Investigation of homocysteine level after bariatric metabolic surgery, effect on vitamin B12 and folate levels

Abstract

Background

Obesity is a serious health problem with increasing incidence. worldwide and remains one of the most important causes of preventable deaths. We aimed to examine the relationship between Vitamin B12 and Folic acid, which have an important role for human life, and homocysteine is widely recognized for its association with the development of cardiovascular disease, although its role as an independent risk factor remains a topic of ongoing debate.

Materials and methods

We evaluated 126 patients who underwent bariatric metabolic surgery between September 2019-September 2020. In addition to demographic characteristics of the patients, weight, Vitamin B12, folate, HbA1c, cholesterol, triglyceride, ferritin, serum iron, albumin levels at preoperative, postoperative 1st month, 6th month, 12th month follow-ups were analyzed.

Results

Patients with the desired biochemical parameters at the determined follow-up points were identified and two groups were formed as RYGB(n = 43) and SG(n = 7) patients. When biochemical parameters were analyzed between the groups, homocysteine, HbA1c, HDL Cholesterol, VLDL Cholesterol, Total Cholesterol, Triglycerides, Ferritin, Serum Iron levels showed a statistical difference (p < 0.001). Folate (p = 0.064) and albumin (p = 0.257) did not show a significant difference over time. The change in vitamin B12 (p = 0.409) over time was not significant in the SG group, whereas a significant difference was observed in the RYGB group (p < 0.001). When we established a marginal model to determine the factors affecting the change in homocysteine over time, vitamin B12 and folate values.

Conclusions

The relationship between Vitamin B12, folate and homocysteine is important in order to better understand the complications that develop in bariatric metabolic surgery patients, to prevent possible complications and to better manage the process.

Introduction

Obesity represents one of the leading health problems worldwide, with its incidence increasing due to the prevalence of sedentary lifestyles. This condition is associated with a myriad of comorbidities, including type 2 diabetes mellitus, dyslipidemia, insulin resistance, hypertension, sleep apnea, polycystic ovary syndrome, and cardiovascular diseases, as well as certain cancers and psychosocial disorders [1,2,3,4]. The increasing prevalence of obesity highlights the need for effective treatment strategies, among which bariatric metabolic surgery plays a critical role.

Bariatric metabolic surgery has become a prominent intervention for managing severe obesity and its associated complications. The primary mechanisms by which these surgical procedures operate include reducing the stomach’s volume, thereby limiting food intake, and altering the gastrointestinal tract to decrease nutrient absorption [5,6,7,8]. Specifically, procedures such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) not only limit caloric intake but also affect the absorption of essential vitamins and minerals, which can lead to significant postoperative nutritional deficiencies [5, 9]. The majority of folic acid is absorbed after several enzymatic reactions on small intestinal surface cells [10,11,12].

One of the critical concerns following bariatric surgery is the potential alteration in the absorption of vitamins B12 and folate. These vitamins play essential roles in various metabolic processes, including the regulation of homocysteine levels, which are implicated in the development of cardiovascular diseases (CVD). Elevated homocysteine levels have been associated with an increased risk of coronary artery disease, peripheral arterial diseases, cerebrovascular events, and venous thromboembolic events [13,14,15,16].

In light of these considerations, our study aims to evaluate the impact of bariatric metabolic surgery on vitamin B12 and folate levels and their subsequent effect on homocysteine metabolism. Understanding these relationships is crucial for identifying potential complications, such as neurological disorders and cardiovascular risks, that may arise due to altered nutrient absorption following bariatric procedures. By examining these parameters, we aim to provide insights into optimizing postoperative management and preventing long-term complications in patients undergoing bariatric surgery. We hypothesize that bariatric surgery, particularly Roux-en-Y Gastric Bypass (RYGB), significantly impacts vitamin B12 and folate levels, leading to alterations in homocysteine metabolism. Given the association between elevated homocysteine levels and cardiovascular disease, this study aims to evaluate these biochemical changes to better understand the potential cardiovascular risks and the need for tailored postoperative care.

