Vitamin B12 Abstracts 12


Vitamin B12 deficiency: a new risk factor for breast cancer
            (Choi, 1999) Download
A prospective epidemiologic study found a threshold level for serum vitamin B12, below which an increased risk of breast cancer among postmeno-pausal women was observed. This is the first observation to suggest that B12 status may influence breast carcinogenesis and therefore may be a modifiable risk factor for breast cancer prevention.

Observations on dementias with possibly reversible symptoms.
            (Farina et al., 1999)  Download
While the evaluation of patients with dementia must also address the possibility of treatable illnesses, recent studies found that reversible diseases are detected in only about 1% of dementia cases. Data on the frequency and evolution of potentially reversible dementias (PRD) in defined clinical settings can be useful in order to optimize diagnostic protocols, thus reducing over-investigation and waste of resources. We reviewed a series of 513 patients (mean age 69.3 +/- 4.2 years, mean education level 7.4 +/- 4.5 years, sex ratio M/F 217/296) referred to a memory clinic by their general practitioner, in order to identify PRD. All the subjects had undergone neurological and neuropsychological examination, and laboratory tests. Patients considered to be demented also underwent CT brain scan. 362 patients (70.6%) met the criteria for dementia. We identified 26 PRD cases (7.2% of dementia cases, 5.1% of the entire sample). In 13 patients (3.6% of dementia cases), a complete clinical and neuropsychological reversal of dementia was seen after treatment. In 5 of them (1.4%), a partial regression was obtained, while 8 showed no improvement. We conclude that potential and actual reversibility do not coincide, and that "true" reversibility is rare (even if not negligible) in clinical practice. Careful clinical history and examination appeared the most useful part of the evaluation to identify PRD. Standard blood tests and vitamin B12 assay were also useful, while CT scan detected PRD causes only in patients with evidence of neurological signs.


Severe Vitamin B12 Deficiency in Pregnancy Mimicking HELLP Syndrome.
            (Govindappagari et al., 2019) Download
Severe vitamin B12 deficiency may present with hematologic abnormalities that mimic thrombotic microangiopathy disorders such as hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. We report a patient diagnosed with severe vitamin B12 deficiency, following termination of pregnancy for suspected preeclampsia and HELLP syndrome at 21 weeks' gestation. When hemolysis and thrombocytopenia persisted after delivery, testing was performed to rule out other etiologies of thrombotic microangiopathy, including atypical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and vitamin B12 deficiency. This work-up revealed undetectable vitamin B12 levels and presence of intrinsic factor antibodies, consistent with pernicious anemia. Parenteral B12 supplementation was initiated, with subsequent improvement in hematologic parameters. Our case emphasizes the importance of screening for B12 deficiency in pregnancy, especially in at-risk women with unexplained anemia or thrombocytopenia. Moreover, providers should consider B12 deficiency and pernicious anemia in the differential diagnosis of pregnancy-associated thrombotic microangiopathy.

Hooked to vitamin B12 since 1955: a historical perspective.
            (Gräsbeck, 2013)  Download
In our pioneering work in 1956, two binders of vitamin B12 (B12) alias cobalamin (Cbl) were identified in gastric juice, S with slow electrophoretic mobility, a 70 kD protein with intrinsic factor (IF) activity and another rapid (R), not IF active but probable digestion product. Numerous sources contained a protein immunologically identical to R (haptocorrin, Hc). Another IF-active component (I) was found. Isoelectric focusing showed that S, I and R were assemblies of "isoproteins" with different pI's due to varying glycosidation. Isolation of S, I and R in microquantities was achieved in 1962 using a series of ion exchange chromatographies and gel filtration. Ponderable products were obtained in 1965-1966. The B12-IF complex was a dimer, contained 13% carbohydrate and showed a different absorption spectrum than B12. Using the Schilling test, B12 absorption was shown to require Ca(++), bound in vitro to the ileal receptor and IF, but most of Ca(++) could be removed with sialidase. The receptor-substrate complex contained Ca(++) and carbohydrate. The purified receptor was shown to contain two main subunits. The Imerslund-Gräsbeck syndrome was discovered 1958-1960; it is caused by mutations in either of two genes, cubilin or amnionless, which form the multiligand receptor cubam. Testicular biopsies during and after B12-treated deficiency showed remarkable improvement after therapy. Studies of the turnover of radioactive B12 revealed biliary and fecal excretion, enterohepatic circulation and allowed calculation of biological half-life and daily need. The B12 coenzymes largely behaved like B12. To study whether radiocobalt in B12 was representative of the rest of the B12 molecule, (32)P and (57)Co labeled hydroxocobalamins were biosynthesized and shown to behave identically when given simultaneously to rats. The complex metabolism of B12 explains the pathogenesis of B12 deficiencies. Some of its mechanisms are not restricted to B12, e.g. the endocytosis of B12-IF also applies to other macromolecules.

