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Holo-transcobalamin concentration and transcobalamin saturation reflect recent vitamin [B.sub.12] absorption better than does serum vitamin [B.sub.12].

Cobalamin (vitamin [B.sub.12]) is an essential nutrient for one carbon metabolism and cell division that must be supplied by dietary meat or diary products; the minimum recommended daily intake is 2.4 [micro]g (1). After ingestion, vitamin [B.sub.12] is bound to haptocorrin present in saliva. In the small intestine, pancreatic enzymes degrade haptocorrin, and vitamin [B.sub.12] is transferred to intrinsic factor (IF), a protein synthesized in the parietal cells of the stomach. The IF-vitamin [B.sub.12] complex is absorbed via the IF-[B.sub.12] receptor, and vitamin [B.sub.12] is subsequently bound to transcobalamin (TC) and released into the circulation (2, 3). TC bound to vitamin [B.sub.12] (holo-TC) facilitates the transport of vitamin [B.sub.12] from blood to various tissues (4). Accordingly, circulating concentrations of holo-TC may be a marker of vitamin [B.sub.12] absorption. However, to date, whether changes in holo-TC reflect vitamin [B.sub.12] absorption has not been evaluated.

In the present study, we evaluated this concept by measuring serum holo-TC and total TC before and after oral intake of three 9-[micro]g doses of vitamin [B.sub.12] in 31 healthy individuals and 7 patients.

Materials and Methods

The participants in the study included 31 healthy individuals recruited in October 2002. None of them suffered from known disorders related to vitamin [B.sub.12] deficiency. Persons with chronic systemic disease; persons taking any kind of medications, including vitamins, within the past week; and persons not able to give written informed consent were excluded. The mean age of the healthy individuals was 40 years (age range, 25-57 years). There were 9 men and 22 women. We also included seven patients (age range, 22-39 years; five men and two women) who had been referred to the outpatient clinic of the internal medicine department during 2003 for suspected vitamin [B.sub.12] malabsorption. Three of the seven patients had previously been diagnosed as having Crohn disease. The diagnoses for the remaining four patients were not clear.

Written informed consent was obtained from all participants, and the Research Ethics Committee of Aarhus County approved the study protocol (2002.0224).

STUDY PROTOCOL

Vitamin [B.sub.12] absorption was evaluated by analysis of serum vitamin [B.sub.12], total TC, and holo-TC in samples obtained before and after oral administration of vitamin [B.sub.12].

In the healthy individuals, samples were taken at 0800 on the day before vitamin [B.sub.12] intake (day -1) and on days 0, 1, 2, and 6. After the blood sample was taken on day 0, the healthy individuals were administered three 9-[micro]g oral doses of vitamin [B.sub.12] (Natur Drogeriet A/5), with 6 h between each dose (0800,1400, and 2000; time points were allowed to deviate [+ or -] 45 min). One healthy individual was unavailable for blood sampling on day 6. Vitamin [B.sub.12] absorption in the seven patients was evaluated by the Schilling test I and by the design described above except that the blood samples were obtained only on days 0 and 1. The Schilling test I was performed after our alternative approach.

The vitamin [B.sub.12] tablets were given with either water or orange juice. The participants were allowed to have a light breakfast 30-60 min before blood sampling, not including any diary products, but were otherwise allowed to eat their typical diet. The blood samples were centrifuged within 60 min and were stored at -80 [degrees]C until further processing.

SCHILLING TEST I

The Schilling test I was performed as described previously (4). Briefly, a fasting patient is given a 1-[micro]g oral dose of vitamin [B.sub.12], which is tagged with radioactive cobalt ([sup.57]Co). Two hours after the oral dose, the patient receives by intramuscular injection 1000 [micro]g of nonlabeled vitamin [B.sub.12]. A 24-h urine collection is initiated. The percentage of the administered dose excreted in the urine over 24 h is then determined. Urinary excretion of 10-40% of the administered dose is considered normal.

BIOCHEMICAL ANALYSES

Serum vitamin [B.sub.12] was determined by a commercial method (Bayer Corporation) on a Centaur analyzer [CV = 6.8% at a mean of 293 pmol/L (n = 272); CV = 5.8% at a mean of 543 pmol/L (n = 280)].