Materials and methods

This study was designed as a retrospective cohort study. A total of 167 patients who underwent either Sleeve Gastrectomy (SG) or Roux-en-Y Gastric Bypass (RYGB) surgery for severe obesity at our tertiary care center between September 2019 and September 2020 were initially considered for inclusion.

Patients were selected based on specific criteria to ensure a homogenous study population. We excluded 41 patients who had preoperative homocysteine levels above the upper limit of the normal range, had any congenital or acquired disease that could cause elevated homocysteine levels, or who did not attend postoperative follow-up. The exclusion of patients with elevated preoperative homocysteine levels was done to focus on evaluating the effects of bariatric surgery on homocysteine levels within a normal range population and to avoid confounding factors that could skew the analysis of postoperative changes.

Ultimately, 126 patients met the inclusion criteria and were included in the final analysis. The study was conducted in accordance with the ethical standards of the institutional review board, and informed consent was obtained from all patients.

All surgeries were performed by experienced bariatric surgeons using either laparoscopic or robotic techniques. Of the 126 patients, 106 (84.13%) underwent RYGB, and 20 (15.87%) underwent SG. The choice of surgical procedure was based on a thorough preoperative evaluation and discussions with each patient, taking into consideration their specific medical conditions and surgical risks.

Postoperatively, all patients were prescribed multivitamin supplements, including 350 µg of vitamin B12 and 400 µg of folic acid daily, along with high-protein preparations to start after discharge. The vitamin and nutritional supplementation regimen was adjusted based on the patients’ 1st-month follow-up blood parameters. Prophylaxis for deep vein thrombosis was provided with low molecular weight heparin preoperatively (single dose, last evening) and postoperatively (up to 2 weeks). Antibiotic prophylaxis was administered with the induction of anesthesia and continued until discharge.

Patient demographics, including age, gender, body mass index (BMI), and associated medical conditions (e.g., diabetes mellitus, hypertension, dyslipidemia), were recorded. Preoperative and postoperative blood samples were collected at 1, 6, and 12 months to evaluate homocysteine, vitamin B12, folic acid, LDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, triglycerides, ferritin, iron, and albumin levels.

Patients were categorized into two groups based on the surgical procedure: the RYGB group (n = 43) and the SG group (n = 7). The low follow-up rate at the 3rd month led to the exclusion of this time point from the statistical analysis. The number of patients who consistently attended the follow-up visits was affected by the COVID-19 pandemic, which limited the ability of some patients to visit healthcare facilities.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software version 26.0. Descriptive statistics were calculated for all collected data. The normality of quantitative data distribution was assessed using the Shapiro-Wilk test, boxplots, and histograms.

For normally distributed independent variables, the significance of differences between groups was evaluated using an independent samples t-test. For non-normally distributed variables, the Mann-Whitney U test was applied. Categorical variables were compared using the chi-square test. A two-way repeated measures analysis of variance was employed to compare the changes in measured variables over time between the two groups. Additionally, a marginal model was constructed to identify factors influencing changes in homocysteine levels over time. This model included variables such as surgical procedure (RYGB or SG), age, gender, folate levels, vitamin B12 levels, and associated medical conditions.

All tests were two-tailed, and a p-value of less than 0.05 was considered statistically significant. The study received ethical approval from the Gazi University Faculty of Medicine Institutional Review Board (Approval No: 122-17.02.2021).

