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Letters to the Editor |
1 Department of Clinical Biochemistry, AS, Aarhus University Hospital, Aarhus, Denmark
2 Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
3 LOCUS for Homocysteine and Related Vitamins and Section for Pharmacology, Institute of Medicine, University of Bergen, Bergen, Norway
Correspondence: Mustafa Vakur Bor, Department of Clinical Biochemistry, AS, Aarhus University Hospital, Tage-Hansens Gade 2 DK-8000 Aarhus C, Denmark. Fax: international +45.89493060. E-mail:vakbor{at}yahoo.com
Key words: oral vitamin B12 treatment, holo-TC, cobalamin, inherited vitamin B12 deficiency.
Parenteral vitamin B12 is considered the treatment of choice for vitamin B12 deficiency, but also treatment with 1–2 mg daily oral vitamin B12 is recommended.1,2 Recently, alternative regimes have been proposed, such as an oral dose of 1 mg vitamin B12 daily for ten days, weekly for four weeks, and monthly or biweekly for life.3,4 One short-term study assessed this regime employing hematologic markers and total plasma cobalamins.4 It is unclear to what extent the patients included had a total or only a partial lack of active absorption of vitamin B12.
In the present study, we examined the long-term efficacy of biweekly oral treatment with 1 mg vitamin B12 by studying hematologic parameters, cobalamins, methylmalonic acid (MMA), total homocysteine (tHcy), and cobalamin saturated transcobalamin (holo-TC) in patients with congenital vitamin B12 deficiency treated for at least five years, patients not following this treatment for at least one year, their biological parents, and healthy controls.
Patients (n=16) were unable to actively absorb vitamin B12 because of defects in the cubilin or amnionless receptors (n=12) or inherited lack of intrinsic factor (IF) (n=4). Genotyping was available for 11 patients.5–7 Lack of vitamin B12 absorption was recently confirmed in all 16 patients.7 After the initial diagnosis, all 16 patients except 2 (patients # 4,16) received 100 µg vitramin B12 intramuscularly daily during the first week, every other day during the second week, twice a week until the hemoglobin had normalized, and every month thereafter. This treatment regime was changed to biweekly 1 mg oral treatment in 1996. Patients #4,16, diagnosed in 1997, received only oral treatment as indicated above after a loading dose of 1 mg oral vitamin B12 daily for ten days and 0.5 mg oral vitamin B12 daily for an additional ten days.3 Cobalamin (cyanocobalamin) (1 mg ampoule, Deva) was mixed with water or fruit juice and was self-administered orally. Blood sampling was performed two weeks after the last oral intake of vitamin B12 in 2003. Four of the patients (#3, 4, 11, 17) initially followed the biweekly oral treatment as described above but did not receive any treatment with vitamin B12 for at least one year prior to the study. We included parents of the patients who were all expected to be heterozygous for the inherited vitamin B12 deficiency (n=19), and healthy controls (n=44) with no clinical evidence for vitamin B12 deficiency. Inclusion criteria were no known disorders related to vitamin B12 deficiency, no chronic systemic disease and no medical treatment, including vitamin tablets, within the previous week.
Laboratory data and other information on all patients and controls are indicated in Tables 1A and 1B. The Research Ethics Committee of Hacettepe University Hospital approved the study protocol.
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All patients with congenital vitamin B12 malabsorption showed an increase in hemoglobin and most of them showed a decrease in MCV between the time of diagnosis and the time of the current study (Table 1B). At the time of the study there was no difference in hematologic parameters (Table 1A) between patients with congenital vitamin B12 malabsorption and the control groups. The four untreated patients had low serum cobalamins, and holo-TC concentrations, elevated tHcy and MMA (p<0.001) as compared to values obtained for the controls, but, unexpectedly, normal hematologic parameters (Table 1A, Figure 1).
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The main findings of the present study on patients with congenital vitamin B12 deficiency are that biweekly oral treatment with 1 mg vitamin B12 ensures normal hematologic parameters, but does not correct all other markers of vitamin B12 deficiency. Thus, vitamin B12 deficiency may exist in this population without hematologic signs, as previously demonstrated in other populations.10
Studies by Gangorase et al.11 and subsequently by Altay and Cetin3 showed that anemia due to inherited vitamin B12 deficiency could be corrected by oral vitamin B12. In the latter study, biweekly 1 mg oral vitamin B12 treatment after a loading dose was sufficient for maintenance of normal hematologic parameters and cobalamin levels during a follow-up period of 12 months. Our study challenges the conclusion that biweekly 1 mg vitamin B12 treatment is sufficient and questions hematologic parameters and plasma cobalamins as measures of inadequate vitamin B12 status.
Elevated plasma concentrations of MMA and tHcy can be used as biochemical markers to aid in the diagnosis of vitamin B12 deficiency and to monitor the response to cobalamin supplementation. In our study, more than 75% of the patients with congenital vitamin B12 deficiency treated biweekly with 1 mg oral vitamin B12 for more than five years had normal levels of MMA and tHcy, but only 33% had a normal holo-TC. This observation agrees with the view that holo-TC is an early marker of a suboptimal vitamin B12 homeostasis.12
In conclusion, biweekly treatment with 1 mg vitamin B12 seems to normalize indices of vitamin B12 status in some, but not all of the patients with congenital vitamin B12 deficiency. We, therefore, believe that a more frequent intake of oral vitamin B12 is required, but we question whether a daily dose of 1–2 mg vitamin B12 is needed.
Acknowledgments
we warmly acknowledge the excellent technical assistance of Anna-Lisa Christensen and Jette Fisker Pedersen.
Footnotes
Funding: this work was supported in part by a European Union demonstration project on the diagnostic utility of holo-TC (QLK3-CT-2002-01775).
References
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