Further evidence on the effects of vitamin B12 and folate levels on episodic memory functioning: a population-based study of healthy very old adults.
            (Hassing et al., 1999) Download
BACKGROUND:  The relationship between vitamin status and cognitive functioning has been addressed in several recent studies with inconclusive results. The purpose of this study was to examine separate and combined effects of serum vitamin B12 and folic acid on episodic memory functioning in very old age. METHODS:  Four study groups were selected from a population-based sample of healthy very old adults (90-101 years of age): normal B12/normal folic acid, low B12/normal folic acid, normal B12/low folic acid, and low B12/low folic acid. Cutoff levels were set at 180 pmol/L for vitamin B12 and at 13 nmol/L for folic acid. Subjects completed two episodic recall tasks (objects and words) and two episodic recognition tasks (faces and words). RESULTS:  Neither vitamin affected recognition or primary memory. Most interesting, although B12 was unrelated to recall performance, subjects with low folic acid levels showed impairment in both word recall and object recall. CONCLUSIONS:  These results replicate and extend previous findings that folic acid may be more critical than B12 to memory functioning in late life. The selective effects of folic acid on episodic recall were discussed in terms of encoding and retrieval mechanisms, as well as in relation to brain protein synthesis.

Age-related hearing loss, vitamin B-12, and folate in elderly women.
            (Houston et al., 1999)  Download
BACKGROUND:  Hearing impairment is 1 of the 4 most prevalent chronic conditions in the elderly. However, the biological basis of age-related hearing loss is unknown. OBJECTIVE:  The objective was to test the hypothesis that age-related hearing loss may be associated with poor vitamin B-12 and folate status. DESIGN:  A thorough audiometric assessment was conducted in 55 healthy women aged 60-71 y. Hearing function was determined by the average of pure-tone air conduction thresholds at 0.5, 1, 2, and 4 kHz and was categorized into 2 groups for logistic regression analyses: normal hearing (<20 dB hearing level; n = 44) and impaired hearing (> or = 20 dB hearing level; n = 11). RESULTS:  Mean age was the same (65 y) for the normal hearing and impaired hearing groups. Pure-tone averages were inversely correlated with serum vitamin B-12 (r = -0.58, P = 0.0001) and red cell folate (r = -0.37, P = 0.01). Women with impaired hearing had 38% lower serum vitamin B-12 (236 compared with 380 pmol/L, respectively, P = 0.008) and 31% lower red cell folate (425 compared with 619 nmol/L, respectively, P = 0.02) than women with normal hearing. Among participants who did not take supplements containing vitamin B-12 or folate, women with impaired hearing had 48% lower serum vitamin B-12 (156 compared with 302 pmol/L, respectively, P = 0.0007) and 43% lower red cell folate (288 compared with 502 nmol/L, respectively, P = 0.001) than women with normal hearing. CONCLUSION:  Poor vitamin B-12 and folate status may be associated with age-related auditory dysfunction.

Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.
            (Kaji et al., 2019)  Download
OBJECTIVE:  To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS). METHODS:  373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset). RESULTS:  No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups. CONCLUSION:  Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early. TRIAL REGISTRATION NUMBER:  NCT00444613.

Vitamin B12 insufficiency is associated with increased risk of gestational diabetes mellitus: a systematic review and meta-analysis.
            (Kouroglou et al., 2019) Download
PURPOSE:  Vitamin B12 deficiency has been associated with a plethora of metabolic abnormalities, such as hyperhomocysteinaemia, insulin resistance and defective synthesis of neurotransmitters and fatty acids. Inconsistency exists as to whether vitamin B12 deficiency is also associated with increased risk of gestational diabetes mellitus (GDM). The purpose of this study was to systematically review and meta-analyze the existing evidence for this association. METHODS:  A comprehensive search was conducted in PubMed, Scopus and Cochrane Central up to April 30, 2019. Data are expressed as odds ratio (OR) with 95% confidence interval (CI). The I RESULTS:  Six studies (n = 1810 pregnant women, 309 GDM cases) fulfilled the eligibility criteria for qualitative and two studies for quantitative analysis. In five studies providing data on vitamin B12 concentrations for both groups, women with GDM had lower vitamin B12 levels when compared with non-GDM women. Women with vitamin B12 deficiency were at higher risk for developing GDM when compared with those who were vitamin B12 sufficient: OR 1.81 (95% CI, 1.25-2.63, I CONCLUSIONS:  Vitamin B12 deficiency seems to be associated with increased risk of GDM. More studies are needed to further strengthen this finding and to clarify possible pathogenetic mechanisms.

