Leptin Levels in Thyroid Cancer

Original Article

Leptin Levels in Thyroid Cancer Melih Akinci,1 Funda Kosova,2 Bahadir Cetin,3 Sabahattin Aslan,3 Zeki Ari4 and Abdullah Cetin,3 1 Department of General Surgery, Ankara Diskapi Education and Research Hospital, Ankara, 2Department of Biochemistry, Celal Bayar University, Manisa, 3Department of General Surgery, Ankara Oncology Hospital, Ankara, and 4Department of Biochemistry and Clinical Biochemistry, School of Medicine, Celal Bayar University, Manisa, Turkey.

BACKGROUND: Leptin has physiological roles in multiple systems, and has possible effects on several carcinogenesis steps. The aim of this study was to investigate the leptin levels in thyroid papillary carcinoma (TPC) patients. METHODS: Forty-three female TPC patients and 30 healthy female control subjects were recruited for the study. TPC was diagnosed by fine needle aspiration biopsy. TPC patients had a bilateral total thyroidectomy operation and their leptin levels were measured before and 20 days after the operation. RESULTS: Serum leptin levels of TPC patients were higher than in control group subjects (21.15 ± 14.12 ng/mL vs. 9.89 ± 0.21 ng/mL, p < 0.05). The leptin levels decreased after total thyroidectomy (13.92 ± 10.55 ng/mL) compared to prethyroidectomy levels (22.94 ± 14.67 ng/mL) in 34 patients who came to the follow-up visit (p < 0.05). However, the decreased post-thyroidectomy levels of leptin were still statistically significantly higher than the control group levels. Multivariate regression analysis showed that the leptin levels in TPC patients were not related to age, menopausal status or pathologic occult status but were directly related to the cancer group. CONCLUSION: Leptin levels were elevated in thyroid cancer, decreased after total thyroidectomy, and might be associated with thyroid papillary carcinogenesis. [Asian J Surg 2009;32(4):216–23] Key Words: body mass index, leptin, thyroid papillary carcinoma

Introduction Leptin, which increases parallel to body mass index (BMI), is becoming attractive to researchers with the increasing prevalence of overweight and obesity in the United States.1 In 1994, Zhang and colleagues reported the cloning of the obese (ob) gene, responsible for the typical phenotype of obesity, diabetes and insulin resistance in ob/ob mice and human homologue gene, which was 84% identical with the mouse protein.2 Leptin receptors were cloned and identified in the choroid plexus and hypothalamus, a region known to be involved in the regulation of appetite, food intake and body weight.3,4 Formerly, it was thought

that leptin had a role in regulating body weight solely by regulating body fat stores, but leptin is not only important in the regulation of food intake and energy balance, it also has a function as a metabolic and neuroendocrine hormone. Leptin has roles in glucose metabolism, normal sexual maturation and reproduction, and effects on the hypothalamic-pituitary-adrenal, thyroid and growth hormone axes, haematopoiesis and the immune system.5 Leptin may modulate different mechanisms in several systems such as activating or inhibiting the ongoing steps of the disorders, and the knowledge of the relationship between obesity and certain cancer types makes leptin a research target for other types of cancers.

Address correspondence and reprint requests to Dr Melih Akinci, 44 Cadde 457, Sokak Lale Apt. No. 4/14, 06520 Cukurambar, Ankara, Turkey. E-mail: [email protected] ● Date of acceptance: 5 September 2008 © 2009 Elsevier. All rights reserved.

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With respect to its diverse functions in immunity, leptin may have a major role in oxidation, which is an important risk factor in carcinogenesis. Indeed, obesity has long been recognised to be a risk factor for tumorigenesis, and accumulating evidence suggests that leptin is a potential link between obesity and cancer development. While leptin serves as a pivotal factor in immune surveillance, it has been shown to act as a mitogenic agent to promote the proliferation and invasiveness of certain cancer cells.6 Leptin, as a product of adipose tissue and a neuroendocrine hormone, with its effects on immunologic events as well as body energy regulation, has physiological roles in multiple systems. It has possible effects on several carcinogenesis steps and roles in renal cell carcinoma, melanoma, breast, colon, prostate, lung, endometrial and ovarian cancer.7–15 Leptin as a cytokine has never been analysed in thyroid cancer patients. The aims of this study were to investigate the leptin levels in thyroid papillary carcinoma (TPC) patients before and after total thyroidectomy, and to compare the leptin levels in TPC patients with healthy controls.

