Signs Of Vitamin B12 Deficiency Research Articles

Vitamin B12 – a scoping review for Nordic Nutrition Recommendations 2023

Vitamin B12 (cobalamin) is essential for normal metabolic function, and even moderate deficiency of this vitamin has negative health effects. Vitamin B12 is found in animal foods, and as vegetarian diets are increasingly popular in Western countries, one might expect a higher prevalence of vitamin B12 deficiency in the Nordic population. Setting recommendations for vitamin B12 intake has proven to be difficult, as uptake of vitamin B12 varies substantially, the clinical deficiency symptoms are often diffuse, and there is no clear agreement on the decision limits for vitamin B12 deficiency. Vitamin B12 deficiency is reported to be particularly common among pregnant women and infants, despite the fact that less than 1% of Norwegian pregnant women have a cobalamin intake below the Nordic Nutrition Recommendations 2012-recommended level of 2.0 µg/day. In addition, the assumption that breast milk contains sufficient vitamin B12 for optimal health and neurodevelopment during the first 6 months of life does not comply with the high prevalence of insufficient vitamin B12 status in this age group. Recommended intakes of vitamin B12 vary among age groups and must be based on markers of cobalamin status, indicating an optimal intracellular biochemical status, and not merely absence of clinical signs of vitamin B12 deficiency.

"Progressive myoclonic ataxia and developmental/epileptic encephalopathy associated with a novel homozygous mutation in TCN2 gene".

Transcobalamin II (TCN2) defect is a rare metabolic disorder associated with a range of neurological manifestations, including mild developmental delay, severe intellectual disability, ataxia, and, in some cases, seizures. Cobalamin, an essential nutrient, plays a crucial role in central nervous system myelination. We present a family with an index patient who exhibited progressive neurodevelopmental regression starting at 9 months of age, accompanied by myoclonic seizures, ataxia, and tremor. No significant hematological abnormalities were observed. Exome sequencing analysis identified a novel homozygous mutation, c.3G>A - P(Met1I), affecting the acceptor site of intron 4 of the TCN2 gene (chromosome 22: 31003321, NM_000355.4), leading to likely pathogenic variant potentially affecting translation. Following treatment with hydroxocobalamin, the patient demonstrated partial clinical improvement. He has a sibling with overt hematological abnormalities and subtle neurological abnormalities who is homozygous to the same mutation. Both parents are heterozygous for the same mutation. In infants presenting with unexplained non-specific neurological symptoms, irrespective of classical signs of vitamin B12 deficiency, evaluation for TCN2 defect should be considered. Early diagnosis and appropriate management can lead to favorable outcomes.

Cutaneous hyperpigmentation as a diagnostic marker of vitamin B12 deficiency: a case report

<p>Cutaneous hyperpigmentation and glossitis are recognized but often overlooked early signs of vitamin B12 deficiency (VB12D). Pernicious anaemia is the most common cause of VB12D. Many clinicians miss the diagnosis of this potentially fatal but treatable condition in the absence of the more often reported life-threatening neuropsychiatric and haematologic features, notwithstanding the concomitant presence of characteristic cutaneous signs. These apperceptions of conspicuous and early dermatologic signs lead to diagnostic delay, which can result in dire consequences for the patient. We report the case of a 24-year-old young woman who for two years had repeated blood transfusions, iron supplementation and haematinics on account of anaemia of undetermined aetiology of a yet to be determined aetiology, despite the simultaneous presence of a constellation of glaring dermatologic clues to vitamin B12 deficiency. Following diagnosis and the institution of the appropriate therapy, the patient made remarkable improvement with a reversal of pigmentation and correction of the anaemia within a month. She continues to see the haematologists for follow-up.</p>

KNUCKLE HYPERPIGMENTATION AS A PRELIMINARY MARKER OF VITAMIN B 12 DEFICIENCY: A CASE SERIES

Vitamin B12 deficiency is common in vegetarian population in India and can present with variable Hematological (megaloblastic anemia), Neuropsychiatric, Mucocutaneous (glossitis, angular stomatitis), Skin (pallor, hyperpigmentation) and Hair changes (dry, brittle, thin, lustreless, prematurely grey). Knuckle hyperpigmentation has been described in vitamin B12 deficiency but usually these patients are dermatologically asymptomatic but they have systemic manifestations like megaloblastic anemia, pancytopenia or neurological deficits. The foreground of this study is highlighting the importance of knuckle hyperpigmentation as an early cutaneous sign of vitamin B12 deficiency which points an important clue towards the aetiology of Megaloblastic anemia.

