Vitamin B12
Background
The main source of cobalamin is from dietary intake of animal and dairy products. Cyanocobalamin, another name for vitamin B12, is an artefactual molecule based on previously used isolation methods from liver specimens and does not have direct biologic activity. The actual biologically active forms proceed from cobalamin. Ingested cobalamin complexes with salivary haptocorrin, which is released from cobalamin by pancreatic proteases in the duodenum. Intrinsic factor secreted from the parietal cells of the stomach then complexes with the released cobalamin. When this complex arrives at the distal ileum, it binds to cubilin on the enterocytes and is endocytosed. The cobalamin molecule is separated from intrinsic factor and transferred to transcobalamin II, which is a plasma transport protein [81, 82].
At the target cell, the complex is endocytosed into the cellular lysosome where cobalamin is released from transcobalamin. It is metabolized to two active forms: adenosylcobalamin in the mitochondria and methylcobalamin in the cytosol.
Methylcobalamin is a methyl-transferring cofactor to the enzyme methionine synthase. Catalyzed by methionine synthase, methyltetrahydrofolate surrenders a methyl group to cobalamin, which then methylates homocysteine and forms methionine. Methionine is an essential amino acid required in the synthesis of nucleotides and phospholipids.
Adenosylcobalamin is formed within mitochondria and is a cofactor for a mutase known as methylmalonyl-CoA-mutase. This enzyme converts methylmalonyl-CoA into succinyl CoA and is important in the catabolism of various aminoacids and fatty acids. These processes may also require pyridoxine (vitamin B6) as a cofactor.
Unlike cobalamin acquired from dietary sources, pharmacologic sources provide either cyanocobalamin or hydroxocobalamin [2]. Gastrointestinal absorption is saturable. After a 5–50 mcg dose, the maximum amount of absorbed B12 is 1.5 mcg [83]. Dairy products, fish, and shellfish appear to continuously increase plasma vitamin B12 levels with increased daily intake. Meat and meat products, on the other hand, appear to have a plateau effect beyond 4 μg/day [83]. Beyond 10 μg/day, plasma vitamin B12 levels plateau, independent of the food source [83].
Total body stores are about 2–5 mg of vitamin B12, 0.1% of which is in serum. The daily utilization of vitamin B12 amounts to approximately 2–5 mcg: several years of deficiency are necessary to deplete body stores [84, 85].
The doses and levels for systemic toxicity in humans have not been established. Reports of pruritus, skin lesions, and diarrhea have been documented. Animal studies with intravenous doses up to 100 mg/kg for 26 weeks did not demonstrate any toxicity [82].
General Population
Epidemiology
Sufficiency Data
Low serum levels may not represent tissue vitamin deficiency. One study observed that approximately 10% of patients with serum levels <150 pmol/l had normal tissue levels [85]. The current definition of vitamin B12 sufficiency is a serum level >210 pmol/l. This definition is based on the analysis of the NHANES cohort and represents the 95th percentile for vitamin B12-replete subjects [86].
Marginal deficiency is defined by a serum level of 148–221 pmol/l; deficiency is defined by a serum level <148 pmol/l; and severe deficiency is defined as serum levels <120 pmol/l. More definite evidence of vitamin B12 deficiency is based on the elevation of serum methylmalonic acid (>270 nmol/l) [87].
In North Americans, the prevalence of vitamin B12 deficiency was 3% of those aged 20–39 years, 4% of those aged 40–59 years, and 6% of persons aged ≥60 years [86]. Marginal deficiency was more common and occurred in 14–16% of those aged 20–59 years and 20% of those ≥60 years. The mean methylmalonic acid level was 137 nmol/l (134–140 nmol/l). These findings demonstrate an increased incidence of deficiency with age [87].
The recommended daily allowance for vitamin B12 is 2.4 mcg/day for adult males and females [88]. This recommendation is based on daily utilization data and the prevention of megaloblastic anemia.
