Clinical evaluation of children referred to paediatric haematology clinics for elevated serum vitamin B12 levels

Association between the Level of Serum Vitamin B12 and Venous Thromboembolism in African American Population

To determine the prevalence of subacute combined degeneration (SCD) patients with normal or elevated serum vitamin B12 level and to identify clinical characteristics of these patients. We searched PubMed, EMBASE, and Cochrane library, without language restriction up to June 2019 and included studies with SCD patients who were diagnosed with normal or elevated serum vitamin B12 levels. Meta-analysis was performed to estimate the prevalence of SCD in patients with normal or elevated serum vitamin B12 levels and compare the differences of clinical data between patients with low and no-low serum vitamin B12 level. Six studies were included in our analysis, with a total number of 181 patients involved. The pooled proportion in patients with no-low serum vitamin B12 level was 31.0% (95% confidence interval [CI]: 22.5-40.8). There was no significant difference in the level of hemoglobin (Mean difference (MD): -3.05, 95% CI: -12.42 to 6.33. P = 0.52) and erythrocyte mean corpuscular volume (MD: -2.37, 95% CI: -11.17 to 6.43, P = 0.60) between SCD patients with no-low and those with low serum vitamin B12 levels. The meta-analysis showed that the functional disability rating scale on admission in patients with low serum vitamin B12 level was no worse than that with normal or elevated serum vitamin B12 level (MD: 0.29, 95% CI: -0.58 to 1.16, P = 0.51). Decreased level of serum vitamin B12 may not be a necessity for the diagnosis of SCD. Approximately one third of the SCD patients have normal or elevated serum vitamin B12 level. No differences were found in clinical severity between patients with normal or elevated serum vitamin B12 level and those with low level of serum vitamin B12 on admission.

Background: Little is known about variation in vitamin B12 and folate status among Chinese women 2 years postpartum. This study assessed intake of vitamin B12 and folate and biomarkers of nutrient status among Chinese women postpartum. Methods: Demographic information, multi-/single-nutrient supplementation, dietary data, serum vitamin B12 and serum folate were assessed in 982 women within 2 years postpartum, using ten investigation sites in Zhejiang Province from the National Nutritional Study 2016–2017, which is a nationally representative cross-sectional study, to form a representative provincial sample of Zhejiang Province. The dietary diversity score (DDS) was used for assessing the dietary pattern. Results: Vitamin B12 increased slightly at the early stage of postpartum and then dropped over time. Serum folate level elevated with postpartum time. The median serum vitamin B12 concentration was 494.59 (373.21–650.20) pg/mL, and folate was 7.58 (5.02–10.34) ng/mL. Correspondingly, vitamin B12 levels suggesting marginal deficiency (200–300 pg/mL) and deficiency (<200 pg/mL) resulted as 9.27% and 3.26%, respectively, and folate level suggesting deficiency (<3 ng/mL) was 9.16%. Multi-/single-nutrient supplementation during pregnancy was associated with log-transformed serum vitamin B12 and folate level after adjusting for potential confounders (vitamin B12: ß (SE) = 0.124 (0.028), p < 0.001; folate: 0.128 (0.035), <0.001). Additionally, postpartum nutrient supplementation was associated with log-transformed serum folate level, especially for lactating women (ß (SE) = 0.204 (0.062), p = 0.001). Increased DDS was significantly associated with elevated serum vitamin B12 and folate levels (vitamin B12: ß (SE) = 0.028 (0.011), p = 0.011; folate: 0.030 (0.014), 0.031). In addition, age and educational level were influencing factors for serum vitamin B12 and folate concentrations among postpartum women. Conclusion: Serum vitamin B12 level decreased and folate level increased with postpartum age among Chinese women. Nutrient supplementation during pregnancy was related to elevated serum vitamin B12 and folate concentrations. Postpartum nutrient supplementation was associated with the increased serum folate level of lactating women. Dietary diversity was related to increased serum vitamin B12 and folate levels, especially among postpartum women with younger age and lower educational level.

