Vitamin B12 deficiency
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5226 (Published 04 September 2014) Cite this as: BMJ 2014;349:g5226All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
In answer to Nicholas Nutt:
Strictly speaking, the term 'vitamin B12' has been defined as cyanocobalamin. This form does not occur in vivo. Nutt correctly states that cyanocobalamin releases a cyanide group for every molecule of B12 that is used. However, it is incorrect that hydroxocobalamin is the active form of the vitamin.
There are two active forms of the B12 enzyme in the human cell. First, Methylcobalamin acts as a co-enzyme for the conversion of homocysteine to methionine. Methionine then acts as a methyl-donor to a great number of reactions that need a methyl group, including the synthesis of myelin, serotonin, dopamine, noradrenalin, DNA and phospholipids.
Second, Adenosylcobalamin is a co-enzyme for the conversion of L-methylmalonyl-CoA into succinyl-CoA which feeds into the citric acid cycle.
Is it important which form is used in treatment? In most people, it does not matter. They can convert cyano- and hydroxo-cobalamin into the active forms needed. However, I have recently reported a case in which it did matter. The severe vitamin B12 deficiency, including dementia and psychosis, responded to treatment with high dose oral methylcobalamin, but not to equally high dose oral hydroxocobalamin. [1]
1. Rietsema WJ. Unexpected Recovery of Moderate Cognitive Impairment on Treatment with Oral Methylcobalamin. Journal of the American Geriatrics Society 2014;62(8):1611-12 doi: 10.1111/jgs.12966[published Online First: Epub Date]|.
Competing interests: No competing interests
This article is still recommending cyanocobalamin when used orally. This is of course rapidly converted to hydroxycobalamin, the active vitamin, but is also giving a dose of cyanide. In very very rare cases this can cause blindness (the optic nerve is the most sensitive part of the nervous system to this neurotoxin).
Oral hydroxycobalamin is well absorbed (see for example The Lancet, Volume 355, Issue 9198, Page 148, 8 January 2000), so it would seem unwise to recommend anything else. Perhaps a minor correction to this article is indicated, and it would seem sensible if cyanocobalamin was banished from the formulary - as I had thought it had been years ago! How about a campaign to do this?
Competing interests: No competing interests
The wholesale price for pure vitamin B12 [cyanocobalamin] is about $4000/kg. At the U.S. recommended daily amount [RDA/DV] for adults of 2.4 micrograms, $4000 would supply the entire U.K. population for about a week. Problem solved at least to a considerable degree for $200,000 per year for vitamin B12.
Adding this non toxic vitamin as a food fortification also has some cost -- but how much is the U.K. spending per year just to analyze B12 in blood samples. Then there is the cost of injected B12 that can be avoided by supplementation since just about anyone ingesting 100 mcg/d for some months will absorb sufficient B12 to take care of any known biological, age or genetic impediment.
Vitamin B12 supplementation lowers homocysteine in many if not most of us. Homocysteine is an undisputed risk factor for stroke, most of the other cardiovascular diseases, Alzheimer's disease, bone fracture and macular degeneration, to name but a few conditions where a medical cure or prevention is not evident. A final cost is the research such as the one in question that is important but that also does not resolve the issue of a cheap, safe and effective path to deal with suboptimal intake of B12 via food fortification or by multivitamin use. For example, a $0.11/day U.S. mail-ordered no child-proof-cap required multivitamin may contain 100 mcg/pill. James Lind would not be happy.
Competing interests: No competing interests
In their excellent review, Hunt et al. (1) do an important service to patients by pointing out that B12 deficiency is very common, easily treated, has important consequences and may be missed if a serum total cobalamin level in the normal range is used to exclude it. There is an important omission from the consequences mentioned, and two additional factors to consider regarding therapy.
As the authors mentioned, vitamin B12 deficiency results in increased levels of total homocysteine (tHcy). High levels of tHcy increase the risk of deep vein thrombosis, retinal vein thrombosis, cerebral sinus thrombosis and quadruple the risk of stroke among patients with atrial fibrillation (2). Atrial fibrillation increases steeply with age, and so do levels of tHcy: among patients attending a stroke prevention clinic a serum tHcy above 14 µmol/L was present in ~ 10-15% of patients at age 35-50, but in 40% of patients age > 80 (3). (Interestingly, it was present in 20% of patients below age 35, perhaps because of different stroke subtypes in that age range.) Metabolic B12 deficiency was present in 12% below age 50, 13% of those age 50-70 and 30% above age 70(4). This is probably why B vitamin therapy reduces the risk of stroke, although reduction of myocardial infarction has not been shown.
