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Background
Vitamin B-12 belongs to the family of cobalamins. It is available in all animal-derived foods, and is absorbed at a rate of 5 mcg per day. After being ingested, vitamin B-12 becomes bound to intrinsic factor, a protein secreted by gastric parietal cells. The vitamin B-12/intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex. The absorbed complex is then transported via plasma and stored in the liver. Since the liver stores 2,000 to 5,000 mcg vitamin B-12 (adequate for up to 5 years), dietary deficiency of cobalamin (Cbl) is rare. In most cases, vitamin B-12 deficiency is due to an inability of the intestine to absorb the vitamin, which may result from an autoimmune disease that reduces the production or blocks the action of intrinsic factor, or from other diseases that result in intestinal malabsorption. The most frequent underlying cause of vitamin B-12 deficiency is pernicious anemia, which is associated with decreased production of intrinsic factor. Abdominal surgery may cause Cbl deficiency in several ways: gastrectomy eliminates the site of intrinsic factor production; blind loop syndrome results in competition for vitamin B-12 by bacterial overgrowth in the lumen of the small intestine; and surgical resection of the ileum eliminates the site of vitamin B-12 absorption. Rare causes of vitamin Cbl deficiency include pancreatic insufficiency; fish tapeworm infection, in which the parasite uses luminal vitamin B-12; and severe Crohn’s disease, resulting in reduced ileal absorption of vitamin B-12.
Cobalamin deficiency is more common in the elderly primarily because of the increasing prevalence with age of Cbl malabsorption due to autoimmune atrophic gastritis.
Most patients with overt Cbl deficiency report serum vitamin B-12 levels of less than 100 pg/ml. The hallmark of vitamin B-12 deficiency is megaloblastic anemia. Vitamin B-12 deficiency also leads to neurological deficits including paresthesias, sensory loss, ataxia, disequilibrium, diminished or hyperactive reflexes, and spasticity. In more advanced cases, cerebral function may also be affected resulting in disturbances of mood, psychoses, and dementia.
In a systematic review of randomized trials on vitamin B-6, B-12, and folic acid supplementation and cognitive function, Balk and colleagues (2007) stated that despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A total of 14 trials met selection criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B-6 and 6 of vitamin B-12 found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes. The authors concluded that there is insufficient evidence of an effect of vitamin B-6, B-12, or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function. This is in agreement with Clarke et al (2007) who stated that randomized trials are needed to ascertain the relevance of vitamin B-12 supplementation for the prevention of dementia.
In a randomized, double-blind, placebo-controlled trial, Albert et al (2008) examined if a combination of folic acid, vitamin B-6, and vitamin B-12 lowers risk of cardiovascular disease (CVD) among high-risk women with and without CVD. A total of 5,442 women aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in this study. Subjects received a combination pill containing 2.5 mg folic acid, 50 mg vitamin B-6, and 1 mg vitamin B-12 or a matching placebo, and were treated for 7.3 years. Main outcome measures were a composite outcome of myocardial infarction, stroke, coronary re-vascularization, or CVD mortality. Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years versus 219.2/10,000 person-years for the active versus placebo group; relative risk [RR], 1.03; 95 % confidence interval [CI]: 0.90 to 1.19; p = 0.65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years versus 39.5/10,000 person-years; RR, 0.87; 95 % CI: 0.63 to 1.22; p = 0.42), stroke (41.9/10,000 person-years versus 36.8/10,000 person-years; RR, 1.14; 95 % CI: 0.82 to 1.57; p = 0.44), and CVD mortality (50.3/10,000 person-years versus 49.6/10,000 person-years; RR, 1.01; 95 % CI: 0.76 to 1.35; p = 0.93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5 % (95 % CI: 12.5% to 24.1%; p < 0.001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95 % CI: 1.54 to 2.96 micromol/L). The authors concluded that after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B-6, and vitamin B-12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.
There are 2 forms of supplemental Cbl: (i) cyanocobalamin and (ii) hydroxocobalamin. However, cyanocobalamin is the only vitamin B-12 preparation available in the United States. Diverse recommendations exist for initial and maintenance vitamin B-12 therapy.
Vitamin B-12 therapy can be administered orally or by injection. Vitamin B12 tablets of up to 5,000 mcg may be obtained over the counter without a prescription.
