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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 541-545
Copyright © 1999 by The Endocrine Society

Original Studies

Occurrence of Hyperhomocysteinemia 1 Year after Gastroplasty for Severe Obesity

Francoise Borson-Chazot, Catherine Harthe, Frederic Teboul, Florence Labrousse, Caroline Gaume, Ludivine Guadagnino, Bruno Claustrat, Francois Berthezene and Philippe Moulin

Service d’Endocrinologie (F.B.C, F.L, C.G, L.G, F.B, P.M.), Hôpital de l’Antiquaille, 69005; Service de Médecine Nucléaire (C.H, B.C.), Hôpital Neurologique, 69003; and Clinique Saint-Louis (F.T.), 69009, Lyon, France

Address all correspondence and requests for reprints to: Dr. F. Borson-Chazot, Service d’Endocrinologie, Hôpital de l’Antiquaille, 69005, Lyon, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Severe obesity exposes one to an increased risk of cardiovascular mortality. Gastroplasty has been shown to induce substantial weight loss and to improve the atherogenic profile of severely obese subjects. However, vitamin deficiencies after gastroplasty have been reported. Because hyperhomocysteinemia, an independent risk factor for cardiovascular disease, is influenced by nutritional status (and especially by folate intake), we hypothesized that a marginal folate deficiency induced by gastroplasty could promote hyperhomocysteinemia. Thus, plasma homocysteine concentrations were measured by high-performance liquid chromatography in 53 severely obese patients (body mass index = 42 ± 1), before and 1 yr after vertical gastroplasty. Plasma homocysteine concentrations increased, on an average, from 9.9 ± 0.4 to 12.8 ± 0.6 µmol/L (P < 0.0001). This increase in homocysteine levels was observed in two thirds of the subjects, leading to clear-cut hyperhomocysteinemia (>15 µmol/L) in 32%. The changes in homocysteine concentrations were correlated to weight loss (P < 0.001) and to decrease in plasma folate concentrations (P < 0.01). Whereas gastroplasty induced a mean 32-kg weight loss and a striking improvement in conventional risk factors, the occurrence of iatrogenic hyperhomocysteinemia might hamper the benefit of surgery on cardiovascular risk in most of the patients. Our results further support use of a systematic efficient folate supplementation after gastroplasty.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENT prospective studies have provided evidence that severe obesity increases the risk of morbidity and mortality from ischemic heart disease (1, 2). Obesity is associated with established cardiovascular risk factors such as high blood pressure, glucose intolerance, hypoalphalipoproteinemia, and hypertriglyceridemia (3, 4). An improvement of this atherogenic profile is observed after weight loss (5, 6). However, medical treatment of obesity has been shown largely ineffective in obtaining long-term substantial weight reduction (6, 7). Gastroplasty, the most common procedure for bariatric surgery, can induce both substantial and long-lasting weight loss associated with subsequent improvement of cardiovascular risk factors (8, 9, 10, 11, 12). Although this procedure has a low morbidity, reduction of food intake and vomiting expose one to a risk of vitamin deficiency (13, 14, 15, 16).

Hyperhomocysteinemia has progressively emerged as an independent risk factor for coronary, cerebrovascular, and peripheral vascular ischemic diseases (17, 18, 19, 20, 21, 22, 23). Efficient metabolism of homocysteine requires adequate supplies of folate, vitamins B6, and B12; and it was reported that plasma folate concentrations were the strongest predictor of plasma homocysteine concentrations (24, 25, 26, 27). We hypothesized that a marginal folate deficiency, induced by gastroplasty, might increase plasma homocysteine concentrations and could thereby minimize the beneficial impact of weight loss on the cardiovascular risk of subjects suffering from morbid obesity. This led us to measure homocysteine and folate concentrations in a cohorte of 53 subjects before and 1 yr after gastroplasty.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Fifty-three consecutive patients (49 women, 4 men; age, 37 ± 1 yr), undergoing gastroplasty for severe obesity in the same center [body mass index (BMI), 42 ± 1; range, 35–68], were studied. Informed consent was obtained, and the study was performed in accordance with the guidelines of the declaration of Helsinki. Surgery had been indicated, according to the guidelines of the NIH consensus statement for surgery in severe obesity (28, 29). Briefly, patients were systematically referred to a multidisciplinary team for medical, psychiatric, nutritional, and surgical expertise. Surgery was indicated for patients with a history of repeated failures with conservative, nonsurgical techniques, whose BMI was above 40 kg/m2 or between 35 and 40 kg/m2, in case of metabolic complications. Patients with overt eating disorders, heavy alcohol consumption, major psychiatric disease, and hepatic or renal failure were excluded. Vertical ring gastroplasty was performed, as described by Eckout (30), using a SILASTIC ring (31). All the patients were operated by the same surgeon. They were requested to participate in a regular follow-up. Daily polyvitamin substitution, including 0.2–0.4 mg folic acid, was recommended postoperatively. However, later evaluation evidenced very low compliance in most of the patients. All of them had interrupted vitamin substitution at least 6 months before the 1-yr postoperative evaluation.