Patients and Methods The study was approved by the hospital’s ethics committee. All the patients and the volunteers involved in the study gave informed consent. Trained physicians recruited subjects by convenience sampling at the General Surgery Clinic of Ankara Oncology Hospital, Turkey. Forty-three TPC patients and 30 control subjects were included in this study. The patients were females presenting with papillary carcinoma of the thyroid. No patient had clinically palpable lymph nodes or lymph nodes detected by ultrasonography. All the patients underwent total thyroidectomy without lymph node dissection and came to a follow-up visit on the 20th postoperative day. None of the patients received thyroid hormone postoperatively in preparation for radioactive iodine therapy. The patients received radioactive iodine administration 5–6 weeks after thyroidectomy. Blood samples for leptin level measurements were taken from the patients preoperatively and on the 20th postoperative day, and once from the control subjects. Patients and control groups were euthyroid with normal thyroid function tests and had normal levels of total cholesterol and triglycerides. Patients and controls with diabetes mellitus, hypertension

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and those on hormonal therapy such as oral contraceptives, thyroxin derivatives, estrogen replacement therapy and also medications for chronic diseases were excluded. The controls were sex-matched healthy volunteers. Patients with tumour size less than 10 mm without capsule invasion and angioinvasion were classified as having occult carcinoma,16 whereas larger tumours were classified as nonoccult carcinoma for subgroup analysis. As leptin is a product of adipose tissue and increases in parallel with obesity, subgroups related to BMI for patients and controls were also analysed. BMI subgroups were defined as underweight, normal, overweight, and obese, i.e. < 18.5 kg/m2, 18.5–25 kg/m2, 25–30 kg/m2, and > 30 kg/ m2, respectively.17 Underweight and normal subjects were grouped together; therefore, three BMI subgroups for both patients and controls were analysed. Blood samples were kept at −40°C until analysis. All samples from each patient were run in the same assay. Serum thyroid hormones were measured by radioimmunoassay kits (Tosoh AIA-600 autoanalyzer; Tosoh Corp., Tokyo, Japan). Total cholesterol and triglycerides were measured by Beckman Coulter DXC 800 autoanalyzer (Beckman Coulter Inc., Fullerton, CA, USA). Leptin levels were determined by human serum ELISA (TiterZyme® Enzyme Immunometric Assay Kit; Assay Designs Inc., Ann Arbor, MI, USA). All statistical analyses were performed using SPSS 11.5 (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov test was used to test the normal distribution of the data. Student’s t-test was used to compare the numeric data between the groups. The paired t-test was used to analyse the variables before and after the operation. Chi-square test was used to analyse categorical variables. Multivariate regression analysis was performed to analyse the effect of the independent variables (group, age, menopausal status) on the dependent variable (leptin levels). Two-tailed probability (p) values were calculated throughout, and statistical significance was defined as p < 0.05.

Results The levels of thyroid hormones, total cholesterol, triglycerides and glucose were within normal limits in all subjects. Sex (all of the subjects were female), weight, height and BMI were not significantly different between the TPC patients and control group subjects (Table 1). TPC patients were younger than the control subjects

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Table 1. Demographic characteristics of thyroid papillary carcinoma patients and control subjects Group

n

Mean

Standard deviation

Age

Thyroid cancer Control

43 30

42.8* 54.6*

± 13.2 ± 8.9

Height (cm)

Thyroid cancer Control

43 30

161.0 159.8

± 6.8 ± 9.2

Weight (kg)

Thyroid cancer Control

43 30

68.1 67.0

± 13.2 ± 12.5

BMI (kg/m2)

Thyroid cancer Control

43 30

26.3 26.2

± 4.9 ± 3.8

*p < 0.05.

