Megaloblastic anemia due to hereditary intrinsic factor deficiency presenting as recurrent anemia in a young girl-a case report.

BackgroundHereditary intrinsic factor deficiency is a rare disease characterized by cobalamin deficiency with the lack of gastric intrinsic factor because of gastric intrinsic factor (GIF) mutations. Patients usually present with cobalamin deficiency without gastroscopy abnormality and intrinsic factor antibodies.Case presentationA Chinese patient presented with recurrent severe anemia since age 2 with low cobalamin level and a mild elevation of indirect bilirubin. The hemoglobin level normalized each time after intramuscular vitamin B12 injection. Gene test verified a c.776delA frame shift mutation in exon 6 combined with c.585C > A nonsense early termination mutation in exon 5 of GIF which result in the dysfunction of gastric intrinsic factor protein. The hereditary intrinsic factor deficiency in literature was further reviewed and the ancestry of different mutation sites were discussed.ConclusionsA novel compound heterozygous mutation of GIF in a Chinese patient of hereditary intrinsic factor deficiency was reported. It was the first identified mutation of GIF in East-Asia and may indicate a new ancestry.

Comparison between Weekly Intravenous Versus Daily Oral Vitamin B12 Supplementation in Vitamin B12 Deficiency Anemia [Courage-12]: A Randomized, Open Label, Single Centre Study

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 We also contacted authors of relevant trials to enquire about other published or unpublished studies and ongoing trials.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.

Folate, vitamin B12, and homocysteine (HCY) are involved in the metabolism of nucleic acid precursors and it has been hypothesized that they also influence telomere length, a biomarker of aging. However, previous studies have reported inconsistent findings, and data for older adults are limited. Our study aimed to evaluate associations between leukocyte telomere length (LTL) and serum folate, vitamin B12, and HCY levels among adults aged 55 years and over. In a cross-sectional study in 798 men and women aged 55-79 years, serum folate, vitamin B12, and HCY levels were measured using chemiluminescent immunometric assays, and relative LTL was assessed using quantitative real-time polymerase chain reaction. To evaluate associations between LTL and serum folate, vitamin B12, and HCY levels, multiple linear regression models were used. In multiple models adjusted for age, sex, serum high sensitive C-reactive protein (hs-CRP) levels, and other potential confounding factors, we found no association between LTL and serum folate, vitamin B12, and HCY levels. However, we did find a significant inverse association between HCY levels and LTL in participants with serum hs-CRP levels of ≥ 2 mg/L (p < 0.05). Moreover, there was a trend toward an association between HCY and vitamin B12 levels in these individuals (p = 0.08). In those with serum hs-CRP levels of < 2 mg/L, HCY was inversely associated with vitamin B12 levels (p < 0.001) and had no association with LTL. Our findings suggest that increased serum HCY levels, when combined with the presence of systemic inflammation, may play a role in accelerating biological aging.

Adequate vitamin B12 levels in infancy are crucial for normal psychomotor and cognitive development of infants. Our aim was to examine serum vitamin B12, folate and ferritin levels in exclusively breastfed healthy full-term infants (age group: 1-6months), and also investigate their correlation with maternal markers. A cross-sectional study was conducted on 100 exclusively breastfed healthy full-term infants (age group: 1-6months) along with their lactating mothers. Serum vitamin B12, folate and ferritin levels were determined for each mother-infant dyad using enzyme-linked immunosorbent assay. The mean serum vitamin B12, folate and ferritin levels were 512 vs. 535 pg/mL, 15 vs. 12 ng/mL and 313 vs. 114 ng/mL in infants and mothers, respectively. Among 100 infants, 26 (26%) had lower vitamin B12 levels and 5 (5%) had inadequate folate levels. In addition, 22 (22%) of 100 lactating mothers were deficient in vitamin B12 levels and 14 (14%) had inadequate folate levels. We found a statistically significant positive correlation between infant and maternal vitamin B12 (r=0.659, P < 0.001) and folate levels (r=0.51, P < 0.001). Vitamin B12 deficiency was observed in 26% of infants and 22% of lactating mothers. Vitamin B12 and folate levels of infants were positively correlated with maternal levels in the state of Punjab, North-West India. Our findings support that maternal vitamin B12 status can be used as a valuable predictor of infant vitamin B12 status.