Isolated Methylmalonic Acidemia
            (Manoli et al., 1993) Download
CLINICAL CHARACTERISTICS:  Isolated methylmalonic acidemia/aciduria, the topic of this  DIAGNOSIS/TESTING:  Diagnosis of isolated methylmalonic acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of methylmalonic acidemia requires cellular biochemical studies (including  MANAGEMENT:  GENETIC COUNSELING:  Isolated methylmalonic acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).

Vitamin B12 deficiency and nitrous oxide.
            (Mayall, 1999)  Download
Sir—Phillip Lee and colleagues (March 13, p 554)1 highlight the danger of giving nitrous oxide to patients who may have unrecognised vitamin B12 deficiency. The number of patients reported to develop neurological problems is now into double figures. Measurements of serum methylmalonic acid and total homocysteine are required to confidently rule out a deficiency in total body stores. If anaesthetists wish to use nitrous oxide, an alternative approach is perhaps to give vitamin B12 to all patients perioperatively for everything but the shortest of procedures.


Hematologic Findings of Inherited Metabolic Disease: They are More Than Expected.
            (Sal et al., 2018)  Download
Inherited metabolic diseases are pathologic conditions that generally develop as a result of impairment of the production or breakdown of protein, carbohydrate, and fatty acids. Early determination of hematological findings has a positive effect on the prognosis of metabolic diseases. Three hundred eighteen patients who were being followed-up within the previous 6 months at Department of Pediatric Nutrition and Metabolism, Gazi University, Turkey, were included in the study. The hematological findings were classified under 7 main groups: anemia of chronic disease, iron deficiency anemia, vitamin B12 deficiency anemia, hemophagocytosis, leukocytosis, and thrombocytosis. Nine hundred twenty-two hematological examinations of the 319 patients were included in the study, and 283 hematological findings were determined, 127 anemia of chronic disease, 81 iron deficiency anemia, 56 cytopenia, and 4 vitamin B12 deficiency anemia. Leukocytosis (n=1), thrombocytosis (n=5), and hemophagocytosis (n=9) were also observed. It was determined that, although anemia of chronic disease and nutritional anemia are the most common hematological findings, these may be diagnosed late, whereas neutropenia, thrombocytopenia, pancytopenia, and hemostasis disorders may be diagnosed earlier. Our study is the most comprehensive one in the literature, and we think it would positively contribute to the monitoring and prognosis of congenital metabolic diseases.

Efficacy of oral compared with intramuscular vitamin B-12 supplementation after Roux-en-Y gastric bypass: a randomized controlled trial.
            (Schijns et al., 2018)  Download
Background:  After Roux-en-Y gastric bypass (RYGB), patients often develop a vitamin B-12 deficiency. Objective:  Our objective was to investigate whether oral supplementation increases and normalizes low vitamin B-12 concentrations (vitamin B-12 > 200 pmol/L) in RYGB patients as compared to intramuscular injections. Design:  A randomized controlled trial in RYGB patients with subnormal serum B-12 concentrations was performed. One group (IM B-12) received bimonthly intramuscular hydroxocobalamin injections (2000 µg as loading dose and 1000 µg at follow-up) for 6 mo. The second group (oral B-12) received daily doses of oral methylcobalamin (1000 µg). Serum vitamin B-12 was determined at baseline (T0) and at 2 (T1), 4 (T2), and 6 mo (T3) after start of treatment. Concentrations of the secondary markers methylmalonic acid (MMA) and homocysteine (Hcy) were measured at T0 and T3. Results:  Fifty patients were included and randomized, 27 in IM B-12 and 23 in oral B-12. The median vitamin B-12 concentration at T0 was 175 pmol/L (range: 114-196 pmol/L) for IM B-12 and 167 pmol/L (range: 129-199 pmol/L) for oral B-12. Vitamin B-12 normalized in all individuals, and there was no significant difference in vitamin B-12 between the two groups. MMA and Hcy concentrations decreased significantly after 6 mo within each group (P < 0.001 and P < 0.001 for MMA and P = 0.03 and P = 0.045 for Hcy, respectively). There was no significant difference between the groups at 6 mo for both MMA and Hcy (P = 0.53 and P = 0.79). Conclusion:  The efficacy of oral vitamin B-12 supplementation was similar to that of hydroxocobalamin injections in the present study. Oral supplementation can be used as an alternative to hydroxocobalamin injections to treat RYGB patients with low values of serum vitamin B-12. This trial was registered at as NCT02270749.