Elevated serum vitamin B12 levels have emerged as a paradoxical prognostic marker associated with increased mortality across various clinical settings, yet their significance in hospitalized dementia patients remains unexplored. Given the high vulnerability of this population, we aimed to investigate the association between elevated serum vitamin B12 levels and all-cause mortality. This retrospective cohort study evaluated 90-day outcomes in hospitalized adults with dementia who had serum vitamin B12 levels measured within 7 days of admission (2010-2024). Patients were categorized into exposure (vitamin B12 ≥ 900 pg/mL) and control (300-900 pg/mL) groups. Propensity score matching balanced baseline characteristics, including demographics, comorbidities, and laboratory parameters. The primary endpoint was all-cause mortality within 90 days. Secondary endpoints comprised sepsis, pneumonia, urinary tract infection, and admission to the intensive care unit (ICU). Sensitivity analyses restricted the cohort to patients with unspecified dementia and to patients with a dementia diagnosis established at least 1 year before the index admission. After propensity score matching, 16,513 patients were included in each cohort. Elevated vitamin B12 was significantly associated with increased 90-day mortality (10.9% vs 8.3%; odds ratio [OR] 1.36, 95% confidence interval [CI] 1.26-1.46, P < .001), sepsis (4.2% vs 3.0%; OR 1.43, 95% CI 1.27-1.61, P < .001), pneumonia (8.3% vs 6.6%; OR 1.28, 95% CI 1.18-1.39, P < .001), and ICU admission (3.9% vs 3.0%; OR 1.31, 95% CI 1.16-1.47, P < .001). No association was observed with urinary tract infection (OR 0.97, 95% CI 0.90-1.04, P = .377). The findings remained robust across sensitivity and subgroup analyses. Elevated vitamin B12 levels are associated with increased short-term mortality, infectious complications, and ICU admission in hospitalized patients with dementia. This readily available biomarker may serve as a potential indicator for risk stratification in this vulnerable population. However, given the observational nature of this study, future prospective studies are warranted to confirm these findings and elucidate the underlying mechanisms.

Despite elevated serum vitamin B12 levels, functional (i.e., metabolically manifest) vitamin B12 deficiency has been reported in a significant proportion of MPN patients. This study aimed to assess the prevalence of functional vitamin B12 deficiency and elevated serum vitamin B12 levels among Indian MPN patients. This cross-sectional study evaluated serum vitamin B12, homocysteine, methyl malonic acid(MMA) and holotranscobalamin levels among 176 MPN patients. Serum vitamin B12 levels between 150 and 950 pg/mL were considered normal. Functional vitamin B12 deficiency was diagnosed based on combination of elevated serum MMA(> 0.4 nmol/mL) and homocysteine(> 15 µmol/L) levels and low serum holotranscobalamin levels(< 25 pmol/L), irrespective of serum vitamin B12 levels and clinical manifestations of deficiency. Among patients enrolled(n = 176), 108(61%) had chronic phase CML, 37(21%) PV, 23(13%) PMF and 8(4%) ET. Nearly one-third were newly diagnosed to have MPNs and treatment naïve. Elevated serum vitamin B12 levels(> 950pg/mL) were seen in about a quarter(n = 45) of MPN patients. Half(n = 89) were detected to have functional vitamin B12 deficiency. No association was found between functional vitamin B12 deficiency and serum vitamin B12 levels and functional deficiency prevalence did not differ significantly between different types of MPNs and between newly diagnosed (treatment-naïve) and already treated MPNs. About a quarter of MPN patients had elevated serum B12 levels and half had functional vitamin B12 deficiency. Functional deficiency was diagnosed independent of serum vitamin B12 levels. Hence, evaluation for functional deficiency should be carried out irrespective of serum vitamin B12 levels. Future studies should evaluate potential benefit of vitamin B12 replacement in MPN patients with functional vitamin B12 deficiency.

