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.

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency.

BACKGROUND: An increasing number of adult individuals are at risk of vitamin B12 deficiency, either from reduced nutritional intake or impaired gastrointestinal B12 absorption. OBJECTIVE: This study aims to review the current best practices for the diagnosis and treatment of individuals with vitamin B12 deficiency. METHODS: A narrative literature review of the diagnosis and treatment of vitamin B12 deficiency. RESULTS: Prevention and early treatment of B12 deficiency is essential to avoid irreversible neurological consequences. Diagnosis is often difficult due to diverse symptoms, marked differences in diagnostic assays' performance and the unreliability of second-line biomarkers, including holo-transcobalamin, methylmalonic acid and total homocysteine. Reduced dietary intake of B12 requires oral supplementation. In B12 malabsorption, oral supplementation is likely insufficient, and parenteral (i.e. intramuscular) supplementation is preferred. There is no consensus on the optimal long-term management of B12 deficiency with intramuscular therapy. According to the British National Formulary guidelines, many individuals with B12 deficiency due to malabsorption can be managed with 1000 µg intramuscular hydroxocobalamin once every two months after the initial loading. Long-term B12 supplementation is effective and safe, but responses to treatment may vary considerably. Clinical and patient experience strongly suggests that up to 50% of individuals require individualized injection regimens with more frequent administration, ranging from daily or twice weekly to every 2-4 weeks, to remain symptom-free and maintain a normal quality of life. 'Titration' of injection frequency based on measuring biomarkers such as serum B12 or MMA should not be practiced. There is currently no evidence to support that oral/sublingual supplementation can safely and effectively replace injections. CONCLUSIONS: This study highlights the interindividual differences in symptomatology and treatment of people with B12 deficiency. Treatment follows an individualized approach, based on the cause of the deficiency, and tailored to help someone to become and remain symptom-free.

Plain language titleDiagnosis and Treatment of Vitamin B12 DeficiencyPlain language summaryThe number of people who are at risk of developing a deficiency of vitamin B12 is steadily increasing. B12 deficiency can develop when people consume too few B12-containing foods of animal origin, or when they develop a form of B12 malabsorption. B12 deficiency can lead to serious complications so prevention and early treatment are essential. Diagnosing B12 deficiency can be challenging: the symptoms vary from patient to patient, and the methods used to measure B12 in the blood, or certain biomarkers associated with B12 metabolism, such as holo-transcobalamin, methylmalonic acid, and total homocysteine are unreliable. When people do not consume enough B12-containing foods, supplementation with B12 tablets is needed. In the case of B12 malabsorption, intramuscular injections of B12 are mandatory. The usual treatment with B12 is starting with injections of 1000 µg hydroxocobalamin twice weekly or on every other day for a period of up to 5 weeks or longer, until all symptoms have disappeared, and thereafter, the frequency of injections is gradually reduced. There is, however, a large group of people who require more frequent administration to become and remain symptom-free: this may range from daily or twice weekly to every 2 to 4 weeks.

Vitamin B12 Deficiency in Clinical Practice-Proceedings of the International B12 Conference, June 2023, Rotterdam.

This supplement of the Food and Nutrition Bulletin is dedicated to the proceedings of "the International B12 Conference in Clinical Practice," held in Rotterdam in June 2023. The conference brought together physicians, scientists, patient groups, and health care professionals with substantial expertise in diagnosing and treating vitamin B12 deficiency from many universities around the world. With a collective commitment to advancing clinical practice and improving patient outcomes, this event was instrumental in addressing the many complex and challenging aspects of vitamin B12 deficiency. The subjects explored at the conference ranged from the latest research findings to real-world case studies, spanning diverse medical disciplines, including pediatrics, obstetrics, neurology, internal medicine, gastroenterology, psychiatry, clinical chemistry, nutrition, public health, biomedical science, and nursing. The broad spectrum of disciplines reflects the multifaceted nature of vitamin B12 deficiency and underscores the necessity of a comprehensive and multidisciplinary approach to its diagnosis and treatment. This supplement aims to distill into a concise and accessible format the knowledge shared by stimulating and provocative presentations at the B12 Conference and to make the information available for the broader scientific and health care community. The compendium bridges the insights generated at the conference and the wider audience of health care practitioners, researchers, and policymakers who recognize the urgency of addressing the critical public health concerns surrounding vitamin B12 deficiency.