The clinical trials of B vitamins for stroke prevention have been misunderstood because of the complexities relating to dose of cobalamin and the key role of renal function (5). B vitamins were harmful in patients with diabetic nephropathy and a GFR <50(6;7), but reduced the risk of stroke in the HOPE 2 trial (8;9), the SuFolOM3 trial (10), the VITATOPS patients not taking anti-platelet agents (11), the VISP patients with an eGFR>47 who did not receive B12 injections (12), and in meta-analysis (13).
In renal failure high dose folic acid leads to high levels of unmetabolized folate and increased levels of asymmetric dimethylarginine, a nitric oxide antagonist (14), while cyanocobalamin leads to a buildup of cyanide (15). Methylcobalamin lowers levels of both tHcy and ADMA in dialysis patients(16). It appears that harm from B vitamins among patients with renal failure cancelled out benefit among patients with good renal function. It may be important, particularly in patients with impaired renal function, to use methylcobalamin in preference to cyanocobalamin (5).
Finally, vitamin B12 deficiency results in loss of intestinal villi, aggravating malabsorption of B12 (17). With the exception of patients with short bowel syndrome or inflammatory bowel disease, most patients with B12 deficiency can be treated with high doses of oral B12 once the intestinal villi have been restored by parenteral B12.
References
(1) Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ 2014; 349:g5226.
(2) Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol 2007; 7:830-838.
(3) Spence JD. Mechanisms of thrombogenesis in atrial fibrillation. Lancet 2009; 373(1006).
(4) Spence JD. Nutrition and stroke prevention. Stroke 2006; 37(9):2430-2435.
(5) Spence JD. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes. Clin Chem Lab Med 2013; 51(3):633-637.
(6) House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 2010; 303(16):1603-1609.
(7) Spence JD, Eliasziw M, House AA. B-Vitamin Therapy for Diabetic Nephropathy: Reply. JAMA 2010; 304(6):636-637.
(8) Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354(15):1567-1577.
(9) Refsum H, Smith AD. Homocysteine, B vitamins, and cardiovascular disease. N Engl J Med 2006; 355(2):207-211.
(10) Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341:c6273.
(11) Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D et al. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial. Lancet Neurol 2012; 11(6):512-520.
(12) Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention for Stroke Prevention Trial: an efficacy analysis. Stroke 2005; 36:2404-2409.
(13) Ji Y, Tan S, Xu Y, Chandra A, Shi C, Song B et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis. Neurology 2013; 81(15):1298-1307.
(14) Loscalzo J. Homocysteine trials--clear outcomes for complex reasons. N Engl J Med 2006; 354(15):1629-1632.
(15) Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant 1997; 12(8):1622-1628.
(16) Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y et al. Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis 2010; 55(6):1069-1078.
(17) Foroozan P, Trier JS. Mucosa of the small intestine in pernicious anemia. N Engl J Med 1967; 277(11):553-559.
Competing interests: No competing interests
Hunt, Harrington and Robinson provide a welcome overview of vitamin B12 deficiency and its treatment. A few aspects, however, could be emphasised more.
First, one of the most common and most debilitating symptoms of vitamin B12 deficiency is extreme fatigue, ‘tired all the time’ and in some patients also insomnia. If a patient’s mood is low at the same time, this can easily be interpreted as depression. Vitamin B12 deficiency is then easily missed.
Second, the presence of risk factors should increase the level of clinical suspicion. One important risk factor is the use of nitrous oxide. Nitrous oxide inactivates vitamin B12 [1] but leaves it detectable on serum B12 essay, thereby increasing the risk of a false negative test. It is used in general anaesthesia, as an analgesic in obstetrics and in ambulances and emergency departments. It is increasingly used as a recreational drug, sometimes in large amounts and for prolonged periods of time. In elderly patients who deteriorate after an operation, or patients whose symptoms worsen after delivery, an operation or a painful emergency, vitamin B12 deficiency should be suspected. Some drug-seeking patients repeatedly obtain nitrous oxide in ambulances and emergency departments. Recreational drug use should be part of the history.
