Research
Featured article for June 2025
It is unknown why many patients with pernicious anaemia are satisfactorily treated with injections of hydroxocobalamin or cyanocobalamin every 1–3 months whereas others require far more frequent replacement regimens, sometimes even weekly. A substantial but inconstant fraction of an injected dose of cobalamin is excreted in the urine within 72 h of injection, with subsequent loss of variable smaller amounts. We hypothesize the existence of ‘hypercobalaminuria’, whereby increased urinary cobalamin losses constitute a currently unrecognized factor influencing treatment refractoriness in some individuals. The hypothesis is testable by comparing cobalamin urinary losses in patients needing frequent as opposed to 1–3-monthly injections of cobalamin to remain symptom-free. It implies that ‘less-responsive’ patients are likely to have significant hypercobalaminuria.
Link: https://www.sciencedirect.com/science/article/pii/S0306987725001033
Featured article for May 2025
The 2024 guidelines from the UK’s National Institute for Health and Care Excellence (NICE) regarding vitamin B12 deficiency are an important step forward but raise concerns—especially around the diagnosis and treatment of a condition called pernicious anaemia (PA). PA is the most common non-dietary cause of B12 deficiency and is often poorly understood and underdiagnosed.
PA is a serious, lifelong condition requiring regular vitamin B12 injections. However, many patients report that current treatment guidelines (one injection every 2–3 months) are not enough to manage their symptoms effectively.
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Controversial Renaming
The 2024 NICE guidelines suggest replacing the term "pernicious anaemia" with "autoimmune gastritis" (AIG). The authors of this article argue that this change is problematic. While AIG and PA are related—AIG can lead to PA over time—they are not the same. PA is a later, more specific stage of the disease, defined by a true inability to absorb B12 due to intrinsic factor deficiency.
Renaming PA could create confusion for both patients and healthcare providers. It might also overlook the fact that PA can occur independently of full-blown AIG and that not everyone with AIG will develop PA. The authors advocate for keeping the name or at least adopting a clearer, more accurate term that reflects the autoimmune nature and B12-related consequences of the disease.
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Challenges in Diagnosis
PA can be difficult to diagnose because its symptoms may be vague and vary from person to person. Some people may not show typical digestive symptoms, which can mislead doctors. Current testing methods also have limitations. The most commonly used test checks for antibodies against intrinsic factor, but this only detects PA in less than half of cases. Other tests like stomach biopsies or checking gastrin levels are underused, despite being helpful.
Surveys show that most PA patients in the UK are not given a gastroscopy (an internal examination of the stomach), which is a standard diagnostic tool in other countries. This is concerning, especially since PA and AIG are linked to a higher risk of stomach cancer and other complications.
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Positive Developments in the Guidelines
Despite the concerns, the new guidelines do include promising changes. They recognize the importance of tailoring treatment to the individual—a shift from the one-size-fits-all model. Many patients feel better with more frequent injections, and some even self-administer B12 at home due to poor access or limited support from healthcare providers.
The guidelines also highlight the need for more research, including how to better support patients in managing their own care. This includes reviewing whether regular monitoring, such as for cancer risk, should be introduced for PA and AIG patients—something currently missing in UK practice but found in some European healthcare systems.
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Source: https://www.nature.com/articles/s41430-025-01583-4
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Featured article for March 2025
Parkinson’s disease (PD) is a complex neurodegenerative disorder that affects movement and a wide range of motor and non-motor functions. Among the various factors studied in relation to PD, vitamins—particularly vitamin B12—have garnered significant attention. Recent research suggests that vitamin B12 deficiency not only exacerbates the symptoms of PD but may also play a role in its progression. This article explores the intricate relationship between vitamin B12 and Parkinson’s disease, including its potential mechanisms, clinical manifestations, and therapeutic implications.
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Given the strong association between B12 deficiency and PD symptoms, supplementation has been proposed as a potential therapeutic strategy. Studies suggest that vitamin B12 supplementation may:
1. Improve gait and balance in PD patients with neuropathy.
2. Reduce homocysteine levels, potentially slowing cognitive decline.
3. Support nerve regeneration and reduce the risk of neuropathy.
4. Enhance overall well-being and quality of life in PD patients.
However, it is important to note that while B12 supplementation can address deficiency-related symptoms, it is not yet proven to modify the course of PD itself. More research is needed to determine whether B12 therapy can alter disease progression in a meaningful way.
For PD patients, regular monitoring of vitamin B12 levels is recommended, especially for those undergoing long-term Levodopa therapy. If a deficiency is detected, supplementation should be considered to prevent further complications. Physicians may also recommend dietary adjustments to include more B12-rich foods or prescribe injectable forms of the vitamin for better absorption.
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Link: https://link.springer.com/article/10.1007/s00702-024-02769-z
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Featured article for February 2025
In this exciting new study, the authors (several of them being CluB-12 members) enrolled 231 healthy elderly volunteers (median age 71.2 years old) with a median B12 blood concentration of 414.8 pmol/L (as measured by automated chemiluminescence assay). They performed a variety of evaluations, including multifocal visual evoked potential testing, processing speed testing, and magnetic resonance imaging to assess neurological status. They also measured serum biomarkers of neuroaxonal injury, astrocyte involvement, and amyloid pathology.