Lingual Linear Lesions: A Clinical Sign Strongly Suggestive of Severe Vitamin B12 Deficiency.

Lingual linear lesions (LLLs) are the oral linear lesions located on the dorsum, lateral borders, and/or ventral surface of tongue. It has been suggested that LLLs might be an early clinical sign of vitamin B12 deficiency. Here, a retrospective study was conducted to further investigate and validate the association between LLL and vitamin B12 deficiency. Based on the clinical examination, patients with LLLs were enrolled and analyzed retrospectively. Data regarding clinical and laboratory features were obtained. Follow-up was done at least 6 months following appropriate supplementation therapy. A total of 57 patients, consisting of 20 males and 37 females with a mean age of 59.12 years (range, 18-80), were enrolled in this study. The hematological examination revealed that 56 (98.25%) of the 57 patients had severe serum vitamin B12 deficiency, and the other 1 patient had a borderline low level of vitamin B12 . All the enrolled patients responded well to cobalamin replacement therapy. LLLs might be a clinical sign strongly suggestive of severe vitamin B12 deficiency.

ROLE OF VITAMIN B12 SUPPLEMENTATION IN METFORMIN INDUCED DIABETIC NEUROPATHY IN INDIAN PATIENTS. CAN SUPPLEMENTATION HELP?

Metformin is one of the most commonly used oral hypoglycemic drug amongst type II diabetes mellitus patients, particularly overweight with normal kidney functions. Literature reports an average of 10-30% of patients taking metformin for longer duration (more than 4 years) have shown some signs of vitamin B12 deficiency.
 Thus the present study was planned to assess the development of peripheral neuropathy in metformin users due to Vitamin B12 deficiency and effect of its supplementation was assessed for improvement in terms of VPT (Vibration perception threshold) score assessed by Biothesiometer which is a simple, portable, reliable, non-invasive method to screen the peripheral neuropath
 Unique about this study is, evaluating the effect of B12 supplementation on Indians patients. They being primarily vegetarian are at more risk to develop Vitamin B12 deficiency, so, metformin induced Cobalamin deficiency assumes greater risk in such patients in terms of development and progression of peripheral neuropathy.

Excessive folic acid intake and relation to adverse health outcome.

The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that "high folic acid intake has not reliably been shown to be associated with negative healeffects". In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999-2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young. Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that excessive intake of folic acid is not always safe in certain populations of different age and ethnical/genetic background.

MODERN DIAGNOSTIC AND TREATMENT OF VITAMIN В12 DEFICIENCY

An article reflects modern concepts of the etiology of vitamin B12 deficiency including medication-induced conditions. Particular attention is paid to diagnostic algorithm in case of overt and latent forms of deficit. As the method of choice for the diagnosis of vitamin B12 deficiency it is recommended to determine the level of holotranscobalamin and use additional methods for detecting metabolic deficiency of vitamin B12 – to study the levels of homocysteine and methylmalonic acid. Diagnostic algorithms for patients with clinical suspicion of vitamin B12 deficiency and the presence of subclinical deficiency. We reviewed the possibility of vitamin B12 oral preparations to correct low levels of cobalamin in asymptomatic patients, as well as maintenance therapy in patients with clinical signs of vitamin B12 deficiency.