Clinical evaluation and biochemical measurements

Patients were evaluated before and 1 yr after surgery. Clinical parameters, such as adverse events, medical treatments, weight, and blood pressure, were recorded. Blood samples for homocysteine, vitamin, and metabolic assessment were drawn on EDTA-containing vacutainer tubes after an overnight fast. Plasma was isolated after centrifugation for 15 mn at 3500 x g and was stored at -80 C until analysis.

Total homocysteine concentration was measured by high-performance liquid chromatography (32). All samples from a single subject were analyzed in the same run. Sensitivity of the assay was 0.5 µmol/L, and intra- and interassay coefficients of variation were 5% and 6%, respectively.

Folate and vitamin B12 were assayed by RIA (Simul TRAC-SNB, JCN Pharmaceuticals, NY), insulin concentrations by immunoradiometry (Biosource, Fleurus, Belgium), and blood glucose by colorimetry (glucose oxidase). Plasma total cholesterol and triglycerides were measured by enzymatic methods (Hitachi 717, Roche Diagnostics, Basle, Switzerland), plasma apo B and A1 by RIA, and lipoprotein (a) by enzyme-linked immunosorbent assay (Immuno, Vienna, Austria). Plasma high-density lipoprotein (HDL) cholesterol was measured, after precipitation of apo B-containing lipoproteins by phosphotungstic acid; and low-density lipoprotein cholesterol was calculated according to the Friedwald formula.

Assessment of food intake

Energy intake was evaluated in each patient (by the same registered dietitian, before and 12 months after gastroplasty) using a detailed dietary checklist over a 7-day period, combined with a history of eating habits. Results were expressed as kilocalories per day.

Statistical analysis

Data are reported as mean ± SEM. Comparisons before and after surgery were performed using a nonparametric Wilcoxon’s signed-rank or {chi}-square test, as appropriate. Correlations between plasma variables were explored by univariate linear regression. Two-tailed P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Effect of gastroplasty on nutritional parameters

One year after gastroplasty, the mean weight loss was 32 kg (range, 12–60 kg), and BMI fell by 28% (Table 1Go). No major adverse clinical events were reported. However, hemoglobin concentration decreased slightly (from 13.7 ± 0.12 to 13.1 ± 0.21 g/L; P < 0.004), and two cases of mild hypochromic microcytic anemia were recorded. Creatininemia (77.57 ± 0.92 vs. 76.86 ± 1.09 mmol/L) and plasma vitamin B12 levels were unchanged, whereas a mild (but significant), 20% decrease in plasma folic acid concentrations was observed (P < 0.03) (Table 1Go).


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  		Table 1. Nutritional effects of gastroplasty and consequences on cardiovascular risk factors

 
Mean plasma homocysteine concentrations rose from 9.9 ± 0.4 to 12.8 ± 0.6 µmol/L (P < 0.0001) (Fig. 1Go). Homocysteine changes were similar in males and in females, and the results remained unchanged upon exclusion of the 4 men from analysis. The increase in homocysteine levels occurred in 40 of 53 patients. Hyperhomocysteinemia, defined as a plasma concentration above 15 µmol/L, was detected in 6% of patients preoperatively and in 32% 1 yr after gastroplasty (P < 0.001). On the other hand, 45% of subjects had preoperative homocysteine concentrations below 9 µmol/L, as compared with only 20% 1 yr after surgery (P < 0.005).



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  		Figure 1. Effect of gastroplasty on plasma homocysteine concentrations. Individual results are shown. Plasma homocysteine increased in 40 of 53 patients. An increase between 5 and 10 µmol/L was observed in 14 patients and greater than 10 µmol/L in 2 patients. For the whole group, homocysteine levels increased from 9.9 ± 0.4 to 12.8 ± 0.6 µmol/L (P < 0.0001).