In a review on vitamin B-12 deficiency, Oh and Brown (2003) noted that, because most clinicians are generally unaware that oral vitamin B-12 therapy is effective, the traditional treatment for B-12 deficiency has been intramuscular injections. The authors cited evidence that demonstrates, however, that oral vitamin B-12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B-12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski et al, 1998; Lederle, 1991). The authors explained that, although the majority of dietary vitamin B-12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 % of a large dose of oral vitamin B-12 is absorbed by simple diffusion which is independent of intrinsic factor or even an intact terminal ileum.
Kuzminzki et al (1998) reported on the outcome of 33 patients with vitamin B-12 deficiency who were randomized to receive oral or parenteral vitamin B-12 therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B-12 intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B-12 levels and lower methylmalonic acid levels than those in the parenteral therapy group.
Adachi et al (2000) reported the results of a study that showed that even in patients who had undergone gastrectomy, vitamin B-12 deficiency could be easily reversed with oral supplementation.
Oh and Brown (2003) explained that intramuscular injections have several drawbacks. Injections are painful, medical personnel giving the injections are placed at risk of needlestick injuries, and administration of intramuscular injections often adds to the cost of therapy.
Lane and Rojas-Fernandez (2002) reported on a meta-analysis of studies of oral versus parenteral therapy for vitamin B-12 deficiency. The investigators concluded that daily oral vitamin B-12 at doses of 1,000 to 2,000 mcg can be used for treatment in most cobalamin-deficient patients who can tolerate oral supplementation. The investigators noted, however, that there are inadequate data at the present time to support the use of oral vitamin B-12 replacement in patients with severe neurologic involvement. The investigators explained that oral cyanocobalamin replacement may not be adequate for a patient presenting with severe neurologic manifestations that could have devastating consequences if the most rapid-acting therapy is not used immediately. Therefore, parenteral cobalamin is preferable in neurologically symptomatic patients until resolution of symptoms and hematologic indices.
Although the daily requirement of vitamin B-12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Lederle, 1991; Oh and Brown, 2003). This high dose is required because of the variable absorption of oral vitamin B-12 in doses of 500 mcg or less. This regimen has been shown to be safe, cost-effective, and well tolerated by patients.
Treatment schedules for intramuscular administration vary widely but usually consist of initial loading doses followed by monthly maintenance injections. Little (1999) recommended an initial treatment of intramuscular injections of vitamin B-12 1,000 mcg daily for 5 days, followed by 1,000 mg weekly for 4 weeks, and a maintenance therapy of 1,000 mcg every 1 to 3 months. Intramuscular injections of Cbl are well-tolerated.
Hematological improvements should commence within 5 to 7 days, and the deficiency should resolve after 3 to 4 weeks of therapy. However, 6 months or longer of Cbl treatment may be needed before appearance of signs of improvement in neurological manifestations of vitamin B-12 deficiency. Total or partial resolution of neurological deficits has been reported in as many as 80 % of patients (Healton et al, 1991). Neurological improvement is less likely to occur in patients with severe or longstanding deficiency, and in patients with less severe accompanying anemia.
Guidelines from the British Columbia Medical Association (2003) state that "[o]ral doses of vitamin B12 are as effective as parenteral administration in treating deficiency in most cases." The guidelines include the following recommendation: “Oral replacement of vitamin B12 is the treatment of choice in most cases, including pernicious anemia. Patients with significant neurological deficits, however, should receive initial intramuscular injections of 1,000 micrograms vitamin B12, followed by oral doses of 1,000-2,000 micrograms/day. The duration of therapy depends on the cause of deficiency. In pernicious anemia treatment is life-long. Early treatment of vitamin B12 deficiency is particularly important because neurologic symptoms may be irreversible.”