P2 – 2736: Vitamin B12 deficiency and neurologic findings: Retrospective analysis of 124 patients

Objective Vitamin B12 is essential for the development and initial myelination of the central nervous system. Because methylation reactions are important in many parts of the central nervous system, deficiency of vitamin B12 deficiency leads to a wide range of neurological symptoms. Methods A total of 124 of 7007 children aged 6th month and 18 years old who addmitted to outpatient child neurology clinic of Giresun Prof. Dr. A.Ilhan Ozdemir State Hospital between September 15th 2014 and January 15th 2015 were selected retrospectively according to neurologic sign and symptoms of vitamin B12 deficiency. Patients who has neurological symptoms of vitamin B12 deficiency together with low B12 and/or elevation of homocysteine levels in serum were objected to the study. Patients were classified as six groups concerning neurological symptoms. Results A total of 124 patients were meet the selection criterias. Male and female patients were 47 and 77 in number respectively with mean age 13.5 (6th month – 18) and mean vitamin B12 levels was 164.9 pg/ml. Although 19 of 124 patients who had vitamin B12 level above 192 pg/ml, they had increased homocystein level concerning age limits. All of 19 patients had neurological symptom and sign of vitamin B12 deficiency. The most frequent signs were dizziness and/or syncope (77/124 patients, 62%) belonging the group III is composed of 77 patient including 23 patient with syncope and 54 patient with dizziness. Conclusion Investigation of vitamin B12 level is essential as a screening test in children with syncope and dizziness, It is useful to insist on investigation of homocysteine level in patients with clinical symptoms and/or signs of vitamin B12 deficiency even with normal vitamin B12 level. We conclude that a normal total blood count is not enough to exclude of diagnosis of vitamin B12 deficiency in children with neurological symptoms.

Vitamin B12 Deficiency Masquerading as Clozapine-Resistant Psychotic Symptoms in Schizophrenia

Vitamin B₁₂ Deficiency Masquerading as Clozapine-Resistant Psychotic Symptoms in Schizophrenia

Bioavailability of folic acid and L‐5‐methyltetrahydrofolic acid in fortified bread: a randomized placebo‐controlled trial

Folic acid fortification has been introduced in several countries to reduce the incidence of neural tube defects. However, it could mask the hematologic signs of vitamin B12 deficiency. L‐5‐methyltetrahydrofolic acid (MTHF), which is unlikely to mask vitamin B12 deficiency, may be a safer fortificant, but is not stable in most food matrices. Microencapsulation of MTHF with antioxidant sodium ascorbate is an effective means of preventing loss during baking and storage. The aim of the study was to investigate the bioavailability of microencapsulated MTHF in bread in a 16‐wk, double‐blind, randomized placebo trial. Healthy volunteers 18–45 y (n=45) were randomly assigned to bread containing MTHF (452 μg), folic acid (400 μg) or placebo. Fasting blood was analyzed for red cell and plasma folate concentrations at baseline, 8, and 16 wks. At 16 wk, after adjustment for baseline concentrations, mean (95% CI) red cell folate was 572 (341, 804) and 428 (200, 656) nmol/L higher in the MTHF (P<0.001) and folic acid (P=0.002) groups, respectively, than in the placebo group. Mean plasma folate was 28 (15, 41) and 26 (13, 39) nmol/L higher in the MTHF (P<0.001) and folic acid (P=0.01) groups, respectively, than in the placebo group. In conclusion, bread fortified with MTHF was at least as effective as folic acid in raising red cell and plasma folate concentrations in this population. (Supported by the Advanced Food Materials Network)

Manifestaciones neurológicas por déficit aislado de vitamina B12

Isolated vitamin B12 deficiency is a common condition in elderly patients but uncommon in patients younger than 30 years, with an average age of onset between 60 and 70 years. This is because the dietary cobalamin, which is normally split by enzymes in meat in the presence of hydrochloric acid and pepsin in the stomach, is not released in the stomachs of elderly patients, usually due to achlorhydria. Although the body may be unable to release cobalamin it does retain the ability to absorb vitamin B12 in its crystalline form, which is present in multivitamin preparations. Other causes are due to drugs that suppress gastric acid production.Neurological signs of vitamin B12 deficiency can occur in patients with a normal haematocrit and red cell indices. They include paresthesia, loss of sensation and strength in the limbs, and ataxia. Reflexes may be slowed down or increased. Romberg and Babinsky signs may be positive, and vibration and position sensitivity often decreases. Behavoural disorders range from irritability and memory loss to severe dementia. The symptoms often do not fully respond to treatment.A case is presented of an isolated vitamin B12 deficiency in 27 year-old female patient who was seen in primary health care. During anamnesis she mentioned low back pain, to which she attributed the loss of strength and tenderness in the right side of the body, as well as the slow and progressive onset of accompanied headache for the previous 4 days.

