Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger-Ellison Syndrome (ZES) Patients.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Vitamin B12-Related Biomarkers.

BACKGROUND: Adult vitamin B12 (B12) deficiency may present itself with nonspecific mainly neurological symptoms, and thus plasma biomarkers are often judged to be of major importance in the further diagnostic process. Four biomarkers are of special relevance: total B12, holotranscobalamin (the part of B12 bound to the active transport protein, transcobalamin, also named holoTC or active B12) and the 2 so-called metabolic markers that accumulate if B12 is lacking, methylmalonic acid (MMA) and homocysteine. OBJECTIVE: This article briefly reviews the inherent limitation of biomarkers, discusses its use in establishing the diagnosis and cause of B12 deficiency, and when following or discontinuing treatment with B12. METHODS: The review is based on published papers, but also on knowledge gained from working within the area. CONCLUSION: It is concluded that a combination of a B12 and a metabolic marker, for example, total B12 and MMA, may prove most useful in daily practice. An unexpectedly high level of total B12 is most often of no clinical importance, though sometimes related to the presence of underlying cancer. Measurement of total B12 is of limited value in patients on treatment with pharmacological doses of B12 but may be helpful if B12 treatment is discontinued.

Plain language titleVitamin B12-Related Blood TestsPlain language summaryBlood-testing is considered an important part of the diagnostic procedure in patients suspected to suffer from B12 deficiency. A deficiency is supported by a low level of plasma B12, and confirmed by a high level of methylmalonic acid, judged according to age and kidney function. Alternatively, a high level of homocysteine may support the diagnosis. Treatment of B12 deficiency is mainly guided by improvement of symptoms, with a very limited need for further blood testing. If B12-treatment is discontinued, B12 status should be judged every 6 months for approximately 2 years to detect a possible reoccurrence of a deficient state. An unexpected high level of plasma B12 is most often of no clinical implication.

Vitamin B12 Deficiency in Children and Adolescents: A Case for Revised Diagnostic Parameters.

BACKGROUND: Vitamin B12 deficiency is commonly diagnosed using thresholds developed for adults, yet emerging evidence indicates these levels may not be appropriate for children and adolescents. This misalignment can lead to underdiagnosis in younger populations, with potential long-term health implications. CASE SUMMARY: Chief Complaint: The 17-year-old female patient experienced severe fatigue, menstrual irregularities, psychological distress, and neurological symptoms over several years. The 13-year-old male patient had behavioral changes, gastrointestinal complaints, and sensory disturbances from an early age.Diagnosis: Both adolescents displayed B12 levels that were considered low-normal based on adult thresholds, complicating their diagnostic processes. Their diverse and atypical symptomatology required a comprehensive review of their medical and family histories, clinical symptoms, and risk factors.Intervention: Treatment included administration of hydroxocobalamin injections, complemented by dietary adjustments.Outcome: Both patients responded well to the treatment, showing significant improvements in their symptoms and overall quality of life. CONCLUSION: The main takeaway from these cases is the importance of tailoring diagnostic adequate thresholds and treatment plans to the pediatric population to address and manage B12 deficiency effectively. This approach can significantly enhance patient outcomes and prevent the progression of potentially severe complications in later life.

Plain language titleRevisiting Diagnostic Criteria for Vitamin B12 Deficiency in Children and Adolescents, a Case ReportPlain language summaryVitamin B12 deficiency is surprisingly common in kids and teenagers, but the problem is, only adult standards are available to diagnose it. Research shows that healthy children can have much different B12 levels than adults, meaning some kids with a deficiency might not get the help they need quickly. We share stories of 2 teenagers who suffered from B12 deficiency with very different symptoms, from extreme tiredness to mood changes and stomach issues. These cases show that diagnosing B12 deficiency can be difficult, especially with symptoms that don't fit the usual pattern. However, once they were properly diagnosed and treated adequate, these young people saw significant improvements in their health. These cases highlight the need for new standards tailored to children, to better identify and treat B12 deficiency early on, improving their quality of life.

