Abstract
Objective
Bariatric surgery has a significant impact on levels of thyroid hormones and various inflammatory markers in obesity. The relationship between changes in thyroid hormones and inflammatory markers after bariatric surgery is unknown. We aimed to investigate the changes in thyroid hormones and their relations to inflammatory changes after laparoscopic sleeve gastrectomy (LSG) in Chinese patients with morbid obesity.
Methods
Eighty-eight patients with morbid obesity (56.8% female; age 30.9 ± 9.5 years; BMI 39.9 ± 5.7 kg/m2) submitted to LSG were selected. Patients were subdivided into euthyroid group and subclinical hypothyroidism (SH) group. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), inflammatory markers, and related metabolic indexes were analyzed pre- and 12 months post-LSG.
Results
SH patients presented significantly higher interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) than euthyroid patients. Twelve-month post-surgery, the SH incidence decreased from 31.8 to 2.3% (P < 0.001). TSH levels were declined significantly in both groups but were more pronounced in SH group (P < 0.001), whereas no change in FT4 in either group. Additionally, we observed marked reduction of IL-6, TNF-α, and CRP in SH group, as well as TNF-α and CRP in euthyroid group. After adjusting for age, baseline BMI, and changes in BMI, decrease in TSH correlated significantly with decreased HOMA-IR and TNF-α in euthyroid group and decreased fasting insulin (FINS), IL-6, TNF-α, and CRP in SH group.
Conclusion
LSG promotes TSH reduction in patients with morbid obesity that is more pronounced in patients with SH and correlated with improved inflammatory state after surgery.
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Introduction
Obesity is often accompanied by thyroid dysfunction. Overt hypothyroidism, characterized by elevated thyroid-stimulating hormone (TSH) level (reference range for our laboratory 0.3–4.0 mIU/L) and decreased free thyroxine (FT4) level below 11.0 pmol/L, has been well studied to be associated with weight gain. Of note, there has been an upsurge of interest in the relationship between subclinical hypothyroidism (SH) and morbid obesity recently. SH is defined as an elevated TSH level above 4.0 mIU/L and normal level of FT4 between 11.0 and 25.0 pmol/L. It can be noted in 14.1% of subjects with a mean body mass index (BMI) of greater than 44.8 ± 6.4 kg/m2 [1] and 25% with a mean BMI of 53.0 ± 10.4 kg/m2 [2]. This rate is significantly higher than that in the general population ranging from 4 to 9% [3]. Recently, SH has been documented to be correlated with a low-grade chronic inflammation [4]. In the clinical study by Turemen et al. [5], they showed that SH patients had significantly higher inflammation markers compared to the normal healthy controls, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and hs-C-reactive protein (CRP). Also, Tuzcu et al. [6] found a positive correlation between CRP and TSH. In addition, Taddai S et al. [7] showed significantly higher CRP and IL-6 levels among patients with SH. These findings indicate that there exists a close relationship between low-grade chronic inflammation and SH.
To date, bariatric surgery is the most effective management method for severe obesity and its complications [8, 9]. Its effects on thyroid function have also been reported with inconsistent results. Abu-Ghanem et al. [10] and Neves et al. [11] demonstrated a significant reduction in TSH but no change in FT4 following sleeve gastrectomy in euthyroid patients with morbid obesity, while MacCuish et al. [12] observed nonsignificant change in TSH but significant increase in FT4 level at 12 months after Roux-en-Y gastric bypass (RYGB) surgery in euthyroid people with morbid obesity. Additionally, the impact of bariatric surgery on inflammatory markers has been recently noted. A systematic review and meta-analysis by Rao et al. [13] concluded significant reductions in inflammatory markers such as IL-6 and CRP but no changes in TNF-α. Recently, laparoscopic sleeve gastrectomy (LSG), as an effective and safe weight-loss surgery, has also been shown to decline the CRP levels [14].
Nevertheless, data regarding the effect of LSG on thyroid hormones in SH patient with morbid obesity and its correlation with changes in inflammatory markers variations after LSG is lacking. Therefore, we conducted the first study to investigate the changes of thyroid hormones and their relations to inflammatory marker variations at 12 months following LSG in Chinese patients with morbid obesity.
Patients and Methods
Study Population
We conducted a retrospective study including 88 patients with morbid obesity aged 30.9 ± 9.5 years who underwent the standard LSG in our institution between July 2012 and January 2019. Inclusion criteria are as follows: subjects with BMI equal or greater than 35 kg/m2 and age ranging from 18 to 65 years. Patients were excluded if they had a history of overt hypothyroidism or hyperthyroidism, autoimmune thyroid disease, previous thyroidectomy or radioiodine treatment, genetic diseases, previous gastrointestinal surgery, severe liver and renal dysfunction, mental illness, current or previous treatment with drugs that might affect the serum thyroid hormone levels, and unable to understand and comply with the study protocol.
