Serum levels of Vitamin B12 are not an accurate indicator of B12 functional status
Blood tests for vitamin B12 can be very misleading
Vitamin B12 levels in the blood are managed differently than in the tissues and don’t accurately reflect B12 functional status.
B12 levels within the specified normal range may still be associated with neurological degeneration and dysfunction.
It’s well known among clinicians trained in clinical nutrition that serum vitamin B12 levels do not correlate reliably celluar tissue, and importantly, functional status. An excellent research article published in Annals of Neurology unpacks the chemistry that shows why in an especially lucid manner.
After reviewing the crucial importance of vitamin B12 for brain and nervous system function and prevention of anemia, they note:
“In addition to affecting general cognition and memory, vitamin B12 deficiency may even lead to dementia and psychosis, suggesting a broader dependence of the brain on B12.8-11”
Then they describe the historical problem of misleading lab results:
“In the United States, the cutoff value for B12 “deficiency” state is currently defined as below 148 pmol/L.1 This value was simply calculated as 3 standard deviations below the U.S. population average, independent of clinical observations.17 The American Society for Nutrition criticized this approach in 2010, arguing that more than 5% of patients who have a syndrome consistent with B12 deficiency and who respond to B12 supplementation have blood levels above that threshold.18 Other studies demonstrated that B-vitamins supplementation was beneficial in people with clinical features of cobalamin deficiency, regardless of the measured levels in the blood.13, 19 Selecting a cutoff value based on clinical observations would better reduce disparities in B12 deficiency diagnosis and management.”
Subclinical cobalamin (B12) deficiency
Vitamin B12 levels can be suboptimal with adverse effects in the absence of overt damage. Since B12 is required for myelin formation (nerve ‘insulation’), this can show up on MRI as abnormal brain white matter, or ‘white matter hyperintensities’ (WMH).
“Cases of biochemical B12 deficiency wherein suboptimal B12 levels have been reported without overt clinical manifestation have been reported as subclinical cobalamin deficiency (SCCD).20 SCCD is most prevalent in the elderly and is associated with greater WMH burden and cognitive decline over time.21, 22 In this context of B12 insufficiency, age might act as a vulnerability factor, accentuating the deleterious effects of low B12.”
Holo-TC versus Holo-HC
How cobalamin (B12) is ferried through the bloodstream turns out to be a vital determinant in whether or not the B12 measured in the blood is available to the tissues and cells.
“Distribution of the fractions of B12 measured in the blood adds another layer of complexity to understanding the neurological manifestation of B12 deficiency. Once cobalamin is absorbed, the transport proteins haptocorrin (HC) and transcobalamin (TC) bind it with great affinity and act as transporters in circulation.25, 26 Since only TC has a specific receptor (CD320) for cellular uptake, Holo-TC1 is usually considered to be biologically available for cells (“active”). On the other hand, Holo-HC hypothetically represents the fraction of B12 that is not immediately available to tissues (“inactive”); it can only bind non-specific asialoglycoprotein receptors on liver cells for reuptake, degradation and excretion in the bile.27"
The authors set out to determine if lower total B12 levels within the typical ‘normal range’ may still permit subtle functional and structural neurological deficits if the active fraction of plasma B12 (Holo-TC) is too low to sustain adequate cellular B12 needs.
“To that end, we evaluated the association of B12 concentrations with markers of myelin integrity (multifocal VEP; mfVEP), cognitive performance, blood biomarkers of neuronal and glial integrity, as well as quantitative brain MRI analyses across a spectrum of measurable B12 levels as well as the active fraction of the plasma B12.”
Even high levels of B12 if unavailable are associated with neurodegeneration
They were able to demonstrate how even though serum B12 was ‘over the top’, when much of it was unavailable to the cells it resulted in neurodegeneration.
“At low levels of B12, specifically when bound to transcobalamin for cellular uptake, evidence of slower conductivity in the brain could point toward impaired myelin. At high levels of B12, specifically when bound to the biologically inert transport protein haptocorrin, biomarkers of neurodegeneration appear in the serum, indicating neuroaxonal injury.”
This graphic explains how high levels of B12 in the currently defined normal range can be associated with neurodegeneration because the available B12 (Holo-TC) is relatively small compared to the unavailable Holo-HC B12. These are not distinguished in the clinically available blood tests for B12.
Rethinking the “biologically sufficient” B12 levels
Key findings of this research include:
Lower B12 associates with a delay in VEP latency, and that it is specific to the biologically available fraction of serum B12 bound to transcobalamin (Holo-TC). They also associate with slowed spatial processing speed.
On MRI, participants with lower Holo-TC have a higher burden of T2 WMH.
High levels of Holo-HC, the biologically unavailable fraction of B12, associate with an increase in the levels of T-Tau proteins in the serum, a biomarker for neurodegeneration.
The observed detrimental effect of low B12 on the CNS is likely related to myelin integrity.
“These findings suggest that current parameters for defining adequate B12 levels may be inappropriate when considering neurophysiological, neuropsychological, serological, and neuroradiological outcomes.”
Further research investigating the adverse effects of high levels of the unavailable holo-haptocorrin (Holo-HC) is needed.
Especially, having a clinical lab step to make the Holo-TC blood test available to practitioners outside of a research setting is an urgent need.
Summarizing their findings, the authors state:
“Our findings are of critical importance for rethinking the “biologically sufficient” B12 levels. The population-based studies that defined healthy micronutrient levels may have missed the subclinical manifestations of low or high B12 at the extremes of the population distribution that can affect people without causing overt symptoms.”
“Notably, during and following B12 repletion therapy, patients often request higher dosing of B12 to treat their neurological symptoms, even after their hematological symptoms have resolved.62 Our findings support the idea that subtle neurological deficits manifest at higher levels than the current threshold defined for deficiency, and most importantly, it could provide an explanation for the often-reported discrepancy between hematological and neurological symptoms.63, 64”
“This slow progression toward deficiency could be better described by a sliding scale of insufficiency, wherein the tissue levels decline until Holo-TC falls below what is necessary to supply critical cells for biochemical reactions in the nervous system, and then the bone marrow. Revisiting the definition for healthy B12 levels could promote earlier intervention and prevention of cognitive decline, especially in the elderly carrying increased risk for B12 malabsorption and insufficiency.67, 68
“…inadequate amounts of vitamin B12 could induce neurological deficits at a threshold that is higher than the one in current use (Graphical abstract). Moreover, we should work on defining a cutoff for higher B12 and study how haptocorrin might be associated with or could induce neuro-axonal damage.”
For an earlier study of the inadequacy of serum B12 testing in the prestigious journal Neurology, see Serum levels of vitamin B12 are not accurate for brain health and cognition.