Serum total TC and holo-TC were measured by ELISA as described recently (5, 6), but modified to allow the use of an automated ELISA analyzer (BEP-2000; Dade Behring). The modification was as follows: all incubations were performed at 37 [degrees]C. The imprecision was 7% for total TC at a mean of 934 pmol/L (n = 91 over 12 months) and was 8% for holo-TC at a mean of 38 pmol/L (n = 41 over 6 months). The reference interval was established by analysis of 161 samples obtained from healthy blood donors (age range, 21-65 years). The reference intervals were 700-1400 pmol/L for total TC, [greater than or equal to] 50 pmol/L for holo-TC, and [greater than or equal to] 0.05 for TC saturation.

Hematologic indices were assessed with the Coulter Counter STKS1 (Beckman Coulter). Plasma creatinine was measured by the Jaffe method on a Roche Cobas Integra 700 analyzer (CV <3%).

STATISTICAL ANALYSIS

The intraindividual variation was calculated from the estimation of variance by ANOVA from the measurements of the analytes from the two samples obtained before the treatment (days -1 and 0).

Changes (increases or decreases) in markers as a function of time were analyzed by comparing the changes obtained for the same individuals relative to baseline (day 0) with the theoretical median "0" assigned for day 0. Because the data did not follow a gaussian distribution, nonparametric testing (Wilcoxon matched-pair test) was used. P values <5% were regarded as statistically significant. Data were analyzed with SP5510.0 (SP55 Inc.) and GraphPad (Prism 3.03) software.

Results

A1131 healthy individuals had normal erythrocyte counts, hemoglobin, mean cell volumes, and creatinine concentrations, as summarized in Table 1. The intraindividual variation was <13% for all analytes (Table 1), as calculated from data obtained for the samples collected before intake of vitamin [B.sub.12] (days -1 and 0).

After oral intake of three 9-[micro]g doses of vitamin [B.sub.12], all markers studied changed as indicated in Fig. 1. The changes relative to baseline (day 0) were highly significant on day 1 (P <0.0002 for all markers) and day 2 (P <0.0005 for holo-TC, TC saturation, and vitamin [B.sub.12]; P = 0.02 for total TC). The maximum percentages and absolute increases [median (range)] were 39 (0-108)% and 34 (0-149) pmol/L for holo-TC and 52 (-2 to 128)% and 0.04 (0-0.22) as a fraction for TC saturation, respectively (n = 31). Maximum increases [greater than or equal to] 15% for holo-TC and TC saturation were observed at day 1 for 29 individuals and at day 2 for one individual. Only one healthy individual did not have increases in holo-TC concentration and TC saturation.

The increases (as a percentage and absolute values) in serum vitamin [B.sub.12] were less dramatic: 14 (-8 to 51)% and 36 (-27 to 290) pmol/L. In four healthy individuals, vitamin [B.sub.12] did not increase, and in 14 healthy individuals it increased <15%.

Small but significant changes were observed for total TC. The maximum percentage and absolute decreases were 5 (-16 to 9)% and 46 (-180 to 77) pmol/L. Twenty-three of the 31 healthy individuals had a decrease in total TC concentration at day 1.

After 1 day, the highest values [median (range)] were for holo-TC [118 (56-344) pmol/L], TC saturation [0.13 (0.06-0.43)], and serum vitamin [B.sub.12] [279 (176-856) pmol/ L], whereas total TC reached its lowest concentration [855 (710-1527) pmol/L; Table 2]. After 6 days, the values for holo-TC, total TC, and TC saturation did not differ significantly from baseline, whereas the concentration of serum vitamin [B.sub.12] remained significantly higher than baseline (P = 0.0086).

[FIGURE 1 OMITTED]

On the basis of these results, the calculated TC saturation appears to be a slightly better marker for vitamin [B.sub.12] absorption because of the observed decrease in total TC together with the increased holo-TC concentration after vitamin [B.sub.12] intake. Thirty healthy individuals had increases of [greater than or equal to] 21% in TC saturation, whereas only 7 had comparable increases in serum vitamin [B.sub.12] concentration (Fig. 2).

