Vitamin B12 deficiency in clinical practice
“Doctor, you gave me my life back!”.
Dr Joseph Chandy
Medical Practitioner 1966-2015 (49 years)
Vitamin B12 is a vital micronutrient, ranking in our view only after oxygen and water in the list of molecules essential for health.
Vitamin B12 deficiency is common in the general population and can manifest at any age. Its prevalence is generally under-recognised. We found a prevalence of 18% in a medical practice population of 5,760 patients in 2015.
Vitamin B12 is crucial for many body systems; the deficiency manifests in an array of different symptoms in different people.
Pernicious anaemia is only one manifestation of vitamin B12 deficiency. In our view it is a late stage of vitamin B12 deficiency and may be preventable. Many B12-deficient patients do not have the symptoms of pernicious anaemia but have other symptoms.
Contrary to accepted belief, the presenting symptoms are frequently neurological or neuropsychiatric and only rarely haematological.
Many people are suffering severely and unnecessarily because of lack of recognition of this condition. Prompt treatment is essential to prevent irreversible neurological damage leading to patients becoming wheelchair-bound.
Neuropsychiatric symptoms such as depression, anxiety, other psychological disorders and even psychosis, are common in vitamin B12 deficiency and there is evidence that the condition may contribute to the onset of dementia.
Guidelines on how to diagnose the varied symptoms are severely lacking.
The serum B12 test in common use has been shown to be unreliable as a stand-alone marker and commonly accepted thresholds for B12 deficiency are questionable.
Causes of B12 deficiency include genetic disorders of B12 absorption, insufficient dietary intake, any gastrointestinal illness (especially atrophic gastritis) or surgery, use of antacid medications and proton-pump inhibitors, and alcoholism.
Vitamin B12 is necessary for several important metabolic processes and contributes to DNA synthesis through its interaction with folate. If these processes are disrupted due to lack of vitamin B12, serious illnesses can result, such as cardiovascular diseases and even cancer.
Like folic acid, vitamin B12 is especially important during pregnancy to ensure a healthy child. Deficiency can lead to severe birth defects.
Based on our experience over many years, we drew up and implemented a Protocol for excluding B12 deficiency (Megaloblastic anaemia, pernicious anaemia) from adult and child presentation in cooperation with the local Primary Care Trust which is given at the end of this book (see Appendix 1).
Vitamin B12 deficiency is linked to autoimmune illnesses and can lead to Autoimmune Polyglandular Syndrome (APS). Another life-threatening illness, hypoadrenalism, is common in vitamin B12-deficient patients. As this is another under-recognised illness in in vitamin B12-deficient patients in which we developed some expertise, we also drew up a Protocol for diagnosis which is included at the end of this book (see Appendix 2).
Vitamin B12 is non-toxic (even at very high doses) and cheap compared with many medications. Therapy with vitamin B12 would result in huge savings to the NHS. It will cure, in contrast to the symptom-modifying (often expensive) medicines that are frequently used to treat conditions which are in reality vitamin B12 deficiency
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https://www.researchgate.net/profile/Hugo-Minney/publication/334604527_Vitamin_B12_deficiency_in_clinical_practice/links/5d357bc392851cd0467b5545/Vitamin-B12-deficiency-in-clinical-practice.pdf?origin=publication_detail
Horden, County Durham, United Kingdom, 1 May 2019
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Something to add about the weird terminology here, just details but might help someone:
1) haptocorrin = transcobalamin I (and I think formerly aka transcobalamin III) = cobalophilin = R-protein = R-factor = R-binder ("R" stands for "rapid electrophoretic mobility"). 2) The intrinsic factor receptor in the terminal ileum is also called "cubilin"; the receptor in the kidney that's responsible for the B12 reabs. is the same like the one in the terminal ileum (it is also cubilin!) with the small difference that megalin was added to this receptor (which means this receptor is more "elaborate" than the one in the terminal ileum). Also, in order for cubilin to work, you need a membrane protein that will make cubilin stay put (and will help in the endocytosis, once B12 bound), this protein being called "amnionless". 3) A mutation in cubilin or amnionless (autosomal recessive) leads to the Imerslund-Gräsbeck syndrome (syn.: defect of enterocyte intrinsic factor receptor, enterocyte cobalamin malabsorption, megaloblastic anemia 1, juvenile pernicious anemia with proteinuria due to selective intestinal malabsorption of vitamin B12), 1:200k in Finland/ Norway --> patients will have problems with both, B12 abs. AND reabs (remember, cubilin/ amnionless is present in both organs). 4) B12 bound to transcobalamin II (the transporter in the blood) is called "Holotranscobalamin" ("active B12"). 5) Haptocorrin is also produced in the stomach, not only by the salivary glands; and, as said in the vid, haptocorrin can bind 80% of the B12 in the blood making it unavailable for use."