Vitamin B12 Deficiency-Induced Neuropathy and Cognitive and Motor Impairment in the Elderly: A Case Study.

Vitamin B12 deficiency can present with a variety of neurological and cognitive symptoms. Especially in elderly patients, vitamin B12 deficiency can be easily overlooked because symptoms may be attributed to comorbid conditions or solely to the aging process. In this case study, we present two patients, a 71-year-old man and a 74-year-old female, with vitamin B12 deficiency. The male patient had a history of (partial) resection of the ileum/jejunum/colon because of intestinal ischemia. The female patient had a history of hypothyroidism, type 2 diabetes with complications (including peripheral neuropathy), mitochondrial myopathy, and chronic lymphocytic leukemia. Both patients presented with severe fatigue, cognitive impairment, and impaired walking. Next to this, the male patient suffered from depressive symptoms and mild disorientation, and the female patient experienced neuropathic pain. She also mentioned a positive family history for B12 deficiency. The first patient had normal to high B12 levels because he was already on B12 injections (once every three weeks) because of an earlier diagnosed B12 deficiency. The female patient had B12 levels within normal range (holotranscobalamin 54 pmol/L) and her diagnosis was confirmed by elevated homocysteine and methylmalonic acid levels. Treatment with frequent hydroxocobalamin injections and other supplements significantly improved their cognitive, emotional, and motor functions. These cases underscore the need for a high level of clinical suspicion in elderly patients, also in cases of normal B12 levels but with clinical signs of deficiency and a positive risk factor, such as stomach or small bowel surgery or positive family history.

Plain language titleA case study of two elderly patients with vitamin B12 deficiency and neurological and cognitive complaintsPlain language summaryVitamin B12 deficiency in elderly patients can be easily overlooked as symptoms can also be caused by other age-related diseases or the aging process. In our article we present two elderly patients, a 71-year-old male and a 74-year-old female, with neurological complaints, such as severe fatigue, cognitive decline, and walking impairment. The male patient had a history of small bowel surgery, and the female patient mentioned that she had several siblings with B12 deficiency. Additionally, the male patient suffered from depressive symptoms and mild disorientation, and the female had severe pain in her legs. The male patient already received B12 injections because of an earlier B12 diagnosis, but with a relatively low frequency. The B12 levels of the female patients were within the normal range. However, her diagnoses could be confirmed with additional laboratory measurements, such as homocysteine and methylmalonic acid. Treatment with frequent B12 injections and other supplements significantly improved their cognitive, emotional, and motor functions. Our study shows that clinicians should carefully consider the possibility of B12 deficiency in elderly patients with cognitive and neurological complaints, also in patients with B12 levels within the normal range, but with risk factors such as family members with B12 deficiency or conditions that may impair the vitamin B12 uptake, such as previous stomach or small bowel surgery.

Lack of Clinical Evidence Regarding the Guidelines for Vitamin B12 Deficiency: An Analysis From Literature and Recommendations From Clinical Practice.

BACKGROUND: Vitamin B12 deficiency is a critical medical condition that, if left untreated, can lead to severe symptoms and potentially serious and life-threatening complications. Clinical guidelines are designed to provide a standardized approach to diagnosis and treatment, aiming for consistency and effectiveness. However, it is well-established that not all patients fit into general guidelines. OBJECTIVE: To investigate the clinical relevance of the submitted research to support these protocols for diagnosing and treating a B12 deficiency. APPROACH: Conducting a literature review of the references focused and used on diagnosing and treating vitamin B12 deficiency in adults and children. RESULTS: No robust clinical trial nor RCT has been found to back up the current protocols. The research used is primarily based on assumptions rather than solid clinical evidence. CONCLUSION: Existing guidelines for vitamin B12 deficiency need to be significantly revised and improved through clinical research, clinical experience by experts in the field with input from patient groups worldwide.

