Vitamin B12 Deficiency in Thrombotic Thrombocytopenic Purpura-Like Cases.

Background: Thrombotic microangiopathies (TMA) are characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage which occur in the setting of endothelial damage and platelet activation. Vitamin B12 (cobalamin) deficiency could lead to a picture that resembles TMA, termed metabolic mediated TMA (MM-TMA). Case Presentation: A 60-year-old female was brought to the hospital after she was found unresponsive. On presentation, she was pale, lethargic, tachycardic, and febrile. Laboratory investigations revealed normocytic anemia, thrombocytopenia, and elevated bilirubin. Blood smear revealed schistocytes and tear drop cells. Given the presence of hemolytic anemia, thrombocytopenia, acute renal failure, and altered mental status, a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) was made with a PLASMIC score of 7 indicating high risk. She received plasma exchange, caplacizumab, and intravenous methylprednisolone. Given the patient's low level of vitamin B12, she was initiated on intramuscular cyanocobalamin 1000 µg daily. The encephalopathy resolved and renal function improved. On day 6, ADAMTS13 activity was normal ruling out the diagnosis of TTP. Accordingly, plasmapheresis, steroids, and caplacizumab were discontinued. With continued aggressive B12 replacement, hemolysis resolved indicating severe vitamin B12 deficiency was the likely culprit of this patient's microangiopathic hemolytic anemia. Conclusion: This case serves to highlight the variable presentation of vitamin B12 deficiency. Severe vitamin B12 deficiency can even mimic TTP. If patients have markers of hemolysis, a low vitamin B12 level, and low reticulocyte count we should consider vitamin B12 deficiency as a likely cause of microangiopathic hemolytic anemia as early detection allows for early initiation of appropriate management. LEARNING POINTS: Vitamin B12 deficiency can be a cause of thrombotic microangiopathy.

Biological properties of vitamin B12.

Vitamin B12, cobalamin, is indispensable for humans owing to its participation in two biochemical reactions: the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A, and the formation of methionine by methylation of homocysteine. Eukaryotes, encompassing plants, fungi, animals and humans, do not synthesise vitamin B12, in contrast to prokaryotes. Humans must consume it in their diet. The most important sources include meat, milk and dairy products, fish, shellfish and eggs. Due to this, vegetarians are at risk to develop a vitamin B12 deficiency and it is recommended that they consume fortified food. Vitamin B12 behaves differently to most vitamins of the B complex in several aspects, e.g. it is more stable, has a very specific mechanism of absorption and is stored in large amounts in the organism. This review summarises all its biological aspects (including its structure and natural sources as well as its stability in food, pharmacokinetics and physiological function) as well as causes, symptoms, diagnosis (with a summary of analytical methods for its measurement), prevention and treatment of its deficiency, and its pharmacological use and potential toxicity.

Crystal structure of l-threonine-O-3-phosphate decarboxylase CobC from Sinorhizobium meliloti involved in vitamin B12 biosynthesis.

Vitamin B12 is involved in many important biochemical reactions for humans, and its deficiency can lead to serious diseases. The industrial production of vitamin B12 is achieved through microbial fermentation. In this work, we determine the crystal structures of the l-threonine-O-3-phosphate (Thr-P) decarboxylase CobC from Sinorhizobium meliloti (SmCobC), an industrial vitamin B12-producing bacterium, in apo form and in complex with a reaction intermediate. Our structures supported the Thr-P decarboxylase activity of SmCobC and revealed that the positively charged substrate-binding pocket between the large and small domains determines its substrate selectivity for Thr-P. Moreover, our results provided evidence for the proposition that the AP-P linker is formed by direct incorporation of AP-P in the biosynthetic pathway of vitamin B12 in S.meliloti.

Effect of roasted purple laver (nori) on vitamin B12 nutritional status of vegetarians: a dose-response trial.