According to different conditions of thyroid function, patients were subdivided into euthyroid group and SH group based on the levels of TSH (reference range 0.3–4.0 mIU/L) and FT4 (reference range 11–25 pmol/L). Euthyroidism was defined as TSH and FT4 levels within the normal reference ranges. SH was considered in the presence of a serum TSH level above 4.0 mIU/L in combination with a normal FT4 level [1].
This study protocol was performed in accordance with Helsinki Declaration and was approved by the ethics committee of Shanghai Tenth People’s Hospital. Written informed consent was obtained from all participants prior to enrolment. The Clinical Registration Number was ChiCTR-OCS-12002381.
Anthropometric Measurements
Preoperative and follow-up data were obtained from all the participants. Height, weight, waist circumference (WC), hip circumference (HC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were directly measured by trained physicians. BMI was calculated as weight (kg) divided by the square of height in meters (m2). The waist/hip ratio (WHR) was calculated as WC in centimeter divided by HC in centimeter. Percentage of total weight loss (%TWL) was calculated by the following formula: %TWL = [initial weight (kg) − current weight (kg)] / [initial weight (kg)] × 100. Percentage of excess weight loss (%EWL) was determined according to the following equation: %EWL = [Initial weight (kg) − current weight (kg)] / [initial weight (kg)-ideal weight (kg)] × 100 based on ideal weight (kg) = 25 (kg/m2) × [height (m)]2. Changes in BMI (ΔBMI) = Initial BMI (kg/m2) − current BMI (kg/m2).
Biochemical Measurements
Fasting blood samples were drawn from all the participants at baseline and 12 months after LSG to measure fasting plasma glucose (FPG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TSH, FT4, and inflammatory markers by the clinical laboratory of our hospital. The levels of TSH and FT4 were measured using the electrochemiluminescence immunoassay method. The reference value for serum TSH and FT4 is 0.3–4.0 mIU/L and 11.0–25.0 pmol/L, respectively. In addition, we measured the inflammatory markers including IL-6, IL-8, TNF-α, and CRP using standard methodologies.
Homeostasis model assessment of insulin resistance (HOMA-IR) was evaluated using the formula [15]: FPG (mmol/L) × FINS (mU/L) / 22.5. Changes in TSH (ΔTSH) were computed by the formula: ΔTSH = [Initial TSH (mIU/L) − current TSH (mIU/L)]. The percentage of TSH variation (%) was determined as [Initial TSH (mIU/L) − current TSH (mIU/L)] / initial TSH (mIU/L) × 100.
Statistical Analysis
All statistical analyses were performed using SPSS 20.0 software. Data were presented as means ± standard deviation (SD) for continuous variables or percentages for categorical variables. Abnormally distributed data were logarithmically transformed before analysis when needed. Comparisons of clinical variables between SH group and euthyroid group were tested using independent Student’s t test or chi-squared test. Paired samples t test was used to compare the data before and after surgery. Pearson’s correlation analysis was used to evaluate the relationship between changes in TSH and various clinical parameters variations after LSG. Multivariate linear regression analyses were used to identify the possible contributing factors that influence changes in thyroid hormones at 12 months after surgery. A two-sided P value of < 0.05 was considered statistically significant.
Results
Clinical Characteristics of Study Participants at Baseline and 12 Months After LSG
We analyzed 88 subjects (50 females and 38 males) with mean age 30.9 ± 9.5 years and mean preoperative BMI 39.9 ± 5.7 kg/m2 (Table 1). At baseline, SH was present in 28 out of 88 patients (31.8%). There were no significant differences between euthyroid and SH groups in relation to weight, BMI, WHR, SBP, DBP, FPG, FINS, HOMA-IR, TC, TG, HDL-C, and LDL-C. Twelve months after surgery, participants’ weight, BMI, WHR, SBP, and DBP decreased significantly in both groups (all P < 0.01). The %TWL and %EWL reached to 32.3 ± 7.5% and 84.9 ± 30.2% over 1-year period in SH group, which were similar to 32.0 ± 5.7% and 86.3 ± 26.3% observed in euthyroid group. Marked reduction in FPG, FINS, HOMA-IR, and TG as well as increase in HDL-C levels after LSG were observed in both groups (all P < 0.05). TC was decreased significantly in euthyroid group, but there was no significant change of LDL-C in either group.