Homocysteine and the Risk of Dementia

Featured Article: Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476–83.3 In the late 1990s, I was working in a tertiary-care academic medical center in India and running a dementia clinic that had enrolled 120 patients in its first year. India is a country where centuries ago the influence of Buddhism and Jainism had persuaded a large proportion of the population to adopt a vegetarian diet; many others simply could not afford meat or fish. Perhaps as a consequence, as many as a fourth of the patients with dementia (and many without it) had low circulating vitamin B12 concentrations, but correcting this deficiency did not improve their dementia. Nor did most of them have macrocytic anemia, peripheral neuropathy, or other clinical signs of vitamin B12 deficiency. Vitamin B12, along with folate and B6, are essential cofactors in the conversion of homocysteine, a …

Solid food refusal as the presenting sign of vitamin B12 deficiency in a breastfed infant

Dietary vitamin B(12) (vitB(12)) deficiency, although common in the elderly, is rare in childhood. We report on an exclusively breastfed 8-month-old infant, presenting with persistent refusal of solid foods. Three months later, developmental regression and failure to thrive led to the diagnosis of vitB(12) deficiency, as a consequence of a subclinical pernicious anaemia with vitB(12) deficiency in the mother. Treating the infant with parenteral vitB(12) induced prompt recovery including acceptance of weaning food. This case illustrates refusal of complementary foods as a presenting symptom of vitB(12) deficiency in a breastfed infant. Symptoms, diagnostic tests and treatment of vitamin B(12) deficiency are reviewed. Early diagnosis and treatment are important to prevent irreversible neurological damage.

The vitamin B12 absorption test, CobaSorb, identifies patients not requiring vitamin B12 injection therapy

Background. Treatment with vitamin B12 has virtually no side effects; however, life-long treatment is inconvenient for the patient and constitutes a cost for society. Objective. To investigate whether vitamin B12 injection treatment reflects the actual need for treatment or whether some patients are treated unnecessarily with vitamin B12 injections. Material and methods. A prospective intervention study was conducted among nine general practitioners in Western Sealand County, Denmark. Forty-four patients older than 18 years who had received injection therapy with vitamin B12 for a median of eight years (range 1–26 years) were included. After discontinuation of vitamin B12 injections, blood samples were analysed monthly for hemoglobin, cobalamin, holotranscobalamin, homocysteine and methylmalonic acid. The capacity to absorb vitamin B12 was examined after a median of 13 months (range 5–32 months) by measurement of holotranscobalamin or cyanocobalamin on transcobalamin before and after 1 and 2 days intake of 3 × 9 μg of vitamin B12. Patients unable to absorb the vitamin continued treatment with vitamin B12 injection. The remaining patients participated in a follow-up study receiving 9 μg oral vitamin B12 daily or no vitamin B12 substitution. Results. Of the 44 patients studied, 35 patients were able to absorb vitamin B12. None of the patients included in the follow-up study showed biochemical signs of vitamin B12 deficiency by the end of the study. Conclusion. Our results suggest that the capacity for absorbing vitamin B12 should be examined prior to the choice of treatment.Trial registration: ClinicalTrials.gov identifier: NCT00326833.