PURPOSE: To investigate the bioavailability of vitamin B12 from nori and to evaluate the required dosage for improving vitamin B12 nutritional status in vegetarians not using supplements. METHODS: The study design is an open-label, parallel, dose-response randomized controlled trial. Thirty vegetarians were assigned to control (no nori), low-dose (5 g nori, aiming to provide 2.4 µg vitamin B12 per day), or high-dose (8 g nori, aiming to provide 4 µg vitamin B12 per day) groups. The primary outcome was changes in vitamin B12 status as measured by serum vitamin B12, holotranscobalamin (holoTC), homocysteine (Hcy), and methylmalonic acid (MMA), and a combined score of these four markers (4cB12 score) during the four-week intervention. Dietary vitamin B12 intakes were assessed at baseline and end of the trial with a 17-item food frequency questionnaire designed for vitamin B12 assessment. General linear model was used to compare least square means of changes in each biomarker of vitamin B12 status, among the three groups, while adjusting for respective baseline biomarker. RESULTS: After adjusting for baseline status, nori consumption led to significant improvement in serum vitamin B12 (among-group P-value = 0.0029), holoTC (P = 0.0127), Hcy (P = 0.0225), and 4cB12 (P = 0.0094). Changes in MMA did not differ significantly across groups, but showed within-group pre-post improvement in the low-dose group (median [p25, p75] = -339 [-461, -198] nmol/L). Vitamin B12 status appeared to plateau at low dose (5 g of nori), which compared with control group, improved serum vitamin B12 (lease square mean [95% CI] = + 59 [25, 93] pmol/L, P = 0.0014); holoTC (+ 28.2 [10.1, 46.3] pmol/L, P = 0.0035); Hcy (-3.7 [-6.8, -0.6] µmol/L, p = 0.0226); and 4cB12 score (+ 0.67 [0.24, 1.09], p = 0.0036). High-dose resulted in similar improvements. There was no significant difference between low-dose and high-dose groups in all biomarkers of vitamin B12. CONCLUSIONS: Consuming 5 g of nori per day for 4 weeks significantly improved vitamin B12 status in vegetarians. A higher dose (8 g) may not confer additional benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05614960. Date of registration: November 14th 2022.

Promoting salt tolerance, growth, and phytochemical responses in coriander (Coriandrum sativum L. cv. Balady) via eco-friendly Bacillus subtilis and cobalt.

In plant production, evaluation of salt stress protectants concerning their potential to improve growth and productivity under saline stress is critical. Bacillus subtilis (Bs) and cobalt (Co) have been proposed to optimize salt stress tolerance in coriander (Coriandrum sativum L. cv. Balady) plants by influencing some physiological activities. The main aim of this work is to investigate the response of (Bs) and (Co) as eco-safe salt stress protectants to resist the effect of salinity, on growth, seed, and essential oil yield, and the most important biochemical constituents of coriander produced under salt stress condition. Therefore, in a split-plot factorial experiment design in the RCBD (randomized complete block design), four levels of salinity of NaCl irrigation water (SA) were assigned to the main plots; (0.5, 1.5, 4, and 6 dS m-1); and six salt stress protectants (SP) were randomly assigned to the subplots: distilled water; 15 ppm (Co1); 30 ppm (Co2); (Bs); (Co1 + Bs); (Co2 + Bs). The study concluded that increasing SA significantly reduced coriander growth and yield by 42.6%, which could be attributed to ion toxicity, oxidative stress, or decreased vital element content. From the results, we recommend that applying Bs with Co (30 ppm) was critical for significantly improving overall growth parameters. This was determined by the significant reduction in the activity of reactive oxygen species scavenging enzymes: superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) and non-enzyme: proline by 5, 11.3, 14.7, and 13.8% respectively, while increasing ascorbic acid by 8% and preserving vital nutrient levels and enhancing plant osmotic potential to buffer salt stress, seed yield per plant, and essential oil yield increased by 12.6 and 18.8% respectively. The quality of essential oil was indicated by highly significant quantities of vital biological phytochemicals such as linalool, camphor, and protein which increased by 10.3, 3.6, and 9.39% respectively. Additional research is suggested to determine the precise mechanism of action of Bs and Co's dual impact on medicinal and aromatic plant salt stress tolerance.