Changes in Thyroid Hormones After LSG
Thyroid hormone levels before and after surgery are presented in Table 1 and Fig. 1. At baseline, patients in SH group presented significantly higher levels of TSH compared with patients in euthyroid group (5.9 ± 2.1 vs 2.4 ± 0.8 mIU/L, P < 0.001), whereas the FT4 levels were not statistically different between the two groups (16.1 ± 3.3 vs 16.3 ± 2.5 pmol/L, P = 0.695). Twelve months after LSG, the TSH levels decreased significantly to 2.3 ± 1.3 mIU/L in SH group (P < 0.001) and to 1.8 ± 0.6 mIU/L in euthyroid group (P < 0.001), whereas there were no significant changes in FT4 levels in either group (P = 0.061, P = 0.060, respectively) (Fig. 1a–d). In addition, changes in TSH and percentage of TSH variations were remarkably greater in SH group than in non-SH group (3.6 ± 1.9 vs 0.8 ± 0.8 mIU/L, P < 0.001; 60.3 ± 21.3 vs 17.8 ± 8.9%, P < 0.001, respectively) (Fig. 1e and f). Furthermore, the incidence of SH among the participants was declined significantly from 31.8% at baseline to 2.3% at 12 months (P < 0.001) (Fig. 1g).
Changes in Inflammatory Markers After LSG
As shown in Table 1, SH group had remarkably higher levels of IL-6, TNF-α, and CRP in comparison with euthyroid group (P = 0.017, P = 0.003, P = 0.001, respectively), while there were no significant differences in IL-8 levels between the two groups (P = 0.141). Twelve months after surgery, in SH group, there was a significant reduction in IL-6, TNF-α, and CRP levels, changing from 1.8 ± 0.5 to 1.0 ± 0.2 pg/mL (P < 0.01), 2.7 ± 0.5 to 2.1 ± 0.3 pg/mL (P < 0.05), and 2.4 ± 0.9 to 0.9 ± 0.5 mg/L (P < 0.01), whereas IL-8 did not change significantly (3.6 ± 0.8 vs 2.9 ± 1.3 pg/mL, P = 0.161). In euthyroid group, there was a significant reduction in TNF-α after surgery (2.3 ± 0.6 vs 1.8 ± 0.5 pg/mL, P = 0.011) but changes in IL-6, IL-8, and CRP failed to reach a statistical significance (all P > 0.05).
Relationship Between Inflammatory Changes and TSH Reduction After LSG
As shown in Fig. 2, ΔTSH at 12 months after LSG correlated significantly with ΔBMI (r = 0.338, P = 0.008), ΔFINS (r = 0.388, P = 0.002), ΔHOMA-IR (r = 0.407, P < 0.001), and ΔTNF-α (r = 0.274, P < 0.034) in euthyroid group, whereas no significant associations were observed between ΔTSH and ΔIL-6, ΔIL-8, and ΔCRP. In SH group, ΔTSH correlated significantly with ΔFINS (r = 0.605, P < 0.001), ΔHOMA-IR (r = 0.427, P = 0.023), ΔIL-6 (r = 0.572, P = 0.001), ΔTNF-α (r = 0.519, P = 0.004), and ΔCRP (r = 0.588, P = 0.001) but did not correlate with ΔBMI and ΔIL-8 (shown in Fig. 3). In order to identify the contribution of changes in inflammatory markers to TSH variation after LSG, we conducted multivariate linear regression analysis (Table 2). After adjusting age, baseline BMI, and changes in BMI, ΔTSH was correlated significantly with ΔFINS (β = 0.251, P = 0.011), ΔIL-6 (β = 0.447, P = 0.017), ΔTNF-α (β = 0.429, P = 0.009), and ΔCRP (β = 0.385, P = 0.035) in SH group, as well as ΔHOMA-IR (β = 0.231, P = 0.018) and ΔTNF-α (β = 0.310, P = 0.002) in euthyroid group. However, ΔTSH did not correlated with ΔIL-8 in SH group, as well as ΔIL-6, ΔIL-8, and ΔCRP in euthyroid group (all P > 0.05).
Discussion
Previous studies have evaluated the effects of bariatric surgery on thyroid function and inflammatory state [16,17,18,19]. Nevertheless, there is lack of data regarding the associations between changes in thyroid hormones and inflammatory changes after bariatric surgery. To our best knowledge, this is the first study to examine the relationship between changes in serum TSH levels and inflammatory markers variations in Chinese patients with morbid obesity following LSG. The results showed that there was a significant reduction in serum TSH levels after LSG, which was more pronounced among patients with SH compared with those with normal thyroid function. In addition, the changes of inflammatory markers were correlated with reduction in TSH, indicating that the improved inflammatory state may be associated with the beneficial effects of LSG on thyroid function.