 
The increase in homocysteine levels was correlated to weight loss (r = 0.48, P < 0.001) (Fig. 2AGo) Plasma folic acid and homocysteine concentrations were correlated (r = 0.28; P < 0.004) (Fig. 2BGo), as were the magnitudes of their changes after surgery (r = 0.37; P < 0.006) (Fig. 2CGo). Moreover, when patients were segregated on the basis of their folate level after gastroplasty, we found that those with folate levels in the low normal range, i.e. between 1.5 and 4 µmol/L, as defined by Kang et al. (25), displayed significantly higher increases in plasma homocysteine levels (+4.70 ± 0.77 vs. +0.90 ± 0.40 µmol/L; P < 0.0001) than those with folate levels above this interval.



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  		Figure 2. Relationship among plasma homocysteine concentration, weight loss, and folate status. A, Relation between the increase in homocysteine concentration (µmol/L) and weight loss (kg; n = 53; r = 0.48; P < 0.0003). B, Relationship between plasma folate and homocysteine concentrations. Black circles show preoperative values, and open circles show the concentrations 1 yr after gastroplasty (n = 106; r = 0.29; P < 0.003). C, Relationship between the percent changes in plasma homocysteine and folate concentrations (n = 52; r = 0.37; P < 0.006). A single subject, with a 240% increase in homocysteine plasma concentration, was removed from this graph. Correlates including this patient were similar (n = 53; r = 0.36; P < 0.009).

 
Effect of gastroplasty on cardiovascular risk factors

Weight loss was associated with a marked decrease in conventional risk factors, as shown in Fig. 3Go. A significant improvement in metabolic parameters was noticed, with a decrease in triglycerides levels, glycemia, insulin resistance (assessed by the insulin/glucose ratio), and Lp(a) concentrations, and an increase in HDL cholesterol (Table 1Go). Systolic blood pressure was significantly reduced. Consequently, the estimated cardiovascular risk, computed according to the multivariate equation of Framingham (33) and expressed as the probability of coronary events at 8 yr, showed a mean 30% reduction (from 2.25 ± 0.41% to 1.55 ± 0.30%; P < 0.0005), although weight was not directly taken into account in the estimation.



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  		Figure 3. Effect of gastroplasty on conventional risk factors. Before gastroplasty, obesity was associated with at least one of the conventional risk factors in most patients. After surgery, insulin resistance (fasting insulin/glucose ratio > 3) was resolved in 28 of 40 patients (P < 0.0001), normotriglyceridemia (<1.5 mmol/L) was obtained in 8 of 12 patients (P < 0.03), and low HDL cholesterol (<0.45 mmol/L) was resolved in 9 of 12 patients (P < 0.01), Additionally, fasting glycemia was normalized in 4 of the 6 diabetic patients; and blood pressure was normalized (<160/90 mm Hg) in 5 of the 8 hypertensive untreated subjects. Of the 4 hypertensive treated patients, treatment had been stopped for 1 and reduced by half in the 3 others. Lp (a) was normalized (<300 mg/L) in 5 of 17 patients. HBP, High blood pressure; TG, Triglycerides; * * *, P < 0.0001; * *, P < 0.01; *, P < 0.03.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, gastroplasty for severe obesity induced, after 1 yr, a substantial weight loss and a striking improvement in cardio-vascular risk factors, offset by a significant increase in plasma homocysteine concentrations close to 30%. To the best of our knowledge, this observation has not been reported before. Homocysteine has been recently measured in a small group of patients, 1 yr after bariatric surgery, and found to be in the upper limit of the normal range, but neither the changes in homocysteinemia induced by surgery nor the folate status of patients was investigated (16). It has been previously demonstrated that homocysteine concentrations usually undergo little change over time when reinvestigated after 1 yr (34); thus, it is unlikely that the absence of a control group might affect the findings of our study.

Because it has been shown that elevated plasma homocysteine concentrations confer an independent increase in risk for coronary, cerebrovascular, and peripheral vascular atherosclerotic disease (17, 18, 19, 20, 21, 22, 23), this iatrogenic hyperhomocysteinemia might hamper the potential cardiovascular risk improvement expected from gastroplasty. Indeed, all the patients of the present study were severely obese, and most of them had metabolic alterations. By extrapolating the data of recent prospective studies (1, 2), we estimated the relative risk of mortality in our patients to be 3 times that of nonobese people. Randomized trials, designed to evaluate the beneficial impact of gastroplasty on morbidity and mortality, are underway (35). On the basis of the curvilinear relationship that has been evidenced between weight and mortality (1, 2), we spectaculate that the overall weight reduction induced by gastroplasty might reduce the risk of mortality by 50%. More specifically, our results are in agreement with previous reports showing a striking improvement in triglycerides, insulin-to-glucose ratio, and blood pressure, together with an increase in HDL cholesterol (8, 9, 10, 11). Computing the changes in individual cardiovascular risk factors (33), we estimated that the probability of coronary events in these patients was reduced by 30% at 8 yr.