Plain language titleAnalyzing the Lack of Research on Vitamin B12 Deficiency Guidelines: Insights from Studies and Clinical AdvicePlain language summaryThis study dives into Vitamin B12 deficiency, stressing its serious health impacts and potential life-threatening complications when not treated. The study aims to investigate the scientific articles supporting these guidelines and their clinical relevance, conducting an in-depth analysis of literature references. The manuscript investigates and criticizes current guidelines for B12 deficiency, pointing out 4 key issues reported by patients and clinicians worldwide. The results are grouped into 4 sections: Maintenance Dose Protocol: The study questions the adequacy of maintenance doses every few months, highlighting a lack of clinical evidence and challenging the idea of sufficient liver stores. Oral Supplementation Protocol: The effectiveness of oral supplements is questioned due to inconclusive trials, focusing on raising blood values rather than assessing actual clinical outcomes. Diagnosing B12 Deficiency in Children: Guidelines neglect B12 deficiency in children despite significant differences in B12 levels between adults and healthy kids, potentially leading to underdiagnosis and unnecessary suffering. Delay in Diagnosis and Treatment: Factors like a lack of awareness and diverse symptoms contribute to delays, emphasizing the ongoing challenge of standardizing B12 assays. In the discussion, the manuscript argues that awareness of guidelines is low, and evidence-based guidelines may lack practical relevance. It suggests a significant revision of guidelines based on robust clinical evidence, advocating for personalized treatment, patient monitoring tools, controlled trials, and age-related healthy levels. Recognizing diverse patient needs and implementing individualized therapies are crucial for improving care for those with vitamin B12 deficiency, emphasizing the importance of early recognition and intervention.

Development of a Vitamin B12 Deficiency Patient-Reported Outcome Measure for Clinical Practice and Research.

BACKGROUND: It is difficult to recognize vitamin B12 deficiency and to evaluate the effect of B12 treatment due to a broad range of variable clinical symptoms overlapping with other diseases and diagnostic biomarkers that quickly normalize during treatment. This poses a risk of delay in diagnosis and a challenge to uniformly monitor the effect of B12 treatment. There is a need for a new clinical outcome measure suitable for clinical practice and clinical evaluation studies. OBJECTIVE: To develop a Patient-Reported Outcome Measure (PROM) which measures the severity of vitamin B12 deficiency symptoms. METHODS: The B12 PROM was developed by (1) gathering input from experts and literature review to define a construct and develop a conceptual model, (2) processing input from health care providers, scientists, and patients to develop items and response options, and (3) improving items based on the feedback from laypersons, test interviews, semi-structured cognitive interviews with patients, and forward and backward translation (ENG-NL). RESULTS: The B12 PROM includes 62 items grouped into 8 categories of symptoms related to vitamin B12 deficiency (General, Senses, Thinking, In limbs and/or face, Movement, Emotions, Mouth & Abdomen, Urinary tract & Reproductive organs). Cognitive interviews demonstrated good comprehensibility and comprehensiveness. CONCLUSIONS: This study is the first step in the development of a disease-specific PROM for vitamin B12 deficiency to measure the burden of symptoms. Further validation and reliability testing are necessary before the PROM can be applied in clinical practice and research.

Plain language titleDevelopment of a Vitamin B12 Deficiency Questionnaire for Clinical Practice and ResearchPlain language summaryThis study is the first step in the development of a questionnaire for vitamin B12 deficiency to measure the severity of vitamin B12 deficiency symptoms. The questionnaire includes 62 items grouped into 8 categories of symptoms related to vitamin B12 deficiency (General, Senses, Thinking, In limbs and/or face, Movement, Emotions, Mouth & Abdomen, Urinary tract & Reproductive organs). Interviews with patients demonstrated good comprehensibility and comprehensiveness of the questionnaire. Further testing is necessary before the questionnaire can be applied in clinical practice and research.

Causes and Risk Factors of Vitamin B12 Deficiency at the Bookends of Life, From Infancy to Old Age.

