Methods
We performed an observational cohort analysis of patients who underwent bariatric surgery between August 2010 and October 2012 at our National Health Service (NHS) university teaching hospital in Greater Manchester, UK. Patients were identified from our bariatric surgery database, and clinical information was collected from electronic patient records. We evaluated all patients who underwent GB (252, 71.4%) or SG (101, 28.6%); 15 patients who underwent other primary bariatric surgical procedures (14 gastric band, 1 biliopancreatic diversion/duodenal switch) were excluded. All 252 GB procedures were performed as laparoscopic Roux-en-Y gastric bypass involving the fashioning of a short 5 cm vertical gastric pouch based on the lesser curvature of the stomach and constructed over a 40-French orogastric tube using staplers. An antecolic antegastric Roux-en-Y gastrojejunostomy was fashioned with the bilioenteric limb measuring 100 cm and the alimentary limb measuring 100–150 cm depending on the patient’s body mass index (BMI). A side-to-side jejunojejunostomy was fashioned using intracorporeal suturing technique, and an end-to-side gastrojejunostomy was constructed using intracorporeally sutured technique over a 40-French orogastric tube. The jejunojejunal and Petersen’s mesenteric defects were routinely closed using nonabsorbable sutures. Laparoscopic SG involved the construction of a vertical gastric sleeve over a 40-French orogastric tube starting 4–6 cm from the pylorus and ending approximately 1 cm lateral to the angle of His using staplers.
All patients were prescribed oral complete micronutrient/multivitamin supplement (Forceval®) including folic acid 400 μg, oral iron (ferrous sulfate 400 mg) and oral combined calcium and vitamin D (elemental calcium 1200 mg and cholecalciferol 800 units) daily, and hydroxocobalamin 1 mg intramuscular injection every 3 months. Scheduled postoperative follow-up appointments were at 6 weeks, 4 months, 12 months and annually thereafter for clinical assessment and blood tests. The data assembled included height, weight and BMI, and serum levels of vitamin B
12, folate, iron, ferritin, haemoglobin and mean corpuscular volume (MCV) at baseline and 4, 12, 24, 36 and 48 months postoperatively. Low levels of vitamin B
12 (< 211.0 ng/L), folate (< 4.0 μg/L), iron (< 9 μmol/L in women and < 11 μmol/L in men), haemoglobin (< 115 g/L in women and < 130 g/L in men) and MCV (< 80 fL) were defined as per their respective laboratory recommended reference ranges [
28]. Ferritin levels were defined as deficient (< 15 μg/L) or insufficient (< 50 μg/L) [
29]. Statistical analysis included descriptive statistics, parametric tests (or non-parametric tests for non-normative data as appropriate) and contingency tables using Fisher’s exact test.
P < 0.05 was deemed to be statistically significant, and 95% confidence intervals (95% CI) were reported where appropriate. Data were analysed using IBM SPSS 25.0 (Armonk, NY) and GraphPad Prism 7.0 (San Diego, CA).
Discussion
We studied deficiencies of haematinics, namely vitamin B
12, folate and iron, before and after bariatric surgery over 4 years of follow-up. Very few patients in our cohort had anaemia preoperatively, lower than in the general population or other studies describing 7–22% [
20,
30]. However, we report deficiencies of iron in three-tenths, vitamin B
12 in nearly one-tenth and folate in one-twentieth of patients preoperatively, rates that are higher than in the general population [
16,
30,
31], and corroborate previous findings of a prevalence of iron deficiency of 30–40% [
26], as well as vitamin B
12 and folate deficiencies prior to surgery [
32,
33].