Red-Shifting B12-Dependent Photoreceptor Protein via Optical Coupling for Inducible Living Materials.

Cobalamin (B12)-dependent photoreceptors are gaining traction in materials synthetic biology, especially for optically controlling cell-to-cell adhesion in living materials. However, these proteins are mostly responsive to green light, limiting their deep-tissue applications. Here, we present a general strategy for shifting photoresponse of B12-dependent photoreceptor CarHC from green to red/far-red light via optical coupling. Using thiol-maleimide click chemistry, we labeled cysteine-containing CarHC mutants with SulfoCyanine5 (Cy5), a red light-capturing fluorophore. The resulting photoreceptors not only retained the ability to tetramerize in the presence of adenosylcobalamin (AdoB12), but also gained sensitivity to red light; labeled tetramers disassembled on red light exposure. Using genetically encoded click chemistry, we assembled the red-shifted proteins into hydrogels that degraded rapidly in response to red light. Furthermore, Saccharomyces cerevisiae cells were genetically engineered to display CarHC variants, which, alongside in situ Cy5 labeling, led to living materials that could assemble and disassemble in response to AdoB12 and red light, respectively. These results illustrate the CarHC spectrally tuned by optical coupling as a versatile motif for dynamically controlling cell-to-cell interactions within engineered living materials. Given their prevalence and ecological diversity in nature, this spectral tuning method will expand the use of B12-dependent photoreceptors in optogenetics and living materials.

Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan.

BACKGROUND: Cobalamin C is the most common inborn error of intracellular cobalamin metabolism caused by biallelic pathogenic variants in the MMACHC gene, leading to impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Biochemical hallmarks are elevated plasma total homocysteine (HCYs) and low methionine accompanied by methylmalonic aciduria. This study aimed to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with CblC defect. METHODS: Medical charts, urine organic acid (UOA) chromatograms, plasma amino acid levels, plasma tHcy and MMACHC gene results of patients presenting at the Biochemical Genetics Clinic, AKUH from 2013-2021 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis. RESULTS: CblC was found in 33 cases (Male:Female 19:14). The median age of symptoms onset and diagnosis were 300 (IQR:135-1800) and 1380 (IQR: 240-2730) days. The most common clinical features were cognitive impairment (n = 29), seizures (n = 23), motor developmental delay (n = 20), hypotonia (n = 17), and sparse/hypopigmented scalp hair (n = 16). The MMACHC gene sequencing revealed homozygous pathogenic variant c.394C > T, (p.Arg132*) in 32 patients, whereas c.609G > A, (p.TRP203*) in one patient whose ancestors had settled in Pakistan from China decades ago. The median age of treatment initiation was 1530 (IQR: 240-2790). The median pre-treatment HCYs levels were 134 (IQR:87.2-155.5) compared to post-treatment levels of 33.3 (IQR: 27.3-44.95) umol/L. CONCLUSIONS: Thirty-three cases of CblC defect from a single center underscores a significant number of the disorder within Pakistan. Late diagnosis emphasizes the need for increased clinical awareness and adequate diagnostic facilities.

Natural resources, quantification, microbial bioconversion, and bioactivities of vitamin B12 for vegetarian diet.

Vitamin B12 is a water-soluble vitamin with a complex chemical structure. It can participate in the synthesis and repair of DNA in the human body and plays an important role in regulating the nervous system. The deficiency of vitamin B12 will lead to megaloblastic anemia and neuropathy. Traditionally, animal foods have been the main dietary source of vitamin B12. However, this review points to certain plant sources (such as algae, mushrooms, fermented vegetables, and fermented beans) as viable vitamin B12 supplements for vegetarians. These sources validate our initial hypothesis that a plant-based diet can adequately provide essential nutrients previously thought to be available only through animal products. In terms of quantification, since the content of vitamin B12 in food samples is low and is easily interfered by impurities, highly sensitive and specific analytical methods are used for the quantification of vitamin B12. The findings from this review could be instrumental in developing fortified plant-based foods that could prevent B12 deficiency in vegetarians and vegans, thereby broadening the scope of nutritional options available to those on plant-based diets.

