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    11 Comments for this article
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    B12 and mortality
    Tomoyuki Kawada, MD | Nippon Medcal School
    I have read the article by Flores-Guerrero et al. (1) with great interest. The authors conducted a prospective study to investigate the association between plasma vitamin B12 concentration and all-cause mortality. Median (interquartile range) plasma concentration of vitamin B12 was 394.42 (310.38-497.42) pg/mL, and 226 participants (4.1%) died during the median (interquartile range) of 8.2 (7.7-8.9) years of follow-up. Adjusted hazard ratio (HR) (95% confidence interval [CI]) of 1-SD increase of plasma vitamin B12 concentration for all-cause mortality was 1.25 (1.06-1.47). I have two concerns about their study.

    First, the authors cited a paper reporting the risk of higher
    plasma vitamin B12 concentrations on all-cause and cardiovascular mortality in the very old women (2). Adjusted HRs (95% CIs) of plasma vitamin B12 concentration with 100 pmol/L increase for all-cause and cardiovascular mortality were 1.10 (1.04-1.16) and 1.10 (1.02-1.18), respectively. Although a significant association between plasma vitamin B12 concentration and mortality was observed in older females in this study, both studies did not handle subjects with absolutely decreased levels of plasma vitamin B12 concentration. There is a need of further study to specify the depletion of plasma vitamin B12 concentration on subsequent mortality.

    Second, Hooshmand et al. investigated the association of plasma vitamin B12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyper-intensity volume in older adults (3). By the multi-adjusted linear mixed models, higher baseline vitamin B12 and holo-transcobalamin levels were associated with a decreased rate of total brain volume loss. The aging was positively related to plasma vitamin B12 and holo-transcobalamin levels and negatively associated with brain volume. I suspect that aging of brain might gradually progress and neuropsychiatric information is also needed to understand the mechanism of the association.


    References

    1. Flores-Guerrero JL, Minovic I, Groothof D, et al. Association of plasma concentration of vitamin B12 with all-cause mortality in the general population in the Netherlands. JAMA Netw Open 2020;3(1):e1919274. doi: 10.1001/jamanetworkopen.2019.19274

    2. Mendonça N, Jagger C, Granic A, et al. Elevated total homocysteine in all participants and plasma vitamin B12 concentrations in women are associated with all-cause and cardiovascular mortality in the very old: The Newcastle 85+ Study. J Gerontol A Biol Sci Med Sci 2018;73(9):1258-1264. doi: 10.1093/gerona/gly035