Plain language title Vitamin B12 Deficiency in Clinical Practice: Proceedings of an International B12 Conference Plain language summary This supplement focuses on vitamin B12, a crucial micronutrient essential for overall human health. It summarizes the proceedings of the "International B12 Conference in Clinical Practice," held in June 2023 in Rotterdam. The conference gathered experts from various fields, including physicians, scientists, patient groups, and health care professionals, to address the complexities of diagnosing and treating vitamin B12 deficiency. The content covers various topics, from the latest research findings to real-world case studies spanning diverse medical disciplines. The aim is to distill the conference's knowledge into an accessible format for the broader scientific and health care community. The supplement emphasizes the need for a comprehensive and multidisciplinary approach to address Vitamin B12 deficiency by bringing together insights from different disciplines. The manuscripts within the supplement delve into the intricacies of vitamin B12 deficiency offering a synthesis of research findings, clinical insights, and innovative approaches to diagnosis and treatment. The goal is to inspire further research, inform clinical practice, and ultimately improve patient care in the critical areas of nutrition and health care. The supplement expresses gratitude to conference contributors, attendees, and supporters who made the event and publication possible. It aims to contribute to preventing or treating B12 deficiency and improving patients' health and well-being. Whether at the beginning or end of life and all ages in between, addressing B12 deficiency can significantly enhance global health and quality of life.

Vitamin B12 deficiency in the setting of nitrous oxide abuse: diagnostic challenges and treatment options in patients presenting with subacute neurological complications.

OBJECTIVE: It is well recognized that nitrous oxide abuse can lead to vitamin B12 deficiency presenting with neurological complications. Nevertheless, establishing this diagnosis can be challenging, and treatment guidelines are lacking. METHODS: In this paper, we present a case series of eight patients and discuss the diagnostic challenges and treatment options for vitamin B12 deficiency due to nitrous oxide abuse presenting with neurologic complications. RESULTS: Biochemical findings are not always straightforward and complementary testing is often necessary. Magnetic Resonance Imaging (MRI) revealed a longitudinally myelopathy extending over a long segment typically involving the dorsal columns of the cervical cord. To increase the lesion conspicuity, dedicated MRI sequences are needed. In our practice, we recommend the use of T2-weighted images (WI) with fat suppression (FS). Treatment consists of cessation of nitrous oxide abuse and supplementation with intramuscular injections of cobalamin. Due to a lack of treatment guidelines, we also describe the treatment schedule used in our neurology clinic and give a brief overview of treatment options suggested in the literature. CONCLUSION: We described diagnostic steps en treatment plans in patients presenting with subacute neurological complications due to nitrous oxide abuse. ABBREVIATIONS: crea: creatinine; HCy: homocysteine; MCA: 2-methylcitric acid; MMA: methylmalonic acid; MRI: magnetic resonance imaging; SEP: somatosensory evoked potentials.

A Brief Review on Vitamin B12 Deficiency Looking at Some Case Study Reports in Adults.

In the era of evidence-based medicine, the randomized clinical trial corresponds to the top step in the qualitative scale of the evidence available in the literature, while small series of cases or the description of individual cases occupy the last place. However, the latter represent an important part of clinical practice and have significantly influenced the evolution of medicine, contributing significantly to the advancement of scientific knowledge. Vitamin B12 deficiency shares several common symptoms that affect several tissues and organs with health aliments, so its diagnosis could be unobvious for the broad array of its effects and investigation methods used. In this review, we focused our attention on some case reports related to the vitamin B12 deficiency associated to anemia, neurologic disorders, and hyperhomocysteinemia. B12 deficiency reversal is simply achieved by prompt therapy, even though it is not the same for several disorders.

Pseudomicroangiopatía trombótica por deficiencia de vitamina B12 en un lactante / Pseudo-thrombotic microangiopathy due to vitamin B12 deficiency in an infant

La seudomicroangiopatía trombótica o síndrome de Moschcowitz es una manifestación infrecuente del déficit de vitamina B12. Se caracteriza por anemia hemolítica con características microangiopáticas, reticulocitos e índices hematimétricos normales o con ligera megaloblastosis, asociados a manifestaciones neurológicas. La vitamina B12 está presente en alimentos proteicos de origen animal. La lactancia materna es una fuente adecuada para los niños cuando los niveles maternos son normales. Se presenta a una paciente de 16 meses que se internó por anemia hemolítica con requerimiento transfusional, plaquetopenia, mal progreso pondoestatural y retraso neuromadurativo. Durante su internación se arribó al diagnóstico de seudomicroangiopatía trombótica secundaria a déficit de vitamina B12.