Severe pancytopenia at the presentation of Imerslund-Gräsbeck syndrome in a 23-month-old Italian boy.

BACKGROUND: Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by megaloblastic anemia due to selective cobalamin malabsorption and benign proteinuria. IGS is caused by a disfunction of the cubam receptor, which mediates the reabsorption of cobalamin in the ileum and the reuptake of albumin in renal proximal tubules. CASE PRESENTATION: We describe the case of a 23-month-old-italian infant presenting with severe pancytopenia and failure to thrive in whom the diagnosis of IGS was made and vitamin B12 replacement therapy was resolutive. Genetic analysis (NGS with CNV analysis including 214 genes involved in bone marrow failure and anemia), showed the presence of two pathogenetic variants in the AMN gene (c-208-2 A > G and c.1006 + 34_1007-31del). These variants have been previously described in the literature, but their combination has never been reported. CONCLUSIONS: Imerslund-Gräsbeck syndrome should be considered in the differential diagnosis of children with severe pancytopenia even in those without neurological involvement. This case emphasizes the importance of an early diagnosis and prompt treatment, to prevent irreversible neurological injury.

Physiological Metabolic Analysis of VB12 Accumulation in Ensifer adhaerens Casida A Enhanced by Oxygen Limitation.

Cobalamin (VB12) is in enormous demand across the fields of medicine, food, and feed additives. However, the oxygen supply plays a critical role in VB12 biosynthesis by Ensifer adhaerens Casida A and has been identified as a bottleneck for economical substrate consumption. This study elucidates the relationship between oxygen limitation and VB12 accumulation with transcriptomic and metabolomic analyses. Under oxygen limitation, E. adhaerens enhances oxygen transport and storage by increasing expression of flavin hemoglobin (Hmp), which was up-regulated 6-fold at 24 h of oxygen restriction compared to the oxygen restriction of 4 h (p < 0.01). Because of the cofactor of Hmp is heme, the demand for heme increases, leading to the upregulation of genes in the heme biosynthesis pathway. Similarly, genes involved in biosynthesis of its precursor, 5-ALA, were upregulated as well. 5-ALA is also a direct precursor of VB12, further leading to the upregulation of genes in the VB12 biosynthesis pathway. This process initiates biosynthesis and accumulation of VB12. As VB12 and heme biosynthesis progresses, genes associated with the biosynthesis and transportation pathways of compounds related to their biosynthesis were likewise upregulated, including genes involved in S-adenosyl methionine (SAM) biosynthesis, and the transport of Fe2+ and Co2+. Additionally, amino acids and organic acids associated with biosynthesis were also extensively consumed, such as methionine, which is used for synthesizing SAM, decreased by 310% after 24 h of oxygen limitation compared to 20% dissolved oxygen (p < 0.05). At the same time, genes related to growth-associated metabolic pathways, such as pentose phosphate pathway (PPP), were significantly downregulated. Therefore, the potential mechanism by which E. adhaerens accumulates VB12 under oxygen-limited conditions by enhancing Hmp expression, which facilitates the porphyrin metabolic pathway and promotes VB12 biosynthesis. This research provides valuable insights for increasing VB12 production through metabolic engineering and process optimization.

Folate and cobalamin status, indicators, modulators, interactions and reference ranges from early pregnancy until birth: The Reus-Tarragona Birth Cohort Study.