    3. Hooshmand B, Mangialasche F, Kalpouzos G, et al. Association of vitamin B12, folate, and sulfur amino acids with brain magnetic resonance imaging measures in older adults: A longitudinal population-based study. JAMA Psychiatry 2016;73(6):606-613. doi: 10.1001/jamapsychiatry.2016.0274
    CONFLICT OF INTEREST: None Reported
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    Correlation consumption animal products and morality
    Frank Van Polanen Petel |
    Seems to me that you might have found (another) correlation between consumption of animal products and mortality? Since animal products are the only source and supplementation was excluded.
    CONFLICT OF INTEREST: None Reported
    High B12 is a known red flag for several common and fatal illnesses not corrected for in this analysis
    George Anstadt, MD | University of Rochester
    B12 physiology and metabolism is very complex. It plays an important role in every cell in the body e.g. as a cofactor in DNA replication and homocysteine metabolism. Microbiome perturbations influence levels. Several medications influence levels. Deficiency diseases are common in western society, ranging from fetal deaths, to anemias and cognitive and mood effects; these requiring supplementation. High levels are less common, but not rare, and are an important red flag for liver diseases, kidney disease, solid tumors and bone marrow dysplastic conditions. This article attempts to draw mortality conclusions from 10-year old single B12 level determinations without corrections for the often fatal diseases associated with high levels; high levels demand a careful work up, and should not be attributed to OTC supplementation. Further, the basic science of B12 elevation diseases so not suggest a casual relationship to the B12 elevation; rather the elevations reflect several passive mechanisms. B12 elevations do not cause of these fatal conditions and these findings should not change clinical practice.
    CONFLICT OF INTEREST: None Reported
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    Worth re-thinking and planning: over interpretation of the observed association between high B12 and mortality
    Rima Obeid, PhD | Department of Clinical Chemistry, Saarland University Hospital, Germany
    With great interest, I studied this paper and tried to figure out what is going on in this specific cohort. A long time ago, Waters et al. have shown that baseline vitamin B12 in community dwelling individuals is not associated with 10-y mortality PMID:5579454. Interestingly, vitamin B12 concentrations show low fluctuations upon repeated measurements over time (PMID: 24647388), thus generally making serum B12 an interesting potential predictor of future outcomes in a healthy population. In 2 large cohort studies (without previous selections), elevated B12 at baseline has been shown to be associated with prevalent albuminuria (OR 1.44 per 1 SD increase, 95% CI 1.10-1.87) and reduced kidney function PMID: 25644490, but not with incident (future) outcomes. The association with albuminuria was homocysteine-dependent .
    The association between plasma B12 and mortality in the PREVEND cohort is a post hoc analyses of data from 2 pooled cohorts that were “selected by” urinary albumin above 10mg/L (conditioning on renal function). The ratio of participants with/without urine albumin > 10 mg/L was 2.3 in the PREVEND (Figure 1), thus the study is dominated by people with microalbuminuria, suggesting possible selection bias and hence limited external validity or generalization to the general population - even if the present cohort is derived from the population. Intuitively, the reader would like to know how was the association in the two cohorts separated.
    Principally, to study an association between B12 and any future outcome we cannot select the participants based on factors causally related to the future Outcomes of interest. Moreover, co-variates to be adjusted for are those known to be associated with high B12 (e.g. pre-existing cancer, liver or renal dysfunction, etc) and factors that affect mortality in the same time (pre-existing diseases and age).
    Adjustments for covariates are expected to be judged from previous knowledge (not data-driven as in eTable 1). Moreover, to be able to adjust for 16-20 variables (including categories of any variable) as in the present work, there should be at least 300 events, which is not the case here. Table 1 shows that people in the upper quartile of serum B12 were more ill compared with the lowest or mid quartiles. In addition, the adjustments for renal function would better be according to albumin level in urine since this was a primary selection criteria for the majority of the participants and a previous report from PREVEND reported that, albuminuria, but not eGFR, was associated with CVD events and mortality PMID: 22835901.
    An additional main concern about the present study is: how would the association change if all subjects were free from albuminuria at baseline?
    eTable7 shows that when individuals with mild to moderate loss of renal function are excluded, and the model was further adjusted for preexisting mutual causes of high B12 and mortality (cancer and CVD), then the association is almost lost. Finally, tHcy is a possible mediator between B12 and the outcome (adjustment for tHcy is questionable). Taken together, it can be argued that previous diseases present in the cohort at baseline have caused high serum B12 and mortality in the same time and thus induced a seemingly meaningful association between high B12 and the study outcome [high B12 ← existing illnesses → future illnesses].
    CONFLICT OF INTEREST: None Reported
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    Harm from B12 is probalby due to cyanocobalamin
    J David Spence, M.D., FRCPC, FAHA | Robarts Research Institute, Western University, London, ON, Canada
    It is likely that harm from B12 in persons with impaired renal function is due to cyanocobalamin. Patients with renal failure have high plasma levels of thiocyanate[1], and cyanocobalamin requires decyanation to become active. In a trial in patients with diabetic nephropathy, B vitamins including 1000 mcg daily of cyanocobalamin accelerated the decline of renal function, and doubled cardiovascular events.[2] All the events occurred in participants with a glomerular filtration rate < 50 mL/ min/1. 73 m2. In the early studies of B vitamins for stroke prevention there was no benefit, but an analysis of the Vitamin Intervention for Stroke Prevention trial excluding patients with impaired renal function (eGFR in the lowest decile, 48 mL/ min/1. 73 m2, and those who received B12 supplements outside the randomized assignment, showed a 34% reduction of stroke/myocardial infarction/vascular death with B vitamins.[3] The Su.Fol.OM3 trial, in patients with the best renal function of all the trials and a much lower dose of cyanocobalamin (only 20 mcg daily) reported a 43% reduction of stroke with B vitamins. It is now becoming apparent that harm from cyanocobalamin among participants with impaired renal function obscured the benefit of B vitamins for lowering of homocysteine.[4]