Table 2. Preoperative and postoperative leptin levels in thyroid papillary carcinoma (TPC) patients and control subjects

TPC, prethyroidectomy, leptin (ng/mL) Control, leptin (ng/mL) TPC, post-thyroidectomy, leptin (ng/mL)

n

Mean

Standard deviation

34 30 34

22.94*/† 9.89*/‡ 13.92*/†/‡

± 14.67 ± 0.21 ± 10.55

*p < 0.05; †p < 0.05; ‡p < 0.05.

(p < 0.05). In multivariate regression analysis with age and group as the independent variables, and preoperative leptin level as the dependent variable, age was not statistically significant (p = 0.27) but the group variable was (p < 0.001). Forty-three female TPC patients and 30 healthy control women had serum leptin levels of 21.15 ± 14.12 ng/mL and 9.89 ± 0.21 ng/mL, respectively. Leptin levels of TPC patients were significantly higher than those in control group subjects (p < 0.05). TPC patients underwent bilateral total thyroidectomy and their leptin levels were remeasured 20 days after the operation. The mean leptin level of 34 TPC patients who had total thyroidectomy and came to the follow-up visit for blood sampling was 13.92 ± 10.55 ng/mL. The mean prethyroidectomy leptin level of these 34 patients was 22.94 ± 14.67 ng/mL, and if this is compared with the post-thyroidectomy leptin level, a significant decrease was observed (p < 0.05) (Table 2). However, the decreased post-thyroidectomy leptin level was still statistically significantly higher than the control group’s leptin level (Table 2). Leptin is secreted from adipose tissue and its level increases with total adipose tissue, correlating with BMI. Mean BMI of TPC patients and the control group was 26.3 ± 4.9 kg/m2 and 26.2 ± 3.8 kg/m2, respectively (p > 0.05).

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As BMI affects leptin levels directly, an analysis of BMI subgroups was also performed (Table 3) and showed that the two groups were similar regarding the number of patients within each BMI subgroup (p > 0.05). In TPC patients, the preoperative and postoperative leptin levels in BMI subgroups are detailed in Table 4. The leptin levels decreased postoperatively in all BMI subgroups in TPC patients (p < 0.05). As a neuroendocrine hormone, leptin may be affected by menopausal status due to associated hormonal change. Subgroups of menopausal status were analysed for both groups. The control group were older and had a higher percentage of postmenopausal subjects than the TPC group (p < 0.05) (Table 3). Statistical analysis of premenopausal and postmenopausal TPC and control subjects’ leptin levels showed no difference (p > 0.05) (Table 5). Multivariate regression analysis showed that leptin levels were related to the group variable (p < 0.001) but not to menopausal status (p = 0.193). The decrease in the leptin level in TPC patients after total thyroidectomy was not related to menopausal status. Preoperatively, the mean ± SD serum leptin level was 18.89 ± 11.01 ng/mL in 30 premenopausal patients and 26.36 ± 19.03 ng/mL in 13 postmenopausal patients. The

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Table 3. Subgroup analysis of thyroid papillary carcinoma (TPC) and control groups* Group TPC

Control

BMI Underweight/normal (< 25 kg/m2) Overweight (25–30 kg/m2) Obese (> 30 kg/m2)

18 (42) 16 (37) 9 (21)

11 (37) 16 (53) 3 (10)

Menopausal status† Premenopausal Postmenopausal

30 (70)† 13 (30)

8 (27) 22 (73)

*Data presented as number of patients (%); †p < 0.05.

Table 4. Mean ± standard deviation leptin levels (ng/mL) in body mass index (BMI) subgroups of thyroid papillary carcinoma patients BMI subgroup Underweight/normal (< 25 kg/m2) Overweight (25–30 kg/m2) Obese (> 30 kg/m2) p between subgroups

n

Preoperative

Postoperative

p

13 12 9

18.4 ± 12.5 22.9 ± 10.2 29.5 ± 20.7 0.225

11.4 ± 10 13.6 ± 7.5 17.9 ± 14.3 0.365

< 0.001 < 0.001 0.002

Table 5. Leptin levels of premenopausal and postmenopausal thyroid papillary carcinoma (TPC) and control subjects Group