The prevalence of vitamin B12 deficiency is increased in the elderly, [2] people with diabetes [3], obesity and in those who have undergone bariatric surgery, [4 5] alcohol abuse, and in eating disorders.
Vitamin B12 deficiency can be easily missed, because its symptoms may be clinically indistinguishable from those of dementia, [6] Parkinson's disease, frailty of old age, diabetic neuropathy, alcoholic central and peripheral neuropathy, and mental illness. It needs to be diligently sought, and treated if there is any clinical suspicion, even if serum B12 levels are within the reference range.
Third, the sensitivity of the serum B12 test is poor. [7] Adding methylmalonic acid and homocysteine improves sensitivity, but may still leave nearly half of patients with B12-responsive symptoms undetected. [8] In patients whose symptoms are consistent with vitamin B12 deficiency but whose serum B12 is within the reference range, a trial of treatment may be used as an adjunct to diagnosis. [6]
1. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology 2008;109(4):707-22 doi: 10.1097/ALN.0b013e3181870a17[published Online First: Epub Date]|.
2. Obeid R, Schorr H, Eckert R, et al. Vitamin B12 status in the elderly as judged by available biochemical markers. Clin Chem 2004;50(1):238-41 doi: 10.1373/clinchem.2003.021717[published Online First: Epub Date]|.
3. Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? Journal of diabetes and metabolic disorders 2013;12(1):17 doi: 10.1186/2251-6581-12-17[published Online First: Epub Date]|.
4. van Rutte PW, Aarts EO, Smulders JF, et al. Nutrient Deficiencies Before and After Sleeve Gastrectomy. Obesity surgery 2014 doi: 10.1007/s11695-014-1225-y[published Online First: Epub Date]|.
5. Stein J, Stier C, Raab H, et al. Review article: the nutritional and pharmacological consequences of obesity surgery. Alimentary pharmacology & therapeutics 2014 doi: 10.1111/apt.12872[published Online First: Epub Date]|.
6. Rietsema WJ. Unexpected Recovery of Moderate Cognitive Impairment on Treatment with Oral Methylcobalamin. Journal of the American Geriatrics Society 2014;62(8):1611-12 doi: 10.1111/jgs.12966[published Online First: Epub Date]|.
7. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012;367(4):385-6 doi: 10.1056/NEJMc1204070[published Online First: Epub Date]|.
8. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105(3):978-85 doi: 10.1182/blood-2004-04-1641[published Online First: Epub Date]|.
Competing interests: No competing interests
Hunt and colleagues highlight various aspects of B12 deficiency in this engaging and valuable review article(1). An important but often overlooked aspect of B12 deficiency is the associated retinal damage. Considerable evidence explores that people with compromised B12 levels are more susceptible to development of age related macular degeneration (AMD) and the prevalence is much reduced in those taking cobalamine supplementation(2). B12 deficiency could also manifest itself as optic neuropathy and present as progressive decline in visual acuity leading to gradual development of bilateral centocecal scotomas(3).
Health care workers need to consider the fact that widespread use of folic acid supplements and food fortification practice can significantly diminish the haematological effects of B12 deficiency(4), and further exhibit a “masking effect” on the detection of retinal symptoms. This may act as a major ground for concealed and irreversible progression of the retinal loss, especially in older persons. Perhaps what we need is a much closer attention on retinal and neurological symptoms in suspected cases of B12 deficiency.
References:
1. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ 2014;349:g5226 doi: 10.1136/bmj.g5226.
2. Gopinath B, Flood V, Rochtchina E, Wang J, Mitchell P. Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. Am J Clin Nutr 2013; 98:129-135.
3. Chavala S, Kosmorsky G, Lee M, Lee M. Optic neuropathy in vitamin B12 deficiency. Eur J Int Med 2005; 16:447–448.
4. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol.2006; 5:949–960.
Competing interests: No competing interests
The clinical review of vitamin B12 deficiency by Hunt et al was concise and informative. However, it did not mention autonomic dysfunction caused by vitamin B12 deficiency. Urinary incontinence, impotence and orthostatic hypotension are well-recognized autonomic manifestations of vitamin B12 deficiency (1) .