Anemia is a prevalent condition in older people, and associated with increased morbidity and mortality. Previous studies identified various causes of anemia in this population. We aimed to determine the frequency and main causes of persistent or recurrent anemia in participants 2 years after their inclusion in the São Paulo Ageing & Health Study (SPAH). The SPAH is a cohort study of 2072 individuals aged 65 years or older living in poor neighborhoods of São Paulo, Brazil. A total of 2 years after inclusion, participants were reassessed; those with anemia at baseline were eligible for this ancillary study. Individuals were invited to a medical re-evaluation, including taking blood samples to determine serum iron, ferritin, total iron-binding capacity, folic acid, vitamin B(12), creatinine and transferrin saturation levels, and blood cell and reticulocyte counts. Anemia diagnosis was based on WHO criteria. Information about cause of death before follow-up assessment was obtained from death certificates. Of the 203 participants with anemia at inclusion, 97 (47.8%) were reassessed, 48 (23.6%) died before follow-up assessment, 33 (16.3%) refused to participate and 25 (12.3%) were not traced. A total of 57 (58.8%) of the 97 re-evaluated participants had persistent or recurrent anemia. Lower baseline hemoglobin was a predictor of anemia during follow up. Major causes of persistent or recurrent anemia at follow up were renal disease (62%) and chronic inflammation (35%). Anemia was a prevalent and persistent disease in this low-income sample of older individuals. Micronutrient-related anemia, chronic blood loss and renal disease are important mechanisms for perpetuating low hemoglobin levels.

Intrinsic factor deficiency (OMIM #261000, IFD) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor (GIF) gene.We report three individuals from an Old Order Mennonite community who presented with B12 deficiency. Two cases are siblings born to consanguineous parents and the third case is not known to be closely related. The older male sib presented at 4 years with gastrointestinal symptoms, listlessness, and pallor. He had pancytopenia with megaloblastic anemia. Serum B12 was 61 (198-615 pmol/L). Methylmalonic aciduria was present. C3 was elevated on acylcarnitine profile. Homocysteine was high at 16.7 (5.0-12.0umol/L). His asymptomatic female sibling was also found to have B12 deficiency. Genetic testing for methylmalonic aciduria (MMAA), transcobalamin deficiency (TCN2), and Imerslund-Gräsbeck syndrome (AMN) showed no mutation in both siblings. The third patient, a 34-year-old woman, had presented in infancy with a diagnosis of pernicious anemia. Mutation analysis of GIF revealed compound heterozygosity for a c.79+1G>A substitution and a c.973delG deletion in all three individuals. Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels. Newborn screening samples on the siblings revealed normal methylcitrate, C3, and C3/C2 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism.A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition.

Vitamin B12 deficiency is a common long-term sequelae after total gastrectomy. Intramuscular injection of vitamin B12 is the only known treatment. We investigated the efficacy and safety of oral vitamin B12 replacement for gastric cancer patients with vitamin B12 deficiency after total gastrectomy. We performed a single-arm, open-label, fixed-drug dosage, prospective study (NCT00699478) involving gastric cancer patients who underwent total gastrectomy. Vitamin B12-deficient (<200 pg/ml) patients (n = 30) received daily oral vitamin B12 (dosage: 1500 μg mecobalamin) administration for 3 months. The primary outcome measurement was serum vitamin B12. The secondary outcome measurements were improvement of neurologic symptoms and hematologic findings (serum folate, homocysteine, ferritin, iron, total iron binding capacity, transferrin, and mean corpuscular volume). For comparison, another group of vitamin B12 deficient patients (n = 30) received intramuscular vitamin B12 injections (dosage: 1000 μg cyanocobalamin) weekly for 5 weeks and monthly thereafter for a total of 3 months in a separate study period. In both groups, mean serum vitamin B12 increased after 30 days of treatment and was maintained up to 90 days. No adverse effects related to oral or intramuscular vitamin B12 replacements were noted. Both groups showed decreased homocysteine levels. Before treatment, 29 patients in the oral vitamin B12 group had neurologic symptoms related to vitamin B12 deficiency. After oral vitamin B12 treatment, 28 patients experienced symptom relief, and 16 patients were symptom free. Oral vitamin B12 replacement is an effective and safe treatment for vitamin B12 deficiency in gastric cancer patients after total gastrectomy.