Their main findings were:
Low B12, especially decreased holo-transcobalamin (sometimes called 'active B12', as this is the form of B12 that can be taken up into the brain), was associated with visual evoked potential latency delay, processing speed impairment (in an age-dependent manner), and larger volumes of white matter hyperintensities on MRI. High levels of holo-haptocorrin (the biologically inactive fraction of B12) correlated with serum levels of Tau, a biomarker of neurodegeneration.
In a press release, the authors wrote: "The current threshold to consider B12 deficiency as a diagnosis and to supplement with vitamin B12, is currently set at 148 pmol/L and is successful at treating most cases of B12-related anaemia. However, a significant amount of people with B12 levels above that threshold have complained of neurological symptoms which improved when getting B12 supplementation. We show that in an older population, lower B12 levels (but above the current threshold of 148 pmol/L) are associated with impaired myelination (slower mfVEPs), neurological function (slower processing speed) and structure (higher WMH lesions on MRI). However, serum biomarkers for neurodegeneration (Tau and UCHL-1) were elevated in people with higher inactive B12 levels." Remember, dear readers, inactive B12 can not be taken up into the brain. It may be a mere marker, and not a cause of higher Tau levels.
The authors have drawn a number of important conclusions:
• The current threshold that defines B12 deficiency must be revisited.
• Clinicians should consider B12 supplementation in older patients with neurological complaints even if B12 levels are higher than 148 pmol/L. But, how do we select these individual;s, and what follow-up do we provide for them?
• Both low active B12 levels and high inactive B12 levels should be considered in future studies about the impact of B12 on neurological function;
• We must invest in more research about the underlying biology of B12 insufficiency since it may impact brain ageing and can be a preventable cause of cognitive decline.
Research grant providers should prioritize research in the aforementioned areas.
Link to the article: https://onlinelibrary.wiley.com/doi/10.1002/ana.27200
Featured article for January 2025
This article from 2023 explores how genetic variations in the gene for the transcobalamin receptor (CD320) affect vitamin B12 uptake into the brain in elderly individuals. Vitamin B12 is vital for producing red blood cells, maintaining the nervous system, and other critical processes. The study found that certain gene variants are linked to higher levels of a specific form of B12 in the blood (holotranscobalamin or holo-TC), which might suggest altered cellular uptake.
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Key findings include:
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Gene Variants Detected: Four specific changes in the CD320 gene were found. About 12% of elderly individuals carry at least one of these variations.
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Impact on B12 Measurement: People with these variants had higher holo-TC levels. Holo-TC is a marker used to measure B12 availability in the body, but this study suggests it might not always reflect true B12 status.
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Clinical Implications: Since B12 status is often assessed using multiple markers like holo-TC, total B12, and methylmalonic acid, these findings suggest that genetic variations could lead to misleading test results in some individuals.
This study highlights the need to adjust current diagnostic tools for B12 deficiency to account for genetic variations in the CD320 gene. Without these adjustments, some individuals might be misdiagnosed as having normal B12 levels despite potential deficiency.
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Link: https://www.clinicalnutritionespen.com/article/S2405-4577(23)00116-X/fulltext
Featured article for December 2024
The article by Pluvinage et al (published in Sci. Transl. Med. 2024; 16:eadl3758) explores a novel autoimmune cause of vitamin B12 deficiency in the central nervous system (CNS), termed "Autoimmune B12 Central Deficiency" (ABCD). Researchers from San Francisco discovered autoantibodies targeting the transcobalamin receptor (CD320), a key protein in vitamin B12 transport, impairing B12 uptake into the brain despite normal serum B12 levels.
The authors have used phage display technology, and demonstrated the presence of a specific autoantibody against the CD320 receptor in a patient with poorly understood progressive neurological symptoms (e.g., tremor, ataxia, speech issues). It was observed that the autoantibody blocks B12 uptake into the brain, causing B12 deficiency in nervous tissue and leading to a variety of neurological symptoms.
CD320 antibodies were also found in other patients with unexplained neurological deficits, neuropsychiatric lupus (21.4% prevalence), and some healthy controls (6% prevalence).
A genome-wide CRISPR screen revealed that an alternate pathway via LDL receptors compensates for CD320 loss in hematopoietic cells but not in the CNS, explaining the tissue-specific effects.
In the index patient, high-dose systemic vitamin B12 supplementation and immunosuppressive therapy showed improvements in CSF B12 levels and clinical symptoms. Larger studies are needed to explore the prevalence and long-term effects of these autoantibodies in people with symptoms suggestive of B12 deficiency, and the therapeutic role of B12 in neuropsychiatric disorders.
Our paper on diagnostics and therapeutics of vitamin B12 deficiency, with emphasis on patient experiences, written on request of the BMJ Editorial Board
Vitamin B12 Deficiency in Clinical Practice: Scientific Insights at the Bookends of Life-Proceedings of the First International B12 Conference, June 2023, Rotterdam'
The supplement consists of 88 pages and 14 peer-reviewed manuscripts published by the Food and Nutrition Bulletin 2024/ Supplement June 2024.
It can be found here:
https://journals.sagepub.com/toc/fnba/45/1_suppl
The congress organisers and authors hope that these publications will lead to a better understanding and knowledge of the complex spectrum of B12 deficiencies.
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