|
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 2000 to 5000 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 5442 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 - 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 - 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 - 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 - 1.35; p = 0.93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5 % (95 % CI, 12.5 % - 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 - 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 B112 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. There are two 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 5000 mcg may be obtained over the counter without a prescription. In a review on vitamin B-12 deficiency, Oh & Brown (2003) note that, because most clinicians are generally unaware that oral vitamin B12 therapy is effective, the traditional treatment for B12 deficiency has been intramuscular injections. The authors cite evidence that demonstrates, however, that oral vitamin B12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski, et al., 1998; Lederle, 1991). The authors explain that, although the majority of dietary vitamin B12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 percent of a large dose of oral vitamin B12 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 B12 deficiency who were randomized to receive oral or parenteral vitamin B12 therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B12 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 B12 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 B12 deficiency could be easily reversed with oral supplementation. Oh & Brown (2003) explain 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 B12 deficiency. The investigators concluded that daily oral vitamin B12 at doses of 1000-2000 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 B12 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 B12 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 & Brown, 2003). This high dose is required because of the variable absorption of oral vitamin B12 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 1000 mcg daily for 5 days, followed by 1000 mg weekly for 4 weeks, and a maintenance therapy of 1000 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 1000 micrograms vitamin B12, followed by oral doses of 1000-2000 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.” In general, the medically necessary initial parenteral dose for medically necessary diagnoses (other than pemetrexed administration, see below) consists of 1000 mcg vitamin B-12 daily for 5 days, then 1000 mg weekly for 4 weeks. For maintenance therapy, 1000 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 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 minutes on day 1 of each 21-day cycle. Patients must take daily doses of folic acid and vitamin B12 to reduce the severity of side effects such as low white blood cell count, nausea, vomiting, fatigue, rash, and diarrhea. Patients must receive one intramuscular injection of 1000 µg vitamin B12 during the week preceding the first dose of Alimta and every 3 cycles thereafter. Current biochemical markers of vitamin B12 deficiency include methylmalonic acid (MMA), homocysteine (Hcy) and cobalamin. Serum concentrations of MMA and Hcy are increased in B12-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 B12 deficiency, although it is usually easier to treat such cases with oral vitamin B12 (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 B12 deficiency, it may not reliably indicate vitamin B12 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 B12 deficiency, some investigators have advocated measuring holoTC. This is performed by giving a small oral dose of vitamin B12 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 B12 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 B12 deficiency (n = 937), Hvas and Nexo (2005) concluded that holoTC shows promise as a first-line test for diagnosing early vitamin B12 deficiency. Despite holoTC exhibits potential as a biomarker for early vitamin B12 deficiency, it cannot be used for determining B12 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 B12 deficiency. Herrmann et al (2003) investigated the diagnostic value of storage (holoTC) of vitamin B12 and functional markers (MMA) of vitamin B12 metabolism in five groups who are at risk of vitamin B12 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 B12. HoloTC is the most sensitive marker, followed by MMA. The use of holoTC and MMA can differentiate between storage depletion and functional vitamin B12 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 cannot be used as a marker of vitamin B12 status in patients with renal dysfunction. The causes of vitamin B12 deficiency in the elderly are only partly understood. van Asselt and colleagues (2003) examined the role of the cobalamin-binding proteins regarding B12 deficiency in older people, and tested the hypothesis that low saturated transcobalamin concentration is an early marker of B12 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 cannot 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 B12 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 B12 status was further confirmed by total Hcy (< 19 micro mol/L) and MMA (< 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. B12 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 B12 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 B12 deficiency, but the sensitivity and specificity of low holoTC in diagnosis of vitamin B12 deficiency need to be further evaluated. In a prospective study, Serefhanoglu et al (2008) assessed circulating holoTC to estimate the diagnosis of vitamin B12 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 B12 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 B12 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 B12 deficiency. In summary, the usefulness of holoTC in diagnosing B12 deficiency in various clinical settings has not been established. Large-scale clinical studies are needed to determine the clinical value of holoTC.
|
Close Window