Most studies have demonstrated increased TSH concentrations in patients with morbid obesity. In the study by Rumińska et al. [20], their data showed significantly increased TSH levels in children with obesity compared to healthy controls without obesity. Bétry et al. [21] also found a positive relationship between serum TSH and BMI in individuals with obesity. Even in euthyroid general population, serum TSH has been observed to be correlated with weight gain [22]. Furthermore, weight loss induced by bariatric surgery has been reported significantly correlated with TSH decrease in euthyroid patients with morbid obesity [11, 23]. Even in patients with a clinical diagnosis of hypothyroidism, the normalization of TSH levels have been observed following bariatric surgery [1, 24]. Previous studies have suggested that the TSH increase may represent a compensatory activation of hypothalamus-pituitary-thyroid axis in response to excessive body weight [25]. Therefore, the rise in TSH in most patients with obesity, along with a fall in TSH after weight loss, may reflect the TSH as part of adaptive thermogenesis to excessive weight and metabolic adaptation to weight loss. However, the mechanism and the clinical implications of this alteration remain to be elucidated.
Previous studies have yielded inconsistent conclusions regarding the effect of bariatric surgery on thyroid function. Most [10, 11, 17, 26, 27], but not all [12, 28], studies have shown a significant reduction of TSH and no change in FT4 after the procedure duo to different baseline characteristics of study population, types of surgical procedures performed, and follow-up durations. In a clinical study including 86 subjects with obesity who had no previous diagnosis of thyroid disorder, submitted to LRYGB or adjustable gastric banding, the authors observed a statistically significant reduction in TSH but nonsignificant change in FT4 at 12 months after surgery [26]. In another study of 949 euthyroid patients with morbid obesity submitted to bariatric surgery (laparoscopic adjustable gastric band, LRYGB, or LSG), patients were subdivided in two groups: normal TSH group (TSH < 2.5 mU/L) and high-normal TSH group (TSH ≥ 2.5 mU/L) [11]. The results showed that there was a significant decrease of TSH 12 months after surgery that was more marked in the high-normal TSH group, and this significant decrease was only observed in the high-normal TSH group (normal TSH group 1.57 ± 0.49 to 1.53 ± 0.69 mIU/L, p = 0.063; high-normal TSH group 3.23 ± 0.59 to 2.38 ± 0.86 mIU/L, p < 0.001). Also, they compared the TSH variation between LSG and LRYGB and found no significant effect was observed between the two groups (β = −0.068, p = 0.278). From a clinical point of view, these findings indicated that patients with morbid obesity and higher TSH levels tend to normalize thyroid function following metabolic surgery. In support of this view, Zendel et al. [27] performed a study including 93 hypothyroid patients who underwent LSG in 77 (82.8%) and LRYGB in 16 (17.2%) patients. The results showed that mean TSH levels were significantly deceased after 6 and 12 months following surgery with no alterations in mean FT4 levels. Similarly, Rudnicki et al. [17] carried out a study in 90 patients with hypothyroidism and 89% patients treated with thyroid hormone replacement therapy (HRT) prior to LSG or LRYGB. After surgery, all patients with deranged TSH prior to surgery (TSH > 4.5 mU/L) had normal TSH levels after surgery in both LSG and LRYGB groups. However, the percentage of patients that stopped HRT completely was significantly higher in the LSG group, indicating that LSG may be a good treatment choice for patients with hypothyroidism, even in those who are treated with thyroid HRT. In contrast, Liu et al. [28] concluded that both TSH and FT4 levels were decreased significantly after RYGB in euthyroid Chinese patients with obesity and T2DM, while MacCuish et al. [12] reported a significant increase in FT4 but no change in TSH after LRYGB in 55 euthyroid patients with morbid obesity. In recent study including 38 euthyroid patients with morbid obesity, Abu-Ghanem et al. [10] revealed a marked decrease in level of TSH but nonsignificant changes in level of FT4 following LSG. However, data regarding thyroid hormone changes after LSG in patients with SH are scarce, especially in China. We therefore performed the first study to evaluate the changes in TSH and FT4 levels after LSG in Chinese patients with SH and compared the TSH variation between SH group and euthyroid group. The results showed a significant decrease in TSH levels with no change in T4 levels after LSG in both SH and euthyroid groups. In addition, the changes in TSH and percentage of TSH variations were remarkably greater in SH group than in non-SH group. Meanwhile, we found a 92.8% normalization of TSH among the SH patients 1-year after LSG, which was similar to a 90% remission of SH at 1-year after LSG described by Ruiz-Tovar et al. [29]. These findings indicate that LSG may be an effective treatment method for normalizing thyroid hormone levels in SH with morbid obesity.
