Serum Methylmalonic Acid Levels Research Articles

The association between serum methylmalonic acid, cobalamin-related biomarkers, and long-term mortality risk in cancer survivors: a prospective cohort study

BackgroundElevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown. ObjectivesTo explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors. MethodsWe analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas. ResultsAmong 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types. ConclusionsSerum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.

Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5years of follow-up. Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.

Increased serum methylmalonic acid levels were associated with the presence of cognitive dysfunction in older chronic kidney disease patients with albuminuria

BackgroundThis study aimed to evaluate the correlation between serum methylmalonic acid (MMA) levels and cognition function in patients with chronic kidney disease (CKD).MethodsIn this cross-sectional study, we included 537 CKD individuals aged ≥ 60-year-old with albuminuria from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. Four cognitive tests including the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Delayed Recall and Word Learning tests, and the Animal Fluency test (AF) were performed. Associations between MMA and cognition scores were assessed with linear regression models.ResultsMMA level was negatively associated with residual renal function and nutrition status. After multivariate adjustment, elevated serum MMA levels were independently correlated with decline of cognition in CKD patients with albuminuria.ConclusionOur study showed that higher serum MMA levels were independently associated with the presence of cognition dysfunction in CKD patients. The exact pathogenesis of MMA and cognition needs further research.

The association between methylmalonic acid, a biomarker of mitochondrial dysfunction, and risk of prostate cancer.

The aim of the study was to investigate the association between methylmalonic acid (MMA), a biomarker of mitochondrial dysfunction, and the risk of prostate cancer (PCa). The relevant data were collected from the National Health and Nutrition Examination Survey (NHANES). Weighted univariable and multivariable logistic regression analyses were performed to investigate the association between MMA and risk of PCa. A stratified analysis was also carried out. The dose-response relationship was elucidated by conducting a restricted cubic spline function. A total of 2451 participants were included, of which 95 were PCa participants. The fully-adjusted model 2 constructed by weighted multivariable logistic regression analysis showed that the risk of PCa decreased by 53% when every MMA unit was added [OR: 0.47 (0.22-1.00), P = 0.049]. And a decrease in PCa risk was associated with a higher MMA level in MMA subgroups [OR: 0.34 (0.15-0.82), P = 0.02]. The results from a stratified analysis showed that participants in subgroups of other race, BMI (> 30kg/m2), smoking (former and now), and hypertension (yes), an increase in every MMA unit was linked to a decrease in PCa risk. MMA and the risk of PCa were negatively correlated in a linear manner. It was discovered in the study that an increase in MMA level is connected to a decrease in PCa risk. The serum MMA level may be helpful in assessing PCa risk.

Association between Methylmalonic Acid and Abdominal Aortic Calcification in Adults: A Cross-Sectional Study

Objective: Methylmalonic acid (MMA) buildup has recently been suggested to contribute to the onset of both age-related conditions and cardiovascular disorders. This research was aimed at examining the link between MMA and abdominal aortic calcification (AAC). Methods: Data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) were analyzed. Serum MMA levels were determined through LC-MS/MS, and MMA levels 250 nmol/L or above were considered high. Dual-energy X-ray absorptiometry was used to assess the presence of AAC. Logistic regression analysis was performed after propensity score matching (PSM) to study the relationship between MMA and AAC. Results: A total of 2483 participants were involved in this study. To eliminate large differences between the AAC and non-AAC groups, 1:1 PSM was performed. Logistic regression analysis indicated that participants with high MMA levels had a significantly greater likelihood of experiencing AAC than those with low MMA levels (OR: 1.38, 95% CI: 1.01–1.90, P = 0.046). No statistically interaction effects between AAC and BMI or the estimated glomerular filtration rate (eGFR) were observed in subgroup analyses. Conclusion: Our study indicated a significant association between high serum MMA levels and AAC incidence.

Association between serum methylmalonic acid and chronic kidney disease in adults: a cross-sectional study from NHANES 2013-2014.