BACKGROUND: Folate and cobalamin status, although essential for pregnancy, are not routinely monitored in prenatal care. OBJECTIVE: To investigate folate and cobalamin status and determinants throughout pregnancy, in the absence of mandatory fortification with folic acid (FA). METHODS: In a cohort study of 831 women recruited at <12 gestational weeks (GW), plasma folate, total homocysteine (tHcy), cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), red blood cell folate (RBCF) concentrations and the combined cobalamin status indicator (cB12) were determined at ≤12, 15, 24-27, 34 GW, labor and in the cord. Single nucleotide polymorphisms affecting folate and cobalamin status were determined. FA, cobalamin, micronutrient supplement use and dietary folate and cobalamin intake (food frequency questionnaire) were recorded. Folate and cobalamin status predictors were assessed by multiple linear regression analysis. RESULTS: Only 36.1% of the participants took FA preconceptionally and 47.4% and 7.3% had suboptimal RBCF (<906 nmol/L) and plasma cobalamin status (≤221 pmol/L), respectively, at ≤12 GW. RBCF status was principally determined by planned pregnancy, FA supplementation, plasma cobalamin and methylenetetrahydrofolate (MTHFR) 677C>T genotype. Cobalamin supplement use was positively associated, while smoking and BMI were inversely associated with plasma cobalamin and holoTC. None of these were associated with plasma MMA. Only participants with the MTHFR 677TT genotype exceeding FA supplement recommendations improved their folate status (interaction term: B (95% CI):0.015 (0.01, 0.29), p: 0.032). Smoking was inversely associated with plasma cobalamin status in participants with the methionine synthase reductase (MTRR) 524CC genotype only(interaction term:0.07 (0.01, 0.04), p: 0.014). Mothers with low early pregnancy cobalamin status and also those with bigger newborns, had lower cobalamin status at labor. CONCLUSIONS: Suboptimal early pregnancy folate or cobalamin status affected47.4% and 7.3% of the participants, respectively. The MTHFR 677TT genotype consistently predicted folate status throughout pregnancy. Smoking and BMI were negatively associated with cobalamin status throughout pregnancy. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: NCT01778205. www. CLINICALTRIALS: gov.

Clinical, biochemical, molecular characteristics and clinical outcome of hyperhomocysteinemia in Malaysian children.

BACKGROUND: Hyperhomocysteinemia can be due to various abnormalities of the complex interaction of methionine, folate and vitamin B12. It has been known to be a cardiovascular risk factor. This study aims to review the clinical presentation, underlying causes and clinical outcome in paediatric patients diagnosed with significant hyperhomocysteinemia in Malaysia. DESIGN AND METHODS: Data were obtained from the medical records and the laboratory information system. Paediatric patients with significant hyperhomocysteinemia were identified from a selective high-risk screening of 96,721 patients, performed between 2010 and 2022. Inclusion criteria for the study were paediatric patients with significant hyperhomocysteinemia (>40 µmol/L). RESULTS: Sixteen patients were identified. The average total homocysteine (tHcy) and methionine were 269 µmol/L and 499 µmol/L in cystathionine ß-synthase deficiency (CBS), 127 µmol/L and 29 µmol/L in patients with remethylation defects and 390 µmol/L and 4 µmol/L in congenital B12 deficiency. We found c.609G>A as the most prevalent mutation in MMACHC gene and possible novel mutations for CBS (c.402del, c.1333C>T and c.1031T>G) and MTHFR genes (c.266T>A and c.1249del). Further subclassification revealed CBS was 5/16 patients (31 %), remethylation defects was 9/16 (56 %) and congenital B12 deficiency was 2/16 (13 %). All patients received standard treatment and regular monitoring of the main biomarkers. The average age at the time of diagnosis were 9.2 years (CBS) and 1.2 years (remethylation defects). Congenital B12 deficiency had slight delay in milestones, remethylation defects had mild to moderate learning disabilities, CBS had variable degree of intellectual disability, delayed milestones, ophthalmological abnormalities, and thrombosis at an early adolescent/adulthood. CONCLUSIONS: The majority of significant hyperhomocysteinemia in Malaysian children was due to remethylation defects. Screening for hyperhomocysteinemia in Malaysian children is recommended for earlier treatment and improved clinical outcome.

MTHFR polymorphisms and vitamin B12 deficiency: correlation between mthfr polymorphisms and clinical and laboratory findings.