Elevated serum vitamin B12 levels have been associated with adverse outcomes in various clinical settings; however, the prognostic significance of pre-existing vitamin B12 elevation measured before sepsis onset remains unclear. This study examined the association between pre-sepsis vitamin B12 levels and clinical outcomes in adults with sepsis. This retrospective cohort study utilized the TriNetX database to identify adults diagnosed with sepsis between 2010 and 2024. Patients with elevated vitamin B12 levels (≥1,000 pg./mL) measured within 3 months before sepsis diagnosis were compared with those having normal levels (300-900 pg./mL) using 1:1 propensity score matching. The primary outcome was 90-day all-cause mortality. The secondary outcomes included major adverse cardiovascular events, organ failure, intensive care unit (ICU) admission, and progression to severe sepsis. After propensity score matching, 18,830 patients per group (37,660 patients in total) were included in this cohort. Elevated pre-sepsis vitamin B12 levels were associated with increased 90-day mortality [26.3% vs. 21.8%; hazard ratio (HR): 1.29, 95% confidence interval (CI): 1.24-1.35, p < 0.001] and progression to severe sepsis (17.3% vs. 15.3%; HR 1.18, 95% CI 1.12-1.24, p < 0.001). Organ failure (HR 1.09, p < 0.001) and ICU admission showed a marginal association (HR 1.05, p = 0.031), while major adverse cardiovascular events showed no significant association. During the 90-365-day follow-up period, the associations were attenuated (mortality: HR 1.07, 95% CI 0.99-1.15, p = 0.077). Dose-response analysis revealed stronger associations at vitamin B12 levels >1,200 pg./mL (HR 1.35 for mortality). Younger patients (18-65 years) exhibited more pronounced associations. Elevated pre-sepsis vitamin B12 levels are associated with increased short-term mortality and adverse outcomes in patients with sepsis, suggesting that elevated pre-sepsis vitamin B12 levels may serve as a risk-associated biomarker, although its independent prognostic utility requires further validation.

Vitamin B12 deficiency is classically associated with anemia and neurological dysfunction. However, recent studies suggest that elevated plasma vitamin B12 may indicate increased short-term cancer risk. This association remains largely unexplored in Middle Eastern populations, including Jordan, where cancer rates are rising and diagnosis often occurs at advanced stages due to limited screening. This study is aimed at investigating the association between serum vitamin B12 levels and the risk of colorectal, breast, and lung cancers in a Jordanian population, evaluating differences by cancer type and stage. A retrospective case-control study was conducted at King Abdullah University Hospital, Jordan, from January 2018 to December 2022. The study enrolled 260 patients diagnosed with colorectal, breast, or lung cancer and 260 matched healthy controls. Data collected included sociodemographic factors, clinical characteristics, and serum vitamin B12 levels. Serum vitamin B12 levels were significantly higher in cancer patients compared with controls (579.23 ± 468.72 vs. 492.70 ± 174.36 pg/mL; p = 0.005). High vitamin B12 levels (> 800 pg/mL) occurred in 15.8% of cancer patients versus 1.5% of controls (p < 0.001). Vitamin B12 levels varied significantly by cancer type, being highest in lung cancer patients (669.53 ± 566.59 pg/mL) compared with breast (594.86 ± 468.9 pg/mL) and colorectal cancer patients (439.62 ± 291.89 pg/mL; p = 0.024). There was a strong positive correlation between vitamin B12 levels and cancer stage, peaking in Stage IV cancers, r = 0.629, p = 0.001. Elevated serum vitamin B12 levels are significantly associated with solid cancers in Jordanian patients, particularly pronounced in lung cancer and advanced stages. These findings do not imply a causal relationship, but rather suggest that serum vitamin B12 may function as a potential biomarker for cancer detection and disease monitoring in resource-limited settings.

