Significant increase of serum B12 levels with high-dose oral vitamin B12 supplementation with or without intrinsic factor after Roux-en-Y gastric bypass: A randomized controlled trial
Introduction
VitB12 or cobalamin (Cbl) is a micronutrient essential for normal erythropoiesis, growth and overall development (Brito et al., 2018; Butler et al., 2006; Henfridsson et al., 2019). Deficiency is frequently defined as serum plasma levels below 148 pmol/L (200 pg/mL) and is associated with low holotranscobalamin (HoloTC) and elevated serum levels of homocysteine and methylmalonic acid (Allen, 2009; Brito et al., 2018; Scott, 1999). Clinical symptoms include anemia, fatigue, neurological complications and cognitive impairment (Brito et al., 2018; Butler et al., 2006; Henfridsson et al., 2019). VitB12 levels are entirely dependent on dietary intake since this necessary micronutrient cannot be produced by the human body itself.
A review of Doets et al. showed that daily vitamin B12 losses probably range from 1.4 to 5.1 μg in apparently healthy adults. Based on the relationship between the ingested dose and the biological availability, the vitamin B12 intake needed for compensation of daily losses ranges from 3.8 to 20.7 μg (Doets et al., 2013).
VitB12 deficiency is observed in 2–18% of obese patients (Saltzman and Karl, 2013). This number rises to 6–30% when, in addition to obesity, a proton pump inhibitor (PPI) is used (Parrott et al., 2017). As early as 2 months after RYGB, the vitB12 absorption capacity is markedly decreased with a negative homeostasis 4 months later (Kornerup et al., 2019). The first year after RYGB, a significant decrease of serum vitB12 level is reported in 17–60% of patients (Alexandrou et al., 2014; Mechanick et al., 2009; Souza et al., 2020; Vargas-Ruiz et al., 2008). Furthermore, Alexandrou et al. described that 4 years after RYGB 42.1% of patients suffered from vitB12 deficiency measured by vitB12 serum levels (Alexandrou et al., 2014).
A generally accepted explanation for vitB12 deficiency after RYGB is the small gastric pouch, where HCl and IF producing cells are both bypassed. This results in an inadequate gastric processing of food, as well as a low secretion of IF, which are both critical for normal vitB12 uptake (Behrns et al., 1994; Brito et al., 2018; Butler et al., 2006; Carvalho et al., 2012; Gesquiere et al., 2017; Parrott et al., 2017). After digestion and liberation of free Cbl, this vitamin binds to IF, whereupon the IF-Cbl complex undergoes a receptor mediated endocytosis in the distal small intestine (Alpers, 2016).
Under normal circumstances the uptake of Cbl from a single dose is limited to 1–2 μg by the amount of IF-Cbl receptor in the intestine (Brito et al., 2018). Apart from the IF-Cbl receptor, a low secretion of IF is also a well-known cause of Cbl malabsorption in pernicious anemia (Green et al., 2017).
After RYGB IF production is low and therefore less IF-Cbl complexes can be formed, resulting in impaired vitB12 absorption (Marcuard et al., 1989; Smith et al., 1993). Gesquiere et al. showed that initially after RYGB the dietary vitB12 intake is significantly decreased, but gradually increases until 12 months post-RYGB, still remaining below the preoperative intake values (Gesquiere et al., 2017).
In practice, oral vitB12-supplementation after RYGB is not always sufficient. As a result, the vitamin is frequently administered by intramuscular injections (Madhok et al., 2018; Worm et al., 2015). These injections can be painful for the patient and also the organization of frequent injections burdens the health care system. A systematic review by Mahawar et al. concluded that low-dose oral preparations (<= 15 μg) are inadequate as prophylaxis after RYGB (Mahawar et al., 2018). High-dose oral vitB12 (1000 mg) can be used instead, as was shown by several studies on healthy cohorts and pernicious anemia patients. High quantities of vitB12 guarantee its unspecific permeability (1–2%), bypassing the malfunctioning specific uptake (Green et al., 2017).
To our knowledge, no clinical trial has been performed in RYGB cohorts to evaluate the effect of high oral B12 with IF added. The current work attempts to address this issue.
Section snippets
Study design
This study is a randomized, monocentric, double blind, placebo-controlled trial. Equal numbers of patients were assigned to one of the three study groups: placebo, oral vitB12 supplement or vitB12 with IF (vitB12IF). The intervention started 2 days after the RYGB surgery and ended 6 months post-surgery. In addition to the study intervention, all patients were instructed to start their multivitamin (without vitB12) intake 6 weeks post-surgery and until 6 months post-surgery, as advised in the
Study population
A total of 225 patients were randomized (1:1:1) over the three treatment groups. The per-protocol analysis included 159 subjects: 59 patients in the placebo group, 52 patients in the VitB12 group and 48 patients in the VitB12IF group. A drop-out of 66 patients (29%) corresponded to 44 who missed the follow-up (67%) plus 22 due to non-compliance (33%).
Mean age was 39.7 (SD ± 12.8) years, mean BMI 41.4 (SD ± 4) kg/m2 and 71.7% of patients were female. At baseline, 32% of patients suffered from
Discussion
This trial confirms the treatment efficacy of daily high dose oral vitB12 supplementation (1000 μg) without IF in the prevention of vitB12 deficiency after RYGB in patients with normal baseline vitB12 serum levels. This effect was also confirmed in a systematic review from 2006 with Cbl deficient patients (Butler et al., 2006). Schijns et al. reported similar plasma vitB12 concentrations after intramuscular injections or oral high-dose vitamin B12 (1000 μg methylcobalamin) (Schijns et al., 2018
Conclusion
This randomized controlled trial shows the efficacy of high-dose oral vitB12 supplements on increasing serum vitB12 levels and therefor avoiding vitB12 deficiency after RYGB surgery and bypassing the need for intramuscular injections.
There is no statistically significant benefit on serum vitB12 levels when adding IF to a high-dose oral vitB12 supplement, at least not for the vitB12 and vitB12IF commercial preparations used in our study.
Declining levels of serum vitB12 in the placebo group
CRediT authorship contribution statement
Melissa Ooms: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Greet Vanheule: Conceptualization, Methodology, Formal analysis, Writing – original draft. Karen Van Langenhove: Conceptualization, Methodology. Nick De Wever: Writing – review & editing. An-Katrien Vynckier: Conceptualization, Resources. Mieke Van Den Driessche: Conceptualization, Resources. Sebastiaan Van Cauwenberge: Supervision. Bruno Dillemans: Supervision, Writing – review &
Declaration of competing interest
Authors 2, 6 and 7 are employees of Metagenics Europe. The other authors declare that they have no conflict of interest.
Acknowledgement
The study products were funded by Metagenics Belgium, Edward Vlietinckstraat 20, 8400, Ostend, Belgium.
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