Reference curves demonstrating the relationship between serum or liver vitamin B12 and weight gain were derived from the examination of 16 published and 48 unpublished N.Z. trials. From these curves probability of obtaining an economic reponse (>10g/day body weight increase) for any serum or liver vitamin B12 can be determined. No significant (P<0.05) weight gain responses occurred to vitamin B12 or cobalt treatment in trials with mean serum vitamin B12 levels above 500 pmol/l or liver vitamin B12 levels greater than 500 nmol/kg. The reference curves were therefore derived from trials with vitamin B12 levels below these levels; 36 trials with serum vitamin B12 and 19 trials with liver vitamin B12 data. The mean vitamin B12 level at the mid point of the weight gain response period was selected from each trial. Examination of serum vitamin B12 reference curves for spring, summer, autumn and winter indicated that curves derived from data closest to the middle of January (summer) adequately reflected response to treatment at any time during the first year of life. Reference curves for liver vitamin B12 also used data closest to middle of January. This was partly because insufficient liver data was available to compare seasonal variations. The fitted response curve approached 0 gram/day at 500 pmol/l for serum vitamin B12 and 375 nmol/kg for liver vitamin B12. The minimum vitamin B12 level at which an economic response to treatment (>10 g/day) is not likely was 336 pmol/l for serum and 282 nmol/kg for liver.

Objective To investigate the clinical significance of serum folic acid and vitamin B12 detection in patients with H-type hypertension. Methods A total of 120 patients with primary hypertension admitted to Shanxi Cardiovascular Hospital from October 2015 to October 2016 were selected. Among them, 64 cases of H-type hypertension were assigned to group A , and 56 cases of simple hypertension to group B. In addition, 60 healthy patients who went to hospital for physical examination during the same period were selected as the control group. Five ml fasting venous blood was taken from patient’s elbows in the morning. Aerum folic acid, vitamin B12 and homocysteine (Hcy) levels were measured after centrifugation. Serum folic acid, vitamin B12 and Hcy levels were observed and recorded. The correlation between serum folic acid, vitamin B12 and Hcy levels and H-type hypertension was analyzed. Results Serum levels of folic acid and vitamin B12 in group A were lower than those in group B and control group, and Hcy levels were higher than those in group B and control group, with statistically significant differences (P 0.05). Pearson correlation analysis showed that serum folate and vitamin B12 levels were negatively correlated with H-type hypertension (r 0, P<0.05), that was, with the decrease of serum folic acid and vitamin B12 levels, the serum Hcy level increased, and the patients had a higher risk of developing H-type hypertension. Conclusions The detection of serum folic acid, vitamin B12 and Hcy has important value in the diagnosis of early H-type hypertension, and provides important basis for the formulation of individualized clinical treatment plan. Key words: H-type hypertension; Serum folate; Vitamin B12

Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient preferences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treatment, in a typical primary care population. Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly assigned to oral or IM treatment. Group O-oral was given 28 tablets of 1000 µg cyanocobalamin in a monthly punch card fitted with an electronic monitoring system. Group I-IM received four, weekly injections of 1000 µg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and analysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adher-ence and percentage of days with 2 dosing events were calcu-lated. Before and after 28 days of treatment, patients were asked to fill in a questionnaire about their preference for the therapy options and associated factors. Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment. Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

Guillain-Barré syndrome (GBS) is an acute-onset polyneuropathy. Several biomarkers have been identified to monitor prognosis in GBS, including serum folate, serum albumin, blood glucose, serum sodium, and plasma cortisol levels. To study the prevalence of serum vitamin B12 deficiency and increased creatine kinase (CK-NAC) levels in GBS patients and ascertain if the levels of serum CK-NAC and vitamin B12 can serve as prognostic indicators in GBS patients. The research recruited 50 patients with GBS from the neurology department of a tertiary care hospital between 2020 and 2021. The study assessed the patients' motor function deficits using the MRC (Medical Research Council) scale as well as the HDS (Hughes Disability Scale). Vitamin B12 and CK-NAC levels were measured, and patients were divided into four groups, one of which had a deficiency in vitamin B12 and a raised CK-NAC level, while another group had normal serum vitamin B12 and CK-NAC levels. Clinical characteristics were compared. Serum vitamin B12 and CK-NAC levels were associated with GBS severity based on HDS and MRC scales, autonomic dysfunction, and respiratory failure. Serum vitamin B12 deficiency along with elevated CK-NAC levels was discovered in 44 and 14% of GBS patients, respectively. Serum vitamin B12 deficiency correlated significantly with GBS severity, including progression duration, admission and nadir HDS scores, and autonomic dysfunction (p < 0.05). CK-NAC level did not correlate with the severity of GBS (p > 0.05). Vitamin B12 levels can predict prognosis in GBS patients.