Chronic kidney disease(CKD) is a global medical problem. Serum methylmalonic acid(MMA) is a serum marker associated with many diseases. This study aimed to investigate the association between MMA and CKD. Data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 were downloaded and analyzed. The association between MMA and CKD was confirmed by using multiple logistic regression modeling. The smooth curve fitting method was used to investigate the nonlinear relationship between them. Subgroup analyses and interaction tests were used to verify the stability of the association between different subgroups. Threshold effect analysis was used to determine the optimal control point for MMA. There was a unique W-shaped nonlinear relationship between MMA and the risk of CKD, with a positive correlation between them (OR=1.66,95% CI:1.27, 2.17; P=0.0002). As the stage of CKD progressed, MMA levels increased. Age, hypertension, and serum vitamin B12 had significant influences on the association between MMA and the risk of CKD. Our findings revealed that serum MMA accumulation was positively associated with the risk of CKD. Serum MMA level may be a novel index to predict the development and course of CKD. This study may help in the early identification of people at risk for chronic kidney disease and provide new ideas and approaches for prevention and treatment.

Electrophysiological profile of serum vitamin B12 levels, correlation with serum methylmalonic acid levels, and determination of subclinical peripheral nerve involvement

Background/Aim: Vitamin B12 is essential for normal neural conduction in peripheral nerves. This study aimed to investigate the electrophysiological profile for varying degrees of serum B12 levels and to determine whether a correlation existed between electrophysiological profiles and serum methylmalonic acid (MMA) levels. Also, determination of subclinical peripheral nerve involvement with cold administration was planned in serum B12 levels. Methods: A total of 101 (63 females, 38 males) subjects with known serum vitamin B12 levels were selected randomly from the neurology outpatient clinic for this study. The subjects were divided into three groups based on the serum total Vitamin B12 levels: (1) B12 deficiency (&lt;126 pg/mL), (2) low B12 (126-250 pg/mL), and (3) normal B12 (250–500 pg/mL). Serum MMA and nerve conduction studies (NCS) were assessed and compared between the three groups. After the cooling procedure was applied to the ulnar and sural nerves, NCS was repeated. Results: There were 13 subjects in the B12 deficiency group, 44 subjects in the low B12 group, and 44 subjects in the normal group. We found that ulnar sensory nerve action potential amplitudes were significantly decreased (P = 0.009), ulnar F latency (P = 0.003; P &lt; 0.001)) was prolonged, and peroneal combined muscle action potential amplitudes decreased (P = 0.026) in the B12 deficiency when compared with the low and normal B12 groups. Sural nerve amplitude and conduction velocities were found to be significantly abnormal after the cold application in all groups (P &lt; 0.001). The increase in sural nerve sensory nerve amplitude potentials (SNAP) amplitudes was higher in the B12 deficiency group than in the other groups. Mean serum MMA levels were high in all groups. A correlation of nerve conduction study (NCS) changes with serum vitamin B12 and MMA was not observed in the groups after cold application. Conclusion: Vitamin B12 deficiency may cause subclinical sensorial and motor axonal nerve conduction changes. Nerve conduction changes may not always reach pathological values based on electrophysiological studies but may be detected after cooling administration even in the normal serum B12 levels. A correlation between serum MMA and vitamin B12 levels was found. Therefore, serum levels of vitamin B12, which is important for nerve conduction, should be carefully evaluated in clinical practice.

Correlations between circulating methylmalonic acid levels and all-cause and cause-specific mortality among patients with diabetes.

Evidence regarding serum methylmalonic acid (MMA) levels and mortality in individuals with diabetes is limited. This study aimed to evaluate the correlation between MMA and all-cause and cause-specific deaths in patients with diabetes. This is a population-based cohort study based on data from both the National Health and Nutrition Examination Survey (NHANES) and National Death Index from 1999 to 2014. We assessed the association of serum MMA concentrations with mortality using Cox proportional hazard models after adjusting for lifestyle, demographic factors, and comorbidities. Among the 3,097 participants, 843 mortalities occurred during a median follow-up of 4.42 years. There were 242 deaths due to cardiovascular disease (CVD) and 131 cancer-associated deaths. After multivariate adjustment, elevated serum MMA levels were markedly correlated with a high risk of all-cause, CVD-, and cancer-related deaths. Each one-unit increase in the natural log-transformed MMA level correlated with increased risk of all-cause mortality (2.652 times), CVD mortality risk (3.153 times), and cancer-related mortality risk (4.514). Hazard ratios (95% confidence intervals [CIs]) after comparing participants with MMA < 120 and ≥250 nmol/L were 2.177 (1.421-3.336) for all-cause mortality, 3.560 (1.809-7.004) for CVD mortality, and 4.244 (1.537-11.721) for cancer mortality. Higher serum MMA levels were significantly associated with higher all-cause, CVD, and cancer mortality. These findings suggest that maintaining lower MMA status may lower mortality risk in individuals with diabetes.