Lately, bariatric surgery has been demonstrated to alleviate the chronic inflammatory state in obesity. Level of CRP was significantly decreased at 12 months following RYGB [30]. Hakeam et al. [14] supported this study by reporting a statistically significant reduction in CRP during 6-month period after LSG. In addition, significant decreases in CRP, IL-6, soluble TNF-α receptor (sTNFαR) 1, and sTNFαR 2 were observed at 12 months after bariatric surgery [31]. Also, in the clinical study of 41 patients with extreme obesity who underwent RYGB, Netto et al. [32] concluded significant decline in both CRP and TNF-α at 6 months post RYGB. However, the effect of bariatric surgery on inflammatory markers remains controversial. Some reported significantly increased TNF-α 6 months post-surgery [33] while others indicated significant decrease in CRP but nonsignificant alteration in IL-6 and TNF-α [34]. In our study, we found a significant reduced TNF-α in euthyroid group as well as reduced CRP, IL-6, and TNF-α in SH group following LSG. Although the exact mechanism underlying the improved inflammatory state following bariatric surgery is unclear, the accompanied improvement of insulin resistance (IR) may, at least in part, mediate the alleviation of inflammatory state post bariatric surgery. As we know, human adipose tissue is an important source of proinflammatory cytokines and anti-inflammatory cytokine. The low-grade inflammation has been suggested as a link between obesity and IR. On one hand, elevated proinflammatory cytokines, such as IL-6 and TNF-α, could cause IR by impairing the phosphorylation of insulin receptor and insulin receptor substrate-1 by upregulation of suppressor of cytokine signaling-3 (SOCS-3) proteins and downregulation of peroxisomal proliferator-activated receptor-γ receptors [35, 36]. On the other hand, obesity-induced IR can lead to elevated inflammation state by interfering with the anti-inflammatory effect of insulin [37]. In addition, Illán-Gómez et al. [38] found that there was a significant decrease in levels of IL-6, hs-CRP, insulin, and HOMA-IR and significant postoperative correlations between IL-6 levels and CRP with HOMA-IR. Also, in our study, we found significant reduction in IR and accompanied improved inflammatory markers. Thus, weight reduction induced by bariatric surgery may be an effective intervention for decreasing adipose tissue mass, leading to improved IR and finally causing the decreases in levels of inflammatory markers [34]. However, the mechanism of interaction between the improved inflammatory state and the well-documented improved IR post-bariatric surgery remains to be elucidated.
Considering that increasing studies have reported a close association between SH and elevated inflammatory markers [5, 39], whether there is a significant association between changes in inflammatory markers and alteration in thyroid function after bariatric surgery is unknown. Therefore, we further investigated the correlation between TSH reduction and inflammatory changes after LSG. As expected, the correlation analysis results revealed that TSH reduction was significantly correlated with decreased IL-6, TNF-α, and CRP in SH group and decreased TNF-α in euthyroid group in addition to decreased FINS and HOMA-IR in both group. No significant correlations between changes in IL-8 and TSH after surgery, indicating that the impact of IL-8 on the changes of thyroid function is limited. Considering that the correlation between weight loss and TSH reduction and between weight loss and decline in inflammatory markers has been well studied [1, 34], it is probable that the correlation between decline in TSH and decline in inflammatory markers is mediated by weight loss. To address this issue, we performed a multiple regression analysis to detect the main factors related to the TSH variation following LSG. After adjusting for age, baseline BMI, and changes in BMI post LSG, we observed that the alteration in TSH was still correlated with decreased FINS, IL-6, TNF-α, and CRP in SH group, as well as decreased HOMA-IR and TNF-α in euthyroid group, suggesting that improved inflammatory state may be associated with the beneficial effect of LSG on TSH reduction in addition to alleviated insulin resistance (IR) and substantial weight loss.