Guidelines from the British Columbia Guidelines and Protocols Advisory Committee (2012) recommend performing a CBC, blood film and serum cobalamin in all patients suspected of cobalamin deficiency. The guidelines recommend interpreting serum cobalamin levels in light of clinical symptoms, because the test has the following limitations: 1) it measures total, not metabolically active cobalamin; 2) the levels of cobalamin do not correlate well with clinical symptoms; elderly patients may have normal cobalamin levels with clinically significant cobalamin deficiency, while women taking oral contraceptives may have decreased blood cobalamin levels due to a decrease in transcobalamin, a carrier protein, but no clinical symptoms of deficiency; 3) there is a large ‘gray zone’ between the normal and abnormal levels; 4) the reference intervals may vary between laboratories. The guidelines state that the conventional cut-off for serum cobalamin deficiency varies from 150-220 pmol/L. Using a more common cut-off of 220 pmol/L, the guidelines recommend the following interpretation:
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Serum cobalamin (pmol/L)
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Probability of symptomatic deficiency
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Less than 75
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High
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75 to 150
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Moderate
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150 to 220
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Low
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Greater than 220
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Rare
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The British Columbia Guidelines and Protocols Advisory Committee (2012) states that oral crystalline cyanocobalamin (commonly available form) is the treatment of choice. Dosing for pernicious anemia or food-bound cobalamin malabsorption is 1000 mcg/day. In most other cases a dose of 250 mcg/day may be used. The guidelines state that oral administration of cobalamin is as effective as parenteral.Advantages of oral supplementation mentioned in the guidelines are comfort, ease of administration, and cost. The guidelines state that prophylactic cobalamin supplementation is recommended for strict vegans and patients with food bound cobalamin malabsorption, and for pernicious anemia. The usefulness of prophylactic administration of cobalamin in elderly is unknown. The guidelines state that parenteral administration should be reserved for those with significant neurological symptoms. It includes 1-5 intramuscular or subcutaneous injections of 1000 mcg crystalline cyanocobalamin daily, followed by oral doses of 1000-2000 mcg/day. The guidelines recommend retesting serum cobalamin levels after 4-6 months to ensure they are in the normal range.
In general, the medically necessary initial parenteral dose for medically necessary diagnoses (other than pemetrexed administration, see below) consists of 1,000 mcg vitamin B-12 daily for 5 days, then 1,000 mg weekly for 4 weeks. For maintenance therapy, 1,000 mcg every 1 to 3 months is usually medically necessary. Requests for vitamin B-12 injections more frequently than the schedule stated above is subject to medical review.
Pemetrexed disodium (Alimta) was approved by the Food and Drug Administration (FDA) on February 5, 2004. It is the first drug approved for mesothelioma. The recommended dose of Alimta is 500 mg/m2 administered as an intravenous infusion over 10 mins on day 1 of each 21-day cycle. Patients must take daily doses of folic acid and vitamin B-12 to reduce the severity of side effects such as low white blood cell count, nausea, vomiting, fatigue, rash, and diarrhea. Patients must receive 1 intra-muscular injection of 1,000 µg vitamin B-12 during the week preceding the first dose of Alimta and every 3 cycles thereafter.
Sánchez-Moreno et al (2009) noted that several studies have reported benefits on lowering the risk of stroke and improving the post-stroke-associated functional declines in patients who ate foods rich in micronutrients, including B vitamins and antioxidant vitamins E and C. Folic acid, vitamin B-6 and vitamin B-12 are all co-factors in homocysteine metabolism. Growing interest has been paid to hyper-homocysteinemia as a risk factor for cardiovascular disease. Hyper-homocysteinemia has been linked to inadequate intake of vitamins, particularly to B-group vitamins and therefore may be amenable to nutritional intervention. Hence, poor dietary intake of folate, vitamin B-6 and vitamin B-12 are associated with increased risk of stroke. Elevated consumption of fruits and vegetables appears to protect against stroke. Antioxidant nutrients have important roles in cell function and have been implicated in processes associated with ageing, including vascular, inflammatory and neurological damage. Plasma vitamin E and C concentrations may serve as a biological marker of lifestyle or other factors associated with reduced stroke risk and may be useful in identifying those at high risk of stroke. After reviewing the observational and intervention studies, there is an incomplete understanding of mechanisms and some conflicting findings; therefore the available evidence is insufficient to recommend the routine use of B vitamins, vitamin E and vitamin C for the prevention of stroke. A better understanding of mechanisms, along with well-designed controlled clinical trials will allow further progress in this area.
Scott (2010) stated that "[v]itamin B12 has been touted as an energy enhancer and metabolism booster. These claims are based on the fact that correcting vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness; however, in the absence of a nutritional deficit, vitamin B12 supplementation does not affect physical performance. No form of vitamin B12 (intra-muscular, oral, or other routes) has been credibly tested as an aid to weight loss. A search of MEDLINE using the search terms "cyanocobalamin OR vitamin B12" and "weight loss OR diet" yielded no clinical studies using vitamin B12 supplements. Although no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy people, weight loss programs that promote vitamin B12, particularly in injectable form, suggest treatment that is not based on sound evidence".