However, the occurrence of hyperhomocysteinemia could antagonize the potential benefit of gastroplasty, resulting from reduction of conventional cardiovascular risk factors. In a metaanalysis of longitudinal studies (20), the relative risk of coronary artery disease was estimated as 1.6 for men and 1.8 for women, per 5 µmol/L increment in fasting plasma homocysteine concentrations. In our study, such an increase was observed in two thirds of the patients, reaching more than 5 µmol/L in one third of the subjects. By extrapolating these data, we estimated that the corresponding increase of the relative risk attributable to this change in plasma homocysteine was 64%, in the 40 out of 53 patients displaying an increase in plasma homocysteine during the study. On the basis of the data reported by Nygaard (23), evaluating the increase of relative cardiovascular risk according to quartiles of plasma homocysteine concentrations, we speculate that the potential benefit attributable to weight loss and improvement of metabolic profile could be lost in 50% of the subjects undergoing gastroplasty, because of a shift toward an upper quartile.

Hyperhomocysteinemia has been shown to be dependent on nutritional factors, especially vitamins B6 and B12 and folate, which determine the efficiency of homocysteine metabolism (24, 25, 26, 27). The prevalence of hyperhomocysteinemia (>15 µmol/L) is on the order of 10% in occidental countries. Only 6% of our patients were hyperhomocysteinemic before gastroplasty. This finding suggests that their preoperative vitamin intake was adequate, although it was not estimated from dietary records. In accordance with previous reports (13, 15), gastroplasty resulted in a marginal plasma folate deficiency. Only a few patients exhibited an increase in plasma folate concentration that could be attributed to an improvement in dietary habits after surgery, following the recommendations of a registered dietitian. The occurrence of hyperhomocysteinemia was clearly related to the changes in folate status. Previous transversal studies have shown that, after adjustment for age and sex, the strongest predictor of total plasma homocysteine level was plasma folate concentration (24). Moreover, it has also been reported that overt folate deficiency was not necessary to induce hyperhomocysteinemia (25); and accordingly, in our study, patients with plasma folate levels in the low normal range exhibited the greatest increases in plasma homocysteine concentration. These results suggest that the ranges of advisable plasma folate concentration should be reconsidered, to provide a better basis for detection of minimal folate deficiency.

Although the interaction between folic acid status and homocysteine is clear, other factors might introduce some variability in the changes in plasma homocysteine after gastroplasty. Homocysteine has been shown to be influenced by renal dysfunction and by hormonal status, neither of which were affected in the patients included in this study (36). The variability of the relation between the changes in plama homocysteine and folate in our study might, in part, reflect the genetic polymorphism of genes involved in the regulation of homocysteine metabolism. A genetic interaction with diet has been evidenced in some individuals with a deficiency in methyltetrahydrofolate reductase, promoting hyperhomocysteinemia when folate intakes were not adapted to the increased requirements.(37). Such an interaction may be particularly likely in the two patients in this study who exhibited an increase in plasma homocysteine concentration above 10 µmol/L.

We found that gastroplasty improved the atherogenic profile of morbidly obese patients but induced, in two thirds of the subjects, a marked increase in plasma homocysteine level related to marginal folate deficiency. A daily supplementation with as little as 0.5 mg folic acid has been shown to normalize moderate hyperhomocysteinemia in most individuals (38). The rationale for a folate supplementation, aiming to normalize plasma homocysteine concentration and potentially reduce the cardiovascular risk, will be established after the completion of randomized trials in the general population. However, because of the potential risk of hyperhomocysteinemia and the innocuity of this treatment, we consider that, after gastroplasty, an adequate and prolonged folate supplementation is advisable to, at least, not minimize the cardiovascular benefit of such surgery.


   Acknowledgments
 
We express our thanks to the nurses who performed the blood sampling. We are indebted to Pascale Arlandis and Gwenaelle Lazzaron for expert secretarial assistance and to Anik Girard-Globa for editorial assistance and helpful suggestions.

Received June 15, 1998.

Revised October 16, 1998.

Accepted November 3, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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