Vitamin B12 deficiency is a common condition that causes a variety of disorders ranging from the development of megaloblastic anemia to the building up of neurological damage. Historically one of the leading causes of B12 deficiency appears to be secondary to malabsorption in part caused by the development of atrophic gastritis in pernicious anemia. More recently B12 deficiency could also depend on dietary restrictions. Cobalamin deficiency also appears to be closely related to folate metabolism, causing a reduction in methionine synthase activity. This results in the accumulation of 5-methyltetrahydrofolate (5-MTHF) and defective DNA synthesis. It has been hypothesized that reduced activity of the enzyme methylene-tetrahydrofolate reductase (MTHFR) could reduce the production of 5-MTHF, thereby shifting folate metabolism to thymidylate synthesis and promoting proper DNA synthesis. Our aim was to investigate the role of the C677T and A1298C MTHFR gene polymorphisms, which are associated with reduced enzyme activity, in predisposing to the development of anemia, neurological symptoms, and atrophic gastritis in a population of 105 consecutive Italian patients with cobalamin deficiency. We found statistically significant correlations between the degree of anemia and thrombocytopenia and the C677T MTHFR polymorphism, while hemoglobin levels alone significantly correlated with A1298C polymorphism, contradicting the potential protective role of these polymorphisms. Furthermore, in patients with atrophic gastritis, we found an association between the absence of parietal cell antibodies and the presence of the C677T polymorphism in homozygosity. Our results suggest a role for MTHFR enzyme activity in the severity of hematologic manifestations of vitamin B12 deficiency and as an independent mechanism of predisposition to the development of atrophic gastritis.

Vitamin B12 deficiency misdiagnosed as TTP: What can we learn from it?

The case report by Dwyre et al. shows that vitamin B12 deficiency may be misdiagnosed as acute thrombotic thrombocytopenic purpura. Together with similar observations, this underlines that acquired vitamin B12 deficiency-besides the inherited disorder of intracellular cobalamin metabolism, cbl C disease-should be listed as a separate entity of the thrombotic microangiopathies. Commentary on: Dwyre et al. Microangiopathic thrombocytopenia caused by vitamin B12 deficiency responding to plasma exchange. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19625.

Implications of hypocobalaminemia as a negative prognostic marker in juvenile dogs with parvovirus enteritis.

Introduction: Canine Parvovirus 2 (CPV-2) infection poses a significant global health risk to susceptible dogs. Hypocobalaminemia, defined as reduced serum cobalamin (CBL) concentrations, is a recognized complication in chronic enteropathies in adult dogs but remains poorly understood in the context of acute enteropathies, especially in young dogs. The aim of this study was to investigate the frequency and severity of hypocobalaminemia in young dogs with parvovirus enteritis and evaluation of CBL as a predictor of outcome. Materials and methods: Thirty client-owned dogs diagnosed with parvovirus infection and thirty healthy controls were enrolled. Clinical, hematological, and biochemical tests, including CBL and serum methylmalonic acid (MMA) concentrations, were assessed. Results: Results indicated a significantly higher prevalence of hypocobalaminemia in dogs with parvovirus enteritis compared to healthy controls, as well as a significant correlation with a disease severity score. Moreover, survivors demonstrated higher CBL concentrations than non-survivors, suggesting an eventual prognostic value of CBL status. However, parenteral CBL supplementation showed no significant effect on serum CBL or MMA concentrations, highlighting potential challenges in CBL uptake at the cellular level. Discussion: Hypocobalaminemia in this population is caused by multiple factors such as reduced nutritional absorption, gastrointestinal losses, and increased metabolic demands. Further research is needed to develop tailored management strategies, evaluate the effectiveness of CBL supplementation, and understand the mechanisms behind hypocobalaminemia in parvovirus infection.

Homocysteine Metabolism, Subclinical Myocardial Injury, and Cardiovascular Mortality in the General Population.

