Med Oncol (2013) 30:589 DOI 10.1007/s12032-013-0589-5
ORIGINAL PAPER
Vitamin D3 levels and insulin resistance in papillary thyroid cancer patients Mustafa S¸ ahin • Bekir Uc¸an • Zeynep Ginis¸ • Oya Topalog˘lu • As¸ kın Gu¨ngu¨nes¸ ¨ ztu¨rk U ¨ nsal • Nujen C ¸ olak Bozkurt • Mu¨yesser Sayki Arslan • I˙lknur O Esra Tutal Akkaymak • Taner Demirci • Melia Karako¨se • Mustafa C ¸ alıs¸ kan • ¨ zbek • Tuncay Delibas¸ ı Erman C ¸ akal • Mustafa O
•
Received: 23 February 2013 / Accepted: 23 April 2013 / Published online: 5 May 2013 Ó Springer Science+Business Media New York 2013
Abstract Both insulin resistance (IR) and vitamin D deficiency (VDD) are found to be associated with many cancer types. In this study, we evaluated the presence of IR and VDD in thyroid cancer patients based on controls. Total 344 papillary thyroid cancer and 116 controls were part of the study. Glucose, insulin, homeostasis model analysis-insulin resistance (HOMA-IR) (control group 2.12 ± 0.9 and patient group 3.6 ± 1.1; p \ 0.0001), LDL were significantly high; HOMA-S and vitamin D3 levels (control group 19.11 ± 8 and patient group 17 ± 16; p = 0.004) were significantly low in the patient group. Vitamin D deficiency (64/108 in controls vs 166/235; p = 0.026) and insulin resistance (24/108; 115/235; p \ 0.0001) were more frequent in papillary thyroid cancer patients. After regression analysis, tumor diameter showed significant association with log-HOMA-IR (B = 0.315; p = 0.017) and log-vitamin D3 (B = 0.207; p = 0.04). Vitamin D deficiency and insulin resistance frequencies show no difference between microand macropapillary thyroid cancers. Receiver operating
M. S¸ ahin (&) Endocrinology and Metabolism Department, Ankara University School of Medicine, ˙Ibni Sina Hastanesi Ek Bina M-blok Kat:1, 06100 Sıhhıye, Ankara, Turkey e-mail:
[email protected];
[email protected];
[email protected] B. Uc¸an O. Topalog˘lu A. Gu¨ngu¨nes¸ ¨. U ¨ nsal N. C ¸ . Bozkurt M. S. Arslan I˙. O E. T. Akkaymak T. Demirci M. Karako¨se M. C¸alıs¸ kan ¨ zbek T. Delibas¸ ı E. C¸akal M. O Endocrinology and Metabolism Department, Ankara Diskapi Training and Research Hospital, Ankara, Turkey Z. Ginis¸ Biochemistry Clinic, Ankara Diskapi Training and Research Hospital, Ankara, Turkey
characteristic curve shows the best cutoff point for tumor diameter showing that the presence of lymph node metastasis was 0.65 cm with 81.2 % sensitivity and 52 % specificity. Best cutoff point for the capsular invasion tumor diameter was 0.75 cm with 83.3 % sensitivity and 60.4 % specificity. No difference between follicular and classical type papillary thyroid carcinomas has been yet discovered. As a result, thyroid cancer patients are more insulin resistant and vitamin D3 deficient. Vitamin D3 levels and HOMA-IR index may affect tumor diameter. Tumor size that is lower than 1 cm (0.65–0.75 cm) may be related with capsular invasion and lymph node involvement. Keywords Vitamin D3 Vitamin B12 Folic acid Insulin resistance Beta cell function Thyroid cancer Thyroglobulin Abbreviations TPOAb Anti-thyroid peroxidase antibody TSH Thyrotropin (thyroid-stimulating hormone)
Introduction Differentiated thyroid carcinomas are the most common endocrine malignancies. Well-differentiated thyroid cancers are follicular cell-derived cancers constituting mostly (75 %) papillary thyroid cancer [1]. Follicular thyroid cancers are the less common version of differentiated cancers [1]. Most common subtypes in papillary thyroid cancers are classical and follicular variants (30–50 %) subtypes [2]. Long-term outcome of the follicular variant is similar to the classical form of thyroid carcinomas [3]. The differences between these two common subtypes are not