The causes and risk factors of vitamin B12 deficiency are many and varied. Importantly, they vary considerably across the lifespan, from infancy to old age. The complexity of the physiology of vitamin B12 bespeaks the myriad of possible causes of deficiency and possible disruptions of its functional integrity. These lead ultimately to the pathobiological effects witnessed in deficiency of this fascinating micronutrient. This brief overview of the multiplicity of mechanisms that can result in vitamin B12 deficiency, and the panoply of its manifestations explores the underlying reasons for the protean presentations of the disease. As the human organism progresses through the chronology and milestones of age, various susceptibility factors arise resulting from the interplay of environmental and genetic factors. Acting independently and in concert, these factors produce the common denominator of vitamin B12 deficiency. However, the rate at which such deficiency develops and the way in which it presents clinically vary widely, subject to such influences as genetic variability, end-organ susceptibility, and concomitant micronutrient status. Some examples of unusual cases of vitamin B12 deficiency are described. Much has been learned about the last of the numbered vitamins in almost a century. Much yet remains to be discovered.

Defining Optimal Cobalamin Status for Neonates and Infants.

BACKGROUND: An optimal cobalamin status is necessary for normal neurodevelopment. OBJECTIVE: To give a description of the epidemiology, pathophysiology and diagnostic challenges related to cobalamin insufficiency in neonates and infants in order to prevent its occurence. RESULTS: Inadequate cobalamin status is prevalent among neonates and young infants, due to a high prevalence of maternal cobalamin deficiency, exclusive breastfeeding for extended periods and late introduction of animal food. Cobalamin insufficiency is associated with delayed neurodevelopment and subtle clinical symptoms like feeding difficulties, regurgitations and constipation in young infants. Early diagnosis and treatment of impaired cobalamin status is important to prevent neurologic damage. CONCLUSION: Clinical suspicion of cobalamin insufficiency in infants should infer immediate biochemical testing and a plasma total homocysteine > 5.0 µmol/L indicate cobalamin insufficiency in need of intramuscular treatment with hydroxycobalamin, followed by introduction of animal food after 4 months of age.

Plain language titleVitamin B12 Is Important for Normal Development in Young ChildrenPlain language summaryVitamin B12, also called cobalamin, is found only in animal-sourced food. As low-meat, vegetarian, and vegan diets are increasingly popular in Western countries, vitamin B12 deficiency has become common, also in pregnant women and babies. Vitamin B12 status is essential for normal development and adequate levels of this vitamin is particularly important during pregnancy and the first years of life. In pregnancy, vitamin B12 is transferred from the mother to the fetus, so the baby has a store of this vitamin at birth. However, if the mother has vitamin B12 deficiency or the baby is born premature or with a low birth weight, the vitamin store may be insufficient and the baby may develop vitamin B12 deficiency. Maternal vitamin B12 status is important as long as the baby is exclusively breastfed. Breast milk contains vitamin B12, but the concentration decreases after 4 to 6 weeks and may be too low to support the baby until animal-sourced foods are introduced. The vitamin B12 content in formula milk is higher than in breast milk, and vitamin B12 deficiency is more common in exclusively breastfed babies. Vitamin B12 deficiency is associated with diffuse symptoms in small babies and may be difficult to detect, and the diagnosis have a mean delay of 4 months in this age-group. Typical symptoms are regurgitations or spitting up, constipation, problems with feeding and swallowing, and delayed psychomotor development. Suspicion of vitamin B12 insufficiency in babies should prompt immediate biochemical testing. Plasma total homocysteine is a metabolic marker of vitamin B12 status and can be measured in a blood sample from the baby. A level >5.0 µmol/L indicates probable vitamin B12 insufficiency and the baby should receive vitamin B12 supplementation, followed by introduction of animal-sourced foods at 3 to 4 months of age.

Indicators of Cobalamin Status During Pregnancy, Pregnancy Outcome and Long-Term Effects on Offspring Health.