However, the underlying mechanism responsible for the alteration in TSH following metabolic surgery is still poorly understood and remains to be investigated. One explanation for this may be the decreased level of leptin after bariatric surgery, which has been well demonstrated in several studies [40,41,42]. Leptin, mainly expressed in adipose tissue, exerts a vital role in energy expenditure and regulation of fat mass and body weight [43]. It can also maintain the expression of thyrotropin-releasing hormone (TRH) in the hypothalamic paraventricular nucleus of the hypothalamus via the JAK/STAT pathway and has a stimulatory effect on the production of thyroid hormones [44]. Thus, surgery-induced reduction of leptin would lead to the reduction of TSH [45]. A second explanation may derive from the reduction in the level of ghrelin induced by bariatric surgery. In view of the fact that serum ghrelin level has been demonstrated positively correlated with TSH level [46], we assume that decreased ghrelin level after RYGB and SG could be associated with the reduction in TSH. Another noteworthy explanation may result from the improved inflammatory state after obesity surgery. There is a growing evidence that inflammatory markers, such as IL-6, TNF-α, and CRP, are increased in patients with SH [5, 7], which could be reversed by bariatric surgery [14, 30,31,32]. Consistently, in our study, we found significantly increased levels of IL-6, TNF-α, and CRP in SH group compared to euthyroid group at baseline, which were decreased significantly at 12 months following LSG. Strikingly, our results revealed a significant correlation between TSH reduction and decrease in IL-6, TNF-α, and CRP in SH group as well as decrease in TNF-α in euthyroid group, indicating that the improvement of inflammatory state may make a contribution to the change of TSH after LSG. However, the causative link between changes in thyroid hormones and changes in inflammatory markers is unclear. On one hand, thyroid hormone levels have been suggested to influence cytokine production. In the study by Antunes et al. [47], IL-6, as a pro-inflammatory cytokine, has been reported to be induced by TSH in preadipocytes through a cAMP protein kinase A pathway. CRP, as a common inflammatory cytokine, has been concluded to be linked to SH [7]. Another inflammatory cytokine, TNF-α, can be induced in bone marrow cells by TSH in the study by Whetsell et al. [48]. In addition, IL-6 level might be correlated with hypothyroidism severity due to that serum IL-6 level has been positively correlated with levothyroxine replacement therapy (LRT) dose and negatively correlated with FT4 level in hypothyroidism due to autoimmune thyroiditis [49]. Moreover, Marchiori et al. [50] found that 1 year of LRT treatment caused significant reduction in pro-inflammatory cytokines including IL-6 and TNF-α. However, there are conflicting results regarding the effects of hypothyroidism treatment on systemic inflammation. In the study by Díez et al. [51], they failed to observe significant reduction in the high levels of TNF-α and TNF-α receptors after normalization of thyroid function in hypothyroid patients. On the other hand, TNF-α and IL-6 have been previously shown to have an inhibitory impact on the hypothalamic-pituitary-thyroid axis. Pang et al. [52] found significantly reduced serum levels of TSH, T4, free T4, T3, and hypothalamic TRH after single injection of 200 μg TNF-α/kg body weight in male Sprague-Dawley rats in comparison with the corresponding items in saline-treated controls and that serum TSH and hypothalamic TRH were significantly decreased with the increasing daily doses of TNF-α. Similarly, van Haasteren et al. [53] showed that continuous intraperitoneal infusion of 15 μg IL-6 per day for 7 days in rats led to transient reduction in plasma levels of TSH and T4. Taken together, these findings indicate that there may be bidirectional relationship between elevated in inflammatory markers and altered thyroid function, which needs to be further investigated. Apart from these factors, we also found significant relationship between TSH reduction and improved IR. In view of that TSH is independently associated with IR [54], significant improvement of IR following LSG may partially explain the changes of thyroid hormones. However, further studies are needed to draw a definitive correlation between changes in TSH and changes in inflammatory markers following LSG.
The authors acknowledge that there are several limitations in this study. Firstly, the relatively small sample size may lead to high variability. Secondly, the short follow-up period is further limitation, which will preclude the definitive conclusions with respect to the long-term predicted outcomes. Thirdly, we did not include all the variables which may involve in the effect of LSG on thyroid function and inflammation state. Future studies with a larger sample size and a longer follow-up period are warranted.
Conclusion
LSG promotes a more pronounced reduction in serum TSH levels in patients with morbid obesity and SH compared to those with normal thyroid function at 12 months. Improvement of inflammatory markers at 12 months after LSG may be associated with the beneficial effect of LSG on the thyroid function. Further studies are needed to confirm our findings and investigate the exact mechanism.
References
Janssen IM, Homan J, Schijns W, et al. Subclinical hypothyroidism and its relation to obesity in patients before and after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2015;11(6):1257–63.
Moulin de Moraes CM, Mancini MC, de Melo ME, et al. Prevalence of subclinical hypothyroidism in a morbidly obese population and improvement after weight loss induced by Roux-en-Y gastric bypass. Obes Surg. 2005;15(9):1287–91.
Villar HC, Saconato H, Valente O, et al. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;18(3):CD003419.
Gupta G, Sharma P, Kumar P, et al. Study on subclinical hypothyroidism and its association with various inflammatory markers. J Clin Diagn Res. 2015;9(11):BC04–6.
Türemen EE, Çetinarslan B, Şahin T, et al. Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr J. 2011;58(5):349–54.
Tuzcu A, Bahceci M, Gokalp D, et al. Subclinical hypothyroidism may be associated with elevated high-sensitive c-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocr J. 2005;52(1):89–94.
Taddei S, Caraccio N, Virdis A, et al. Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2006;91(12):5076–82.
Inge TH, Courcoulas AP, Jenkins TM, et al. Weight loss and health status 3 years after bariatric surgery in adolescents. N Engl J Med. 2016;374(2):113–23.
Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes-5-year outcomes. N Engl J Med. 2017;376(7):641–51.
Abu-Ghanem Y, Inbar R, Tyomkin V, et al. Effect of sleeve gastrectomy on thyroid hormone levels. Obes Surg. 2015;25(3):452–6.