Pseudo-thrombotic microangiopathy, or Moschcowitz syndrome, is a rare manifestation of vitamin B12 deficiency. It is characterized by microangiopathic hemolytic anemia, reticulocytes, and hematimetric indices that can be normal or that might present a mild megaloblastosis, and which are associated with neurological manifestations. Vitamin B12 can be found in animal-based protein foods. Breastfeeding is an adequate source of this vitamin for children, when maternal serum levels are normal. The case of a 16-month-old infant is presented. She was admitted for hemolytic anemia with transfusion requirement, thrombocytopenia, failure to thrive and developmental delay. During her hospitalization, she was diagnosed with pseudothrombotic microangiopathy caused by vitamin B12 deficiency.

Enteral Vitamin B12 Supplementation Is Effective for Improving Anemia in Patients Who Underwent Total Gastrectomy.

BACKGROUND: This study aimed to investigate the efficacy of enteral supplementation of vitamin B12 for vitamin B12 deficiency in patients who underwent total gastrectomy for gastric cancer. METHODS: The study enrolled 133 patients who underwent total gastrectomy for gastric cancer at Kochi Medical School. Clinical data were obtained to investigate associations between vitamin B12 supplementation and vitamin B12 levels. Vitamin B12 deficiency was defined as serum vitamin B12 less than 200 pg/mL. Baseline characteristics and changes in hematological variables, including vitamin B12 levels, were examined. RESULTS: Vitamin B12 deficiency was present in 71.4% of the 133 patients. Vitamin B12 levels at 3, 6, and 12 months after enteral supplementation were 306 pg/mL, 294 pg/mL, and 367 pg/mL, respectively, which were all significantly higher than those before supplementation (p < 0.001 for all comparisons). The median red blood cell count at 3, 6, and 12 months after enteral supplementation were 380 × 104/mm3, 394 × 104/mm3, and 395 × 104/mm3, respectively, which were all significantly higher than those before supplementation (p = 0.020, p = 0.001, and p = 0.003, respectively). Vitamin B12 levels at 3, 6, and 12 months after supplementation were significantly higher in patients supplemented enterally than those supplemented parenterally (p < 0.001 for all comparisons). CONCLUSIONS: Vitamin B12 deficiency was found in 71.4% of postoperative patients who underwent total gastrectomy for gastric cancer, and enteral vitamin B12 supplements might be effective to improve anemia in these patients.

Metabolic and Toxic Myelopathies.

PURPOSE OF REVIEW: This article describes the clinical presentation, relevant diagnostic investigations, and treatment of metabolic and toxic myelopathies. RECENT FINDINGS: Metabolic myelopathies, including those due to deficiency of vitamin B12, folate, copper, or vitamin E, are preventable and typically respond to supplementation. In metabolic myelopathy, early recognition and treatment are important to reduce morbidity, particularly due to subacute combined degeneration of the spinal cord. Toxic myelopathies, including those due to medical interventions (eg, methotrexate, radiation), dietary toxins (eg, lathyrism, konzo), and drugs of abuse (eg, heroin), typically result in permanent neurologic deficits. Toxic myelopathy due to hepatic dysfunction may be reversible if patients receive early intervention, whereas nitrous oxide myelopathy responds to vitamin B12 replacement and cessation of exposure. In toxic myelopathy, it is best to avoid the provoking factor when possible or attempt to mitigate risk by identifying risk factors for developing myelopathy. SUMMARY: Metabolic and toxic myelopathies are important causes of morbidity that require a high index of suspicion for diagnosis.

Review of Vitamin B12 deficiency in pregnancy: a diagnosis not to miss as veganism and vegetarianism become more prevalent.

Vegetarianism and veganism are increasingly popular. The Food Standards Agency, biennial Food and You Survey of adults aged 16 years and over living in the UK, found that between 2012 and 2018 the proportion of people who reported never consuming dairy products had increased from 2% to 5%. However, veganism risks development of vitamin B12 deficiency as it is not available from plant sources. Moreover, its impact may be slow to be detected because body stores of vitamin B12 can last years. There is currently no published guidance on antenatal diagnosis and management of vitamin B12 deficiency. This paper reviews the metabolism, diagnosis and treatment of vitamin B12 in pregnancy. It concludes that national screening policymakers should consider introducing screening for B12 deficiency into the Antenatal and Newborn Screening Programmes for mothers and their infants if at risk of vitamin B12 deficiency. In the interim, national policy should be developed for prophylactic vitamin B12 supplementation in high-risk groups around the time of pregnancy.