The prognostic value of vitamin B12 blood levels remains controversial. An association between elevated vitamin B12 and mortality has been reported, particularly among elderly patients with cancers and liver or blood diseases. The present study explored the relationship between mortality and elevated vitamin B12 levels in a population of unscheduled inpatients in an internal medicine unit. This retrospective observational analysis was conducted between August 2014 and December 2018. We compared 165 patients with elevated plasma vitamin B12 levels (>600 pmol/l) with a random sample of 165 patients with normal B12 levels who were hospitalized during the same period. Demographic, clinical, and biological characteristics were assessed during hospitalization. The primary endpoint was all-cause death at 1 year. Patients with elevated B12 were younger, with a lower body mass index and lower plasma albumin than those with normal B12 (75 ± 16 years vs 79 ± 13 years, p = 0.047; 23 ± 5 vs 26 ± 7 kg/m2, p < 0.001; and 33 ± 5 vs 35 ± 5 g/l, p < 0.001, respectively). The prevalence of auto-immune disease and referral from an intensive care unit was higher among patients with elevated B12 (11% vs 5%, p = 0.043 and 36% vs 10%, p < 0.001, respectively). After 1 year of follow-up, 64 (39%) patients with elevated B12 had died compared to 43 (26%) patients with normal B12 (p = 0.018). Multivariate analysis using the Cox proportional hazards regression model adjusted for age, gender, body mass index, intensive care unit hospitalization, albumin level, and the presence of solid cancer or autoimmune disease revealed elevated B12 to be associated with a significant risk of death in the first year of follow-up (hazard ratio: 1.71 [1.08-2.7], p = 0.022). Elevated B12 is an early warning indicator of increased short-term mortality, such as independently of age, cancer, or comorbidities, in patients hospitalized in an internal medicine department.

The previous studies have suggested that serum homocysteine (Hcy) and vitamin B levels are potentially related to autism spectrum disorder (ASD). However, the causality between their concentrations and ASD risk remains unclear. To elucidate this genetic association, we used a Mendelian randomization (MR) design. For this MR analysis, 47 single-nucleotide polymorphisms (SNPs)-13 related to Hcy, 13 to folate, 14 to vitamin B6, and 7 to vitamin B12-were obtained from a large-scale Genome-Wide Association Studies (GWAS) database and employed as instrumental variables (IVs). Our study used three approaches to calculate the MR estimates, including inverse-variance weighted (IVW) method, MR-Egger method, and weighted median (WM) method. Among these, the IVW method served as our primary MR method. False discovery rate (FDR) was implemented to correct for multiple comparisons. We also performed a series of sensitivity analyses, including Cochran's Q test, MR-Egger's intercept, MR-PRESSO, leave-one-out analysis, and the funnel plot. Univariable Mendelian randomization (UVMR) analysis revealed a statistical association between serum vitamin B12 levels and ASD risk (OR = 1.68, 95% CI 1.12-2.52, P = 0.01) using the IVW method. However, neither the WM method (OR = 1.57, 95% CI 0.93-2.66, P = 0.09) nor the MR-Egger method (OR = 2.33, 95% CI 0.48-11.19, P = 0.34) was significantly association with higher levels of serum vitamin B12 and ASD risk. Additionally, we found no evidence of causal relationships between serum levels of vitamin B6, folate, Hcy, and ASD risk. After correcting for the FDR, the causality between serum vitamin B12 levels and ASD risk remained significant (q value = 0.0270). Multivariate Mendelian randomization (MVMR) analysis indicated an independent association between elevated serum vitamin B12 levels and the risk of ASD (OR = 1.74, 95% CI 1.03-2.95, P = 0.03) using the IVW method, but this finding was inconsistent when using the WM method (OR = 1.73, 95% CI 0.89-3.36, P = 0.11) and MR-Egger method (OR = 1.60, 95% CI 0.95-2.71, P = 0.08). Furthermore, no causal associations were observed for serum levels of vitamin B6 and folate in MVMR analysis. Sensitivity analyses confirmed that these results were reliable. Our study indicated that elevated serum vitamin B12 levels might increase the risk of ASD. The potential implications of our results for ASD risk warrant validation in randomized clinical trials.

Clinical Relevance of MTHFR, eNOS, ACE, and ApoE Gene Polymorphisms and Serum Vitamin Profile among Malay Patients with Ischemic Stroke

Title: Association of blood levels of homocysteine, vitamin B12, and serum cholesterol with age related macular degeneration in the elderly population of India.Aim: To determine any association of Age related macular degeneration (ARMD) with blood levels of homocysteine, vitamin B12, and serum cholesterol. Methods: The levels of homocysteine, vitamin B12, and serum cholesterol in patients who were diagnosed with Age related macular degeneration (ARMD) in either eye (n=109) were compared to a control group with no retinal pathology (n=134). Diabetic patients were excluded from the study.Results: Raised serum cholesterol levels were more common in ARMD cases (47.5%) compared to controls (28.4%). This association was found to be statistically significant (p<0.01). Levels of serum homocysteine were higher in the ARMD group than in the control group whereas serum vitamin B12 levels were lower in the ARMD group than in the control group but was not statistically significant (p=0.68 and p=0.51).Serum homocysteine level was significantly higher in males compared to females in both case and controls (p<0.01).Conclusion: Raised serum cholesterol levels were significantly associated with increased risk of age related macular degeneration.Our study did not find elevated serum homocysteine or low serum vitamin B12 as significantly associated with age related macular degeneration.