In four of the seven patients suspected of having decreased vitamin [B.sub.12] absorption, serum holo-TC and vitamin [B.sub.12] values were below the reference interval (Fig. 3), although their hematologic tests were normal (data not shown). Three of these four patients were previously diagnosed as having Crohn disease. After vitamin [B.sub.12] intake, the three patients with Crohn disease showed negligible increases in holo-TC (3, 7, and 14 pmol/L) and TC saturation (0.004, 0.01, and 0.01; Fig. 3).

[FIGURE 2 OMITTED]

In the seven patients who underwent the Schilling test I (Fig. 3), its results (expressed as percentage of vitamin [B.sub.12] excreted in the urine) were not significantly correlated with the changes in serum holo-TC after vitamin [B.sub.12] intake (r = 0.14; P = 0.77). In six of these patients, however, the two tests were significantly correlated (r = 0.81; P = 0.05; n = 6). One of three patients with Crohn disease had an abnormal Schilling test I (2%). The other two had Schilling test I results within the reference interval (10-40%), but their values were in the lower part of the reference interval (10% and 15%, respectively).

Discussion

To our knowledge this is the first study to document that serum holo-TC concentration and TC saturation reflect active vitamin [B.sub.12] absorption. One day after receiving three 9-[micro]g oral doses of vitamin [B.sub.12], healthy individuals had median increases of ~50% in holo-TC concentration and TC saturation, whereas the increase for serum vitamin [B.sub.12] was only 14%. These findings strongly suggest that measurement of holo-TC and/or TC saturation after an oral dose of vitamin [B.sub.12] provides more information regarding active absorption of vitamin [B.sub.12] than does measurement of serum vitamin [B.sub.12].

To date, little attention has been paid to the dose of vitamin [B.sub.12] administered to patients to study the active uptake of vitamin [B.sub.12] by use of blood tests. Most previous studies have used a relatively larger single oral dose of vitamin [B.sub.12] (1000 [micro]g) (7, 8). The crucial point here is that with this large dose of vitamin [B.sub.12], the non-IF-mediated absorption of 1% alone will increase the plasma concentration, thereby giving false results. This increase does not reflect active IF-mediated absorption and thus has limited diagnostic impact regarding the active vitamin [B.sub.12] absorption.

In our study we designed the intake of vitamin [B.sub.12] to meet two criteria: (a) we wanted to minimize passive absorption, which accounts for ~1% of the dose supplied (4); and (b) we wanted as much actively absorbed vitamin [B.sub.12] as possible to accumulate to provide an optimum signal. To meet these two demands, we chose to use a high physiologic dose (9 [micro]g) and to administer this dose three times at 6-h intervals. Absorption of vitamin [B.sub.12] enters a refractory phase of ~3 h after ingestion of vitamin [B.sub.12] (4). An additional dose of vitamin [B.sub.12] is absorbed normally when given ~4-6 h after the initial dose (4). The highest amount of IF-bound vitamin [B.sub.12] is obtained at a vitamin [B.sub.12] dose of 10 [micro]g. The dose of 9 [micro]g was chosen because this is commercially available and quite close to 10 [micro]g (4).

We examined seven patients with suspected vitamin [B.sub.12] malabsorption by both the Schilling test I and our alternative approach. Four of the patients had small increases in holo-TC and TC saturation (Fig. 3), whereas three patients had increases comparable to those for the healthy individuals studied. One of these four patients also had an abnormal Schilling test. The other three had normal Schilling I tests, but the absolute values (urinary excretion of radioactive vitamin [B.sub.12]) for these three patients were in the lower part of the reference interval (Fig. 3). The increase in holo-TC (87 pmol/L) and the result of Schilling test I (12%) were discrepant for one patient. Because this patient had serum vitamin [B.sub.12] (360 pmol/L) and holo-TC (100 pmol/L) concentrations within the appropriate reference intervals, we believe it most likely that the result obtained by the Schilling test I was falsely low, which is a known problem with this test, most often caused by inappropriate urine collection. As stated in the Results, the correlation was excellent between our approach and the Schilling test I for the remaining six patients. These results thus suggest that our alternative test may be able to identify patients with vitamin [B.sub.12] malabsorption, but further studies are needed to evaluate the usefulness of the test in the clinical setting. In the context of the present report, the results for the three patients with Crohn disease may be useful, as discussed below. These patients are likely to have no or only limited active absorption of vitamin [B.sub.12].