BACKGROUND: Little attention has been given to prenatal cobalamin insufficiency in settings where dietary cobalamin intake is presumed adequate, such as populations with habitual intake of foods from animal sources. RESULTS: However, low cobalamin status in women of fertile age has been reported in Europe, United States, and Canada. In India, where cobalamin deficiency is highly prevalent, it has been associated with an increased risk of miscarriage, intrauterine growth retardation, as well as insulin resistance and lower neurodevelopment scores in the offspring. Low cobalamin status in pregnancy has been associated with similar outcomes as those reported in the Indian studies although the evidence is scant and conflicting. CONCLUSIONS: Consideration should be given to maternal cobalamin status in the context of prevention of adverse pregnancy outcomes as well as cobalamin insufficiency both in the mother and the offspring during lactation. Further attention is now justified with the increasing tendency toward plant-based diets. Reference intervals for cobalamin status during each trimester of pregnancy are needed and further investigation of the long-term conse-quences of low cobalamin status during pregnancy for health and development in the offspring is warranted.

Plain language titleInadequate cobalamin status during critical periods of growth and development can have negative consequences on maternal and childhood health.

A Systematic Review of Symptoms of Pernicious Anemia.

BACKGROUND: Pernicious anemia (PA) is a type of macrocytic anemia caused by autoimmune gastritis. To facilitate timely diagnosis and treatment of PA there is a pressing need for improved understanding among Healthcare providers of the condition's symptoms and diagnostic criteria. OBJECTIVE: This systematic review aims to extend existing clinical knowledge on the presentation of PA by determining which symptoms and clinical complications are reported in published adult case studies. METHODS: Relevant studies were identified through electronic searches of PsycINFO, Embase, and MEDLINE, via OvidSP. During data extraction symptoms were categorized according to the International Classification of Diseases and were grouped based on frequency. RESULTS: Symptoms were documented for 103 adults with a diagnosis of PA; the most frequent symptoms were fatigue (55%), loss of sensation in limbs (32%), excessive weight loss (27%), and a sore tongue (23%). CONCLUSIONS: This review highlights the diverse symptomology of adults who are diagnosed with PA. Most symptoms documented in case studies are consistent with the core signs of B12 and folate deficiencies. Research is needed to identify if there are common clusters of PA symptoms that can be used as prompts for diagnostic testing in patients with suspected B12 deficiency.

Plain language titleA Review of Symptoms of Pernicious AnemiaPlain language summaryThis study reviewed case studies that have been written about adults with pernicious anemia, it has documented the frequency of the core symptoms and the impact these have on health.

The contribution of milk substitutes to the nutritional status of children with cow's milk allergy.

BACKGROUND: The impact of alternative milk substitutes on the nutritional status of children with cow's milk allergy (CMA), the prevailing cause of food allergies, is unresolved. METHODS: A cross-sectional study was performed in children older than 2 years with IgE-mediated CMA. Patients' clinical characteristics, anthropometric measurements, dietary intake (by 3-day food diary), and biochemical markers of nutritional status were assessed. RESULTS: One hundred two children with CMA (68.6% boys; median age, 3.7 years; 51% multiple food allergies) were evaluated. 44.1% of the children consumed plant-based beverages (PBB), 19.6% therapeutic formula and 36.3% did not consume any milk substitutes. In all age groups, dietary calcium, riboflavin, and vitamin D intake of those who did not use milk substitutes were lower than those who consumed formula or PBB (p < .01). Also in the 2-3 years old age group, dietary zinc (p = .011) and iron intake (p = .004) of the formula-fed group was higher. Formula-fed patients had higher levels of 25-OH vitamin D (µg/L) and serum vitamin B12 (ng/L) than PBB-fed patients (respectively; p < .001, p = .005) and those who did not consume any milk substitute (p < .001). Patients of all ages who did not utilize a milk substitute failed to obtain an adequate amount of dietary calcium. CONCLUSION: The use of milk substitutes positively affects dietary calcium, riboflavin, and vitamin D intake in CMA, but their contribution is variable. Those who do not use milk substitutes are at greater risk inadequate of dietary calcium intake. Personalized nutritional advice, given the clinical diversity and the impact of individual differences, is required.

Serum levels of vitamin B12 combined with folate and plasma total homocysteine predict ischemic stroke disease: a retrospective case-control study.