Vitamin B12 deficiency - A 21st century perspective .
            (Shipton and Thachil, 2015)  Download
Vitamin B12 deficiency is a common condition which can present with non-specific clinical features, and in severe cases with neurological or haematological abnormalities. Although classically caused by pernicious anaemia, this condition now accounts for a minority of cases and vitamin B12 deficiency occurs most often due to food-bound cobalamin malabsorption. Since missing the diagnosis can result in potentially severe complications, including degeneration of the spinal cord and pancytopaenia, vitamin B12 deficiency must be diagnosed early and managed appropriately. Intramuscular injections have been the mainstay of treatment, but oral replacement therapy can be effective in many cases. There is accumulating evidence that high vitamin B12 levels (values varied from 350-1,200 pmol/l) are associated with haematological and hepatic disorders, in particular with malignancy. This review focuses on the developments in the clinical features and management of vitamin B12 deficiency over the last decade.

Treatable causes of adult-onset rapid cognitive impairment.
            (Wang et al., 2019) Download
OBJECTIVES:  Acute and subacute cognitive decline, defined collectively as rapid cognitive impairment (RCI), is attributed to diverse disorders and brings great challenges for differential diagnosis. In this study we investigated the RCI patients to determine the underlying causes and the cognitive outcome of the treatable RCI. PATIENTS AND METHODS:  We reviewed medical records of consecutively hospitalized patients (n = 346) with significant and new cognitive dysfunction between January 2014 and December 2015. Based on the duration of their cognitive dysfunction, patients were divided into two groups with the RCI (< 12 months) and the chronic cognitive impairment (CCI, ≥ 12 months), respectively. Etiologies of the RCI and the CCI were analyzed; the cognitive outcomes of the RCI patients with the treatable disorders were assessed in the follow-up visits. RESULTS:  Potentially treatable or reversible causes were identified in 134 (72%) of 187 RCI patients and in 34 (21%) of 159 CCI patients. The causes in the 134 (72%) RCI patients were immune/inflammation (50, 37%), infection (30, 22%), vascular diseases (29, 22%), neoplasm (16, 12%), metabolic/toxic disorders (7, 5%), and others (2, 1%). The treatable disorders found in both the RCI and the CCI patients were vascular diseases, autoimmune encephalitis, viral encephalitis, inflammatory demyelinating diseases, Hashimoto encephalopathy, neurosyphilis, hydrocephalus, and Vitamin B12 deficiency. Total 114 RCI patients with the treatable disorders were followed up for 6∼39 (median 21) months. Poor cognitive outcomes were found in 24 (21%) of the 114 followed-up patients, comprising patients with infection (1, 3%), immune/inflammation (12, 25%), vascular diseases (8, 28%), and metabolic/toxic disorders (3, 43%). CONCLUSIONS:  Treatable or reversible causes are common underlying RCI. Poor outcomes with severe cognitive deficits are considerably present in the treatable RCI patients and result in permanent dementia.

The Many Faces of Cobalamin (Vitamin B12) Deficiency.
            (Wolffenbuttel et al., 2019)  Download
Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult to establish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia. In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.

A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer.
            (Wu et al., 1999)  Download
To investigate the incidence of breast cancer and prediagnostic serum levels of folate, B12, and pyridoxal 5'-phosphate (B6), we conducted a nested case-control study using resources from the Washington County (Maryland) serum bank. In 1974, 12,450 serum specimens were donated, and in 1989, 14,625 plasma specimens were donated by female residents of Washington County. One hundred ninety-five incident breast cancer cases and 195 controls were matched by age, race, menopausal status at donation, and cohort participation as well as by date of blood donation. In both cohorts and all menopausal subgroups, median B12 concentrations were lower among cases than controls. Differences reached statistical significance only among women who were postmenopausal at donation (1974 cohort, 413 versus 482 pg/ml, P = 0.03; 1989 cohort, 406 versus 452 pg/ml, P = 0.02). Among women postmenopausal at blood donation, observed associations of B12 suggested a threshold effect with increased risk of breast cancer in the lowest one-fifth compared to the higher four-fifths of the control distribution [lowest versus highest fifth: 1974 cohort, matched odds ratio = 4.00 (95% confidence interval = 1.05-15.20); 1989 cohort, matched odds ratio = 2.25 (95% confidence interval = 0.86-5.91)]. We found no evidence for an association between folate, B6, and homocysteine and breast cancer. Findings suggested a threshold effect for serum B12 with an increased risk of breast cancer among postmenopausal women in the lowest one-fifth compared to the higher four-fifths of the control distribution. These results should stimulate further investigations of potentially modifiable risk factors, such as these B-vitamins, for prevention of breast cancer.