Increased serum methylmalonic acid levels were associated with the presence of cardiovascular diseases.

BackgroundFunctional vitamin B12 deficiency is common in cardiovascular diseases (CVDs), such as heart failure and myocardial infarction. Methylmalonic acid (MMA) is a specific and sensitive marker of vitamin B12 deficiency. However, there are scarce data in regard to the relationship between MMA and CVDs.Materials and methodsIn this cross-sectional study, we analyzed data of 5,313 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2013–2014. Associations between MMA and other variables were assessed with linear regression models. Univariable and multivariable logistic regression models were employed to explore the association between MMA and CVDs.ResultsThe weighted prevalence of CVDs was 8.8% in the general population of the USA. Higher MMA levels were found in participants with CVDs (p < 0.001). Linear regression models revealed positive associations between serum MMA level and age (p < 0.001), glycohemoglobin (p = 0.023), fasting glucose (p = 0.044), mean cell volume (p = 0.038), and hypertension (p = 0.003). In the multivariable logistic model adjusting for age, gender, ethnicity, smoking, hypertension, glycohemoglobin, body mass index (BMI), low-density lipoprotein-cholesterol (LDL-C), renal dysfunction and vitamin B12, serum MMA (adjusted odds ratio, 3.08; 95% confidence interval: 1.63–5.81, p = 0.002, per ln nmol/L increment) was associated with CVDs.ConclusionOur study demonstrated that elevated serum MMA levels were independently associated with the presence of CVDs and may be used to predict the occurrence of CVDs.

Deprescribing: What About Vitamins, Minerals, and Other Nutritional Supplements?

Deprescribing: What About Vitamins, Minerals, and Other Nutritional Supplements?

Measurement of Vitamin B12 and Serum Methylmalonic Acid Levels: Role of Stepwise Cascade Testing in Diagnosing Vitamin B12 Deficiency

Abstract Introduction Varied presentations of vitamin B12 (B12) deficiency include hematologic (megaloblastic anemia) and neurologic (myelopathy, peripheral neuropathy). Delayed recognition and treatment may have serious consequences. Assessing B12 status can be challenging due to diverse laboratory assays and thresholds, resulting in a wide range of reported prevalence of B12 deficiency from 3-26%. Comorbidities may also spuriously elevate or suppress B12 levels. Methylmalonic acid (MMA) level, often used as a companion test to assess for B12 deficiency, may also be affected by differing laboratory thresholds and other medical comorbidities, such as renal dysfunction. Our institutional approach to B12 assessment, termed the pernicious anemia (PA) cascade, consists of reflexive testing to 1) document low B12 stores (B12 levels with or without MMA), and 2) diagnose pernicious anemia (intrinsic factor binding antibody [IFBA] with or without gastrin assay). In this study, our objectives were: (1) assess the usefulness of our B12 testing algorithm and associated laboratory thresholds for identifying B12 deficiency, and (2) evaluate clinical follow-up of test results as part of a quality project. Methods In this retrospective study, adult (age ≥18 years) inpatients who had B12 testing from 2007 to 2013 were identified. Medical records for those patients with B12 levels 150-400 ng/L were reviewed. Data abstracted included patient demographics, indication for B12 testing, B12 levels, results for MMA, IFBA, gastrin, serum creatinine, complete blood count, and clinical outpatient follow-up. The PA cascade algorithm is as follows: 1) for B12 &lt;150 ng/L, IFBA is performed; 2) if IFBA is negative or indeterminate, then gastrin is performed; 3) for B12 150-400 ng/L, MMA is performed; 4) if MMA is &gt;0.40 nmol/mL, then IFBA is performed. Reference range for B12 is 180-914 ng/L. Patients were determined to be B12 deficient if B12 level was &lt;180 ng/L, or if B12 was 150-400 ng/L with elevated MMA and macrocytosis in the absence of significant renal dysfunction, defined as serum creatinine ≥2.0 mg/dL. Results Records of 326 patients (150 female) were reviewed. Indications for B12 testing were: hematologic, 175 patients (53.7%); neurologic, 127 patients (39.0 %), psychiatric, 18 patients (5.5%); other, 4 patients (1.2%). Fifty-nine of 326 (18.1%) patients were B12 deficient, of whom 17 of 59 (28.8%) had PA. There were 54 cases of elevated MMA, &gt;0.40 nmol/mL, of which 30 cases had mildly elevated MMA, &gt;0.40 nmol/mL and ≤0.60 nmol/mL, considered to be the MMA "gray zone". Thirty-two of the total 326 patients had serum creatinine ≥2.0 mg/dL, of which 23 patients also had elevated MMA. Elevated MMA in 13 of these 23 patients was more likely due to renal dysfunction than to B12 deficiency. B12 testing results were not mentioned in hospital discharge summaries for 173 patients, including 8 patients with B12 deficiency. For 22 B12-deficient patients, there was no documentation of B12 replacement. Conclusions The PA cascade detected B12 deficiency in a significant number of inpatients with low-normal B12 levels that might have otherwise been missed; 28.8% of this group had PA for whom long-term B12 replacement is indicated. As treatment for B12 deficiency is inexpensive, non-toxic, and non-invasive, it is reasonable to evaluate B12 status by cascade testing which may provide additional diagnostic data beyond B12 level. Notable clinical practice findings from this study include the lack of B12 results in 173 of 326 discharge summaries, and no record of B12 supplementation in 22 of 59 patients with B12 deficiency. These gaps in documentation and follow-up may be associated with the relatively long turnaround time of MMA testing. Efforts at improving documentation, communication, and treatment of B12 deficiency are ongoing. Disclosures No relevant conflicts of interest to declare.

Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.

Vitamin B12 deficiency is common, and the incidence increases with age. Most people with vitamin B12 deficiency are treated in primary care with intramuscular (IM) vitamin B12. Doctors may not be prescribing oral vitamin B12 formulations because they may be unaware of this option or have concerns regarding its effectiveness. To assess the effects of oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. We searched CENTRAL, MEDLINE, Embase, and LILACS, as well as the WHO ICTRP and ClinicalTrials.gov. The latest search date was 17 July 2017. We applied no language restrictions. We also contacted authors of relevant trials to enquire about other published or unpublished studies and ongoing trials. Randomised controlled trials (RCTs) comparing the effect of oral versus IM vitamin B12 for vitamin B12 deficiency. We used standard methodological procedures expected by Cochrane. Our primary outcomes were serum vitamin B12 levels, clinical signs and symptoms of vitamin B12 deficiency, and adverse events. Secondary outcomes were health-related quality of life, acceptability to patients, haemoglobin and mean corpuscular volume, total homocysteine and serum methylmalonic acid levels, and socioeconomic effects. We used GRADE to assess the quality of the evidence for important outcomes. We did not perform meta-analyses due to the small number of included trials and substantial clinical heterogeneity. Three RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to IM vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 38.6 to 72 years. The treatment frequency and daily dose of vitamin B12 in the oral and IM groups varied among trials. Only one trial had low or unclear risk of bias across all domains and outcome measures. Two trials reported data for serum vitamin B12 levels. The overall quality of evidence for this outcome was low due to serious imprecision (low number of trials and participants). In two trials employing 1000 μg/day oral vitamin B12, there was no clinically relevant difference in vitamin B12 levels when compared with IM vitamin B12. One trial used 2000 μg/day vitamin B12 and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B12. Two trials reported data on adverse events (very low-quality evidence due to risk of performance bias, detection bias, and serious imprecision). One trial stated that no treatment-related adverse events were seen in both the oral and IM vitamin B12 groups. One trial reported that 2 of 30 participants (6.7%) in the oral vitamin B12 group left the trial early due to adverse events. Orally taken vitamin B12 showed lower treatment-associated costs than IM vitamin B12 in one trial (low-quality evidence due to serious imprecision). No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health-related quality of life, or acceptability of the treatment scheme. Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low-quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related-quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting.

Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B₁₂ Deficiency.

