Review ArticleMetabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke
Graphical Abstract
Plasma total homocysteine increases at serum B12 levels less than 300-400 pmol/L. Only 26% of patients referred to a stroke prevention clinic had serum B12 levels greater than 400 pmol/L. Among patients with serum B12 in the borderline range, tests of functional B12 such as holotranscobalamin, methylmalonic acid, or (in folate-replete patients) plasma total homocysteine are necessary to exclude metabolic B12 deficiency.
Introduction
There is widespread misunderstanding of the complexity of interpreting clinical trial results of vitamin B12 (B12) for prevention of stroke and dementia. In this narrative review, insights into reasons why many of the randomized trials appeared to be negative are discussed. The literature reviewed was from reference databases of the author and of Profs David Smith and Helga Refsum, who advised the author on early drafts. Randomized trials, although rightly regarded as first-tier evidence, are blunt instruments for studying vascular biology; they must be interpreted with knowledge of the biology of the conditions being studied.
Section snippets
Importance of metabolic B12 deficiency
Both stroke and dementia increase steeply with age. With the aging of the population, the burden of dementia and stroke, in both human and economic terms, is expected to increase markedly. A policy statement from the American Heart Association [1] predicted that stroke in the United States will more than double by 2030, with total annual costs of stroke of ~$240 billion. In view of recent calls for integrated approaches to prevention of dementia [2], it is timely to address a potentially
Level of serum B12 that would define adequacy of functional B12
Vogiatzoglou et al [10] reported in the Hordaland study that levels of MMA and tHcy begin to rise already at a serum B12 of 350-400 pmol/L, with a much steeper rise in MMA in the elderly. That level coincides with the inflection point of serum B12, 400 pmol/L, below which tHcy levels began to rise in the National Health and Nutrition Examination Survey (NHANES) [11] (Fig. 1). A more complex relationship between serum B12 and MMA has recently been described in the NHANES cohort, with 33% of
Frequency of metabolic B12 deficiency among vascular patients
In vascular patients, evidence of metabolic B12 deficiency is common and increases with age. For instance, in a Canadian secondary stroke prevention clinic population, metabolic B12 deficiency was present in 12.5% of those younger than 71 years and in 30% of those older than 71 years [13]. Fig. 2 shows the frequency of serum B12 levels by age in the clinic population. Levels less than 160 pmol/L (the lower reference limit of for that laboratory), that is, B12 deficiency, were present in 9% of
Causes of metabolic B12 deficiency
There are many ways for B12 status to become inadequate besides deficiency of intrinsic factor and gastric acid. The acquired causes increase with age, and this probably accounts for the finding that higher doses of oral B12 are needed to achieve adequate absorption in the elderly [14]. Among elderly patients with low serum B12 levels (≤221 pmol/L) and elevated MMA, peroral doses of up to 1000 μg of cyanocobalamin were required to achieve normal MMA levels [14]. An unexpected potential cause of
Metabolic B12 deficiency and cognitive decline
Metabolic B12 deficiency is also important in cognitive decline. Approximately half of patients presenting with megaloblastic anemia will have cognitive impairment [20], [21], but this association is not limited to those with frank B12 deficiency. In community-dwelling elderly, the risk of cognitive impairment extends across the normal range of holotranscobalamin [22], [23], and many prospective studies show that raised tHcy is a strong risk factor for dementia [24]. Patients with serum B12 in
Metabolic B12 deficiency and vascular disease
An important aspect of preventing dementia is the prevention of stroke [33], [34], and B12 deficiency is an easily treated contributor to stroke risk [35], [36]. B12 deficiency raises levels of tHcy, increasing carotid plaque [37]; the risk of deep vein thrombosis, retinal vein thrombosis, and cerebral vein thrombosis; as well as stroke risk in patients with atrial fibrillation [36]. High levels of tHcy quadruple the risk of stroke in patients with atrial fibrillation [38].