Determinants of Sufficiency
Diet is an important determinant of vitamin B12 status. Dietary vitamin B12 consumption increases from 0.4 mcg/day in vegans to 7.2 mcg/day in people who eat meat [88]. These dietary patterns directly correlate with serum B12 levels. Current data suggest that, in general, serum B12 levels respond similarly for supplements, fortified cereals, and animal sources.
Malabsorption is another important determinant. Increasing age leads to gastric inflammation and atrophy. The resulting hypochlorhydria prevents the release of vitamin B12 from salivary haptocorrin and subsequent ileal absorption. This is corroborated by the observation of increased gastrin levels with increasing age [89]. Other causes of malabsorption include proton pump inhibition [90], immunologic, intrinsic factor status, transcobalamin variants [91], postgastric surgery, bowel disease, or constipation [92].
This malabsorption may be circumvented by providing supplemental vitamin B12. Some authorities recommend routine supplemental vitamin B12, especially for the elderly [93, 94].
Megaloblastic Anemia
Macrocytic anemia is the most common manifestation of vitamin B12 deficiency; it is rarely seen with serum levels >148 pmol/l [85]. The macrocytosis may be normalized with folate repletion, leading to delay in recognition and possible worsening of neurologic sequelae [61, 66].
Hyperhomocysteinemia
Vitamin B12 deficiency is the major cause of elevated plasma total homocysteine in folate-fortified populations [95]. Determinants of homocysteine levels include the status of folic acid, vitamin B6, and vitamin B12. A normal homocysteine level is <10 μmol/l [96]. The estimated prevalence of hyperhomocysteinemia is between 5% and 10%. It can be categorized as mild (12–30 μmol/l), intermediate (31–100 μmol/l), and severe (>100 μmol/l) [97].
Homocysteine has been proposed as a vascular toxin ever since the first observations of premature vascular morbidity in patients with inherited homocysteinemia [98]. Observational studies, summarized in a recent Cochrane review [97], have convincingly demonstrated an association between increasing homocysteine levels and cardiovascular outcomes. Approximately 4.1% of cardiovascular events can be attributed to elevated homocysteine levels [99].
Cognitive Status
Impairment of cognitive status is observed with vitamin B12 deficiency, usually in elderly people. Homocysteine levels have been predictive of cognitive decline in healthy older people [100]. Other studies have found methylmalonic acid levels, but not B12 levels, to predict cognitive status, perhaps because this is the better marker of sufficiency [101]. Neuropsychiatric disorders related to B12 deficiency present without anemia or metabolic derangements in the elderly in about 30% of cases [102].
Neurologic Complications
Long-standing vitamin B12 deficiency can lead to various neurologic sequelae including peripheral neuropathy, cognitive impairments, and subacute combined degeneration of the spinal cord.
Prostate Cancer
Elevated vitamin B12 levels (>376 pmol/l) showed a trend toward an increased risk of prostate cancer (OR 1.17 CI 0.95–1.43 p = 0.06). Other metabolites in the vitamin B12 cascade were also weakly linked to prostate cancer. This association remains to be confirmed, but it is relevant to the debate about food fortification with vitamin B12 as a public health measure [103].
Trials
Deficiency
Patients with frank deficiency can present with hematologic or neuropsychiatric syndromes. The risk for deficiency and symptom presentation increases with age. Traditional treatment involves parenteral replacement of vitamin B12. A recent Cochrane review identified two randomized trials comparing oral vs. intramuscular vitamin B12 therapy, and concluded that oral vitamin B12 therapy may be as effective as intramuscular therapy [87].
