Vitamin B12 deficiency.

No international treatment standard for B12 deficiency exists. Current practice predominantly relies on more than 50 years old data. Consequently, this review investigates that we still recommend five injections with 1 mg B12 over 10 days followed by maintenance therapy with 1 mg oral B12 daily or injections, of which the interval is guided by symptom relief rather than normalization of biomarkers. Clinical studies are highly warranted and should include formulation and administration of B12. Subcutaneous self-injection may prove cost-effective and benefit an individualized treatment strategy.

Vitamin B12 Supplementation in Psychiatric Practice.

PURPOSE OF REVIEW: Vitamin B12 (B12, cobalamin) deficiency has been associated with neuropsychiatric symptoms, suggesting a role for B12 supplementation both as a treatment for psychiatric symptoms due to B12 deficiency and as an augmentation strategy for pharmacological treatments of psychiatric disorders. This critical review discusses the major causes of B12 deficiency, the range of psychiatric and non-psychiatric manifestations of B12 deficiency, the indications for testing B12 levels, and the evidence for B12 supplementation for major psychiatric disorders. RECENT FINDINGS: We find that high-quality evidence shows no benefit to routine B12 supplementation for mild depressive symptoms or to prevent depression. There is very limited evidence on the role of B12 supplementation to augment antidepressants. No high-quality evidence to date suggests a role for routine B12 supplementation in any other major psychiatric disorder. No formal guidelines indicate when clinicians should test B12 levels for common psychiatric symptoms, in the absence of major risk factors for deficiency or cardinal symptoms of deficiency. No robust evidence currently supports routine B12 supplementation for major psychiatric disorders. However, psychiatrists should be aware of the important risk factors for B12 deficiency and should be able to identify symptoms of B12 deficiency, which requires prompt testing, medical workup, and treatment. Testing for B12 deficiency should be considered for atypical or severe psychiatric presentations.

Vitamin B12 deficiency in diabetic patients treated with metformin: A cross-sectional study.

Metformin is a cornerstone medication in the management of type 2 diabetes. Metformin is safe, effective, and inexpensive; however, it is associated with vitamin B12 deficiency. This study set out to evaluate the rate of vitamin B12 deficiency in Vietnamese patients with type 2 diabetes who were treated with metformin and to investigate factors associated with vitamin B12 deficiency. This is a cross-sectional study that was conducted in Vinmec Central Park Hospital from February to June 2023. The clinical and paraclinical characteristics of the participants were recorded, and the levels of vitamin B12 and folate were measured. The rate of vitamin B12 deficiency in patients treated with metformin was found to be 18.6%. Further, the duration of diabetes, duration of metformin use, metformin dose, and hemoglobin levels were statistically associated with vitamin B12 deficiency with OR (95% CI) = 1.12 (1.03-1.19), 1.01 (1.00-1.02), 1.002 (1.001-1.002), 0.74 (0.55-0.99), respectively. After adjusting for covariates, a metformin dose greater than the median dose remained the only parameter associated with vitamin B12 deficiency, with OR (95% CI) = 4.10 (1.62-10.36). Moreover, when combining both long-term use of metformin and a metformin dose greater than the median dose, the OR increased to 5.25 (95% CI: 2.11-13.15). These results demonstrate that vitamin B12 deficiency in patients treated with metformin is quite prevalent in Vietnam and that those with long-term use of metformin (48 months or more) and high metformin dose (1000 mg/day or more) are at high risk of experiencing this adverse effect and so require screening.

New data supporting that early diagnosis and treatment are possible and necessary in intracellular cobalamin depletion: the case of transcobalamin II deficiency.

OBJECTIVES: Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected. CASE PRESENTATION: Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment. CONCLUSIONS: This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving.

Iron deficiency in pernicious anemia: Specific features of iron deficient patients and preliminary data on response to iron supplementation.

