Oral B12 treatment
Putting the results of the Kwong paper into a broader context

Summary

The paper by Kwong et al. (1) describes the conversion of 55 patients from intramuscular vitamin B12 therapy to oral vitamin B12 therapy, 1000 µg daily. The study supplies a qualitative description of the patients’ experience with a switch from parenteral to oral vitamin B12 therapy. 39 of the patients were satisfied with the latter treatment option and wished to continue. Among  39 patients where serum vitamin B12-measurements were available at baseline (one month after last injection) and after 6 months of oral treatment, 10 subjects had only a non-significant increase  in B12-values (less than 100 pmol/L), and one subject experienced even a decrease in serum B12 values after oral supplementation. These findings and observations confirm previous case reports that oral vitamin B12 treatment is feasible in most but not all of cases of patients in need of B12-supplementation.

Figure 1. Baseline serum vitamin B12 was assayed one month after the last injection (trough value). The second value is after six months of oral vitamin B12 treatment. Among the 40 patients, only one showed a decrease of serum vitamin B12.

 

The background

A careful meta-analysis (2,3) of the randomised controlled trials (RCT) on intramuscular vitamin B12 therapy versus oral vitamin B12 treatment affirmed that there were only two published studies that met the predefined inclusion criteria (4, 5). Both were short-term trials of remission treatment in patients with mild to moderate deficiency and had even these two studies had serious shortcomings. The study of Kuzminski et al. (4)  may not have done justice to intramuscular therapy, which in the setting of the study appeared to be inferior to oral therapy, because trough values (one month after last injection) in the group of patients with intramuscular supplemention were compared with on-going oral therapy (6). In contrast, the oral dose in the Bolaman study (5) was insufficient with regard to dosage intervals (7).

During the last decade, a further three studies that compared intramuscular and oral vitamin B12 supplementation have been published (1,8, 9). In addition, the majority of patients on maintenance B12-therapy in Sweden are treated orally (10,11).

The aim of the present commentary is to put the paper by Kwong and al. (1) into a wider context of the current scientific evidence on the efficacy of oral B12 treatment.

Material and methods

The study was performed in two academic family practice units and in one community health centre in Toronto. All patients who had received intramuscular vitamin B12 therapy on a regular basis (every 1-3 months) were eligible for the trial on oral vitamin B12 therapy (one tablet, 1000 µg, daily) for 6 months, without regard to the patients’ age or aetiology of vitamin B12 deficiency. 133 patients met the inclusion criteria. Of these, 63 were willing to switch, 55 actually switched to oral vitamin B12, but only 47 completed the trial. After the trial 39 chose to continue with oral therapy, while 8 patients preferred intramuscular treatment.

Out of the 86 patients who returned the initial questionnaire 23 patients (27%) were not willing to participate, 8 changed their minds prior to study entry, and 5 withdrew f after entry, while further three were lost on follow-up.

Results

Serum vitamin B12 measurements were available at baseline (one month after the last injection) and after 6 months of oral supplementation from 40 patients (Fig 1). The scatter of individual values at baseline was considerable and increased during the course of the trial. In one patient, serum vitamin B12 actually decreased. In a further 10 patients, the change in vitamin B12 from baseline was less than 100 pmol/L, which may be considered a non-significant change taking biological and assay variability into account. The others increased their serum vitamin B12 values significantly.

Discussion

The main conclusion of the authors was that a switch from intramuscular to oral vitamin B12 therapy for maintenance treatment of deficiency is feasible in a substantial portion of patients, and that a high degree of acceptance may be achieved among those patients who actually tried oral B12 treatment (1).

On the other hand, using an intention to treat analysis, only about 30% of the patients were switched successfully. This number contrasts experience from  countries with long tradition of oral treatment, such as Sweden, where - in the year 2005 - oral vitamin B12 accounted for 73% of the total vitamin B12 prescribed (10).

The relatively low conversion rate reported by Kwong at al. might be related to the fact that the study was performed in a country without traditions of oral vitamin B12 treatment which may explain the higher degree of scepticism among the Canadian patients.

Vitamin B12 shows a considerable within-person biological variability (about 15%) (12) and the between-day variability of immunological B12-assay used in clinical routine is quite high (11-14%) (13). This means that the reference change value, that is how much two consecutive measurements in the same subject must deviate to be considered significant, is substantial and may approach 50-60% (14). As a consequence, an increase of less than 100 pmol/L may not be considered a significant treatment response but could be explained by biological and analytical variability alone.

Assuming a bioavailability (through passive absorption) of at least 1%, an oral dose of 1000 μg approximately corresponds to a B12 loading of 10 µg per day which theoretically should suffice to meet B12 requirements (2-3 μg/d) in the majority of cases (11).

In fact, Kwong et al. observed mean post-supplemention B12 values of about 700 pmol/L, which is a concentration close to the upper reference range of many laboratories, just as observed in comparable studies (4,8,9).

However, in the study of Kwong et al. about 10 out of the 39 patients  showed non-significant responses according (< 100 pmol/L increase in serum B12). Of note, the majority of these “poor responders” also had baseline B12 values in the lower range.