    Koyama et al reported that methylcobalamin had the intended metabolic effects in patients with renal failure.[5] B vitamins to lower homocysteine do reduce the risk of stroke, but we should be using methylcobalamin or oxocobalamin rather than cyanocobalamin. For patients with the T allele of methylenetetrahydrofolate reductase we should probably also add folate supplementation beyond the dose achieved by folate fortification of the grain supply.[6]

    1. Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant. 1997;12(8):1622-8.
    2. House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010;303(16):1603-9.
    3. Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention For Stroke Prevention trial: an efficacy analysis. Stroke. 2005;36(11):2404-9.
    4. Spence JD, Yi Q, Hankey GJ. B vitamins in stroke prevention: time to reconsider. Lancet Neurol. 2017;16(9):750-60.
    5. Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y, et al. Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis. 2010;55(6):1069-78.
    6. Qin X, Spence JD, Li J, Zhang Y, Li Y, Sun N, et al. Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke. Neurology. 2020.
    CONFLICT OF INTEREST: None Reported
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    Observations and musings about B-12
    William Liljequist, Esquire | The famous Staying out of the Hospital
    As a non-doctor, only commons sense is available to me.
    1) Hence, I figure that B-12 coming in the Cyanocobalamin variety might have more side effects than the Methylcobalamin variety. To be determined.

    2) While I have zero knowledge about how B-12 is absorbed, used, digested and excreted by the human body, I know that people who get B-12 prescribed might fall into two categories:

    a) Those that drink too much alcohol. If drinking alcohol is so prevalent in a patient that the doctor
    decides that a B-12 injection might be of use, then it stands to reason that both liver and kidney
    might already be overtaxed from both the liver trying its utmost to keep processing the alcohol,
    from the liver or kidney being strained by processing the acetaminophen or ibuprofen or other
    NSAID's that an alcoholic might consume, given the frequent headaches an alcoholic will experience.

    b) Those who are so old, that their liver and kidney no longer functions properly, such that any
    assimilation of B-12, whether of the Methyl - or Cyano variety, is so slowed down that more B-12
    remains in the plasma, instead of being used anywhere in the body, where it might be of use.

    3) I agree that Cyanocobalamin ought to be phased out, as I figure the less cyanide the body has to deal with, the better.

    All these musings are to be researched and the outcome determined. Let me know if I am wrong. I am just a tax accountant, so any doctor can prove me wrong, if they can. Occasionally I cut myself shaving
    with Occam's razor, but pretty rarely.
    CONFLICT OF INTEREST: None Reported
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    RESPONSE to Tomoyuki Kawada
    Jose L Flores-Guerrero | University Medical Center Groningen, Groningen, The Netherlands.
    Dear Tomoyuki Kawada
    We appreciate your interest on the article and your nice summary. Your insightful comment on the potential role of 1-Carbon metabolism on brain aging is also welcomed. Future investigation on the role of B-12 metabolism in the context of the brain aging deserves attention.