Vitamin B12 (Cobalamin) Deficiency (Causes, Symptoms, Diagnosis & Management)
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Remember:
Cobalamin deficiency is a megaloblastic anemia plus neurological symptoms, whereas folate deficiency is just a megaloblastic anemia.
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Dementia? Schizophrenia? Parkinsonism? Could It Be B12?
What do all the following have in common?
- Cognitive decline, including conditions commonly labeled dementia and Alzheimer’s
- Multiple sclerosis, Parkinson’s and other neurological disorders
- Depression, anxiety, schizophrenia and other mental disorders
- Diabetic neuropathy
- Cardiovascular disease
- Learning or developmental disorders in kids, including autism spectrum disorder
- Autoimmune conditions
- Age-related macular degeneration
- Osteoporosis
- Male and female infertility
- Hyperpigmentation of the skin
Answer: They can all mimic the signs and symptoms of vitamin B12 deficiency.
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Holotranscobalamin (HoloTC, Active-B12) and Herbert’s model for the development of vitamin B12 deficiency: a review and alternative hypothesis
Abstract
The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency.
Victor Herbert proposed a model for the staged development of vitamin B12 deficiency, in which holotranscobalamin (HoloTC) is the first indicator of deficiency.
Based on this model, a commercial immunoassay has been controversially promoted as a replacement for the total vitamin B12 test.
HoloTC is cobalamin (vitamin B12) attached to the transport protein transcobalamin, in the serum, for delivery to cells for metabolism.
Although there have been many published reports supporting the claims for HoloTC, the results of some studies were inconsistent with the claim of HoloTC as the most sensitive marker of vitamin B12 deficiency.
This review examines the evidence for and against the use of HoloTC, and concludes that the HoloTC immunoassay cannot be used to measure vitamin B12 status any more reliably than total vitamin B12, or to predict the onset of a metabolic deficiency, because it is based on an erroneous hypothesis and a flawed model for the staged development of vitamin B12 deficiency.
The author proposes an alternative model for the development of vitamin B12 deficiency.
Background
Herbert’s model
In his Herman Award Lecture of 1986, Victor Herbert proposed his Sequential stages in the development of vitamin B 12 deficiency (Herbert 1987). Herbert’s hypothesis, describing the Biochemical and hematological sequence of events as negative vitamin B 12 balance progresses, two decades later formed the basis for the introduction of the commercial holotranscobalamin (HoloTC, Active B12) immunoassay for the diagnosis of vitamin B12 deficiency.
The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency
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Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis (ME)and Fibromyalgia
Introduction
Myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) and fibromyalgia (FM) are chronic clinical conditions characterized by a variety of symptoms including myalgia, fatigue and sleep disturbances. Disability to manage activities of daily life is a most common consequence of both ME and FM.
Substantial overlap exists between the two syndromes, and their similarities and differences have been much debated. They do not share a listing in the International Classification of Diseases (ICD), and they are not even classified in the same section. ME is classified as an organic neurological disorder with the code G93.3, and FM is classified in the section of Soft Tissue Disorders with the code M79.0. Both diagnoses are based on criteria and there is no specific laboratory marker. Women are affected more often than men.
ME and FM are unexplained disorders with molecular and immunological abnormalities. In ME patients, hypomethylation is seen in a majority of certain immune cells [1] and of DNA in genes associated with immune cell regulation [2].
Although the reason for such hypomethylation can only be speculated upon, for the time being, it is interesting that the combined action of the vitamins B12 and folate (Fig 1) play a fundamental role in providing methyl groups to hundreds of substrates in various elementary cell processes.