In a pilot study, Bertoglio and colleagues (2010) examined if methyl B-12 treatment improves behavioral measures in children with autism and whether improvement is associated with increased plasma concentrations of glutathione (GSH) and an increased redox ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), both of which have been previously identified to be low in children with autism. This was a 12-week, double-blind, placebo-controlled, cross-over clinical trial of injectable methyl B-12. Following this 12-week study, subjects were given the option of entering a 6-month open-label trial of methyl B-12. Subjects were 3 to 8 years old with autism. All subjects received 6 weeks of placebo and 6 weeks of methyl B-12 at a dose of 64.5 mcg/kg every 3 days administered subcutaneously into the buttocks. Blood for GSH analysis and behavioral assessments were obtained at baseline, week 6, and week 12. A total of 30 subjects completed the 12-week, double-blind study, and 22 subjects completed the 6-month extension study. No statistically significant mean differences in behavior tests or in glutathione status were identified between active and placebo groups. Nine subjects (30 %) reported clinically significant improvement on the Clinical Global Impression Scale and at least 2 additional behavioral measures. More notably, these responders exhibited significantly increased plasma concentrations of GSH and GSH/GSSG. The authors concluded that comparison of the overall means between groups suggests that methyl B-12 is ineffective in treating behavioral symptoms of autism. However, detailed data analysis suggests that methyl B-12 may alleviate symptoms of autism in a subgroup of children, possibly by reducing oxidative stress. An increase in glutathione redox status (GSH/GSSG) may provide a biomarker for treatment response to methyl B-12. They statedthat additional research is needed to delineate a subgroup of potential responders and ascertain a biomarker for response to methyl B-12.
O'Leary et al (2012) noted that poor vitamin B-12 status may lead to the development of cognitive decline and dementia but there is a large variation in the quality, design of and results reported from these investigations. These researchers performed a systematic review of the evidence for the association between vitamin B-12 status and cognitive decline in older adults. A database search of the literature to 2011 was undertaken, using keywords related to vitamin B-12 and cognition. All prospective cohort studies assessing the association of serum vitamin B-12 or biomarkers were included. Quality assessment and extraction of the data were undertaken by 2 researchers. The quality assessment tool assigns a positive, neutral or negative rating. Of 3,772 published articles, 35 cohort studies (14,325 subjects) were identified and evaluated. No association between serum vitamin B-12 concentrations and cognitive decline or dementia was found. However, 4 studies that used newer biomarkers of vitamin B-12 status (methylmalonic acid and holoTC) showed associations between poor vitamin B-12 status and the increased risk of cognitive decline or dementia diagnosis. In general, the studies were of reasonable quality (21 positive, 10 neutral and 4 negative quality) but of short duration and inadequate subject numbers to determine whether an effect exists. The authors concluded that future studies should be of adequate duration (at least 6 years), recruit subjects from the 7th decade, choose markers of vitamin B-12 status with adequate specificity such as holoTC and/or methylmalonic acid and employ standardized neurocognitive assessment tools and not screening tests in order to ascertain any relationship between vitamin B-12 status and cognitive decline.
Doets et al (2012) stated that current recommendations on vitamin B-12 intake vary from 1.4 to 3.0 μg per day and are based on the amount needed for maintenance of hematologic status or on the amount needed to compensate obligatory losses. In a systematic review, these investigators evaluated whether the relation between vitamin B-12 intake and cognitive function should be considered for under-pinning vitamin B-12 recommendations in the future. The authors summarized dose-response evidence from randomized controlled trials (RCTs) and prospective cohort studies on the relation of vitamin B-12 intake and status with cognitive function in adults and elderly people. Two RCTs and 6 cohort studies showed no association or inconsistent associations between vitamin B-12 intake and cognitive function. Random-effects meta-analysis showed that serum/plasma vitamin B-12 (50 pmol/L) was not associated with risk of dementia (4 cohort studies), global cognition z scores (4 cohort studies), or memory z scores (4 cohort studies). Although dose-response evidence on sensitive markers of vitamin B-12 status (methylmalonic acid and holotranscobalamin) was scarce, 4 of 5 cohort studies reported significant associations with risk of dementia, Alzheimer's disease, or global cognition. The authors concluded that current evidence on the relation between vitamin B-12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B-12 recommendations. They stated that further studies should consider the selection of sensitive markers of vitamin B-12 status.
Current biochemical markers of vitamin B-12 deficiency include methylmalonic acid (MMA), homocysteine (Hcy) and cobalamin. Serum concentrations of MMA and Hcy are increased in B-12-deficient patients due to inhibition of methylmalonyl-CoA mutase and methionine synthase, respectively. Some authorities have recommended measurement of Hcy and MMA in persons with borderline vitamin B-12 deficiency, although it is usually easier to treat such cases with oral vitamin B-12 (BCMA, 2003).