The efficacies of four methods, used for the prophylaxis of cobalt deficiency in sheep as measured by the elevation of liver and serum vitamin B12 levels, were compared in marginally deficient sheep over 14 weeks. The methods used were weekly drenches of either cobalt sulphate or cobalt chelate (EDTA) three-weekly injections of hydroxocobalamin, and ruminal cobalt pellets. On the basis of elevated liver and serum vitamin B12 levels, chelated cobalt was shown to be available to rumen microflora for the synthesis of vitamin B12. However, at no stage were liver and serum vitamin B12 levels of sheep receiving the chelate significantly different from those receiving the same amount of cobalt as the sulphate. After five, three-weekly injections of hydroxocabalamin liver vitamin B12 levels were significantly higher (p<0.01) than for the other treatments, with the exception of cobalt sulphate. Cobalt pellets led to an initial rapid and significant rise in serum vitamin B12 when compared with the other treatments. However, at four weeks there was no significant difference between treatment groups for serum vitamin B12. Fourteen weeks after the administration of cobalt pellets, serum and liver.vitamin B12 levels in this group were not significantly different from those of untreated sheep. At this time, three out of 12 sheep had lost their pellets.

Does an Elevated Serum Vitamin B12 Level Mask Actual Vitamin B12 Deficiency in Myeloproliferative Disorders?

Summary. Chronic myeloid leukaemia (CML) and pernicious anaemia (PA) coexisted in a 51‐yr‐old man (who also had myasthenia gravis). His serum vitamin B12 level was normal instead of the high value expected in CML, or the low value expected in PA. Short‐term culture of his peripheral blood cells showed deranged DNA synthesis of the type observed in vitamin B12 deficiency, indicating that his ‘normal’ serum vitamin B12 level was not associated with normal amounts of vitamin B12 available to his CML cells. A tracer dose of 0.45 μg of[57 Co]vitamin B12 disappeared abnormally slowly from his serum over 24 hr (as previously observed by others in patients with either CML or PA). A therapeutic injection of vitamin B12 appeared to disappear abnormally slowly from his serum over a period of 2 yr. His serum showed a markedly elevated unsaturated vitamin B12 binding capacity, with a less sharp increase in percentage of vitamin B12 binding α as compared to β globulin than usually expected in CML.Withholding therapeutic vitamin B12 for 2 yr has been associated with stabilization of his WBC at the 40 000‐50 ooo/μl range. Although this association could be chance rather than cause and effect, the patient does represent an ‘experiment of nature’ involving vitamin B12 metabolism and does raise the question as to whether his leukaemia is retarded by his deficiency of vitamin B12, which results from inadequate absorption of vitamin B12 and possibly from elevated serum vitamin B12 binding a globulin rendering his circulating vitamin B12 metabolically inert.

An 86-year-old male patient developed paresthesia in both hands, and six months later, pancytopenia was noted. He was diagnosed with myelodysplastic syndrome following bone marrow aspiration. Despite high serum vitamin B12 level, elevated level of serum homocysteine, positive anti-intrinsic factor antibody, and T2-weighted hyperintense lesions on spinal cord MRI led to a diagnosis of subacute combined degeneration of the spinal cord. Treatment with intramuscular mecobalamin injections improved the pancytopenia and resolved the MRI lesions. The pancytopenia in this patient was considered to be caused by pernicious anemia. The presence of anti-intrinsic factor antibody can cause falsely normal or elevated serum vitamin B12 levels. When patients with pancytopenia report numbness, even without a decrease in serum vitamin B12 levels, pernicious anemia and subacute combined degeneration of the spinal cord should be suspected, and measurements of serum homocysteine and anti-intrinsic factor antibodies should be considered.