Homocysteine and Cardiovascular Effects and Mortality
As folic acid, vitamin B6, and vitamin B12 have a role in the generation of homocysteine, many cardiovascular studies examining the effects of vitamin supplements employed all three vitamins. To date, there are at least four major meta-analyses [97, 104-106]. Dosing varied for each vitamin depending on the trial: folic acid 0.5–40 mg/day, vitamin B12 0.4–2 mg/day, and vitamin B6 25–100 mg/day. Follow-up in these studies ranged from 6 months to 7.3 years. The main primary outcome measures were myocardial infarction, stroke, and all-cause mortality. Most studies also reported the effect of vitamin B supplementation on total homocysteine levels. Details of these trials are summarized in Table 4.
Vitamin B supplementation reduced homocysteine levels especially in populations that were not exposed to dietary folate fortification. Baseline levels were between 10 and 13 μmol/l and net reduction was between 2 and 4 μmol/l (20–40%) over the course of follow-up [97, 104-106].
Myocardial infarctions and other cardiac outcomes were not improved with vitamin B supplementation. The pooled relative risks for these events consistently surrounded unity with strong evidence of homogeneity in the trials pooled (low I2 values) [RR 1.03 (CI 0.94–1.13, 7 RCTs, I2 0%) [98], RR 1.04 (CI 0.94–1.16, I2 31%) [106], RR 1.03 (CI 0.97–1.1) [106]]. Significant heterogeneity was not demonstrated in these analyses.
The effect of B12 supplementation on stroke outcomes remains debatable, with some studies showing a tendency or marginally statistically significant reduction in the risk of stroke [107, 108], and others observing no benefit [104-106, 109, 110].
Vitamin B supplementation did not impact all-cause or cardiovascular mortality. In most studies, mortality was either part of a combined primary outcome or a secondary outcome [RR 1.00 (CI 0.92–1.09, 6 RCTs, I2 0%) [98], RR 1.01 (CI 0.95–1.07, 13 RCTs, I2 0%) [106], RR 1.02 (CI 0.97–1.08) [106]].
Cognitive Status
The evidence for vitamin supplementation on cognitive status is sparse [111]. Most studies show no benefit in dementia, including Alzheimer's disease, or in cognitive deficits [112-119]. A Cochrane review in 2009 identified only three trials evaluating the ability of vitamin B12 supplementation to prevent or retard cognitive deficits in elderly patients with low vitamin B12 levels [120]. Cognitive and dementia scores did not improve. This review, however, was limited by small studies with less than one-year follow-up. Another Cochrane review of combined folic acid and vitamin B12 supplementation reached similar conclusions [72].
People with Low Glomerular Filtration Rate & End-Stage Renal Disease
Sufficiency Data
Vitamin B12 status in the renal population is dependent on the extent of uremia and the impact on nutrition. At baseline, in a recent trial in dialysis patients, mean plasma vitamin B12 level was around 350 pmol/l (ranging from 154 to 932 pmol/l) [121].
Extended duration hemodialysis (>15 hours/week), hemofiltration or hemodiafiltration does not lead to increased risk of vitamin B12 deficiency in comparison with standard hemodialysis [17, 122].
Homocysteine and Cardiovascular and Mortality Outcomes
Elevated homocysteine levels in renal patients are not necessarily due to vitamin B insufficiency, but may reflect reduction in the enzymes present in normal kidney parenchyma. Uremia may also reduce the activity of methionine synthase. Average homocysteine levels in people with ESKD are approximately 25 μmol/l in patients who eat a folate-fortified diet and 35 μmol/l in patients eating an unfortified diet [123].
A recent meta-analysis assessed the influence of homocysteine levels on cardiovascular outcomes in patients with end-stage renal disease [123]. Most studies involved hemodialysis patients. The pooled risk estimate for all-cause mortality was not significant (RR 1.02), nor was the risk of cardiovascular events (HR 0.99). However, when analyzing studies where there was no supplementation or folate fortification, there was a small, statistically significant association with mortality (HR 1.07 CI 1.03–1.13 p = 0.001) and morbidity (HR 1.09 CI 1.03–1.14).