In an editorial that addressed whether clinicians should routinely measure Hcy levels and treat patients with mild hyperhomocysteinemia, Rosenberg and Mulrow (2006) stated that clinicians need not routinely measure Hcy levels nor routinely treat mild hyperhomocysteinemia with folic acid or vitamin B supplementation.
Although total serum cobalamin is used to diagnose B-12 deficiency, it may not reliably indicate vitamin B-12 status. A normal serum cobalamin concentration does not reliably rule out a functional cobalamin deficiency. Previous studies have reported problems of sensitivity and specificity with this test (Green, 1996; Stabler, 1998). On the other hand, serum level of holotranscobalamin (holoTC), a metabolically active cobalamin bound to the transport protein transcobalamin, becomes reduced prior to the development of metabolic dysfunction. To enhance the sensitivity and specificity in diagnosing vitamin B-12 deficiency, some investigators have advocated measuring holoTC. This is performed by giving a small oral dose of vitamin B-12 and assessing the subsequent increase in the amount of holoTC in the serum. However, there is currently no gold standard or true reference method to diagnose subtle vitamin B-12 deficiency, which makes evaluation of the clinical usefulness of holoTC and the estimation of sensitivity and specificity problematic.
In comparing the performance of holoTC with other markers of vitamin B-12 deficiency (n = 937), Hvas and Nexo (2005) concluded that holoTC shows promise as a first-line test for diagnosing early vitamin B-12 deficiency. Despite holoTC exhibits potential as a biomarker for early vitamin B-12 deficiency, it can not be used for determining B-12 status in patients with renal diseases since serum concentrations of holoTC can be affected by renal impairment. In this regard, normal holoTC in patients with renal insufficiency may not exclude B-12 deficiency. Herrmann et al (2003) investigated the diagnostic value of storage (holoTC) of vitamin B12 and functional markers (MMA) of vitamin B-12 metabolism in five groups who are at risk of vitamin B-12 deficiency: (i) 93 omnivorous German controls, (ii) 111 German and Dutch vegetarian subjects, (iii) 122 Syrian apparently healthy subjects, (iv) 127 elderly Germans, and (v) 92 German pre-dialysis renal patients. These investigators concluded that their data support the concept that measurements of holoTC and MMA may provide a better index of cobalamin status than the measurement of total vitamin B-12. HoloTC is the most sensitive marker, followed by MMA. The use of holoTC and MMA can differentiate between storage depletion and functional vitamin B-12 deficiency. However, renal patients have a higher requirement of circulating holoTC (i.e., a higher serum concentration of circulating holoTC is needed to deliver sufficient amounts of holoTC into the cells). Thus, holoTC can not be used as a marker of vitamin B-12 status in patients with renal dysfunction.
The causes of vitamin B-12 deficiency in the elderly are only partly understood. van Asselt and colleagues (2003) examined the role of the cobalamin-binding proteins regarding B-12 deficiency in older people, and tested the hypothesis that low saturated transcobalamin concentration is an early marker of B-12 deficiency. Saturated (holo) and unsaturated (apo) transcobalamin and haptocorrin concentrations were measured in healthy middle-aged volunteers, healthy older volunteers, cobalamin-deficient older volunteers and cobalamin-deficient older patients. Holo and apo concentrations of transcobalamin and haptocorrin were similar in healthy middle-aged and older subjects. HoloTC concentrations were significantly reduced in cobalamin-deficient subjects but did not differ between healthy volunteers and patients. Furthermore, the relative amount of cobalamin on transcobalamin was similar in all four groups. These researchers concluded that abnormalities of the cobalamin-binding proteins are not a cause of vitamin B12 deficiency in the elderly. Plasma holoTC concentration did not differ between stages of vitamin B12 deficiency in the elderly. As a result, plasma holoTC is not an early marker of vitamin B12 deficiency in the elderly and has no additional value in the diagnostic work-up of reduced plasma cobalamin concentrations in older people.