[FIGURE 3 OMITTED]

One important concern about our study is whether we report, as we anticipate, active absorption of vitamin [B.sub.12] or whether the results are caused by passive absorption of the vitamin. Comparing our data on patients with Crohn disease with the remaining group makes it very unlikely that our results were caused by passive absorption. In our design, passive absorption is expected to be ~5% of the total absorption (9). The median increases in the three patients with Crohn disease were 7 pmol/L for holo-TC and 0.01 for TC saturation. These values were ~20% of the median increase observed for healthy controls. We think it more likely that these results reflect a remaining small capacity for active absorption of vitamin [B.sub.12] in addition to the passive absorption of ~5% (9). Independent of the interpretation, it was possible to distinguish patients with expected low vitamin [B.sub.12] absorption (patients with Crohn disease) from the healthy individuals.

Evaluation of the intestinal absorption of vitamin [B.sub.12] is essential to clarify the cause of vitamin [B.sub.12] deficiency and has also been used to evaluate the absorptive capacity of the small intestine (10). The standard test for vitamin [B.sub.12] absorption is the Schilling test. The Schilling test is problematic mainly because it uses labeled vitamin [B.sub.12] and because it requires normal renal function, a complete 24-h urine collection, and large parenteral doses of vitamin [B.sub.12] that can occasionally obscure the diagnosis (11-13). There thus is a need to find alternative tests for estimating vitamin [B.sub.12] absorption to both diagnose the cause of vitamin [B.sub.12] deficiency and estimate the absorptive capacity of the small intestine.

Evaluation of vitamin [B.sub.12] absorption by the use of blood tests has been explored for a long time. To date such studies have not been unequivocal, most likely because the test used has been serum vitamin [B.sub.12] (7, 8,14). Vitamin [B.sub.12] includes vitamin [B.sub.12] bound to two binding proteins. The major part is bound to a protein of unknown function, haptocorrin. This portion of the plasma vitamin has a slow turnover with a half-life of 240 h (15,16), and changes reflecting increased absorption occur relatively late in this fraction of plasma vitamin [B.sub.12]. The minor portion of plasma vitamin [B.sub.12] is attached to TC. TC transports vitamin [B.sub.12] to all cells of the body. The turnover is rapid with a half-life 1-12 h (17,18). Holo-TC appears to be a superior marker for reflecting sudden changes in vitamin [B.sub.12] homeostasis (19, 20), but only recently have reliable assays for measurement of holo-TC as well as total TC become available (6, 21).

Our study gave very promising results. All but two healthy individuals showed an increase in holo-TC 15 pmol/L (15%) and a fractional increase in TC saturation 0.02 (21%) or more above the baseline values. According to these results, we suggest that vitamin [B.sub.12] absorption can be considered normal when one of the following two criteria is fulfilled: (a) the increase in serum holo-TC is at least 15 pmol/L and at the same time [greater than or equal to] 15% above the baseline value; (b) the increase in TC saturation is 0.02 and at the same time [greater than or equal to] 20% above the baseline value.

In healthy individuals, total TC was significantly decreased after the oral dose of vitamin [B.sub.12]. This is in agreement with previous studies (22, 23), but the reason for this decrease is unknown. One possibility is that tissues take up TC to which vitamin [B.sub.12] is bound more rapidly than unsaturated TC. The consequence of the observed decrease in total TC together with the increased holo-TC concentration after vitamin [B.sub.12] intake is that calculated TC saturation becomes a slightly better marker for vitamin [B.sub.12] absorption than measurement of the holo-TC concentration alone. This has been emphasized both in our present study and in a previous study (23) in which a pharmacologic dose of oral vitamin [B.sub.12] was used. Interestingly, after vitamin [B.sub.12] intake, total TC was not decreased in the three patients with Crohn disease. It is logical to assume that those patients cannot absorb vitamin [B.sub.12] and that no increased amount of holo-TC is therefore delivered to the tissues.

The changes in the TC-related markers did not last very long in healthy individuals. The values had returned toward normal by the second day after ingestion of vitamin [B.sub.12]. After 6 days, holo-TC concentrations and TC saturation did not differ significantly from the baseline. It therefore would be possible to repeat the evaluation of vitamin [B.sub.12] absorption after 1 week.