Objective To investigate the relationship between serum vitamin B12 level and arsenic methylation and the risk of arsenic poisoning in the arsenic exposed population. Methods Three villages in Midu County, Dali City, Yunnan Province were investigated. Cross-sectional study was used to select 103 subjects. The population was divided into three groups according to drinking water arsenic exposure situation and whether arsenic poisoning patients: 28 cases of control group (not exposed to high arsenic), 30 cases of arsenic patient group and 45 cases of non patient group. Instant peripheral blood samples and urine samples were collected. The content of arsenic in urine was determined by hydride generation cold trap and atomic absorption spectrophotometry. The levels of vitamin B12 in serum were determined by chemiluminescence immunoassay. The urine arsenic and serum vitamin B12 contents in different groups were compared, the arsenic poisoning prevalence rate in people with different levels of serum vitamin B12 was investigated, and the correlation between serum vitamin B12 level and the metabolism of arsenic methylation was analyzed. Results The level of urinary inorganic arsenic (iAs), monomethylated arsenic (MMA) and dimethylated arsenic (DMA), total arsenic (tAs) were significantly different between groups (F= 13.032, 20.778, 21.978, 22.155, all P < 0.05). The levels of urine arsenic in patients with arsenic exposure [(94.56 ± 107.62), (75.76 ± 54.31), (270.19 ± 185.10), (444.02 ± 323.28) μg/g Cr] and non patient with arsenic exposure [(40.05 ± 47.47), (45.11 ± 46.06), (183.91± 151.45), (270.84 ± 231.45) μg/g Cr] were significantly higher than those in control group [(7.58 ± 4.82), (4.27 ± 2.01), (26.89 ± 11.45), (38.91 ± 13.34) μg/g Cr, all P < 0.05]. The serum levels of vitamin B12 were significantly different between groups (F= 6.650, P < 0.05), patients exposed to arsenic [(366.05 ± 120.03) ng/L] was significantly lower than the control group [(533.70 ± 180.12) ng/L, P < 0.05]. There were significant differences in the detection rate of arsenic poisoning among different levels of serum vitamin B12 (χ2= 8.13, P < 0.05), the lower dose of vitamin B12, the more serious the incidence of arsenic poisoning. The content of vitamin B12 was negatively correlated with MMA% (r=-0.21, P < 0.05), and positively correlated with SMR (r= 0.21, P < 0.05). Conclusion Low levels of vitamin B12 in serum may increase the risk of arsenic poisoning. Key words: Vitamin B12; Arsenic poisoning; Methylation

Associations between low levels of folate and vitamin B12 and cognitive impairment in patients with dementia have been reported. Some studies revealed correlations between low levels of vitamin B12 and behavioural and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) patients. Given the lack of studies in frontotemporal dementia (FTD) and on folate and given the methodological shortcomings of former publications, we set up a prospective study. At inclusion, AD (n=152) and FTD (n=28) patients underwent a neuropsychological examination. Behaviour was assessed using a battery of behavioural assessment scales. Determination of serum vitamin B12 and red cell folate levels were performed within a time frame of two weeks of inclusion. In both patient groups, significantly negative correlations between levels of serum vitamin B12 and red cell folate and the degree of cognitive deterioration were found. No correlations with BPSD were found in the AD patient group. In FTD patients, levels of vitamin B12 were negatively correlated with both hallucinations (p=0.022) and diurnal rhythm disturbances (p=0.036). The observed negative correlations between levels of vitamin B12 and folate and cognitive impairment in both AD and FTD patients, raise the possibility of a non-specific etiological role. Although levels of vitamin B12 and folate did not correlate with BPSD in AD patients, negative correlations between serum vitamin B12 levels and BPSD in FTD patients were revealed. Decreased serum vitamin B12 levels may predispose FTD patients to develop hallucinations and diurnal rhythm disturbances.

Introduction: Severe acute malnutrition (SAM) is a severe form of malnutrition affecting nearly 20 million children worldwide. Besides increasing the risk of death and disease, malnutrition also leads to growth retardation and impaired psychosocial and cognitive development. Vitamin B12 and folate are water-soluble essential micronutrients critical in average growth and development, particularly during infancy and childhood. A deficiency of folate and vitamin B12 can result in anemia, poor growth, and increased infections, and vitamin B12 deficiency can cause irreversible neurologic damage to the developing brain. We conducted this study to assess serum folate and vitamin B12 levels in children with SAM at admission and determine its relation with their developmental milestones. Materials and Methods: One hundred admitted SAM children between ages 6 and 59 months were taken to assess serum folate and vitamin B12 levels status in a tertiary care hospital and determine its relation with their developmental milestones. Results: The majority of the participants were in the age group 6–12 months (64%), rural (95%), the lower class of socioeconomic status (76%), and incomplete immunization (63%). Serum vitamin B12 and folate levels were found to be significantly associated with different domains of childhood development. Conclusion: This analysis revealed a high prevalence of vitamin B12 deficiency among malnourished children aged 6–59 months. We found that serum vitamin B12 level and folic acid were significantly associated with developmental delay in all domains (gross motor, fine motor, language, and social) of milestones.