I have seen patients with long-standing drenching night sweats responding dramatically to intramuscular vitamin B12. Physiologically it is not surprising since changes in the peripheral autonomic nervous system may be the earliest manifestations of small-fiber neuropathy and hyperhidrosis frequently accompanies small-fiber peripheral neuropathy (2) . Episodic hyperhidrosis also occurs commonly in patients with familial dysautonomia, a hereditary sensory and autonomic neuropathy (3) . Autonomic dysfunction resulting in long- and short-term heart rate variability has been found to be significantly lower in vitamin-B12 deficient subjects compared to controls (4,5). Beitzke et al found major hemodynamic and autonomic impairment in patients with vitamin-B12 deficiency (6) . Defective sympathetic activation and decreased catecholamine release has been postulated as pathogenic mechanisms. Reduction of sudomotor sympathetic unmyelinated fibers has been described in patients with vitamin-B12 deficiency and orthostatic hypotension (7) .
The exact mechanism of excessive sweating in vitamin-B12 deficiency is a matter of speculation and will require further studies. Spinal sympathetic over-activity is one plausible explanation.
As the authors state, using serum cobalamin assay to diagnosis vitamin B12 deficiency has its limitations. “Functional” vitamin B12 deficiency is a syndrome where a wide variety of symptoms in the presence of “normal” serum levels of the vitamin respond to vitamin B12 therapy. Megaloblastic anemia and sub-acute combined degeneration of spinal cord are only the extreme manifestations observed at the far end of the spectrum with severe deficiency. On the other hand, non-specific symptoms like fatigue are the earliest manifestations. Autonomic dysfunction, it seems, is a common manifestation of functional vitamin B12 deficiency and seems to occur early in the course of disease process. This spectrum of disease usually presents in the absence of any changes in red blood cell indices and is easily misdiagnosed since serum levels of vitamin are in the “normal” range. Indeed, short-term fluctuations in HCy and MMA levels may also result in normal levels of these metabolites, thus obscuring the deficiency. This has been described previously in a patient who had total absence of vibratory sensation in the iliac crest, knees and ankles and normal levels of vitamin and metabolites, which resolved completely after 2 months of vitamin B12 therapy (8) . In this study, only 16% of patients with clinical response to cobalamin therapy had low serum levels of the vitamin and values were above 300pg/mL in 54% of cases. In addition, HCy and MMA values were in the normal range in 49% and 23% of cases respectively. Both metabolite levels were normal in 21% of cases.
The preferred route of administration of vitamin B12 has also been debated for a long time. Majority of cobalamin in the circulation is bound to haptocorrin and is unavailable for cellular uptake. Only cobalamin bound to transcobalamin is taken up by endocytosis mediated by the cell surface transcobalamin receptor. Only 6-20% of total plasma vitamin B12 is in the active form, bound to transcobalamin II (9) . Most of the studies of oral vitamin B12 therapy used serum levels of vitamin and its metabolites as the markers of response to therapy. However, correction of an abnormal laboratory value does not mean successful outcome. An objective improvement in health outcome is only meaningful if accompanied by a clinical response. For example, in a study of 80 patients over a 3-month period, although 80-90% of patients achieved normal serum cobalamin levels on an oral dose of 650 to 1000mcg daily, clinical improvement was observed only in 20 - 30% of patients (10) . Similarly, in an open study of vitamin B12 deficiency related to food-cobalamin malabsorption in 10 patients, oral crystalline cobalamin was prescribed at a dose of 650mcg per day for at least 3 months. Normalization of vitamin levels was seen in 80% of patients, along with significant increase in hemoglobin levels and decrease in mean corpuscular volume but clinical improvement occurred only in 20% of patients (11) . We can only speculate the reasons behind lack of response to oral vitamin B12 and it may be that cobalamin somehow undergoes a transformation in the portal circulation so is made less able to be internalized by the cells and only when cobalamin is able to bypass portal circulation, the cells internalize it. This seems to be a saturable process since a minority of patients responds clinically to oral therapy.
1- Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Med Baltimore1991;70:229-45.
2- Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006;34:57-61.
3- Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001;68:598-605.
4- Sözen AB, Demirel S, Akkaya V, Kudat H, Tükek T, Yeneral M, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998;71:25-7.