A higher rate of preoperative low serum iron levels in men was observed in our study, in contrast to previous work which has demonstrated male gender to be protective against iron deficiency [
26]. We report an early improvement in iron levels in both men and women, irrespective of type of surgery, but with a similar proportion of patients with low iron levels at 48 months. Women under 50 years had a lower mean serum iron level than those 50 and over, corroborating previous findings of a higher frequency of iron deficiency in menstruating women [
34]. There was a significant improvement in iron deficiency in men over this time; however, tendencies towards abrogation of iron deficiency in women and according to each type of surgery remained statistically non-significant. A recent meta-analysis of twenty studies between 2000 and 2015 reported similar absolute rates of iron deficiency when comparing procedures, with a frequency of 22.5% post-GB and 12.4% post-SG, but with an increased risk of iron deficiency after GB but not SG, from a baseline of 14.7% and 36.6%, respectively [
35]. This worsening of iron status after GB has been noted elsewhere [
20] and is likely due to bypassing of the stomach and duodenum, precluding efficient iron absorption [
24]. Iron deficiency may also reflect loss of iron in those women who menstruate, in addition to the population in whom menstruation resumes after bariatric surgery following correction of obesity-related anovulation and insulin resistance [
24].
Although mean ferritin levels increased over the course of follow-up in our study, probably related to the supplementation regime and initial good adherence, a higher proportion of patients had insufficiency by 48 months despite an initial rise at 4 and 12 months. This has been noted elsewhere and is thought to correlate with a heightening of the inflammatory state associated with the greater degree of weight loss over the first 6 months postoperatively [
36]. In this study by de Cleva et al. [
36], iron deficiency anaemia replaced anaemia of chronic disease as the predominant cause of anaemia after GB, attributed to postoperative food aversions, malabsorption, menstruation, and reduction in the obesity-related proinflammatory state.
Obesity is not known as a risk factor for vitamin B
12 deficiency per se, but may occur in the context of use of metformin and proton pump inhibitors, and poor nutrient intake [
16]. Metformin use in our cohort was not associated with vitamin B
12 deficiency. Vitamin B
12 deficiency has been reported to be more frequent after GB compared to SG [
37‐
40], probably as a consequence of reduced gastric acid and intrinsic factor production [
20], although no significant difference was observed in our study. A meta-analysis of nutrient deficiencies after bariatric surgery found a prevalence of cobalamin deficiency increasing from 2.3% at baseline to 7.2% at 36 months post-GB despite supplementation [
20]. This contrasts our findings of a decrease in prevalence of cobalamin deficiency; however, this is unsurprising as previous studies predominantly involved the use of oral multivitamins to provide vitamin B
12 with only half supplementing with intramuscular cobalamin. Other work has shown that either intramuscular or high-dose oral cobalamin supplementation is required to prevent deficiency [
31].
An improvement in the proportion of patients with folate deficiency after GB has been noted [
20], which may be attributed to supplementation with multivitamins postoperatively as well as fortification of a host of foodstuffs with folic acid [
31]. There is increased risk of folate deficiency post-GB related to decreased gastric acid secretion and reduced absorption due to bypassing of the upper segment of the small intestine [
39]. We observed an increased frequency of folate deficiency after SG, but not GB, which has been noted elsewhere [
37,
38], although the cause of this remains to be elucidated. Higher preoperative BMI was associated with folate deficiency. This corroborates previous findings [
41], and may be related to a high-calorie diet deficient in micronutrients [
31].
Weng et al. evaluated nine studies from 2009 to 2014 and found an increase from 12% of patients with anaemia prior to GB to 23% at 36 months, despite supplementation with multivitamins in most reports [
20]. We found lower prevalence of anaemia, probably due to our regimen of supplementation with iron tablets containing higher doses of iron. Data regarding the relative risk of anaemia after SG compared to GB remains conflicting. A study of 306,298 patients described a two-fold higher risk of anaemia after GB compared to SG [
42], with similar findings reported recently [
35]. In contrast, a meta-analysis by Kwon et al. in 2014 did not demonstrate a significant difference in the rates of anaemia between the two types of surgery [
43].