Since vitamin B12 occurs in substantial amounts only in foods derived from animals, vegetarians and particularly vegans are at risk of developing deficiencies of this essential vitamin. The chlorella used for this study is a commercially available whole-food supplement, which is believed to contain the physiologically active form of the vitamin. This exploratory open-label study was performed to determine if adding 9 g of Chlorella pyrenoidosa daily could help mitigate a vitamin B12 deficiency in vegetarians and vegans. Seventeen vegan or vegetarian adults (26-57 years of age) with a known vitamin B12 deficiency, as evidenced by a baseline serum methylmalonic acid (MMA) level above 270 nmol/L at screening, but who otherwise appeared healthy were enrolled in the study. Each participant added 9 g of C. pyrenoidosa to their daily diet for 60 ± 5 days and their serum MMA, vitamin B12, homocysteine (Hcy) levels as well as mean corpuscular volume (MCV), hemoglobin (Hgb), and hematocrit (Hct) were measured at 30 and 60 days from baseline. After 30 and 60 days, the serum MMA level fell significantly (P < .05) by an average ∼34%. Fifteen of the 17 (88%) subjects showed at least a 10% drop in MMA. At the same time, Hcy trended downward and serum vitamin B12 trended upward, while MCV, Hgb, and Hct appeared unchanged. The results of this work suggest that the vitamin B12 in chlorella is bioavailable and such dietary supplementation is a natural way for vegetarians and vegans to get the vitamin B12 they need.

Diagnosis of Vitamin B12 Deficiency in Patients With Myeloproliferative Disorders

BackgroundMyeloproliferative disorders are characterized by proliferation of 1 or more lineage of hematologic cells. Rapid proliferation of cells may lead to depletion of vitamin B12, which may be falsely elevated...

Asymptomatic methylmalonic acidemia in a homozygous MUT mutation (p.P86L)

Deficiency in methylmalonyl-coenzyme A mutase (MCM) is associated with accumulation of methylmalonic acid (MMA) and clinical outcomes that include early death and neurological impairment. Reported here are two unrelated patients with a homozygous p.P86L mutation in the MUT gene, which encodes MCM, diagnosed following newborn screening. This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. Both in vitro and in vivo testing did not find a response to supplemental hydroxocobalamin. After discontinuation of hydroxocobalamin in one patient, serum MMA level remained elevated but stable, while urine MMA increased. Both patients have remained asymptomatic with normal development. The observed homozygous p.P86L mutation in the N-terminal extended segment may yield reduced MCM activity and is refractory to hydroxocobalamin supplementation, while not inducing a metabolically unstable phenotype. These genotype-phenotype associations further enhance the understanding of methylmalonic acidemia, which will continue to improve patient care.

Laboratory Evaluation for Vitamin B12 Deficiency: The Case for Cascade Testing

Potential vitamin B(12) deficiency is a common clinical diagnostic problem, and many providers have a low threshold for initiating therapy. The goal of this study was to systematically evaluate current practice patterns regarding the laboratory evaluation of suspected vitamin B(12) deficiency. This retrospective study reviewed the electronic medical records of 192 patients initiated on intramuscular vitamin B(12) injections. Only 12 patients had objectively documented hematologic responses: decrease of mean corpuscular volume by ≥5 fL with stable or improved hemoglobin. Another 5 patients had equivocal hematologic responses. There was one plausible neurologic response. Thus, only 18 (9.4%) of 192 patients had data supportive of a clinical response. In these 18 patients, the baseline serum B(12) level was ≤107 pg/mL; only 3 patients also had a baseline serum methylmalonic acid level, which was ≥1.29 μmol/L in all 3 patients. Currently, only a small minority of patients initiated on intramuscular vitamin B(12) supplementation derive any meaningful clinical benefit. Furthermore, current testing recommendations for vitamin B(12) deficiency are usually not followed. Up-front ordering of a diagnostic testing cascade is recommended to improve compliance; an example is presented with decision points chosen to improve specificity for clinically evident vitamin B(12) deficiency without loss of sensitivity. Ultimately, a better understanding of vitamin B(12) physiology is needed to develop and evaluate laboratory tests that more accurately reflect true intracellular vitamin B(12) status.