Causes and Early Diagnosis of Vitamin B12 Deficiency: Risk Group includes infants

The authors say that even persons with vitamin B12 concentrations in the reference range may show signs of vitamin B12 deficiency. They recommend measuring biomarkers (serum holotranscobalamin, plasma methyl malonic acid, and plasma homocystein). Measuring MMA in spontaneous urine provides a reliable, simple, and cost effective alternative (1, 2). This can be done by using gas chromatography with subsequent mass spectrometry (GC-MS). In the medical fee schedule, number 3783, organic acids profile is rated at 570 points (= ca. 33.22 euros). Measuring MMA in urine as a screening method would shorten and simplify the flow chart suggested by the authors to diagnose vitamin B12 deficiency (figure 2). The authors’ listed risk group for deficiency includes pregnant and breast feeding women. However, it is important to also include infants, in whom prenatal and postnatal vitamin B12 deficiency can cause severe and partly irreversible neurological damage. We recently reported the case of 4 infants, in 2 of whom vitamin B12 deficiency was caused by the mother’s unidentified pernicious anemia and in the other 2 by the mother’s vegan diet. None of the mothers had clinical symptoms; severe developmental disorders in the babies, however, triggered diagnostic investigation, and raised excretion of MMA in the urine pointed the way. All babies showed neurological symptoms in later examinations (3). With regard to the severe pathology and the associated costs it is worth considering whether examination for vitamin B12 deficiency by measuring MMA in the urine by using GC-MS should be offered to all pregnant women.

What is an Adequate Dose of Oral Vitamin B<SUB>12</SUB> in Older People with Poor Vitamin B<SUB>12</SUB> Status?

The prevalence of vitamin B12 deficiency increases in the elderly, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish, and dairy foods. Depending on the biochemical criterion that is used, 5% to more than 20% of older adults have marginal or frank vitamin B12 deficiency. Adults over 50 years of age should meet the Recommended Dietary Allowance by consuming vitamin B12 in the crystalline form, which does not require gastric acid or enzymes for initial digestion. A recent clinical trial suggests that an oral dose of 500 μg/d of crystalline vitamin B12 is needed to reverse biochemical signs of vitamin B12 deficiency in older adults.

What is an Adequate Dose of Oral Vitamin B12in Older People with Poor Vitamin B12Status?

The prevalence of vitamin B12 deficiency increases in the elderly, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish, and dairy foods. Depending on the biochemical criterion that is used, 5% to more than 20% of older adults have marginal or frank vitamin B12 deficiency. Adults over 50 years of age should meet the Recommended Dietary Allowance by consuming vitamin B12 in the crystalline form, which does not require gastric acid or enzymes for initial digestion. A recent clinical trial suggests that an oral dose of 500 microg/d of crystalline vitamin B12 is needed to reverse biochemical signs of vitamin B12 deficiency in older adults.

Development and Validation of an Automated Chemiluminometric Immunoassay for Human Intrinsic Factor Antibodies in Serum

The cobalamins, also referred to as vitamin B12, are a group of closely related enzymatic cofactors involved in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A and in the synthesis of methionine from homocysteine (1)(2)(3). Vitamin B12 deficiency can lead to megaloblastic anemia and neurologic deficits (4). The latter may exist without anemia or precede it. Adequate replacement therapy will generally improve or cure cobalamin deficiency. Unfortunately, many other conditions, which require different interventions, can mimic the symptoms and signs of vitamin B12 deficiency (4). Moreover, even when cobalamin deficiency has been established, clinical improvement may require different dosages or routes of vitamin B12 replacement, depending on the underlying cause (3)(4). In particular, patients with pernicious anemia, possibly the commonest type of cobalamin deficiency in developed countries, require either massive doses of oral vitamin B12 or parenteral replacement therapy (3)(4)(5). The reason is that in pernicious anemia, patients suffer from gastric mucosal atrophy, which leads to diminished or absent gastric acid, pepsin, and intrinsic factor (IF) production. Because gastric acid, pepsin, and IF are required for liberation of cobalamin from binding proteins and efficient cobalamin absorption in the gut, respectively, vitamin B12 deficiency ensues (3)(4). Most of these patients have autoantibodies against gastric parietal cells or IF, with the latter being very specific but present in only ∼50% of cases (1). The aim of the work-up of patients with suspected vitamin B12 deficiency is therefore to confirm the presence of deficiency and to establish its most likely etiology. Many different testing algorithms have been proposed to achieve maximum sensitivity and specificity for both tasks, but almost all involve measurement of serum vitamin B12 and IF antibodies (IFABs) at …

Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid.

The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.