5- Aytemir K, Aksoyek S, Buyukasik Y, haznedaroglu I, Atalar E, Ozer N, et al. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 2000;23:975-8.
6- Beitzke M, Pfister P, Fortin J, Skrabal F. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic and Clin 2002;97:45-54.
7- Toru S, Yokota T, Inaba A, Yamawaki M, Yamada M, Mizusawa H, et al. Autonomic dysfunction and orthostatic hypotension caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry 1999;66:804-5.
8- Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978-85.
9- Hall CA. The carriers of native vitamin B12 in normal human serum. Clin Sci Mol Med 1977;53:453-7.
10- Andrès E, Perrin AE, Demangeat C, et al. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med 2003;14:221-6.
11- Andrès E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med 2001;111:126-9.
Competing interests: No competing interests
Reading through the first page I see no reference 4 in the text. The authors then claim that ‘In the United Kingdom and United States the prevalence of vitamin B12 deficiency is around 6% in people aged less than 60 years, and closer to 20% in those aged more than 60 years’, a statement which is not referenced. References 7-9 are missing on that page, but they do appear in the reference section. As in our surgery we do not see deficiency ‘closer to 20% in those aged more than 60 years’, I looked up ref 10 from the list. Ref 10 states that:
‘Serum vitamin B-12 concentrations in the US population were reported in the National Health and Nutrition Examination Surveys from 1999 to 2002 (1, 5). The prevalence of deficiency (serum vitamin B-12 less than 148 pmol/L) varied by age group and affected ≤3% of those aged 20–39 y, 4% of those aged 40–59y, and 6% of persons aged ≥70 y. .....The prevalence of vitamin B-12 deficiency (serum B-12 less than 150 pmol/L) increased substantially after age 69 y in 3 UK surveys (combined number 3511); it affected about 1 in 20 people aged 65–74 y and at least 1 in 10 of those aged ≥75 y (7, 8)’. It appears that the authors have not checked and/or quoted the reference correctly.
Further down the authors state that ‘The clinical manifestations of vitamin B12 deficiency (fig 2⇓),3 5-7, 9, 13 represent the effects of depletion on multiple systems and vary greatly in severity.....
However, it is important to recognise that clinical features of deficiency can manifest without anaemia and also without low serum vitamin B12 levels’.
Looking at figure 2 made me realise that we have found the cure for some common, debilitating and devastating conditions and diseases. Should I be writing letters to my patients with cardiomyopathy, unexplained infertility, depression, psychosis, impaired cognition, even though they have no anaemia and no low vitamin B12 levels, to come and see me so I can start treating them immediately? In the cases of unexplained infertility I only need to decide if I need to treat the male, the female or both (just be sure).
According to this review the potential of vitamin B12 is so great, that I urge the BMJ to send a copy to all GPs, infertility specialists, psychiatrists, cardiologists and geriatrians forthwith, and not just in the UK and the US but all over the world, especially those working in low income countries. They even don’t need to test for anaemia or vitamin B12 levels because according to review ‘clinical features of deficiency can manifest without anaemia and also without low serum vitamin B12 levels’.
Ahhh, how would one cope if the BMJ authors, peer reviewers and editors were to tighten up and were to stop publishing this kind of wrong assertions and unsubstantiated claims? One would lose the entertainment factor, but would save time as he would not need to read the original references plus the impact factor of the BMJ might improve. On balance the latter is much better.
Competing interests: No competing interests
In response to N.R. Nutt's suggestion to ban cyanocobalamin
The cyano group represents 2% of cyanocobalamin which itself is taken in microgram amounts. I fail to see the points of those arguing toxicity from such small amounts, especially considering that in the U.S. 1 litre of water may contain up to 200 mcg of cyanide -- and then there is the 'cyano' in almonds, lima beans, soy, spinach, some seeds and other food items. Obviously, the greater dangers from B12 are in not getting enough, an almost universal problem and not the form it comes in. Since the cost 'per serving' of any form of B12 is probably comparable to the price of the glue on a stamp, cost is not an issue. The provided references for cyano-B12 having any negative effect are somewhat flimsy or anecdotal and/or contradictory. Cyano-B12 is widely reported to be the most stable form and that has to be a benefit.
Competing interests: No competing interests