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

Elevation of the methylmalonic acid level is a sensitive marker of vitamin B(12) deficiency. Our cross-sectional observational study of 33 patients with myeloproliferative disorders found that 9 patients, 27.27% had occult deficiency despite having normal to elevated serum vitamin B(12) levels. Early detection of vitamin B(12) deficiency by using the methylmalonic acid measurement may prevent significant neurologic and hematologic complications in patients with myeloproliferative disorders. In patients with myeloproliferative disorders, normal to high serum vitamin B(12) concentrations have often been reported. The primary objective of this study was to determine whether normal or elevated serum vitamin B(12) levels in myeloproliferative disorders might actually mask the true underlying vitamin B(12) deficiency in some patients. Thirty-three patients (12 men, 21 women; mean age, 70.55 years [range, 37-90 years]) with polycythemia vera (n = 13), essential thrombocythemia (n = 12), chronic myelogenous leukemia (n = 5), and idiopathic myelofibrosis (IMF) (n = 3) were accrued over a period of 1 year, from March 2009 to February 2010. From all of the subjects, serum vitamin B(12) level, methylmalonic acid level, a basic complete blood cell count panel, and liver and renal function tests were obtained. Normal to elevated serum vitamin B(12) levels were recorded in all the patients. However, elevated serum methylmalonic acid levels were found in 9 (27.27%) patients, with a prevalence of 2 patients with polycythemia vera, 23% in polycythemia vera, 4 patients with essential thrombocythemia, 33.3% in essential thrombocythemia, 1 patient with chronic myelogenous leukemia, 20% in chronic myelogenous leukemia, and 2 patients with idiopathic myelofibrosis, 66.7% in IMF. Our data suggest that 27.27% of the total enrolled patients had occult vitamin B(12) deficiency despite normal to elevated vitamin B(12) levels on regular serum vitamin B(12) testing.

Comparing the Efficacy and Tolerability of a New Daily Oral Vitamin B 12 Formulation and Intermittent Intramuscular Vitamin B 12 in Normalizing Low Cobalamin Levels: A Randomized, Open-Label, Parallel-Group Study

Background Vitamin B 12 deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B 12. Oral vitamin B 12 formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. Objective The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B 12 formulation (oral B 12) with intramuscular (IM) vitamin B 12 (IM B 12) in restoring normal serum B 12 concentrations in patients with low cobalamin levels (<350 pg/mL). Methods Patients were recruited from 5 centers and randomly assigned to receive oral B 12 1000 μg, taken daily for 90 days, or IM B 12 1000 μg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged ≥60 years or aged ≥18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (≥350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B 12 levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B 12) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. Results Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B 12 group and 26 patients [100%] in the IM B 12 group). All patients (100%) in both treatment groups and in both populations had a cobalamin level ≥350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance ( P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 ( P = 0.033), with lower values in the oral B 12 group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels ≥40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. Conclusions In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B 12 (1000 μg/d) or IM B 12 (1000 μg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831.

Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial

BackgroundEvidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo.MethodsThis multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland), parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26) or placebo (N = 24) for four weeks. The institution's pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA) levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland). Trial registration: ISRCTN 22063938.ResultsBaseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26) lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19) more than the change observed in the placebo group (N = 23). The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4). A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months), significant differences in MMA levels were no longer detected.ConclusionsOral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency. However, a one-month daily treatment with1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months, and treatment had no effect on haematological signs of B12 deficiency.

Subclinical vitamin B12 deficiency in pregnant women attending an antenatal clinic in Nigeria

SummaryInadequate vitamin B12 status in a pregnant woman increases the risk for adverse maternal and fetal outcomes. The use of serum vitamin B12 concentration alone to assess vitamin B12 status in pregnant women is unreliable because of the decrease in serum vitamin B12 levels in normal pregnancy. The combination of serum vitamin B12 and methylmalonic acid (MMA) concentrations may provide a better estimate of vitamin B12 status. We obtained blood samples from 98 pregnant women in the third trimester at an antenatal clinic in Jos, Nigeria. All subjects were taking iron and folate supplements. Twelve of the subjects had a serum vitamin B12 concentration <148 pmol/l and 18 subjects had a serum MMA level >271 nmol/l. Using a combination of low serum vitamin B12 and elevated MMA concentrations, eight subjects were classified as having subclinical vitamin B12 deficiency. Because of the potential harmful consequences of vitamin B12 deficiency in pregnant women, it would be advisable to add vitamin B12 supplements to the existing regimen of folate and iron supplements currently provided to pregnant women in Nigeria.