Encefalopatía grave y deficiencia de vitamina B12: reversibilidad tras la terapia nutricional / Severe encephalopathy and vitamin B12 deficiency: reversibility after nutritional therapy

INTRODUCCIÓN: la vitamina cobalamina es esencial para el buen funcionamiento del SNC, la hematopoyesis y la síntesis de ADN. Su déficit es frecuentemente secundario a la anemia perniciosa o a las dietas vegetarianas estrictas. CASO CLÍNICO: lactante varón de 18 meses con disminución del nivel de conciencia y trastorno del movimiento (temblor y movimientos coreiformes) de horas de duración. Como antecedentes, presenta retraso de la adquisición de los hitos motores (no bipedestación, lenguaje monosilábico) y pérdida progresiva de los mismos en las últimas semanas (sostén cefálico y sedestación). Alimentado mediante lactancia materna desde el nacimiento. La familia sigue una alimentación vegetariana. En las pruebas de neuroimagen, la TC y la RM craneales muestran atrofia supratentorial generalizada de ambas sustancias y de los ganglios basales. Se inicia tratamiento con vitamina B12 intramuscular, aumentando sus niveles. Posteriormente se procede a la diversificación alimentaria y la administración de cianocobalamina oral, con normalización clínica al cabo de 6 meses y radiológica al cabo de 7 meses. DISCUSIÓN: recalcamos la importancia de la suplementación con B12 durante el embarazo y la lactancia tanto en la mujer como en el lactante

INTRODUCTION: the vitamin cobalamin is essential for a proper functioning of the CNS, hematopoiesis, and DNA synthesis. Its deficiency is frequently secondary to pernicious anemia or strict vegetarian diets. CASE REPORT: an 18-month-old male infant presented with a decreased level of consciousness and movement disorder (tremor and choreiform movements) of several hours' standing. He had a history of delayed acquisition of motor milestones (not standing, monosyllabic language), and progressive loss of these over the last few weeks (head support and sitting). He had been breastfed from birth. His family has a vegetarian diet. In neuroimages, cranial CT and MRI scans showed generalized supratentorial atrophy involving both matters and the basal ganglia. Treatment was started with intramuscular vitamin B12, which increased its levels. Subsequently, the patient was subjected to dietary diversification and oral cyanocobalamin, with clinical normalization after 6 months and radiological normalization after 7 months. DISCUSSION: we emphasize the importance of vitamin B12 supplementation during pregnancy and lactation in vegetarian mothers and their infants

[Severe encephalopathy and vitamin B12 deficiency: reversibility after nutritional therapy]. / Encefalopatía grave y deficiencia de vitamina B12: reversibilidad tras la terapia nutricional.

INTRODUCTION: Introduction: the vitamin cobalamin is essential for a proper functioning of the CNS, hematopoiesis, and DNA synthesis. Its deficiency is frequently secondary to pernicious anemia or strict vegetarian diets. Case report: an 18-month-old male infant presented with a decreased level of consciousness and movement disorder (tremor and choreiform movements) of several hours' standing. He had a history of delayed acquisition of motor milestones (not standing, monosyllabic language), and progressive loss of these over the last few weeks (head support and sitting). He had been breastfed from birth. His family has a vegetarian diet. In neuroimages, cranial CT and MRI scans showed generalized supratentorial atrophy involving both matters and the basal ganglia. Treatment was started with intramuscular vitamin B12, which increased its levels. Subsequently, the patient was subjected to dietary diversification and oral cyanocobalamin, with clinical normalization after 6 months and radiological normalization after 7 months. Conclusions: we emphasize the importance of vitamin B12 supplementation during pregnancy and lactation in vegetarina mothers and their infants.

