achieving many times normal physiological levels, so much larger amounts of cyanide will be around. For the vast majority of people this will be perfectly safe; but I recall as a student being told by a consultant ophthalmologist of someone going blind with IM cyanocobalamin soon after replacement B12 therapy was started, and cases are recorded of blindness in the literature with as little as 3 injections of cyanocobalamin. See also the discussion on Tobacco-Alcohol Amblyopia in (3) where it quotes papers where raised cyanide levels were reduced with hydroxocobalamin with clinical benefit.
The bottom line however is that it is unnecessary to give any cyanide, so why take the risk? You will see Dr Freeman was arguing exactly the same in 1988 (1), and he was just ignored! Surely it is time to do the right thing.
1) Optic Neuropathy and chronic cyanide intoxication: A.G.Freeman Jour. Roy.Soc.Med. vol 81 Feb 1988 p 103-106
2) Leber's Hereditary Optic Atrophy: R.Ayesh & R.L.Smith in "Xenobiotic Metabolism and Disposition: Proceedings of the 2nd. International ISSX Meeting" p.462
3) Cigarette Smoking and Eye: V. Sehgal, T. Arora & R. Sinha in dos-times.org
Competing interests: No competing interests
Dear K Thompson,
Thank you very much for your rapid response on 15th September 2014.
At present we are not aware of any tests which measure cellular damage or neurological damage specifically caused by vitamin B12 deficiency.
During the last 25 years we have seen the move away from microbiological assays and radioisotope-dilution assays for the serum B12 test to the use of automated platforms based on competitive-binding luminescence technologies. Examples of diagnostic failures with this type of assay have previously been reported e.g. failure rates of cobalamin assays in the analysis of samples from patients with proven pernicious anemia (Ralph Carmel NEJM 2012). No consensus view for diagnostic cut offs for the markers of vitamin B12 status (serum B12, holoTC, MMA or tHCY) has been achieved. This is an ongoing barrier to the comparison of different markers of vitamin B12 status. There is also no consensus with regards to the significance or otherwise of low B12 status (rather than overt deficiency states).
Your response highlights your concerns with serum B12 monitoring in determining deficiency. Although not in widespread use, we have found HoloTC and MMA more useful in determining functional B12 deficiency. Moridani et al report higher specificity and we anticipate increased detection of functional B12 deficiency as these assays become more widely available to GPs. Clearly, the result has to be placed in the broader context of the patient presentation, clinical features and other laboratory results such as full blood count and blood film.
For the dosing schedule we advocate that described in the BNF and the BSCH guidelines (reference in text). These both state that for ‘maintenance treatment, following the loading doses of alternate days, for patients presenting without neurological deficit is with hydroxocobalamin 1000μg every 3 months. Those with initial neurological deficit should receive hydroxocobalamin 1000μg on a two-monthly basis. No further testing for cobalamin levels is required. Although there is little evidence that more frequent dosing is harmful, specific objective studies demonstrating clinical benefit are absent, and the Guideline Working Group cannot make specific recommendations.’
Laboratory Investigation of Vitamin B12 Deficiency, Majid Moridani, Shana Ben-Poorat, Lab medicine. March 2006. Volume 37 Number 3
Competing interests: No competing interests
Dear Dr Bradley,
Thank you very much for your rapid response on 14th September 2014.
Vitamin B12 status is assessed predominantly by total serum B12 alone because it is a simple automated test to perform and affordable. However it is also understood that using this test in isolation brings poor sensitivity in the detection of deficiency in the early stages. The specificity of a low serum B12 for diagnosing diminished B12 status is also poor. In addition examples of diagnostic failures with the current class of assay (which are based on competitive-binding luminescence technologies that superseded microbiological assays and radioisotope-dilution assays) have previously been documented (Ralph Carmel NEJM 2012). Some centres have now begun to provide additional testing in the way of HoloTC and MMA. Adoption of the holoTC assay for example is increasingly widespread in Australia, Austria, Canada, Germany, Holland, Nordic countries, and Switzerland. More details regarding these tests can be found in the references.