Late Life Vitamin B12 Deficiency.
            (Zik, 2019) Download
Vitamin B12 deficiency can present with a wide array of symptoms, and, if unrecognized, lead to significant morbidity especially with regard to the hematologic and neurologic complications. Vitamin B12 is far more prevalent in the elderly population than in the general population. _In particular, the elderly are at higher risk of vitamin B12 deficiency due to higher incidence of polypharmacy, pernicious anemia and food cobalamin malabsorption.



Choi, SW (1999), ‘Vitamin B12 deficiency: a new risk factor for breast cancer’, Nutr Rev, 57 (8), 250-53. PubMed: 10518411
Farina, E, S Pomati, and C Mariani (1999), ‘Observations on dementias with possibly reversible symptoms.’, Aging (Milano), 11 (5), 323-28. PubMed: 10631882
Govindappagari, S, et al. (2019), ‘Severe Vitamin B12 Deficiency in Pregnancy Mimicking HELLP Syndrome.’, Case Rep Obstet Gynecol, 2019 4325647. PubMed: 31019819
Gräsbeck, R (2013), ‘Hooked to vitamin B12 since 1955: a historical perspective.’, Biochimie, 95 (5), 970-75. PubMed: 23274132
Hassing, L, et al. (1999), ‘Further evidence on the effects of vitamin B12 and folate levels on episodic memory functioning: a population-based study of healthy very old adults.’, Biol Psychiatry, 45 (11), 1472-80. PubMed: 10356630
Houston, DK, et al. (1999), ‘Age-related hearing loss, vitamin B-12, and folate in elderly women.’, Am J Clin Nutr, 69 (3), 564-71. PubMed: 10075346
Kaji, R, et al. (2019), ‘Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.’, J Neurol Neurosurg Psychiatry, 90 (4), 451-57. PubMed: 30636701
Kouroglou, E, et al. (2019), ‘Vitamin B12 insufficiency is associated with increased risk of gestational diabetes mellitus: a systematic review and meta-analysis.’, Endocrine, 66 (2), 149-56. PubMed: 31463884
Manoli, I, JL Sloan, and CP Venditti (1993), ‘Isolated Methylmalonic Acidemia’, GeneReviews PubMed: 20301409
Mayall, M (1999), ‘Vitamin B12 deficiency and nitrous oxide.’, Lancet, 353 (9163), 1529. PubMed: 10232347
Sal, E, et al. (2018), ‘Hematologic Findings of Inherited Metabolic Disease: They are More Than Expected.’, J Pediatr Hematol Oncol, 40 (5), 355-59. PubMed: 29746437
Schijns, W, et al. (2018), ‘Efficacy of oral compared with intramuscular vitamin B-12 supplementation after Roux-en-Y gastric bypass: a randomized controlled trial.’, Am J Clin Nutr, 108 (1), 6-12. PubMed: 29931179
Shipton, MJ and J Thachil (2015), ‘Vitamin B12 deficiency - A 21st century perspective .’, Clin Med (Lond), 15 (2), 145-50. PubMed: 25824066
Wang, S, et al. (2019), ‘Treatable causes of adult-onset rapid cognitive impairment.’, Clin Neurol Neurosurg, 187 105575. PubMed: 31715517
Wolffenbuttel, BHR, et al. (2019), ‘The Many Faces of Cobalamin (Vitamin B12) Deficiency.’, Mayo Clin Proc Innov Qual Outcomes, 3 (2), 200-14. PubMed: 31193945
Wu, K, et al. (1999), ‘A prospective study on folate, B12, and pyridoxal 5’-phosphate (B6) and breast cancer.’, Cancer Epidemiol Biomarkers Prev, 8 (3), 209-17. PubMed: 10090298
Zik, C (2019), ‘Late Life Vitamin B12 Deficiency.’, Clin Geriatr Med, 35 (3), 319-25. PubMed: 31230733