BACKGROUND & AIMS: While vitamin B12 (B12) deficiency is considered as the hallmark of pernicious anemia (PA), iron deficiency (ID) is also prevalent. Indeed, this auto immune gastritis is responsible for parietal cell atrophy and increase in gastric pH, leading to impaired iron absorption. We compared PA patients' features according to their iron status at PA diagnosis, and we assessed the iron status recovery after oral or intravenous iron supplementation. METHODS: We prospectively included patients presenting with a newly diagnosed PA in a tertiary referral hospital between November 2018 and October 2020. Iron status was assessed at PA diagnosis then regularly during a standardized follow-up. In case of ID, the decision of treatment with oral and/or intravenous iron supplementation was left to the clinician convenience. RESULTS: We included 28 patients with newly diagnosed PA. ID was observed in 21/28 (75.0%) patients: from the PA diagnosis in 13 patients, or during the follow-up in 8 patients. Iron deficient PA patients had higher plasma B12 (p = 0.04) and lower homocysteine levels (p = 0.04). Also, ID was independently associated with the 'APCA (anti-parietal cell antibodies) alone' immunological status (absence of anti-intrinsic factor antibodies) after adjustment for age, gender and B12 level (aOR 12.1 [1.1-141.8], p = 0.04). High level of APCA was associated with lower ferritin level. After 3 months of supplementation, 3/11 PA patients normalized the iron status with oral iron supplementation, versus 7/8 with intravenous iron supplementation (p = 0.02). CONCLUSION: The high frequency of iron deficiency in PA highlights the interest of regular assessment of iron status in this condition. ID was associated with a profile including APCA alone and less pronounced B12 deficiency. Intravenous iron supplementation seemed to be more efficient than an oral supplementation in these preliminary data.

The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.

Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 µM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 µM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.

Efficacy and tolerance of oral versus parenteral cyanocobalamin supplement in hypocobalaminaemic dogs with chronic enteropathy: a controlled randomised open-label trial.

OBJECTIVES: Determine comparative tolerance of daily oral and weekly parenteral cobalamin supplementation, in hypocobalaminaemic dogs with chronic enteropathy. Determine whether oral is as effective as parenteral supplementation at achieving eucobalaminaemia, in hypocobalaminaemic dogs with protein-losing enteropathy, severe hypocobalaminaemia or high canine inflammatory bowel disease activity index at inclusion. MATERIALS AND METHODS: Thirty-seven client-owned dogs with hypocobalaminaemia and clinical signs of chronic enteropathy were prospectively enrolled in three UK referral centres. Dogs were randomly allocated to daily oral for 12 weeks or weekly parenteral cobalamin supplementation for 6 weeks and one additional dose 4 weeks later. Serum cobalamin, body condition score, canine inflammatory bowel disease activity index and bodyweight were assessed at inclusion, weeks 7 and 13. Serum methylmalonic acid concentration was evaluated at inclusion and at week 13. Owners completed treatment adherence, palatability, tolerance and satisfaction questionnaires at week 13. RESULTS: Nineteen dogs completed the study. All dogs orally supplemented achieved normal or increased cobalaminaemia at weeks 7 and 13. There was no statistical difference in cobalamin concentration at week 13 in dogs treated with oral or parenteral supplementation, regardless of presence of protein-losing enteropathy, severity of hypocobalaminaemia or canine inflammatory bowel disease activity index at inclusion. Serum methylmalonic acid concentration was not significantly different between oral and parenteral groups, neither were treatment adherence, satisfaction, and tolerance scores at week 13. CLINICAL SIGNIFICANCE: Oral is as effective and as well-tolerated as parenteral cobalamin supplementation in hypocobalaminaemic dogs with chronic enteropathy and severe clinical or biochemical phenotypes, and should be considered as a suitable treatment option regardless of disease severity.

Knuckle hyperpigmentation in a young male: A clinical sign of B12 deficiency not to be missed.