We agree that it is very difficult to ascertain exact prevalence data for vitamin B12 deficiency across population groups. Prevalence varies depending on age, ethnic group and nutritional status. The data selected is from the study by Allen in the American Journal of Clinical Nutrition, referenced in the text. Definition is also hampered by a lack of consensus view for diagnostic cut offs for the markers of vitamin B12 status.
Regarding the symptom spectrum of mild deficiency, we appreciate that these can be non-specific and difficult to attribute in the context of borderline vitamin B12 levels. In these situations, an overview of the entire clinical picture is required; absent other causes for symptoms and in the event of response to treatment, the weight of evidence would point towards B12 deficiency.
When considering implications for testing, and given the problems discussed with regards to testing, we feel that more emphasis should be placed upon evaluating efficacy of newer assays such as holoTC and MMA. Population replacement would not address the issue of the cause of the B12 deficiency, which is extremely important to identify.
Some other reference you may be interested to read include:
Green R. Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies. Food Nutr Bull 2008;29:S52–63.
Elin RJ, Winter WE. Methylmalonic acid: a test whose time has come? Arch Pathol Lab Med 2001;125:824–7.
Scott JM. Folate and vitamin B12. Proc Nutr Soc 1999;58:441–8.
Carmel R, Green R, Rosenblatt S, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 2003: 62-81
Competing interests: No competing interests
I enjoyed reading the review of vitamin B12 deficiency, which covers most aspects of this condition very thoroughly, but I am concerned that the authors have not highlighted the potential risks of blood transfusion in patients with severe anaemia, where circulatory overload can be precipitated in patients due to high output cardiac failure. Fortunately severe anaemia due to either B12 or folate transfusion is rarely seen now, but the temptation to transfuse large volumes of blood should be resisted: most patients will improve rapidly with haematinic replacement and supportive measures such as oxygen, so transfusion is rarely necessary. The UK Transfusion Guidelines recommend that if transfusion is deemed essential "single units should be transfused over 4 hours with close monitoring and diuretic cover. Red cell exchange transfusion may also be considered". It is important that haematologists are involved in these decisions.
Reference: Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee Transfusion Handbook http://www.transfusionguidelines.org.uk/transfusion-handbook/8-effective...
Competing interests: No competing interests
In their review Hunt et al do not highlight that bariatric surgery, in particular gastric bypass, is a risk factor for vitamin B12 deficiency.
Vitamin B12 deficiency after bariatric surgery has been linked with megaloblastic anaemia1 and optic atrophy2 and, in children who are breastfed after maternal gastric bypass, developmental delay3 and failure to thrive.4
Gastric bypass may lead to malabsorption of vitamin B12 for several reasons, including: poor digestion of protein-bound vitamin B12 due to achlorhydria and rapid intestinal transit,5 inadequate secretion of intrinsic factor from parietal cells,6 and proteolysis of intrinsic factor (before it binds B12) by pepsin and trypsin.7
This may explain why 80% of 137 patients developed low cobalamin concentrations in the first 2 years after gastric bypass surgery, despite daily supplementation with multivitamins containing vitamin B12.8
The good news is that vitamin B12 deficiency after gastric bypass is readily preventable. Patients with severe obesity tend to have normal serum cobalamin concentrations before surgery9 and prospective studies show that serum cobalamin concentrations are maintained or increased if patients receive regular parenteral supplementation with B12 after surgery.10 Guidelines from the British Obesity & Metabolic Surgery Society (BOMSS) are underway, which discusses the risks for deficiency in vitamin B12 and other nutrients after bariatric surgical procedures, and how clinically important nutrient deficiencies can be prevented.