Yet another and recently revealed role of vitamin B12 is related to detoxification, by having substantial antioxidant properties [3–4]. Altogether, B12 and folate are utterly important in keeping the good health, and our paper will focus on B12/folate as a mean to improve well-being for patients with ME, with or without FM.
Schematic view of where enzyme MTHFR is contributing to synthesis of methyl-folate, and the subsequent methyl group transition from folate to B12 to homocysteine, which transforms into methionine. Activated methionine (S-Adenosyl Methionine; SAM) is the most important methyl donor in cell metabolism.
In 1997, we published an investigation [5] on homocysteine and vitamin B12 (cobalamin) in the cerebrospinal fluid (CSF), drawn from patients who fulfilled the criteria of both FM and chronic fatigue syndrome, the former name for ME. In comparison with a large healthy control group, all eleven patients in the study had increased homocysteine levels in CSF, although the blood levels were usually not increased. The CSF-B12 level appeared to be generally low, and CSF-homocysteine and CSF-B12 levels correlated significantly with ratings of mental fatigue. The results suggested a blockage of B12 transport over the blood brain barrier.
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Vitamin B12 Deficiency Induces Imbalance in Melanocytes Homeostasis—A Cellular Basis of Hypocobalaminemia Pigmentary Manifestations
Abstract
Vitamin B12 deficiency causes significant changes in cellular metabolism leading to various clinical symptoms, such as hematological, psychiatric, and neurological disorders.
We hypothesize that skin pigmentation disorders may be a diagnostically important manifestation of vitamin B12 deficiency, however the cellular and molecular mechanisms underlying these effects remain unknown.
The aim of this study was to examine the effect of vitamin B12 deficiency on melanocytes homeostasis. Hypocobalaminemia in vitro model was developed by treating epidermal melanocytes with synthesized vitamin B12 antagonist—hydroxycobalamin(c-lactam). The cells were examined using immunoenzymatic, spectrophotometric, and fluorimetric assays as well as image cytometry. Significant melanogenesis stimulation—the increase of relative melanin content and tyrosinase activity up to 131% and 135%, respectively—has been indicated. Cobalamin-deficient cells displayed the elevation (by 120%) in reactive oxygen species level. Moreover, the redox status imbalance was stated.
The study provided a scientific evidence for melanocytes homeostasis disturbance under hypocobalaminemia, thus indicating a significant element of the hyperpigmentation mechanism due to vitamin B12 deficiency.
Furthermore, the implication between pigmentary and hematological and/or neuropsychiatric symptoms in cobalamin-deficient patients may be an important issue.
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Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia
Background:
It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.
Objective:
To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).
Methods:
We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia.
Results:
For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.
Conclusion:
We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.
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Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency
Abstract
Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM).
Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively.
In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status.
Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death.
Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders.
Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker.
Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12.
This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.
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Subacute Combined Degeneration of the Spinal Cord
Subacute combined degeneration of the spinal cord is a neurological complication of vitamin B12 deficiency.
It is characterized by degeneration of the dorsal columns and the lateral columns of the spinal cord due to demyelination.
This activity describes the evaluation, treatment, and management of subacute combined degeneration of the spinal cord, and reviews the role of the interprofessional team in improving care for patients with this condition.
Objectives:
- Identify the etiology of subacute combined degeneration of the spinal cord.
- Summarize the evaluation of patients with subacute combined degeneration of the spinal cord.
- Outline the management options available for patients with subacute combined degeneration of the spinal cord.
Introduction
Subacute combined degeneration of the spinal cord is a neurological complication of vitamin B12 (cobalamin) deficiency.
A deficiency of vitamin B12 can occur as a result of nutritional deficiency, reduced absorption due to altered gastrointestinal anatomy or function, or due to the intake of certain drugs.
Subacute combined degeneration is characterized by degeneration of the dorsal columns and the lateral columns of the spinal cord due to demyelination.
It commonly presents with sensory deficits, paresthesia, weakness, ataxia, and gait disturbance.
In severe untreated cases, it can lead to spasticity and paraplegia.
It is crucial to promptly identify and treat vitamin B12 deficiency to prevent the development of this serious neurological complication.
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A Brief Review on Vitamin B12 Deficiency Looking at Some Case Study Reports in Adults
Abstract
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