Menopausal status

n

Mean leptin (ng/mL)

Standard deviation

TPC

Premenopausal Postmenopausal TPC, total

30 13 43

18.89* 26.36* 21.15

± 11.01 ± 19.03 ± 14.11

Control

Premenopausal Postmenopausal Control, total Total

8 22 30 73

9.92† 9.88† 9.89 16.52

± 0.08 ± 0.24 ± 0.21 ± 12.14

*/†p > 0.05.

serum leptin level in the TPC group on postoperative day 20 did not significantly differ between premenopausal (12.81 ± 8 ng/mL, n = 22) and postmenopausal patients (15.95 ± 14.1 ng/mL, n = 12) (p > 0.05). The postoperative pathological examination of 43 TPC patients showed that seven specimens had occult and 36 had nonoccult thyroid cancer. The comparison of leptin levels of these two groups showed no difference (p > 0.05). On postoperative day 20, the mean ± SD leptin levels of six occult (11.93 ± 7.89 ng/mL) and 28 nonoccult (14.34 ± 11.1 ng/mL) cancer patients showed no difference when compared with the preoperative leptin levels in seven occult (17.82 ± 14.85 ng/mL) and 36 nonoccult (21.79 ± 14.10 ng/mL) patients, respectively.

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Prethyroidectomy leptin levels of both occult and nonoccult TPC patients were higher than those in the control group (p < 0.05); after total thyroidectomy, the decreases in both groups were statistically significant (p < 0.05) (Table 6).

Discussion In this study, we found that the serum leptin levels of TPC patients were higher than those in control group subjects. The leptin levels decreased after total thyroidectomy compared to prethyroidectomy levels. However, the decreased post-thyroidectomy leptin levels were still statistically significantly higher than the control group levels. The leptin

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Table 6. Leptin levels of occult and nonoccult thyroid papillary carcinoma (TPC) patients compared with pre- and post-thyroidectomy status Group

n 30 7 6

9.89*/† 17.82* 11.93†

± 0.21 ± 14.85 ± 7.89

36 28

21.79* 14.34†

± 14.10 ± 11.11

Occult

Prethyroidectomy Post-thyroidectomy

Control TPC TPC

Nonoccult

Prethyroidectomy Post-thyroidectomy

TPC TPC

Mean leptin (ng/mL)

Standard deviation

*/†p < 0.05.

levels in TPC patients were not related to age, menopausal status or pathologic occult status, but were directly related to the cancer group. First of all, the association between leptin and thyroid hormones should be explored. Leptin and thyroid hormones have similar effects on thermogenesis and energy metabolism; the possibility has been raised that they both exert their effects through the same pathways, i.e. regulation of sympathetic nervous system activity, mainly adrenergic upregulation.5 At the level of the pituitary gland, leptin was recently shown to be expressed by thyroid stimulating hormone (TSH) cells too.18 Prolonged fasting is associated with a fall in leptin levels and in thyroid hormones. Leptin administration to fasted mice decreased the fall in thyroxine (T4)/TSH induced by fasting,19 restored the reduced plasma levels of total and free triiodothyronine (T3) and T4 to normal levels, and suppressed proTRH mRNA in paraventricular neurons.20 However, thyroid hormones have an inhibitory effect on leptin expression or secretion since thyroid hormones have a permissive role on the effects of catecholamines on beta-adrenergic receptors, and since stimulation of these receptors suppresses leptin expression.21 Leptin was elevated in thyroidectomised rats compared with controls, and infusion of T3 or T4 to these rats decreased leptin levels.22 Administration of T3 to hypothyroid rats also decreased leptin mRNA expression in adipose tissue and circulating leptin levels.21 Possible effects of low versus high thyroid hormone levels on leptin levels were studied in hypothyroid and hyperthyroid patients, with conflicting results.5 Although thyroid dysfunction seems not to have a significant effect on leptin levels in man, we included euthyroid subjects in our study for both TPC patients and control subjects for standardisation. One of the main questions is what the leptin level is in other types of thyroid diseases, such as benign