Results

A total of 126 patients were included in the study, of which 26 (20.63%) were male and 100 (79.37%) were female. The mean BMI was 41.30 kg/m² (± 5.75), and the median age was 37 years (range 18–72). Among the participants, 62 (49.21%) had Type 2 diabetes mellitus, 64 (50.79%) had dyslipidemia, and 27 (21.43%) had hypertension. The majority of the surgeries were Roux-en-Y Gastric Bypass (RYGB) (106 patients, 84.13%), while 20 patients (15.87%) underwent Sleeve Gastrectomy (SG). Most of the surgeries were performed using robotic techniques (97.61%), with the remainder conducted laparoscopically. Postoperative complications occurred in 2 (1.59%) patients, both of which were Clavien-Dindo Class II (gastrointestinal bleeding and pulmonary infection). The median length of hospitalization was 2 days (range 1–10) (Table 1).

Table 1 Analysis of patient population demographic data and associated medical problems

When comparing biochemical parameters over time within and between the RYGB and SG groups, several significant findings were observed.

Homocysteine

Homocysteine levels showed a statistically significant increase over time in both groups (RYGB: p < 0.001; SG: p < 0.001). The increase was most notable at the 1st and 6th-month follow-ups, with levels starting to stabilize by the 12th month. However, there was no statistically significant difference in homocysteine level changes between the two surgical groups (p = 0.494) (Table 2; Fig. 1).

Table 2 Statistical analysis of blood parameters of bariatric surgery patients over time and between groups

Fig. 1

Homocysteine, Vitamin B12 and folate change over time

Vitamin B12

In the RYGB group, Vitamin B12 levels showed a significant decrease over time (p < 0.001), with the most pronounced decrease occurring by the 12th month. In contrast, the SG group did not exhibit a significant change in Vitamin B12 levels over time (p = 0.409) (Table 3).

Folate

The change in folate levels over time was not statistically significant in either group (RYGB: p = 0.064; SG: p = 0.973). There was also no significant difference between the groups (p = 0.973) (Table 2).

Lipid profile

Significant changes were observed in the lipid profiles of patients postoperatively. LDL cholesterol levels significantly decreased in the RYGB group (p < 0.001), while no significant change was observed in the SG group (p = 0.486). HDL cholesterol levels showed an increase over time in both groups, but this change was only statistically significant in the RYGB group (p = 0.002). Triglycerides and VLDL cholesterol levels decreased significantly over time in both groups (Triglycerides: p < 0.001; VLDL: p = 0.001) (Table 3).

Ferritin and iron

Ferritin levels increased significantly in the RYGB group over time (p = 0.011), while iron levels also showed a significant increase in the same group (p = 0.001). The SG group did not show significant changes in ferritin or iron levels (Ferritin: p = 0.730; Iron: p = 0.937) (Table 2).

Albumin

No significant changes were observed in albumin levels over time in either group (p = 0.257). There was also no significant difference between the groups in terms of albumin levels (p = 0.103) (Table 2).

Table 3 Statistical analysis of vitamin B12 and LDL cholesterol levels over time and between groups

To identify factors that may influence homocysteine levels postoperatively, a marginal model was constructed. The analysis revealed that both folate and vitamin B12 levels were inversely correlated with homocysteine levels. Specifically, each unit increase in folate was associated with a 0.35 unit decrease in homocysteine, and each unit increase in vitamin B12 was associated with a 0.006 unit decrease in homocysteine (p < 0.05). Additionally, male patients had higher homocysteine levels compared to female patients, with an average increase of 1.498 units (p = 0.038) (Table 4).

Table 4 Statistical analysis of parameters that may be associated with homocysteine elevation

Discussion

Obesity remains a critical public health challenge globally, with its prevalence steadily rising due to lifestyle changes, including increased sedentary behavior and unhealthy dietary habits [1, 2]. As a response to the growing burden of obesity-related comorbidities, bariatric metabolic surgery has become a well-established intervention. The present study aimed to evaluate the effects of bariatric surgery, specifically Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG), on homocysteine levels, alongside vitamin B12 and folate, which are crucial in homocysteine metabolism [17].