In conclusion, holo-TC concentrations and TC saturation appear to reflect vitamin [B.sub.12] absorption better than does serum vitamin [B.sub.12]. Measurement of holo-TC concentrations and/or TC saturation before and after oral ingestion of vitamin [B.sub.12] could possibly be developed into a test that is suitable as an alternative to the Schilling test I.

This study was supported by European Union BIOMED Project QLK3-CT-2002-01775 and by EUREKA Project CT-T2006. We warmly acknowledge the excellent technical assistance of Anna-Lisa Christensen and Jette Fisker.

References

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(2.) Seetharam B, Alpers DH. Absorption and transport of cobalamin (vitamin [B.sub.12]). Annu Rev Nutr 1982;2:343-69.

(3.) Quadros EV, Regec AL, Khan KM, Quadros E, Rothenberg SP. Transcobalamin II synthesized in the intestinal villi facilitates transfer of cobalamin to the portal blood. Am J Physiol 1999; 277(1 Pt 1):G161-6.

(4.) Chanarin I. The megaloblastic anaemias. Oxford: Blackwell Scientific Publications, 1979:93-123.

(5.) Nexo E, Christensen AL, Petersen TE, Fedosov SN. Measurement of transcobalamin by ELISA. Clin Chem 2000;46:1643-9.

(6.) Nexo E, Christensen AL, Hvas AM, Petersen TE, Fedosov SN. Quantification of holo-transcobalamin, a marker of vitamin [B.sub.12] deficiency. Clin Chem 2002;48:561-2.

(7.) Henze E, Manner S, Clausen M, Malfertheiner P, Hellwig D, Ditschuneit H, et al. The Schilling test cannot be replaced by an absorption test with unlabeled vitamin [B.sub.12]. Klin Wochenschr 1988;66:332-6.

(8.) Moridani MY, Hoffman B, Pritzker K, Bromberg I. Vitamin [B.sub.12] absorption test [Abstract]. Clin Chem 2002;48:A146.

(9.) Heinrich HC, Gabbe EE. Experimental basis of oral and parenteral therapy with cyano and aquacobalamin. In: Linnell JC, Bhatt HR, eds. Biomedicine and physiology of vitamin [B.sub.12]. London: The Children's Medical Charity, 1990:51-63.

(10.) Yeoh E, Horowitz M, Russo A, Muecke T, Robb T, Maddox A, et al. Effect of pelvic irradiation on gastrointestinal function: a prospective longitudinal study. Am J Med 1993;95:397-406.

(11.) Zuckier LS, Chervu LR. Schilling evaluation of pernicious anemia: current status. J Nucl Med 1984;25:1032-9.

(12.) Nexo E, Hansen M, Rasmussen K, Lindgren A, Grasbeck R. How to diagnose cobalamin deficiency [Review]. Stand J Clin Lab Invest Suppl 1994;219:61-76.

(13.) Ward PC. Modern approaches to the investigation of vitamin [B.sub.12] deficiency. Clin Lab Med 2002;22:435-45.

(14.) Magnus E, Muller C. A new, peroral non-radioactive vitamin [B.sub.12] absorption test compared with the Schilling test. Eur J Haematol 1995; 54:117-9.

(15.) Hom BL. Plasma turnover of 5'cobalt-vitamin [B.sub.12] bound to transcobalamin I and II. Stand J Haematol 1967;4:321-32.

(16.) Nexo E, Gimsing P. Turnover in humans of iodine-and cobalamin-labeled transcobalamin I and of iodine-labeled albumin. Stand J Clin Lab Invest 1975;35:391-8.

(17.) Hom BL, Olesen HA. Plasma clearance of 57cobalt-labelled vitamin B12 bound in vitro and in vivo to transcobalamin I and II. Stand J Clin Lab Invest 1969;23:201-11.

(18.) Schneider RJ, Burger RL, Mehlman CS, Allen RH. The role and fate of rabbit and human transcobalamin II in the plasma transport of vitamin B12 in the rabbit. J Clin Invest 1976;57:27-38.

(19.) Herzlich B, Herbert V. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12 balance. Lab Invest 1988; 58:332-7.