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multinodular goitre or follicular adenomas that undergo surgical treatment. Serum leptin levels were reported to be unchanged in Basedow-Graves and multinodular goitre patients.23 However, serum leptin levels were found to be high in postpartum thyroiditis patients.24 The association of increased leptin levels in thyroiditis and in cancer patients could be explained by the fact that the immune system is one of the targets of leptin activity. Our study included euthyroid patients who underwent total thyroidectomy after fine needle aspiration had showed malignant features. It would have been interesting to have a control group of patients with a benign disease such as goitre in our study, but total thyroidectomy is rarely performed for benign disease and euthyroid patients. Although there have been conflicting reports on the effects of hypothyroidism and hyperthyroidism on leptin levels and on the interaction between leptin and the pituitary-thyroid axis in humans,25 it has been documented that plasma leptin levels are elevated in hypothyroid patients and decreased in hyperthyroid patients.21,22,25–29 Contrastingly, other authors have not reported any significant changes in leptin levels in hypo- or hyperthyroidism.30–32 Elevation of or no significant change in leptin levels after total thyroidectomy in hypothyroidism is an acceptable condition but the decreased levels as seen in our study are unexpected, and therefore support the idea of a relationship between leptin and thyroid cancer. It would be interesting to follow leptin levels serially in these postoperative patients until the point when the patients are on chronic thyroid hormone replacement therapy. The synthesis of leptin in adipocytes is influenced by different humoral factors, most notably insulin,33,34 tumour necrosis factor-alpha (TNF-α),2 glucocorticoids,35,36 reproductive hormones,37 and prostaglandins.38 Importantly, many of these factors have been shown to be associated with neoplastic processes39 and

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support our findings in this study. Leptin expression can be induced under hypoxic conditions, which often occur in solid tumours.39,40 Hypoxia and chemical inducers of cellular hypoxia are able to activate the leptin gene promoter through the hypoxia-induced factor-1 in human adipocytes and fibroblasts.40,41 These data suggest that leptin may play a role in vascular remodelling.42 Indeed, leptin has been shown to regulate neoangiogenesis by itself and in concert with vascular endothelial growth factor and fibroblast growth factor.43,44 In addition to its proangiogenic function, leptin can enhance endothelial cell growth43,44 and suppress apoptosis through a Bcl-2dependent mechanism.45 The role of leptin in neovascularisation is supported additionally by the observation that the hormone can increase the levels and activity of enzymes involved in angiogenesis, for example, matrix metalloproteinases 2 and 9.46,47 In addition to its involvement in endothelial cell function, leptin has been shown to act as a mitogen, transforming factor, or migration factor for many different cell types, including smooth muscle cells,48 normal and neoplastic colon cells,49,50 and normal and malignant mammary epithelial cells.51,52 Higher levels of leptin in the TPC group than in the control group and the significant decrease after total thyroidectomy in the same subjects make leptin a possible etiologic factor in thyroid carcinogenesis, at least in one step. However, the decreased post-thyroidectomy levels of leptin were still significantly higher than the control group levels of leptin, which may be related to hypothyroidism during the postoperative period for TSH stimulation. Leptin levels have been shown to increase with hypothyroidism.53 Leptin is synthesised and secreted mainly by fat cells, and its plasma levels in humans are strongly correlated with BMI.54 Thus, we analysed the BMI subgroups in both TPC and control groups and found no significant differences in these BMI subgroups. The leptin levels decreased postoperatively in all BMI subgroups in TPC patients. In this study, all the patients and healthy control subjects were female because it is known that an increase in testosterone is associated with a decrease in the plasma concentration of leptin.55 All the patients had the diagnosis of TPC for standardisation. Although leptin levels in male thyroid carcinoma subjects and in benign thyroid disorders remain unknown with this series, this is a pioneer study and the authors primarily aimed to compare

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the leptin levels in thyroid carcinoma in a homogeneous group. Another study including benign thyroid disorder subgroups would be interesting in order to see the relationship between leptin and malignancy. In spite of the fact that we still do not know about benign thyroid disorders, leptin levels were elevated in thyroid cancer and they decreased after total thyroidectomy. Therefore, this pioneer study suggests a possible association between TPC and leptin.

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