Vitamin B12 and folate deficiency are reversible causes of megaloblastic anemia. Strict vegetarians are at risk of megaloblastic anemia due to low cobalamin in their diet. Knuckle hyperpigmentation in patients with megaloblastic anemia is due to excess melanin synthesis in skin. Here we present a case of a young vegetarian male with megaloblastic anemia with knuckle hyperpigmentation managed successfully with intravenous followed by oral vitamin b12 and folate supplementation.

A new perspective on vitamin B12 deficiency in rheumatology: a case-based review.

Vitamin B12 (cobalamin) deficiency is common in patients with rheumatic diseases. Pernicious anemia is a well-known cause, but recent reports suggest that autoimmune-derived deficiency may not be limited to this cause alone. Symptoms of low vitamin B12 concentration are often deceptive, mimicking and overlapping with symptoms of other conditions. Neuropsychiatric manifestations, anemia, and fatigue are frequently attributed to a rheumatic disease without further evaluation. In this study, we present three cases of patients with neuropathic pain, depression, fatigue, and muscle weakness, initially attributed to a rheumatic disease, which almost completely resolved after implementing vitamin B12 supplementation. Furthermore, we provide an overview of current scientific reports regarding the potential use of cobalamin in rheumatology. Treatment of pain and neuropathy, often very challenging in long-lasting rheumatic diseases, can be more effective after a course of vitamin B12, even when no apparent deficiency is detected in laboratory tests. Considering recent research demonstrating vitamin B12's nerve-protecting properties, we recommend that physicians should assess vitamin B12 levels early in the diagnostic process of rheumatic diseases. In specific cases, physicians should consider cobalamin supplementation regardless of vitamin B12 serum concentration.

Subacute Combined Degeneration of the Spinal Cord Induced by Nitrous Oxide Abuse: A Rare Patient Presentation to a Spine Surgery Clinic: Illustrative Case.

Subacute combined degeneration (SCD) of the spinal cord is a disease involving the lateral and posterior columns of the spinal cord that can manifest in patients with vitamin B12 deficiency. Nitrous oxide (N2O)-induced SCD of the spinal cord is a result of N2O interfering with the metabolism of vitamin B12 and results in nervous system demyelination. This is an infrequent complication of N2O anesthesia; however, cases are rising with recreational N2O use. This case report describes a patient with SCD of the spinal cord induced by recreational N2O abuse. The patient presented to a spine surgery clinic with a 3-week history of progressive global weakness and paresthesias. After a detailed history and physical examination, the diagnosis was made and supported by various tests and imaging findings. Despite marked neurologic deficits, the patient's symptoms improved markedly with therapy and vitamin B12 supplementation. Spine surgery clinicians may be confronted with these cases and should be aware of this atypical presentation of SCD. As in our case, patients may present with neurologic deficits of unclear etiology. Neurologic dysfunction may be irreversible; therefore, accurate diagnosis, medical treatment, and complete neurologic evaluation are of the utmost importance to prevent additional progression.

Efficacy of different routes of vitamin B12 supplementation for the treatment of patients with vitamin B12 deficiency: A systematic review and network meta-analysis.

BACKGROUND: This systematic review and network meta-analysis aimed to evaluate the three different administration routes of vitamin B12: oral, intramuscular (IM), and sublingual (SL) routes. METHODS: We searched four electronic databases (PubMed, Scopus, Web of Science, and Cochrane CENTRAL Register of Controlled Trials). We included only comparative studies. We performed a frequentist network meta-analysis to measure network estimates for the relative outcomes. Moreover, we conducted a pairwise meta-analysis using a random effect model to obtain direct estimates for outcomes. All outcomes were continuous, and the relative treatment effects were pooled as mean difference (MD) with 95% confidence intervals. RESULTS: Thirteen studies were included in the meta-analysis, with a total of 4275 patients. Regarding increasing vitamin B12 levels, the IM route ranked first, followed by the SL route (MD = 94.09 and 43.31 pg/mL, respectively) compared to the oral route. However, these differences did not reach statistical significance owing to the limited number of studies. Regarding the hemoglobin level, the pooled effect sizes showed no difference between all routes of administration that could reach statistical significance. However, the top two ranked administration routes were the oral route (78.3) and the IM route (49.6). CONCLUSION: All IM, oral, and SL routes of administration of vitamin B12 can effectively increase the level of vitamin B12 without significant differences between them, as thought previously. However, the IM route was the top-ranked statistically but without clinical significance. We found no significant difference among studied administrated routes in all other CBC parameters and homocysteine levels.