Background: Homocysteine (Hcy) is a recognized cardiovascular disease (CVD) risk factor linked with atherosclerosis. However, the association between Hcy and myocardial injury is little known. Objectives: This study aimed to examine the associations between Hcy metabolism, subclinical myocardial injury, and cardiovascular mortality. Methods: We included 10,871 participants without diagnosed CVD. Generalized linear regression was used to investigate the relationship between Hcy-related indicators (plasma total Hcy [tHcy], vitamin B12, and folate) and myocardial injury biomarkers (high-sensitivity troponin T [hs-cTnT], high-sensitivity troponin I [hs-cTnI] measured using 3 assays [Abbott, Siemens, and Ortho], and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Results: Among 10,871 participants, the weighted mean levels for tHcy, folate, and vitamin B12 were 8.58 µmol/L, 32.43 nmol/L, and 447.08 pmol/L, respectively. Plasma tHcy levels were positively associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP, whereas folate and vitamin B12 were not inversely related to myocardial injury biomarkers. Multivariable-adjusted odds ratios for elevated hs-cTnT (19 ng/L) and NT-proBNP (125 pg/mL) per doubling of tHcy were 2.80 (95% CI: 1.17-6.73; P < 0.001) and 1.58 (95% CI: 1.20-2.08; P < 0.001), respectively. The associations of tHcy levels with elevated hs-cTnI (Abbott: 28 ng/L; Siemens: 46.5 ng/L; Ortho: 11 ng/L) were consistent. Indirect effects of tHcy on cardiovascular mortality risk via hs-cTnT and NT-proBNP explained up to 26.6% and 12.3% of the total effect, respectively. Conclusions: Plasma tHcy, not folate or vitamin B12, is significantly associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP in adults without CVD. Subclinical myocardial injury may substantially mediate Hcy-related cardiovascular mortality risk.

Recreational Nitrous Oxide Causing Deep Vein Thrombosis and Subacute Combined Degeneration: Whip It Real Good.

Nitrous oxide (N2O) has been thought to be a harmless recreational substance by public perception, but it has been linked to subacute combined degeneration (SACD) due to induction of a functional vitamin B12 deficiency via oxidation and inactivation of the cobalt ion in its molecular structure. N2O has been rising in popularity due to several factors including accessibility, low cost, and low perceived risk, leading otherwise healthy people to develop what used to be a neurological disease experienced by select patient populations with dietary restrictions or medical conditions leading to low levels of vitamin B12. Vitamin B12 plays a crucial role in many cellular processes, and loss of functional vitamin B12 cannot be detected by measuring it directly. Substrates from its metabolic pathways such as homocysteine and methylmalonic acid must be measured to check its functional status. Vitamin B12 deficiency also leads to a hypercoagulable state due to the build-up of homocysteine in the blood. We present the case of a 26-year-old male who had reportedly used N2O for six months leading to SACD and a popliteal deep vein thrombosis. The options for treatment are abstaining from substance use and vitamin B12 supplementation; however, full recovery after SACD develops is unlikely and patients may be left with permanent neurological dysfunction from N2O use.

Improved biochemical and neurodevelopmental profiles with high-dose hydroxocobalamin therapy in cobalamin C defect.

Cobalamin C (Cbl-C) defect causes methylmalonic acidemia, homocystinuria, intellectual disability and visual impairment, despite treatment adherence. While international guidelines recommend parenteral hydroxocobalamin (OH-Cbl) as effective treatment, dose adjustments remain unclear. We assessed OH-Cbl therapy impact on biochemical, neurocognitive and visual outcomes in early-onset Cbl-C patients treated with different OH-Cbl doses over 3 years. Group A (n = 5), diagnosed via newborn screening (NBS), received high-dose OH-Cbl (median 0.55 mg/kg/day); Group B1 (n = 3), NBS-diagnosed, received low-dose OH-Cbl (median 0.09 mg/kg/day); Group B2 (n = 12), diagnosed on clinical bases, received low-dose OH-Cbl (median 0.06 mg/kg/day). Biochemical analyses revealed better values of homocysteine, methionine and methylmalonic acid in Group A compared to Group B1 (p < 0.01, p < 0.05 and p < 0.01, respectively) and B2 (p < 0.001, p < 0.01 and p < 0.001, respectively). Neurodevelopmental assessment showed better outcome in Group A compared to low-dose treated Groups B1 and B2, especially in Developmental Quotient, Hearing and Speech and Performance subscales without significant differences between Group B2 and Group B1. Maculopathy was detected in 100%, 66% and 83% of patients in the three groups, respectively. This study showed that "high-dose" OH-Cbl treatment in NBS-diagnosed children with severe early-onset Cbl-C defect led to a significant improvement in the metabolic profile and in neurocognitive outcome, compared to age-matched patients treated with a "low-dose" regimen. Effects on maculopathy seem unaffected by OH-Cbl dosage. Our findings, although observed in a limited number of patients, may contribute to improve the long-term outcome of Cbl-C patients.