A recent study has reported higher rates of anaemia and iron and vitamin B
12 deficiencies at two and 3 years postoperatively after gastric bypass [
44]. Two other studies have reported differing findings regarding the effect of surgery on haematinic status. Misra et al. [
45] described no significant difference in rates of anaemia or deficiencies in ferritin, vitamin B
12 or folate between GB and SG at 3 years’ follow-up, a result echoed in our study. Ledoux et al. [
46] similarly reported no effect of type of procedure on vitamin B
12 deficiency or anaemia, although rates of anaemia increased more substantially after GB; there was a higher frequency of folate deficiency after SG compared to GB.
Clearly there is some heterogeneity, and further work is required to delineate the risk of anaemia attributed to each procedure. Despite an increase in iron and folate deficiency throughout 48 months of follow-up, this was not correlated with a concomitant rise in the frequency of anaemia. Low serum iron levels became more frequent beyond 12 months after surgery. This suggests reduced adherence to recommended supplementation. Haematinic deficiencies remain a risk for development of anaemia, and longer follow-up is required to determine whether these deficiencies would ultimately progress to anaemia.
In an effort to improve the frequency of haematinic deficiencies and consequent anaemia post-bariatric surgery, a multidisciplinary team approach is crucial to encourage patient engagement to continue taking supplements postoperatively, with a particular focus on women of childbearing age [
19]. Our practice includes multidisciplinary, patient-focused approach with peer-group support and the improvements in haematinic levels in our study provide evidence of high levels of medication adherence by patients. Additionally, given the high frequency of iron deficiency preoperatively, there may be a case for consideration of providing supplementation even prior to surgery. Obesity itself is associated with reduced serum iron levels, firstly due to poor iron intake and secondly because of hepcidin upregulation as part of the inflammatory milieu, thereby resulting in functional deficiency [
47]. Thus, supplementation may not be enough to prevent iron deficiency in either non-surgical candidates or those postoperatively but remains the main treatment option to optimize iron status at present. Parenteral iron is expensive and more difficult to administer, but is effective in cases of refractory iron deficiency anaemia [
36].
Studies support the use of a pharmaceutical-grade multivitamin, the use of which resulted in reduction in rates of haematinic deficiencies and anaemia after GB [
48,
49]. The multivitamin used in the study by Homan et al. included 350 μg of vitamin B
12 [
48], which may be sufficient to overcome deficiency as 1–5% of vitamin B
12 is absorbed by an intrinsic factor-independent mechanism [
16]. However, other studies demonstrated higher doses of oral hydroxocobalamin are required, with 1000 μg per day proving optimal to manage vitamin B
12 deficiency after GB [
50]. Furthermore, in a study comparing oral and intramuscular cobalamin, there was no significant difference in improvement in vitamin B
12 levels, suggesting that high-dose oral vitamin B
12 (1000 μg per day) is sufficient to overcome deficiency [
51]. Whether oral vitamin B
12 can prevent deficiency in a real-world setting remains to be seen.
Limitations of this study include its retrospective design (although data was accumulated prospectively) and data attrition due to patients lost to follow-up. It was beyond the scope of this pragmatic, real-world, retrospective observational study to accurately confirm adherence to recommended post-surgical supplementations. Previous studies have reported adherence to vitamin supplementation post-bariatric surgery may be as low as 30%, and risk factors for poor adherence include male gender, full-time work and attachment anxiety [
52]. Poor adherence with iron therapy is well-documented, resulting from various factors including frequent side effects, unavailability of supplements, lack of education and/or support by healthcare professionals, and low demand for treatment due to lack of symptoms of anaemia [
53]. In cases where iron deficiency persists despite good adherence, parenteral supplementation is usually required especially in menstruating and pregnant women [
54]. It was beyond the scope of this work to ascertain menstruation status in women of childbearing age. We also did not evaluate albumin, copper and zinc levels which can rarely contribute to anaemia.
In summary, we report a high proportion of haematinic deficiencies preoperatively, especially in iron. A strong focus on encouragement of patients to continue taking supplements post-bariatric surgery is imperative, and there may even be an argument for consideration of iron supplementation prior to surgery, especially in pre-menopausal women.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.