(20.) Herbert V, Fong W, Gulle V, Stopler T. Low holotranscobalamin II is the earliest serum marker for subnormal vitamin [B.sub.12] (cobalamin) absorption in patients with AIDS. Am J Hematol 1990;34: 132-9.

(21.) Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, et al. Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 2002; 48:526-32.

(22.) Donaldson RM Jr, Brand M, Sertilippi D. Changes in circulating transcobalamin II after injection of cyanocobalamin. N Engl J Med 1977;296:1427-30.

(23.) Nexo E, Hvas AM, Bleie 0, Refsum H, Fedosov SN, Vollset SE, et al. Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem 2002;48:1768-71.

MUSTAFA VAKUR BOR, * EBBA NEXO, and ANNE-METTE HVAS

Department of Clinical Biochemistry, AKH, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark.

* Author for correspondence. Fax 45-89493060; e-mail vakurbor@ hotmail.com.

Received September 18, 2003; accepted March 9, 2004.

Previously published online at DOI: 10.1373/clinchem.2003.027458
Table 1. Characteristics of the 31 healthy individuals
and intraindividual variation in vitamin B12, serum
holo-TC, total TC, and TC saturation. (a)

 Baseline
 values, (b)
 median (range)

Age, years 40 (25-57)
Blood hemoglobin, mmol/L 8.5 (7.8-10.2)
Mean cell volume, fL 89 (79-98)
Erythrocyte count, [10.sup.12]/L 4.4 (3.9-5.6)
Plasma creatinine, [micro]mol/L 78 (61-106)
Holo-TC, pmol/L 73 (36-281)
Total TC, pmol/L 947 (747-1471)
TC saturation, (e) fraction 0.08 (0.02-0.22)
Vitamin [B.sub.12], pmol/L 250 (163-661)

 Reference intervals (b)

 Males Females
Age, years
Blood hemoglobin, mmol/L 8.4-10.8 7.4-9.6
Mean cell volume, fL 85-100 85-100
Erythrocyte count, [10.sup.12]/L 4.1-6.1 3.7-5.5
Plasma creatinine, [micro]mol/L 62-133 44-115
Holo-TC, pmol/L [greater than or equal to] 504 (d)
Total TC, pmol/L 700-14004
TC saturation, (e) fraction [greater than or equal to] 0.05 (d)
Vitamin [B.sub.12], pmol/L 200-6504

 Intraindividual variation, (c) %

Age, years
Blood hemoglobin, mmol/L
Mean cell volume, fL
Erythrocyte count, [10.sup.12]/L
Plasma creatinine, [micro]mol/L
Holo-TC, pmol/L 11
Total TC, pmol/L 8
TC saturation, (e) fraction 13
Vitamin [B.sub.12], pmol/L 6

(a) Laboratory values were determined from the blood samples
obtained day -1.

(b) References intervals for holo-TC, total TC, and TC saturation
were based on analyses of 161 samples obtained from healthy blood
donors.

(c) Intraindividual variation was calculated based on values
obtained on days -1 and 0 from the 31 healthy individuals before
administration of vitamin B12.

(d) Same reference interval for males and females.

(e) Calculated as holo-TC:total TC.

Table 2. Absolute values for TC saturation, holo-TC,
and vitamin [B.sub.12] before (day 0) and at timed intervals
after oral intake of vitamin [B.sub.12] in 31 healthy
individuals.

 Median (range)

 Day 0 Day 1

Holo-TC, pmol/L 72 118
 (39-298) (56-344)
Total TC, pmol/L 905 855
 (734-1599) (710-1527)
TC saturation, fraction 0.08 0.13
 (0.03-0.26) (0.06-0.43)
Vitamin[B.sub.12], pmol/L 234 279
 (154-566) (176-856)

 Median (range)

 Day 2 Day 6

Holo-TC, pmol/L 87 80
 (41-319) (37-302)
Total TC, pmol/L 850 885
 (687-1540) (717-1446)
TC saturation, fraction 0.11 0.09
 (0.04-0.32) (0.04-0.27)
Vitamin[B.sub.12], pmol/L 253 274
 (172-830) (174-627)
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Title Annotation:Nutrition
Author:Bor, Mustafa Vakur; Nexo, Ebba; Hvas, Anne-Mette
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Jun 1, 2004
Words:4246
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