Neurological complications of excessive recreational nitrous oxide use: a case series based on a text mining algorithm.

BACKGROUND: The recreational use of nitrous oxide (N2O) has gained popularity over recent years. We present a case series of excessive N2O users with neurological complications. METHODS: In this retrospective three-centre study, we used a text mining algorithm to search for patients who used N2O recreationally and visited a neurologist. RESULTS: We identified 251 patients. The median duration of N2O use was 11 months (interquartile range [IQR], 3-24) and the median amount of N2O used per occasion 1.6 kg (IQR 0.5-4.0). Clinically, polyneuropathy (78%), myelopathy (41%), and encephalopathy (14%) were the most common diagnoses. An absolute vitamin B12 deficiency of < 150 pmol/L was found in 40% of cases. In 90%, at least one indicator of functional vitamin B12 status (vitamin B12, homocysteine, or methylmalonic acid) was abnormal. MRI showed signs of myelopathy in 30/55 (55%) of cases. In 28/44 (64%) of those who underwent electromyography, evidence of axonal polyneuropathy was found. Most (83%) patients were treated with vitamin B12 supplementation, and 23% were admitted to the hospital. Only 41% had follow-up for ≥ 30 days, and 79% of those showed partial or complete recovery. CONCLUSIONS: In this case series of excessive N2O users, we describe a high prevalence of polyneuropathy, myelopathy, and encephalopathy. Stepwise testing for serum levels of vitamin B12, homocysteine, and methylmalonic acid may support the clinical diagnosis. Due to low sensitivity, MRI of the spinal cord and electromyography have limited value. Effective treatment should incorporate supplementation of vitamin B12 and strategies to prevent relapses in N2O use.

Biochemical, Nutritional, and Clinical Parameters of Vitamin B12 Deficiency in Infants: A Systematic Review and Analysis of 292 Cases Published between 1962 and 2022.

Pooled data from published reports on infants with clinically diagnosed vitamin B12 (B12) deficiency were analyzed with the purpose of describing the presentation, diagnostic approaches, and risk factors for the condition to inform prevention strategies. An electronic (PubMed database) and manual literature search following the PRISMA approach was conducted (preregistration with the Open Science Framework, accessed on 15 February 2023). Data were described and analyzed using correlation analyses, Chi-square tests, ANOVAs, and regression analyses, and 102 publications (292 cases) were analyzed. The mean age at first symptoms (anemia, various neurological symptoms) was four months; the mean time to diagnosis was 2.6 months. Maternal B12 at diagnosis, exclusive breastfeeding, and a maternal diet low in B12 predicted infant B12, methylmalonic acid, and total homocysteine. Infant B12 deficiency is still not easily diagnosed. Methylmalonic acid and total homocysteine are useful diagnostic parameters in addition to B12 levels. Since maternal B12 status predicts infant B12 status, it would probably be advantageous to target women in early pregnancy or even preconceptionally to prevent infant B12 deficiency, rather than to rely on newborn screening that often does not reliably identify high-risk children.

Vitamin B12 insufficiency and deficiency: a review of nondisease risk factors.