In addition to
B12 deficiency, elevated tHcy, and stroke
In the Framingham study, the proportion of strokes due to atrial fibrillation increased steeply with age, from 1.5% at age 50 years to 23% at age 80-89 years [44]. Among patients attending the Stroke Prevention Clinic at University Hospital in London, Ontario, stroke subtypes changed markedly with improved treatment of dyslipidemia: the proportion of strokes identified as cardioembolic increased from 26% in 2002 to 56% in 2012 [45]. In that same population, the prevalence of tHcy >14 increased
How could B vitamins cause harm in persons with renal failure?
Possible mechanisms for toxicity of high-dose B vitamins in patients with renal failure were discussed by Spence and Stampfer [61]. One possibility relates to unmetabolized folic acid that has not been converted to tetrahydrofolate [17]; this may interact with metabolic B12 deficiency via the “methylfolate trap,” in which B12 deficiency prevents metabolism of 5-methyltetrahydrofolate [62], [63]. Another relates to cyanide from cyanocobalamin. Koyama et al [64] showed that dialysis patients
Beyond dementia and stroke
Besides increasing the risk of stroke and dementia, functional B12 deficiency causes neuropathy and myelopathy; it is likely also that loss of position sense from myelopathy contributes to the risk of falls in the elderly. B12 deficiency is also associated with orthostatic hypotension (possibly due to autonomic neuropathy), another cause of falls in the elderly [72]. Raised tHcy, for which the main nutritional cause in countries with folic acid fortification is B12 deficiency [37], also
Treatment of B12 deficiency
It should be noted that B12 supplementation for the population should not be implemented until there is evidence from trials of benefit but no harm; however, in individual patients, it is important to improve detection and treatment of metabolic B12 deficiency, which should not be regarded as “subclinical.”
Most B12 deficiency is due to malabsorption of B12, but adequate absorption of B12 can be achieved with high doses of oral B12 in most patients, even in the absence of intrinsic factor and
What is not known; need for future research
Lacking are large-scale randomized trials of supplementation with B12 (preferably methylcobalamin) in persons with metabolic B12 deficiency. Future research is needed into the effects of thiocyanate from cyanocobalamin on H2S and effects of treatment with methylcobalamin on cognitive function and stroke, particularly in patients with renal failure. Clinical trials in elderly persons with metabolic B12 deficiency should study effects on stroke and cognitive decline. In addition, because B12
Conclusion
Metabolic B12 deficiency is common, is frequently missed, is easily treated, and contributes importantly to cognitive decline and stroke in older people. Measuring serum B12 alone is not sufficient for diagnosis; it is necessary to also measure markers of B12 adequacy such as MMA or tHcy. Undiagnosed metabolic B12 deficiency may be an important missed opportunity for prevention of dementia and stroke. In patients with metabolic B12 deficiency, it would be prudent to offer inexpensive and
Disclosures
None relevant to the topic of this article. There was no funding.
Acknowledgment
The author is indebted to A. David Smith, University of Oxford, and Helga Refsum, Oxford University and University of Norway, for important revisions of the manuscript.
References (78)
- et al.
Biomarkers of vitamin B-12 status in NHANES: a roundtable summary
Am J Clin Nutr
(2011) - et al.
Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility
Am J Clin Nutr
(2011) - et al.
Modeling a methylmalonic acid–derived change point for serum vitamin B-12 for adults in NHANES
Am J Clin Nutr
(2013) - et al.
Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate
Am J Clin Nutr
(2009) - et al.
Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors
Am J Clin Nutr
(2010) Vitamin B12, folic acid, and the nervous system
Lancet Neurol
(2006)- et al.
Vitamin B-12 and cognition in the elderly
Am J Clin Nutr
(2009) - et al.
Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals
Am J Clin Nutr
(2014) - et al.
Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis
Lancet Neurol
(2009) Homocysteine-lowering therapy: a role in stroke prevention?
Lancet Neurol
(2007)