Neuropsychiatric Complications
The association of vitamin B12 and homocysteine with cognitive status, to our knowledge, has not been investigated in the renal population despite the high prevalence of cognitive abnormalities. Lower cobalamin levels have been associated with depression in hemodialysis patients [124].
Trials
Homocysteine and Cardiovascular and Mortality Outcomes
Because the intrinsic factor pathway is saturable and independent of intrinsic factor absorption has limited capacity, leading to the absorption of about 1% of an oral dose, intravenous therapy has the potential to raise B12 levels to a larger extent than achievable with oral therapy. It has been suggested that these pharmacologic effects may lead to more dramatic homocysteine lowering than therapeutic or near-therapeutic replacements [125]. Intravenous hydroxycobalamin given to vitamin B12-replete patients on dialysis led to 14-fold increases in B12 and 23% reductions in homocysteine [126]. In a randomized crossover trial, hydroxycobalamin 1 mg intravenously every 4 weeks resulted in a 40-fold increase in serum B12 levels in patients on hemodialysis, whereas cyanocobalamin levels increased 10-fold; however, reduction in homocysteine was similar with both treatments, around 33% [127]. Oral vitamin B12 combined with folic acid and pyridoxine has been shown, in randomized controlled trials, to reduce total homocysteine levels by 30–50% in patients with low glomerular filtration rate or end-stage renal disease [121, 128-130].
In a recent, multicenter, randomized trial, 650 patients with end-stage renal disease who had average homocysteine levels of 28.2–30.0 μmol/l were randomized to two B vitamin regimens given postdialysis [121]. The active regimen consisted of 5 mg folic acid, 50 μg cobalamin, and 10 mg vitamin B6, whereas the placebo regimen consisted of 0.2 mg folic acid, 4 μg cobalamin, and 1 mg vitamin B6. Homocysteine levels fell significantly with active treatment (−10.4 μmol/l vs. −1.8 μmol/l). However, there was no difference in all-cause mortality (31% vs. 28%) or cardiovascular events (25% vs. 30%). Interestingly, the change in cobalamin levels from baseline was similar in both groups despite differing doses of cobalamin supplementation (100–125 pmol/l rise).
Multiple studies have demonstrated similar effects of vitamin B12 therapy on homocysteine levels and a lack of efficacy with regard to cardiovascular outcomes in patients with low glomerular filtration rate and on dialysis [129-131].
Cognitive Effects
As in the nonrenal population, supplementation has not been shown to improve cognitive outcomes. A 1-year study involving patients with low glomerular filtration rate and patients on dialysis found that supplementation with a vitamin B complex reduced homocysteine levels in the treatment group, but had no beneficial outcomes on cognitive functioning in comparison with placebo [49].
Summary
Vitamin B12 is an important vitamin in the catabolism of aminoacids and fatty acids. Deficiency has been linked to neurologic, hematologic, and cognitive effects. Current recommendations require a daily intake of 2.4 μg to maintain sufficiency. Given the effects of age and the prevalence of vitamin B12 malabsorption, use of routine low-dose supplementation to prevent overt deficiency in elderly patients, whether or not on dialysis, may be reasonable [132].
Given the strong observation of the association between homocysteine and cardiovascular outcomes, many studies have examined the effects of vitamin B12 in the prevention of these outcomes. Unfortunately, the evidence overall shows no role of vitamin B12 therapy with other B vitamins for the reduction of cardiovascular, cerebrovascular, or mortality outcomes.
Water soluble vitamins (summary)
Vitamin B2 (Riboflavin), Vitamin B3 (Niacin = nicotinic acid; niacinamide = nicotinamide)
Vitamin B7 (biotin), Vitamin B9 (folic acid, folate)
Vitamin B12
Clase, C. M., Ki, V. and Holden, R. M. (2013), Water-Soluble Vitamins in People with Low Glomerular Filtration Rate or On Dialysis: A Review. Seminars in Dialysis, 26: 546–567. doi: 10.1111/sdi.12099
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