Vitamin B12 Deficiency Manifesting As Pancytopenia, Lymphadenopathy, and Fever: A Clinical Mimic of Hematologic Malignancies.

Pancytopenia is a complex medical condition characterized by decreased levels of red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). It can arise from impaired production, peripheral destruction, or a combination of both. The causes of pancytopenia range from reversible factors like infections and medication reactions to irreversible conditions. Vitamin B12 deficiency is a notable reversible cause that can take years to manifest in adults due to stored reserves. However, deficiencies caused by impaired absorption, especially due to the lack of intrinsic factors (IFs), can lead to rapid deterioration within two to five years. A healthy 39-year-old male with an athletic lifestyle presented with symptoms such as dizziness, nausea, vomiting, palpitations, and fainting over a few days. These symptoms were preceded by weeks of persistent body aches, headaches, weakness, daily fevers, chills, and night sweats. Vital signs were stable. The physical examination revealed conjunctival pallor and lymphadenopathy in the submandibular and superficial cervical regions. Initial blood tests showed normocytic anemia (Hgb 4.9, MCV 80), leukopenia (2.99), thrombocytopenia (142), and elevated liver enzymes (AST 199, ALT 96, and total bilirubin of 2.04). The peripheral smear showed tear-drop cells and hypochromic cells. The initial impression was hematologic malignancy, including but not limited to leukemia, lymphoma, or myelofibrosis given clinical findings such as B-symptoms like night sweats, neck lymphadenopathy, and subjective daily fever, along with pancytopenia. The patient received a bolus of normal saline and a transfusion of two units of packed RBCs. CT scans of the chest, abdomen, and pelvis showed no adenopathy or splenomegaly. Although initial clinical assessment pointed toward a potential hematologic malignancy, comprehensive testing, including SPEP, reticulocyte count/fraction, serum folate, and serum vitamin B12, revealed only severe vitamin B12 deficiency, with a level of less than 150, with the presence of IF antibodies. Treatment involved intensive in-patient vitamin B12 injections followed by a detailed outpatient regimen. The patient completed a daily dose of vitamin B12 injections for seven consecutive days, followed by weekly injections for the next four weeks. Subsequent laboratory results demonstrated an increase in WBC count to 8.39, Hgb level to 13.2, and PLT count of 249, indicating a continued positive response to the vitamin B12 replacement therapy. In summary, pancytopenia poses a diagnostic challenge that demands careful evaluation of patient data and comprehensive testing. Vitamin B12 deficiency, which encompasses pernicious anemia (PA), is among the reversible factors to consider. This aspect holds significance before opting for more invasive measures like a bone marrow biopsy. Nutritional deficiencies need to be considered first as differentials in pancytopenia, even in the absence of typical signs of vitamin B12 deficiency (like macrocytosis and hypersegmented neutrophils) and in the presence of compelling clinical indications pointing to a hematologic malignancy.

Management of Alzheimer's disease and related neurotoxic pathologies: Role of thiamine, pyridoxine and cobalamin.

Alzheimer's disease (AD) remains one of the most debilitating disease and most common neurological disorder in the world at large. However, with many years of multiple research and billions of dollars invested for the purpose of research, not many therapeutic options exist for the management of this disease. As at 2023, the number has only increased to 7, one of which is a combination of two existing therapies. However, research has continued still in the search for a cure. The roles and functions of thiamine, pyridoxine and cobalamin in the proper function of the nervous system has been well researched over time and their role in the management of neurological diseases have been of interest in the last decade. This review describes the roles of the aforementioned chemicals in the management of different models of AD and AD-like pathologies as mono-therapeutic agents and prospective adjuvant for combination therapy.