PURPOSE: This study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke. MATERIALS AND METHODS: This retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke. RESULTS: Serum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098-4.770), SVD (aOR = 4.471, 95% CI = 1.110-4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733-5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954-6.449), CEI (aOR = 2.809, 95% CI = 1.073-4.991), SVD (aOR = 5.376, 95% CI = 1.708-6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535-7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008-5.148), CEI (aOR = 2.212, 95% CI = 1.247-5.946), SVD (aOR = 2.957, 95% CI = 1.324-6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586-4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR. CONCLUSIONS: Vitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.

Exploring the Association between Serum B Vitamins, Homocysteine and Mental Disorders: Insights from Mendelian Randomization.

Previous studies show that B vitamins and homocysteine (Hcy) may be associated with mental disorders, but the accurate causal relationship remains unclear. This study aimed to elucidate the potential causal relationship of serum B vitamins and Hcy levels with five common mental disorders through a two-sample Mendelian randomization (MR) study. In this MR analysis, 50 single-nucleotide polymorphisms (SNPs)-13 related to folate, 17 to vitamin B6, 8 to vitamin B12 and 12 to Hcy-were obtained from a large-scale Genome-Wide Association Studies (GWAS) database and employed as instrumental variables (IVs). The MR analyses were conducted using the inverse variance weighted (IVW), weighted median (WM), MR-Egger methods and sensitivity analyses were further performed to test the robustness. This MR study found a suggestive causal relationships between serum vitamin B12 levels and the risk of anxiety disorders (odds ratio (OR): 1.34, 95% confidence interval (CI): 1.01-1.78, p = 0.046) and bipolar affective disorders (OR: 1.85, 95% CI: 1.16-2.96, p = 0.010). However, folate, vitamin B6 and Hcy levels may not be causally associated with the risk of mental disorders. In conclusion, this study reveals that elevated serum vitamin B12 levels might suggestively increase the risk of anxiety and bipolar affective disorders, even though horizontal pleiotropy cannot be completely eliminated. The potential implications of our results warrant validation in larger GWAS based on diverse populations.

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

BACKGROUND: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. OBJECTIVES: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. RESULTS: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. CONCLUSION: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Plain language titleExcess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?Plain language summaryIt has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12.

Serum vitamin D, hemoglobin A1c and vitamin B12 levels in patients with gingivitis and periodontitis stages.

Aim: To compare the serum vitamin D, hemoglobin A1c (HbA1c) and vitamin B12 levels in patients with gingivitis and four different periodontitis stages diagnosed according to the 2017 Periodontal Disease Classification. Materials & methods: A total of 606 patients were included in the study who were diagnosed with gingivitis and stage I-IV periodontitis. Patients were divided into groups based on disease stage, and the HbA1c, vitamin D and B12 levels of the patients were compared and analyzed. Result: The highest HbA1c level and the lowest vitamin D level were seen in stage III-IV periodontitis. The highest vitamin D and B12 levels were seen in the gingivitis group. Conclusion: Serum HbA1c, vitamin D and B12 levels might vary depending on the presence or severity of periodontitis.Clinical Trial Registration: NCT05745779 (This study was registered and approved by www.clinicaltrials.gov).

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Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Non-causal relationship of polycystic ovarian syndrome with homocysteine and B vitamins: evidence from a two-sample Mendelian randomization.