INTRODUCCIÓN: Introducción: la vitamina cobalamina es esencial para el buen funcionamiento del SNC, la hematopoyesis y la síntesis de ADN. Su déficit es frecuentemente secundario a la anemia perniciosa o a las dietas vegetarianas estrictas. Caso clínico: lactante varón de 18 meses con disminución del nivel de conciencia y trastorno del movimiento (temblor y movimientos coreiformes) de horas de duración. Como antecedentes, presenta retraso de adquisición de hitos motores (no bipedestación, lenguaje monosilábico) y pérdida progresiva de los mismos en lúltimas semanas (sostén cefálico y sedestación). Alimentado mediante lactancia materna desde el nacimiento. La familia sigue una alimentación vegetariana. En las pruebas de neuroimagen, la TC y la RM craneales muestran atrofia supratentorial generalizada de ambas sustancias y de los ganglios basales. Se inicia tratamiento con vitamina B12 intramuscular, aumentando sus niveles. Posteriormente se procede a la diversificación alimentaria y la administración de cianocobalamina oral, con normalización clínica al cabo de 6 meses y radiológica al cabo de 7 meses. Conclusiones: recalcamos la importancia de la suplementación con B12 durante el embarazo y lactancia tanto en la mujer como en el lactante.

Profile of anemia in acute lymphoblastic leukemia patients on maintenance therapy and the effect of micronutrient supplementation.

BACKGROUND: Anemia is a common finding and important cause of morbidity in patients with acute lymphoblastic leukemia (ALL) at diagnosis or during the course of its protracted treatment. We studied profile of anemia in ALL patients on maintenance therapy and evaluated specific micronutrients as cause of this anemia. PATIENTS AND METHODS: ALL patients who were on maintenance therapy and had grade ≥ 2 anemia were recruited for the study. Serum iron studies, folate, and vitamin B12 were done to identify micronutrient deficiency and to initiate supplementation with specific components if found to be deficient. Toxicities, improvement of anemia, micronutrient levels, and disease outcome were studied after 3 months. RESULTS: From March 2015 to September 2016, 105 ALL patients were found to be on maintenance fulfilling the inclusion criteria. Overall, the proportion of anemia was 80%(N = 84). Majority had normocytic normochromic anemia (71%). Macrocytic anemia was seen in 18% and microcytic hypochromic in 9.5%. In patients with anemia of grade ≥ 2 (N = 84), 38 patients (45%) had biochemical deficiency of serum folate, and 7 (8%) had vitamin B12 deficiency. No biochemical evidence of iron deficiency was found. Supplementation of deficient micronutrients improved anemia: mean hemoglobin significantly increased from 8.06 ± 1.63 to 10.78 ± 1.53 (p < 0.001) at 3 months; and reduced treatment toxicities, mean number of febrile neutropenia episodes (p = 0.007), and treatment interruptions of > 2 weeks (p = 0.002) were lowered. Patients with anemia had significantly more relapses (N = 14,64%) compared to patients without anemia (N = 8,36%), (p = 0.040). CONCLUSION: Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.

The impact of vitamin B12 deficiency on infant gut microbiota.

Although physiologic and neurologic consequences of micronutrient deficiencies have been addressed extensively, less is known about their impact on developing gut microbiota. Vitamin B12 deficiency is a common micronutrient deficiency in infants. We aimed to analyze the gut microbial composition of exclusively breastfed infants aged between 4 and 6 months with and without vitamin B12 deficiency by 16S rRNA gene sequencing. In a subgroup of infants with vitamin B12 deficiency, stool samples are recollected and reanalyzed after vitamin B12 supplementation. A total of 88 infants' stool samples (median age 4 months [IQR 4-5], 50% males) were analyzed, of which 28 (31.8%) were vitamin B12 sufficient and 60 (68.2%) were vitamin B12 insufficient. Comparisons between vitamin B12-sufficient and vitamin B12-insufficient infants revealed no evidence of differences in the microbiota. Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes were the most abundant phyla in all groups. There was no difference between the pre- and post-treatment composition of gut microbiota.Conclusion: Vitamin B12-deficient infants have similar gut microbial composition as vitamin B12-sufficient infants. Since the samples were collected at an early period of life and the exposure to deficiency was relatively short, it may be possible that the effects were not fully established.What is Known: • Vitamin B12 is an essential vitamin for humans and also a crucial compound for human gut microbiota. • Vitamin B12 deficiency is common in exclusively breastfed infants. • In contrast to the adult gut microbiota, infant gut microbiota has been shown to have decreased capacity for de novo synthesis of vitamin B12 and depend on dietary source of vitamin B12.What is New: • There is no difference in the gut microbial composition of vitamin B12-deficient and vitamin B12-sufficient infants.