    On behalf of the authors,

    Jose L. Flores-Guerrero
    University Medical Center Groningen, Groningen, The Netherlands.
    CONFLICT OF INTEREST: None Reported
    RESPONSE to Rima Obeid,
    Jose L Flores-Guerrero | University Medical Center Groningen, Groningen, The Netherlands.
    Dear Rima Obeid,

    We appreciate your careful comment. Please note that adjustment for eGFR and urinary albumin excretion did not affect the association of vitamin B12 with all-cause mortality (Table 2, model 5). However, in a sensitivity analysis after excluding individuals with mild to moderate loss of kidney function (eGFR <60 mL/min/1.73m2), there was indeed no significant association of plasma concentration of vitamin B12 with all-cause mortality after adjustment for history of CVD (eTable 7 in the Supplement). This might be explained by the intrinsic relationship of CVD with CKD, and consequently the highly collinearity that such variables
    display in our data set. Importantly, in order to further investigate if our results could be applicable to the general population, we performed a Design-Based Analysis to weight the albuminuria enriched component in the PREVEND cohort. In this analysis, the association of plasma concentration of vitamin b12 with risk of all-cause mortality was significant after full adjustment.

    On behalf of the authors,

    Jose L. Flores-Guerrero
    University Medical Center Groningen, Groningen, The Netherlands.
    CONFLICT OF INTEREST: None Reported
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    RESPONSE to George Anstadt,
    Jose L Flores-Guerrero | University Medical Center Groningen, Groningen, The Netherlands. 
    Dear George Anstadt,

    We agree with your comment that 1-carbon metabolism is complex, and that the cause of high circulating vitamin B12 levels requires careful evaluation in individual patients. Please note that patients with active cancer did not participate in the second screening round of the PREVEND study, which was the starting point of our study. The results presented in the main text show that higher plasma concentrations of vitamin B12 were associated with all-cause mortality after adjustment for ferritin, hemoglobin and mean corpuscular volume (Table 2, model 3), as well as after additional adjustment for a history
    of cancer and cardiovascular disease (Table 2, model 4). In addition, excluding patients with a history of cancer, low plasma concentrations of vitamin B12, or high plasma concentrations of homocysteine did not materially change the results (supplemental tables). Further analysis showed that the association remained unchanged after excluding those participants who developed hematological or bone marrow dysplasias before, during and after the second screening round of the PREVEND. In such analysis, age- and sex-adjusted Cox regression that examined the vitamin B12 plasma concentration as a categorical variable with quartile 1 as the reference group, the fourth quartile of vitamin B12 plasma concentrations was associated with increased risk of mortality (HR, 1.63 [95% CI, 1.11-2.39]; P = .01). The association remained significant after full adjustment (adjusted HR, 1.75 [95% CI, 1.09- 2.80]; P = .02). Taken together, we believe it would be unlikely that the association of vitamin B12 levels with all-cause mortality was to a considerable extent attributable to undetected (hematological) malignancies or bone marrow dysplasias.
    We agree that our findings as such should not change clinical practice regarding vit B12 substitution therapy in patients diagnosed with vitamin B12 deficiency. However, our report may provide a rationale to re-evaluate the safety of vitamin B12 supplementation in the absence of vitamin B12 deficiency.

    On behalf of the authors,

    Jose L. Flores-Guerrero
    University Medical Center Groningen, Groningen, The Netherlands.
    CONFLICT OF INTEREST: None Reported
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    RESPONSE to J David Spence,
    Jose L Flores-Guerrero | University Medical Center Groningen, Groningen, The Netherlands.
    Dear J David Spence,

    We appreciate your interest on the article and your insightful comment. Future investigation on the role of thiocyanate and the activation of cyanocobalamin in renal function and mortality deserves attention.
    On behalf of the authors,
    Jose L. Flores-Guerrero
    CONFLICT OF INTEREST: None Reported
    RESPONSE to Frank Van Polanen Petel
    Jose L Flores-Guerrero | University Medical Center Groningen, Groningen, The Netherlands. 
    Dear Frank Van Polanen Petel,
    We appreciate your interest on the article and your insightful comment. As the only dietary source of vitamin B12 are animal products, it is possible that the present association could also be explained by the already reported association of higher animal protein intake with all-cause mortality. (JAMA Intern Med. 2016 November 1; 176(11): 1728., Am J Clin Nutr. 2019 May 1;109(5):1462-1471.). Unfortunately, the PREVEND cohort does not include data on dietary patterns.
    Our analysis were conducted after the exclusion of individuals who were prescribed with injectable vitamin B12 supplementation at the baseline measurements,
    nonetheless the Pharmacy records have no available information about the over-the-counter tablets of vitamin B12, and therefore our results cannot be adjusted for such variable.
    On behalf of the authors,
    Jose L. Flores-Guerrero
    University Medical Center Groningen, Groningen, The Netherlands.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Geriatrics
    January 15, 2020