Nilsson et al (2004) examined if low holoTC concentrations are congruent with other biochemical signs of cobalamin deficiency in a group of psychogeriatric patients. The findings in their study showed that holoTC is strongly related to serum cobalamin (0.68; p < 0.001 in both patients and controls). Distribution of the different markers for cobalamin/folate status in the 33 patients with low levels of serum holoTC (below 40 pmol/L) showed that 17 patients had normal levels of the other markers for cobalamin status. This may indicate poor specificity of low holoTC for cobalamin deficiency. In 23 out of 176 patients with normal levels of holoTC, pathological levels of other markers for cobalamin deficiency was observed. The use of holoTC did not provide significant additional information other than that given by serum cobalamin and thus can not be recommended in this clinical setting.
Loikas et al (2003) assessed a commercial holoTC radioimmunoassay, determined reference values, and evaluated holoTC concentrations in relation to other biochemical markers of vitamin B-12 deficiency. The reference population consisted of 303 subjects 22 to 88 years of age, without disease or medication affecting cobalamin or Hcy metabolism. In elderly individuals (65 years or older), normal B-12 status was further confirmed by total Hcy (less than 19 micro mol/L) and MMA (less than 0.28 umol/L) concentrations within established reference intervals. HoloTC in B12 deficiency was studied in a population of 107 elderly individuals with normal renal function. B-12 deficiency was graded as potential (total vitamin B12 of 150 pmol/L or less; OR total Hcy of 19 umol/L or more), possible (total B-12 of 150 pmol/L or less; AND either total Hcy of 19 micro mol/L or more, OR MMA of 0.45 umol/L or more), and probable (total Hcy of 19 umol/L or more, AND MMA of 0.45 umol/L or more). These investigators concluded that the holoTC radioimmunoassay is precise and simple to perform. Low holoTC is found in persons with biochemical signs of vitamin B-12 deficiency, but the sensitivity and specificity of low holoTC in diagnosis of vitamin B-12 deficiency need to be further evaluated.
In a prospective study, Serefhanoglu et al (2008) assessed circulating holoTC to estimate the diagnosis of vitamin B-12 deficiency in the first ischemic cerebrovascular attack. These researchers also compared the efficacy of the measurement of plasma holoTC with the other standard biochemical and hematological markers used to reach the diagnosis of Cbl deficiency. A total of 45 patients (age 71 years; range of 35 to 90; 16 men and 29 women) within the first ischemic cerebrovascular event were included in this study. All the enrolled patients received 1-mg vitamin B-12 intramuscular injection once-daily for 10 days. At the baseline and on the 10th day of treatment, plasma levels of holoTC and the proper biochemical and hematological markers in diagnosing Cbl deficiency were measured. After admission, anemia and diminished serum vitamin B-12 levels were determined to be only 20 % (9/45) and 44 % (20/45), respectively; 78 % (35/45) of the patients had low serum holoTC (less than 37 pmol/L). Serum Hcy was higher in patients (49 % of them) who had suffered a stroke. Thrombocytopenia, hyper-segmentated neutrophils, and indirect hyper-bilirubinemia were observed in 20 % of the patients. Leukopenia and macrocytosis were not evident in any of them. In 18 of 27 patients (67 %) that had low holoTC levels after joining the study and who remained in the study until the end of Cbl treatment, serum holoTC levels returned to normal values. Cobalamin deficiency should be considered in patients with CVD, even if anemia, elevated mean cell volume, depression of the serum Cbl, or other classic hematological and/or biochemical abnormalities are lacking. The authors noted that measurement of serum holoTC looks promising as a 1st-line of tests for diagnosing early vitamin B-12 deficiency.
In summary, the usefulness of holoTC in diagnosing B-12 deficiency in various clinical settings has not been established. Large-scale clinical studies are needed to determine the clinical value of holoTC.
Appendix
Several commercial laboratories use different methods (chemiluminescence or radioassay) for measuring vitamin B12 (Schrier, 2011). As a result, there are different normal ranges and no "gold standard". In general, however, serum vitamin B12 levels can be interpreted, as follows:
- > 300 pg/ml (> 241 pmol/L): Normal result; vitamin B12 deficiency is unlikely (i.e., probability of 1 to 5 %).
- 200 to 300 pg/ml (148 to 241 pmol/L): Borderline result; vitamin B12 deficiency possible.
- < 200 pg/ml (< 148 pmol/L): Low; consistent with vitamin B12 deficiency (specificity of 95 to 100 %).
Note: The prescribing information of cyanocobalamin (vitamin B12) states that the drug is for intramuscular (IM) or subcutaneous (SC) use only. The prescribing information also notes that administration of the drug via the intravenous (IV) route should be avoided since IV use of cyanocobalamin will result in almost all of the vitamin being lost in the urine.
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