Objective: Previous observational studies have identified a correlation between elevated plasma homocysteine (Hcy) levels and polycystic ovary syndrome (PCOS). This study aimed to determine whether a causal relationship exists between Hcy and PCOS at the genetic level. Methods: A two-sample Mendelian Randomization (TSMR) study was implemented to assess the genetic impact of plasma levels of Hcy, folate, vitamin B12, and vitamin B6 on PCOS in individuals of European ancestry. Independent single nucleotide polymorphisms (SNPs) associated with Hcy (n=12), folate (n=2), vitamin B12 (n=10), and vitamin B6 (n=1) at genome-wide significance levels (P<5×10-8) were selected as instrumental variables (IVs). Data concerning PCOS were obtained from the Apollo database. The primary method of causal estimation was inverse variance weighting (IVW), complemented by sensitivity analyses to validate the results. Results: The study found no genetic evidence to suggest a causal association between plasma levels of Hcy, folate, vitamin B12, vitamin B6, and PCOS. The effect sizes, determined through random-effect IVW, were as follows: Hcy per standard deviation increase, OR = 1.117, 95%CI: (0.842, 1.483), P = 0.442; folate per standard deviation increase, OR = 1.008, CI: (0.546, 1.860), P = 0.981; vitamin B12 per standard deviation increase, OR = 0.978, CI: (0.808, 1.185), P = 0.823; and vitamin B6 per standard deviation increase, OR = 0.967, CI: (0.925, 1.012), P = 0.145. The fixed-effect IVW results for each nutrient exposure and PCOS were consistent with the random-effect IVW findings, with additional sensitivity analyses reinforcing these outcomes. Conclusion: Our findings indicate no causal link between Hcy, folate, vitamin B12, vitamin B6 levels, and PCOS.

Folate and Vitamin B12 Levels in Chilean Women with PCOS and Their Association with Metabolic Outcomes.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; p < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.

Association of Diabetic Peripheral Neuropathy with Micronutrients.

INTRODUCTION: Diabetes mellitus (DM) is a common metabolic disorder that has been defined by hyperglycemia. Diabetic patients usually have high levels of oxidative stress. Mitochondrial dysfunction and inflammation of blood vessels are associated with a greater need for micronutrients in diabetic patients. These micronutrients may have an association with the complications in diabetics. The purpose of this study was to show the association of diabetic peripheral neuropathy (DPN) with levels of micronutrients such as copper (Cu), zinc (Zn), magnesium (Mg), and vitamin B12 (Vit B12). MATERIALS AND METHODS: This cross-sectional study was conducted in the Department of Medicine, Lala Lajpat Rai Memorial Medical College, Meerut. A total of 130 randomly selected cases of confirmed type-2 diabetic patients were included in this study. DPN cases were identified using the Michigan neuropathy screening instrument. Out of 130 diabetic patients, 28 patients were found to have diabetic neuropathy. The level of various micronutrients was assessed and correlated with the development of DPN. RESULTS: The association of DPN with Zn (p-value of 0.02) and Vit B12 (p-value of 0.008) was found to be significant, whereas Cu (p-value of 0.57) and Mg (p-value of 0.24) were found to be insignificant.

Docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, and neural tube defects in Tunisian population.

OBJECTIVE: To determine the effect of maternal status in (plasma and red blood cell) folate, vitamin B12, homocysteine, and vitamin D, as well as their interaction with MTHFR (C677T and A1298C) and MTRR A66G polymorphisms, on maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) levels and the risk of neural tube defects (NTDs). METHODS: ARA, EPA, and DHA composition was assessed using capillary gas chromatography. RESULTS: ARA and DHA levels were higher in controls than in case mothers for low plasma folate status. For low red blood cell folate status, DHA levels were higher in controls than in case mothers. For high homocysteine levels, ARA and DHA levels were higher in controls than in case mothers. NTD mothers had lower EPA and DHA levels for low vitamin B12 levels. NTD mothers had lower DHA levels for low vitamin D levels. For low plasma folate status, DHA levels in the MTHFR C677T gene and ARA and EPA levels in MTHFR A1298C gene were different among the three genotypes in case mothers. DHA levels in the MTHFR C677T gene were different among the three genotypes in case mothers for both low and high homocysteine levels. For low vitamin B12 levels, ARA and DHA levels were different among the three genotypes of the MTHFR C677T gene in case mothers. In the MTHFR C677T gene, ARA and DHA levels were different among the three genotypes in case mothers for low vitamin D levels. CONCLUSIONS: More advanced research is required to verify a suitable biochemical parameter status in relation to the genotypes in pregnant women.