    Association of Plasma Concentration of Vitamin B12 With All-Cause Mortality in the General Population in the Netherlands

    Author Affiliations
    • 1University Medical Center Groningen, Division of Nephrology, Department of Internal Medicine, University of Groningen, Groningen, the Netherlands
    • 2University Medical Center Groningen, Department of Laboratory Medicine, University of Groningen, Groningen, the Netherlands
    • 3Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
    • 4University Medical Center Groningen, Division of Endocrinology, Department of Internal Medicine, University of Groningen, Groningen, the Netherlands
    JAMA Netw Open. 2020;3(1):e1919274. doi:10.1001/jamanetworkopen.2019.19274
    Key Points español 中文 (chinese)

    Question  Are plasma concentrations of vitamin B12 associated with risk of all-cause mortality among adults from the general population of the Netherlands?

    Findings  In this population-based cohort study including 5571 adults, higher plasma concentrations of vitamin B12 were associated with a 25% increased adjusted risk of all-cause mortality per 1-SD increase.

    Meaning  These findings suggest that higher plasma concentrations of vitamin B12 are associated with all-cause mortality, independent of traditional risk factors.

    Abstract

    Importance  Higher plasma concentrations of vitamin B12 have been associated with mortality in elderly and hospitalized populations, including patients with chronic kidney disease, but the association of plasma concentrations of vitamin B12 with mortality in the general population remains unclear.

    Objective  To investigate the association of plasma concentrations of vitamin B12 with all-cause mortality.

    Design, Setting, and Participants  This longitudinal cohort study used post hoc analysis to examine data from participants of the Prevention of Renal and Vascular End-stage Disease Study in Groningen, the Netherlands. Participants included individuals who completed the second screening visit beginning January 1, 2001, excluding those who were missing values of vitamin B12 plasma concentrations or used vitamin B12 supplementation. Follow-up time was defined between the beginning of the second screening round to end of follow-up on January 1, 2011. Data analysis was conducted from October 2, 2018, to February 22, 2019.

    Exposures  Plasma vitamin B12 concentration level.

    Main Outcomes and Measures  Death as recorded by the Central Bureau of Statistics of Groningen, the Netherlands.

    Results  A total of 5571 participants (mean [SD] age, 53.5 [12.0] years; 2830 [50.8%] men) were included in analyses. Median (interquartile range) plasma concentration of vitamin B12 was 394.42 (310.38-497.42) pg/mL. During the median (interquartile range) of 8.2 (7.7-8.9) years of follow-up, 226 participants (4.1%) died. According to quartiles of the distribution of plasma vitamin B12 concentration levels, mortality rates were 33.8 deaths per 10 000 person-years for the quartile with the lowest plasma concentration of vitamin B12 and 65.7 deaths per 10 000 person-years for the quartile with the highest plasma concentration of vitamin B12. After adjustment for multiple clinical and laboratory variables, Cox regression analyses found a significant association between higher vitamin B12 plasma concentration level and increased risk of all-cause mortality (hazard ratio per 1-SD increase, 1.25 [95% CI, 1.06-1.47]; P = .006).

    Conclusions and Relevance  These findings suggest that higher levels of plasma concentrations of vitamin B12 were associated with increased risk of all-cause mortality after adjusting for age, sex, renal function, and other clinical and laboratory variables. The mechanisms underlying this association remain to be established.

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