Our findings indicate a significant increase in homocysteine levels postoperatively in both the RYGB and SG groups, with the most pronounced elevation observed within the first six months [26]. This observation aligns with previous studies suggesting that bariatric procedures, especially those affecting the absorption of essential nutrients, may disrupt homocysteine metabolism. The increase in homocysteine levels raises concerns, as elevated homocysteine is associated with an increased risk of cardiovascular diseases (CVD), including coronary artery disease, stroke, and peripheral vascular disease [13,14,15,16]. Although our study observed elevated homocysteine levels postoperatively, bariatric surgery has been shown to provide cardiovascular protection. This protective effect could be attributed to mechanisms unrelated to homocysteine, such as improvements in lipid metabolism, inflammation reduction, and better glycemic control. Future studies should explore these alternative pathways to fully understand the cardiovascular benefits of bariatric procedures. This behavior of homocysteine, which tends to increase over time for both SG and RYGB groups, especially up to the first 6 months and reaches normal levels towards the end of 1 year, has been supported by Poglitsch M et al. [18].

The marginal model analysis further highlighted that decreases in vitamin B12 and folate levels were inversely correlated with homocysteine elevation. This suggests that the decline in these vitamins, likely due to altered absorption post-surgery, plays a significant role in the observed increase in homocysteine. These findings are consistent with existing literature, which underscores the importance of monitoring and supplementing these vitamins in bariatric patients to mitigate the risk of hyperhomocysteinemia and its associated cardiovascular risks [19, 20].

In our study, vitamin B12 levels significantly decreased over time in the RYGB group but not in the SG group [21]. In our study, despite the administration of oral B12 supplementation postoperatively, a significant decrease in B12 levels was observed. This suggests that malabsorption issues may persist after bariatric surgery, and oral supplementation alone may not be sufficient in some patients. The observed decrease, particularly in Roux-en-Y Gastric Bypass (RYGB) patients, could be attributed to the lack of parenteral support, highlighting the need for closer postoperative monitoring. Welbourn R. et al. [22] found that the female gender was slightly higher, and our study showed similar demographic characteristics, with the majority of patients being female. This result reflects the differing impacts of these two surgical procedures on nutrient absorption, with RYGB being more likely to cause malabsorption due to its more extensive alteration of the gastrointestinal tract. The lack of a significant change in folate levels in either group suggests that folate deficiency may not be as common as vitamin B12 deficiency in bariatric patients, but this does not diminish the importance of regular monitoring [21]. Lewis CA et al. [21] found, as we did, that the prevalence of folate deficiency did not show a significant change over time.

Our results are supported by the findings of Guan et al., who reported similar trends in vitamin B12 levels post-RYGB [19]. Furthermore, the observed inverse relationship between homocysteine and these vitamins reinforces the need for a comprehensive postoperative care plan that includes vitamin supplementation and regular monitoring to prevent potential complications [19, 20].

Given the significant alterations in homocysteine levels and the associated risks, it is crucial to consider the clinical implications of our findings. The persistent elevation of homocysteine, even in the presence of vitamin supplementation, suggests that current postoperative care protocols may need to be reevaluated. It may be beneficial to explore higher doses or different forms of vitamin B12 and folate supplementation, as well as additional interventions to manage homocysteine levels effectively.

Moreover, our findings highlight the need for a personalized approach to postoperative care, tailored to the specific surgical procedure and individual patient needs. This includes more frequent monitoring of homocysteine and vitamin levels, particularly in the first year post-surgery, when the most significant changes occur.

This study is not without limitations. The relatively small sample size, particularly in the SG group, limits the generalizability of our findings [23,24,25,26]. Additionally, the retrospective nature of the study and the exclusion of patients with preoperative hyperhomocysteinemia may have introduced selection bias. The COVID-19 pandemic also impacted the follow-up rate, potentially affecting the reliability of our long-term data.

Future research should aim to include larger, more diverse patient populations and consider prospective study designs to validate our findings. Investigating the long-term cardiovascular outcomes of bariatric patients with elevated homocysteine levels would also provide valuable insights into the clinical significance of our results.