Neves JS, Castro Oliveira S, Souteiro P, et al. Effect of weight loss after bariatric surgery on thyroid-stimulating hormone levels in patients with morbid obesity and normal thyroid function. Obes Surg. 2018;28(1):97–103.
MacCuish A, Razvi S, Syed AA. Effect of weight loss after gastric bypass surgery on thyroid function in euthyroid people with morbid obesity. Clin Obes. 2012;2(12):25–8.
Rao SR. Inflammatory markers and bariatric surgery: a meta-analysis. Inflamm Res. 2012;61(8):789–807.
Hakeam HA, O'Regan PJ, Salem AM, et al. Inhibition of C-reactive protein in morbidly obese patients after laparoscopic sleeve gastrectomy. Obes Surg. 2009;19(4):456–60.
Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9.
Neves JS, Souteiro P, Oliveira SC, et al. Preoperative thyroid function and weight loss after bariatric surgery. Int J Obes. 2019;43(2):432–6.
Rudnicki Y, Slavin M, Keidar A, et al. The effect of bariatric surgery on hypothyroidism: sleeve gastrectomy versus gastric bypass. Surg Obes Relat Dis. 2018;14(9):1297–303.
Mallipedhi A, Prior SL, Barry JD, et al. Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes. Surg Obes Relat Dis. 2014;10(6):1123–8.
Fenske WK, Dubb S, Bueter M, et al. Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis. 2013;9(4):559–68.
Rumińska M, Witkowska-Sędek E, Majcher A, et al. Thyroid function in obese children and adolescents and its association with anthropometric and metabolic parameters. Adv Exp Med Biol. 2016;912:33–41.
Bétry C, Challan-Belval MA, Bernard A, et al. Increased TSH in obesity: evidence for a BMI-independent association with leptin. Diabetes Metab. 2015;41(3):248–51.
Svare A, Nilsen TI, Bjøro T, et al. Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway. Clin Endocrinol. 2011;74(6):769–75.
Yang J, Gao Z, Yang W, et al. Effect of sleeve gastrectomy on thyroid function in Chinese euthyroid obese patients. Surg Laparosc Endosc Percutan Tech. 2017;27(4):e66–8.
Fazylov R, Soto E, Cohen S, et al. Laparoscopic Roux-en-Y gastric bypass surgery on morbidly obese patients with hypothyroidism. Obes Surg. 2008;18(6):644–7.
Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol. 2010;316(2):165–71.
Chikunguwo S, Brethauer S, Nirujogi V, et al. Influence of obesity and surgical weight loss on thyroid hormone levels. Surg Obes Relat Dis. 2007;3(6):631–5.
Zendel A, Abu-Ghanem Y, Dux J, et al. The impact of bariatric surgery on thyroid function and medication use in patients with hypothyroidism. Obes Surg. 2017;27(8):2000–4.
Liu F, Di J, Yu H, et al. Effect of Roux-en-Y gastric bypass on thyroid function in euthyroid patients with obesity and type 2 diabetes. Surg Obes Relat Dis. 2017;13(10):1701–7.
Ruiz-Tovar J, Boix E, Galindo I, et al. Evolution of subclinical hypothyroidism and its relation with glucose and triglycerides levels in morbidly obese patients after undergoing sleeve gastrectomy as bariatric procedure. Obes Surg. 2014;24(5):791–5.
Kim MK, Jang EH, Hong OK, et al. Changes in serum levels of bone morphogenic protein 4 and inflammatory cytokines after bariatric surgery in severely obese Korean patients with type 2 diabetes. Int J Endocrinol. 2013;2013:681205.
Pallayova M, Steele KE, Magnuson TH, et al. Sleep apnea determines soluble TNF-α receptor 2 response to massive weight loss. Obes Surg. 2011;21(9):1413–23.
Netto BD, Bettini SC, Clemente AP, et al. Roux-en-Y gastric bypass decreases pro-inflammatory and thrombotic biomarkers in individuals with extreme obesity. Obes Surg. 2015;25(6):1010–8.
Tussing-Humphreys L, Pini M, Ponemone V, et al. Suppressed cytokine production in whole blood cultures may be related to iron status and hepcidin and is partially corrected following weight reduction in morbidly obese pre-menopausal women. Cytokine. 2011;53(2):201–6.
Vázquez LA, Pazos F, Berrazueta JR, et al. Effects of changes in body weight and insulin resistance on inflammation and endothelial function in morbid obesity after bariatric surgery. J Clin Endocrinol Metab. 2005;90(1):316–22.
Rehman K, Akash MSH, Liaqat A, et al. Role of interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr. 2017;27(3):229–36.
Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab. 2000;11(6):212–7.
Danona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001;86(7):3257–65.