References
1. Crowley LV, Olson RW. Megaloblastic anemia after gastric bypass for obesity. Am J Gastroenterol 1983;78:406-10.
2. Moschos M, Droutsas D. A man who lost weight and his sight. Lancet 1998;351:1174.
3. Wardinsky TD, Montes RG, Friederich RL, Broadhurst RB, Sinnhuber V, Bartholomew D. Vitamin B12 deficiency associated with low breast-milk vitamin B12 concentration in an infant following maternal gastric bypass surgery. Arch Pediatr Adolesc Med 1995;149:1281-4.
4. Grange DK, Finlay JL. Nutritional vitamin B12 deficiency in a breastfed infant following maternal gastric bypass. Pediatr Hematol Oncol 1994;11:311-8.
5. Rhode BM, Arseneau P, Cooper BA, Katz M, Gilfix BM, MacLean LD. Vitamin B-12 deficiency after gastric surgery for obesity. Am J Clin Nutr 1996;63:103-9.
6. Marcuard SP, Sinar DR, Swanson MS, Silverman JF, Levine JS. Absence of luminal intrinsic factor after gastric bypass surgery for morbid obesity. Dig Dis Sci 1989;34:1238-42.
7. Schilling RF, Gohdes PN, Hardie GH. Vitamin B12 deficiency after gastric bypass surgery for obesity. Ann Intern Med 1984;101:501-2.
8. Gasteyger C, Suter M, Gaillard RC, Giusti V. Nutritional deficiencies after Roux-en-Y gastric bypass for morbid obesity often cannot be prevented by standard multivitamin supplementation. Am J Clin Nutr 2008;87:1128-33.
9. Aasheim ET, Hofsø D, Hjelmesæth J, Birkeland KI, Bøhmer T. Vitamin status in morbidly obese patients: a cross-sectional study. Am J Clin Nutr 2008;87:362-9.
10. Aasheim ET, Björkman S, Søvik TT, Engström M, Hanvold S, Mala T, Olbers T, Bøhmer T. Vitamin status after bariatric surgery: a randomized study of gastric bypass and duodenal switch. Am J Clin Nutr 2009;90:15-22.
Competing interests: No competing interests
The paper by Hunt et al has clearly sparked long overdue interest in the subject of b12 deficiency and surprise at the unreliability of the serum b12 test.
It may be worth looking closer into three issues: firstly, what were the deficient levels intended to identify? A brief look back at history in the 1940s and 50s shows that pharmaceutical companies interests were related to the identification and treatment of anaemia. A condition, which at the time was believed to precede neurological damage. Yet in the 1960s the metabolic functions of b12 were established and indicated that the neurological damage most likely would precede the anaemia. Yet were the deficient ranges adjusted accordingly?
The second issue relates to treatment and returning the serum b12 levels to normal. Even back in 1926 this was, in respect of the anaemia, recognised as being a symptom that was quickly and easily treated. Yet even then (at a time when the anaemia was thought to precede the neurological damage) the nerve damage proved difficult to treat and reverse fully even with intensive care and treatment. In short, returning a patient's b12 levels to within the normal range has no relationship to whether or not the neuro damage has been resolved.
Indeed it would be interesting to note how the serum b12 test or any other, could establish what cellular damage has taken place and if and when that damage is rectified. Thus a patient needs to be treated according to symptoms.
Finally, treatment protocols in the UK are lacking comparative to most developed nations. Admittedly the UK use hydroxocobalamin rather than cyanocobalamin, but surely this does not warrant patients having to wait two months longer than those in France or the US, for a maintenance dose?
So, when it comes to GPs reporting that their patients are not deficient - is that assertion made relative to whether or not their patients have deficient serum b12 levels? Should that level be raised how many more would have symptoms attributed to a deficiency. Or, if another, more reliable test relative to possible neurological injury, came into common usage, would the percentage reported by GPs go up substantially?