It is not known whether poor biochemical response was due to poor compliance or insufficient oral doses. At least, the reported compliance in the study of Kwong et al. was high (92%) (1) and suboptimal dosing in some patients with certain cause of B12 deficiency might be an alternative explanation.

The serum levels that can be achieved by an oral dose of 1000 μg are influenced by rate of passive absorption and active absorption through intrinsic factor (residual intrinsic factor production), possible competition with B12-consuming bacteria in the gut flora, the rate of enterohepatic recycling, the pre-treatment status (depletion) of the body stores of vitamin B12, the total B12-binding capacity of transport proteins in serum, and renal re-absorption and excretion of vitamin B12 into urine (11). These factors could explain higher B12-demands of some patients.

In any case, an oral dose of 1 mg B12 seemed to suffice in 70-80% of cases, which would mean that possibly twice as many patients might have been supplemented successfully with oral B12, if oral treatment had gained higher initial patient acceptance 

The study of Kwong et al. has many limitations. The study was not randomized and did not include a control group. Furthermore, no clinical endpoints and  only one biochemical parameter were evaluated. Still, the findings of Kwong et al. suggest that oral B12-therapy is feasible, and that one might achieve an initial “conversion rates” of approximately 30% from parenteral to oral supplementation in a country without tradition of oral treatment. In this respect, the Canadian experience resembles the situation in Great Britain (9).

Furthermore, the study of Kwong et al. indicates that - from the patient view - major factors that may hamper a switch to oral therapy are the following: Reluctance to taking too many pills (polypharmacy), swallowing problems, fear of side effects and allergic reactions, and fear that contact with health care providers is reduced. In addition, there is still a lot of scepticism against oral B12-treatment among general practitioners. 

It is evident that proper RCTs are difficult to conduct, and this is partly due to the great variability in the study populations and among the causes of vitamin B12 deficiency, as well as unknown sizes of body stores at baseline and unpredictable compliance (cf 6,7).

Furthermore, for ethical reasons it is in most cases unacceptable to include an untreated control group in long-term clinical trials.

Possibly, long-term cohort studies with sequential B12-measurements in the same patients before and after oral therapy might be more acceptable and could provide more robust results.

The findings of Kwong et al emphasise that a tight follow-up of patients on oral B12 treatment is necessary to maintain high compliance and to discover poor responders at an early stage (1).

Conclusions

The study of Kwong et al (1) suggests that oral B12 treatment is feasible for a large proportion of patients receiving parenteral supplementation. Still, Kwong et al. observed a relatively low initial acceptance rate compared to countries where oral B12-treatment is well-established. This may be partly due to unfounded scepticism among patients (and doctors). Among the patients who switched to oral treatment significant increases in serum B12 concentrations were observed in about 70-80 % of cases and most patients preferred this treatment option.

Jörn Schneede, MD, PhD

Medical Bioscience,
Clinical Chemistry and Clinical Pharmacology
University Hospital of Northern Sweden
SE-901 85 Umeå, Sweden

E-mail: jorn.schneede@medbio.umu.se

 

Jörn Schneede, born 1961 in Ratzeburg, Germany. He studied medicine in Kiel, Lübeck and Bergen, Norway. He defended his theses on functional markers of cobalamin deficiency in 1996(http://libris.kb.se/bib/7490409). In the period 1990 to 2004, he was part of the Ueland team doing homocysteine research in Bergen. He moved to Umeå, Sweden, in 2004 for family reasons.

 

References

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2. Vidal-Alaball J, Butler C, Cunnings-John R, Hood K, McCaddon A, McDowell J, Papaioamou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency (reviews). Cochrane Database of Systematic Reviews 2005, Issue 3

3. Butler CC, Vidal-Alaball J, Cunnings-John R, McCaddon A, Hood K, Papaioamou A, McDowell J, Goringe A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency; a systematic review of randomized controlled trials. Family Practice , april 3, 2006

4. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency sith oral cobalamin. Blood 1998; 92:1191-8

5. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barultca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: A single-center, prospective, randomized, open-label study. Clin Ther 2003; 25:3124-34

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8. Roth M, Orija I. Oral vitamin B12 therapy in vitamin B12 deficiency Amer J Med 2004; 116:358

9. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightinggale P, Fegan C. Oral vitamin B12 can change our practice. Postgrad Med J 2003; 79:218:209

10. Norberg B. Deficiency of vitamin B12 and folate – the branded generic for optimal oral therapy [editorial]. Rondel 2008; 28. URL: http://www.rondellen.net/publisher28_eng.htm

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12. Westgard JO. Westgard QC: Desirable specifications for total error, imprecision, and bias, derived from biologic variation, Annex 1, part 1 [Internet]. [cited 2009 Feb 23 ] Available from: http://www.westgard.com/biodatabase1.htm

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14. Omar F, van der Watt GF, Pillay TS. Reference change values: how useful are they? J Clin Pathol. 2008 Apr ;61(4):426-7