Vitamin B12 deficiency and insufficiency can lead to both hematological and neurological impairments. This review examines nondisease causes and risk factors associated with dietary availability, such as eating habits, food processing, cooking techniques, and bioavailability, as well as increased physiological needs and iatrogenic factors linked to medication use or surgical procedures. As a result of these nondisease influences, groups at higher risk include vegans, vegetarians, older adults, individuals with limited diets, breastfed and preterm infants, and those who primarily consume foods prepared or cooked in ways that reduce vitamin B12 content, as well as individuals on certain medications or who have undergone specific surgeries. Recognizing these diverse risk factors helps develop strategies for prevention and intervention to minimize the adverse health effects related to B12 deficiency and insufficiency.

Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5'-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200-900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.

Autoimmune gastritis as an unexpected cause of diarrhea in a young adult with type I diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a lifelong diagnosis that involves immune-mediated damage of pancreatic beta cells and subsequent hyperglycemia, manifesting as: polyuria, polydipsia, polyphagia, and weight loss. Treatment of type 1 diabetes centers on insulin administration to replace or supplement the body's own insulin with the goal of achieving euglycemia and preventing or minimizing complications. Patients with T1DM are at risk for developing other autoimmune conditions, most commonly thyroid or celiac disease. CASE PRESENTATION: A 20-year-old African American female with T1DM was referred by her endocrinologist to pediatric gastroenterology for 2 months of nocturnal, non-bloody diarrhea, left lower quadrant pain, and nausea; she was also being followed by neurology for complaints of lower extremity paresthesias and pain. The patient's initial lab-workup was remarkable for a low total Immunoglobulin A (IgA) level of < 6.7 mg/dL. As IgA deficiency is associated with an increased risk of celiac disease, the patient underwent upper and lower endoscopy, which was grossly unremarkable; however, histology revealed a pattern consistent with autoimmune gastritis. Subsequent serum evaluation was remarkable for an elevated fasting gastrin level and an elevated parietal cell antibody level without macrocytic anemia, iron deficiency, or vitamin B12 depletion. The patient was diagnosed with autoimmune gastritis (AIG) and subsequently initiated on parenteral B12 supplementation therapy with improvement in her neurologic and gastrointestinal symptoms. CONCLUSION: This case illustrates the importance of recognition of red flag findings in a patient with known autoimmune disease. Following well-established health maintenance recommendations for individuals with T1DM ensures that common comorbidities will be detected. Autoimmune gastritis, while a rarer pathology in the pediatric population, deserves consideration in patients with pre-existing autoimmune conditions and new gastrointestinal or neurologic symptoms, as AIG can be associated with poor outcomes and risk of malignancy. Initial lab findings associated with an eventual diagnosis of AIG typically include anemia, iron deficiency, or Vitamin B12 deficiency. However, as demonstrated in this case, symptoms of AIG can rarely present before anemia or Vitamin B12 deficiency develops. To prevent permanent neurological damage, parenteral Vitamin B12 therapy must be considered even in the absence of Vitamin B12 deficiency, especially in those patients already experiencing neurological symptoms.

Epileptic Spasms During Recovery From Nutritional Infantile Vitamin B12 Deficiency.

Development of epileptic spasms in infants with vitamin B12 deficiency is uncommon. In some cases, infants presenting with epileptic spasms have been found to have concurrent vitamin B12 deficiency. Treatment with vitamin B12 and adrenocorticotropic hormone (ACTH) resulted in resolution of epileptic spasms. In others, epileptic spasms have developed during recovery from vitamin B12 deficiency. Treatment with ACTH or other seizure medications resulted in resolution of epileptic spasms, although response has been less predictable. We describe three infants who initially presented with clinical and laboratory features of vitamin B12 deficiency. Treatment with vitamin B12 resulted in rapid resolution of symptoms. However, recovery was interrupted by the development of epileptic spasms. All infants showed hypsarrhythmia on electroencephalography. Treatment with prednisolone, with or without other antiseizure medications, resulted in slow resolution of spasms. Cognitive and language delays were noted in two infants. Epileptic spasms may supervene during recovery from vitamin B12 deficiency affecting outcomes.