Illán-Gómez F, Gonzálvez-Ortega M, Orea-Soler I, et al. Obesity and inflammation: change in adiponectin, C-reactive protein, tumour necrosis factor-alpha and interleukin-6 after bariatric surgery. Obes Surg. 2012;22(6):950–5.
Sharma R, Sharma TK, Kaushik GG, et al. Subclinical hypothyroidism and its association with cardiovascular risk factors. Clin Lab. 2011;57(9–10):719–24.
Terra X, Auguet T, Guiu-Jurado E, et al. Long-term changes in leptin, chemerin and ghrelin levels following different bariatric surgery procedures: Roux-en-Y gastric bypass and sleeve gastrectomy. Obes Surg. 2013;23(11):1790–8.
Kalinowski P, Paluszkiewicz R, Wróblewski T, et al. Ghrelin, leptin, and glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass-results of a randomized clinical trial. Surg Obes Relat Dis. 2017;13(2):181–8.
Kruljac I, Mirošević G, Kirigin LS, et al. Changes in metabolic hormones after bariatric surgery and their predictive impact on weight loss. Clin Endocrinol. 2016;85(6):852–60.
Gale SM, Castracane VD, Mantzoros CS. Energy homeostasis, obesity and eating disorders: recent advances in endocrinology. J Nutr. 2004;134(2):295–8.
Flier JS, Harris M, Hollenberg AN. Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. J Clin Invest. 2000;105(7):859–61.
Kozlowska L, Rosolowska-Huszcz D. Leptin, thyrotropin, and thyroid hormones in obese/overweight women before and after two levels of energy deficit. Endocrine. 2004;24(2):147–53.
Emami A, Nazem R, Hedayati MI. Association between thyroid hormones and gut peptides, ghrelin and obestatin, able to suggest new regulatory relation between the HPT axis and gut? Regul Pept. 2014;189:17–21.
Antunes TT, Gagnon A, Bell A, et al. Thyroid-stimulating hormone stimulates interleukin-6 release from 3T3-L1 adipocytes through a cAMP-protein kinase A pathway. Obes Res. 2005;13(12):2066–71.
Whetsell M, Bagriacik EU, Seetharamaiah GS, et al. Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties. Cell Immunol. 1999;192(2):159–66.
Papanas N et al. Thyroxine replacement dose in patients with Hashimoto disease: a potential role for interleukin-6. Cytokine. 2006;35:166–70.
Marchiori RC, Pereira LAF, Naujorks AA, et al. Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment. BMC Endocr Disord. 2015;15:32.
Díez JJ et al. Serum concentrations of tumor necrosis factor-alpha and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after treatment. Clin Endocrinol. 2002;57(4):515–21.
Pang XP et al. Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-alpha (cachectin). Endocrinology. 1989;125(1):76–84.
van Haasteren GA, van der Meer MJ, Hermus AR, et al. Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis. Endocrinology. 1994;135(4):1336–45.
Zhu P, Liu X, Mao X. Thyroid-stimulating hormone levels are positively associated with insulin resistance. Med Sci Monit. 2018;24:342–7.
Acknowledgments
We are thankful for the work of all the endocrinologists, surgeons, and nutritionists in National Metabolic Management Center in our hospital.
Funding
This work was supported by National Natural Science Foundation of China (NSFC 81500650, 81700752), National Key R&D Program of China (Grant No. 2018YFC1314101, 2016YFC1305600), Shanghai Committee of Science and Technology of China (Grant No. 18411951803), Program for Outstanding Medical Academic Leader (Grant No. 90), and Shanghai Hospital Development Center (SHDC12015127).
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Cuiling Zhu analyzed the data and drafted this manuscript. Jingyang Gao and Fangyun Mei collected the data for the work. Liesheng Lu and Donglei Zhou performed the surgery and involved in the discussion of the study results. Shen Qu designed the study and approved the final manuscript for publication. All authors take responsibility for the content of this study.
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This study protocol was performed in accordance with Helsinki Declaration and was approved by the ethics committee of Shanghai Tenth People’s Hospital. Written informed consent was obtained from all participants prior to enrolment. The Clinical Registration Number was ChiCTR-OCS-12002381.
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The authors declare that they have no conflict of interest.
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This study was approved by the ethics committee of the Shanghai Tenth People’s Hospital of Tongji University. Informed consent was obtained from all individual participants of the study.
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Zhu, C., Gao, J., Mei, F. et al. Reduction in Thyroid-Stimulating Hormone Correlated with Improved Inflammation Markers in Chinese Patients with Morbid Obesity Undergoing Laparoscopic Sleeve Gastrectomy. OBES SURG 29, 3954–3965 (2019). https://doi.org/10.1007/s11695-019-04063-4
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DOI: https://doi.org/10.1007/s11695-019-04063-4