Competing interests: No competing interests
This review raises enough clinical questions to be quite genuinely alarming. A respondent has already noted that the authors, without batting an eyelid, state that serum B12 (the only measure of B12 routinely available in primary care) is insensitive to point of being unreliable for the purpose for which it is deployed. No data are given for negative predictive value etc. though, presumably because this necessary information is not available.
They also give a huge prevalence of B12 deficiency in the West which is well out of keeping with the impression of GPs, or this one at least, and I don't think I'm alone here. I can't ascertain from the references provided exactly how these figures were arrived at. In fact, arriving at an accurate prevalence would seem extremely difficult once we appreciate that testing is so riddled with difficulties. So where's the data from?
Thirdly, the symptom spectrum of mild B12 deficiency is, as claimed, entirely consistent with the everyday range of symptology due to many causes or none, familiarly to every primary care physician. How has causation been established?
The implications are huge:
If the information is correct then there should, presumably, be a national decision as to the best way to supplement B12 on a population scale and then a concerted effort to implement it.
If the claimed data is less than concretely proven, however, then we can scrap the above but still have no practical way to determine who actually does need B12.
As a ps, I was wondering why the authors supply a table entitled 'common causes', given that their combined prevalence is miniscule compared to the vast numbers of people they claim have B12 deficiency.
Competing interests: No competing interests
Re: Vitamin B12 deficiency
I feel I can resolve a few possible anomalies suggested by Dr Bradley and others:
Firstly, when it comes to treating B12 deficiency, it should be noted that back in the 1950’s, E. Lester Smith and his team were assigned to establishing dosage for treating the anaemia aspect of the illness. The effective dosage for treating neurological injury was assigned to another team at a hospital in England. Because at the time it was believed that the anaemia caused the neuro damage, then once Smith’s team had established dosages effective for reversing the anaemia it was this information which was released by Glaxo - the effective treatment for neurological injury was archived - and there it remains.
Secondly, as Dr Bradley quite rightly observes, there is an inconsistency between the common causes of B12 deficiency listed in the review and the number of people said to suffer from it. One aspect rarely focused upon today is that previous to 1926 it was well known that all patients suffering from pernicious anaemia (all B12 deficiencies then went under this classification) also had acholorhydria or hypochlorhydria. At the time it was reported, by such authorities as Hurst and James Samuel Risien Russell, that 100% of these patients had this condition. Later research, by I believe, Kinnier-Wilson, claimed it to be 75%. Either way the statistics are staggering. Yet, despite these figures and the fact that stomach acid needs to be acidic rather than alkaline to cleave B12 from food, few patients are tested for this condition. In fact there is no test available to primary care physicians throughout Europe. The new Best Practice Guidelines from the BMJ do suggest checking for increased gastrin levels which would suggest alkaline stomach acid, however it remains to be seen whether this suggestion is taken on board or whether a direct pH test will be introduced.
Another issue remaining is the contradiction relating to the progression of the illness: is anaemia ‘end stage’ as we often hear, or does it precede the neurological damage? Certainly it can’t always be both and certainly patients do present with the anaemia and few signs of neurological injury, whereas others present with severe neuro injury and few signs of anaemia. Worth noting may be the fact that in the late 1800s and early 1900s, only about 20% of patients were recorded as dying from anaemia. The remainder died from neuro degeneration or associated heart attacks/strokes etc. The patients identified by Addison (1847) did die of anaemia, but they were later (from the 1880s onwards) considered to be the 20% arm.
In short, it would seem that a primary causation of this illness, alkaline stomach acid, requires more investigation, and also consideration should be given to the possibility that anaemia is only one possible symptom which may appear at any stage of the disease progression as well as appearing in isolation.
Competing interests: In December 2016 Mike Newman and Karen Thompson wrote Vitamin B12 Deficiency and Chronic Illness, published by CreateSpace Independent Publishing Platform. [Response modified on 4 July 2017 by Sharon Davies, The BMJ]