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clear [3]. Compared to males, thyroid cancers are mostly seen in females. Other risk factors that contribute to the formation of thyroid cancers are iodine intake status (low for follicular thyroid cancer), neck radiation, hereditary conditions, family history, and the radioactive fallout from nuclear accidents [1, 4]. Vitamin D deficiency is reported to be a risk factor for diabetes and several cancers [5]. In vitro cell culture studies the growth inhibitory effects of active vitamin D3 as seen in several cancer lines [6]. We know that active vitamin D3 has differentiating effect and apoptosis [7, 8]. The evaluation of status of vitamin D stores the level of the 25 (OH) vitamin D3 in the circulation is seen to be the most reliable measure. Recently, unlike the high rate of deficiency in many cancer types, vitamin D deficiency prevalence in 79 thyroid cancer patients is reported to be similar to controls [9]. But in this study, the control group had nodular thyroid disease. In another study, 50 thyroid cancer patients were compared with 26 healthy controls. The results showed that there were no differences in vitamin D deficiency [10]. It is obvious that more studies are needed in different populations because the numbers of studies are low since the different ethnic and geographic backgrounds affect the results. There are also report cases that support the association between prognosis of various cancers and the serum level of 25 (OH) vitamin D3 [11]. Prognostic factors in thyroid cancer such as tumor size may be connected with 25 (OH) vitamin D3 levels. Vitamin D deficiency is also linked with autoimmune thyroid disease in recent studies [12, 13]. Also, vitamin D3 levels are linked to thyroid-stimulating hormone (TSH) levels in another study [14]. Insulin resistance (IR) and hyperglycemia are reported to be the important risk factors responsible for carcinogenesis [15, 16]. Insulin resistance is found to be associated with nodular thyroid disease [17]. High prevalence of IR was reported in 20 differentiated thyroid cancer women [18]. Also many factors may affect IR in thyroid cancer patients as TSH and vitamin D3 levels. Prevalence of folic acid and vitamin B12 deficiencies are associated with thyroiditis [19]. We could not find any study related with the associating thyroid cancer and the level of these compounds. Thyroglobulin levels are good predictors of the recurrence or the persistence disease after the thyroidectomy and the radioactive iodine therapy. Many associated factors are linked with the serum thyroglobulin levels [20]. Goiter, smoking, family history of thyroid disease, presence of thyroid autoantibodies, and serum TSH levels are the known factors affecting thyroglobulin levels [20]. We do not know the effect of vitamin D3, B12 or folic acid levels or insulin resistance on thyroglobulin levels in thyroid cancer patients.
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We evaluated vitamin D3 levels, plasma calcium phosphor, vitamin B12 levels, folic acid, iron, ferritin, whole blood counts, lipid levels insulin resistance, insulin sensitivity, and the beta cell function in thyroid cancer patients according to the healthy controls. We aimed to study the effects of vitamin D3 levels, vitamin B12 levels, folic acid levels and insulin resistance on TSH levels, thyroglobulin levels, and prognostic factors in thyroid cancer patients. We evaluated whether there are any difference in the insulin resistance and vitamins status between micro- and macropapillary thyroid cancer patients.
Materials and methods Our study was conducted at the Diskapi Yildirim Beyazid Training and Research Hospital, Endocrinology and Metabolism Diseases Department, Ankara, Turkey, in between July 10, 2010 and January 1, 2012. Three hundred and forty-four differentiated thyroid cancer patients were examined, and afterward, they underwent total thyroidectomy and 100 mci RAI therapy. 116 controls were compared with the patient group. All the patients had definite histopathological results. Smoking status, family history of goiter and thyroid cancer, ear side of mobile phone usage were investigated and reported. All patients have shown histopathological results, lymph node status, and other prognostic factors. There were follow-up measurements every 3 months. The measurements were to examine the presence of the repetitive basal and stimulated thyroglobulin, anti-thyroglobulin levels in patients. We also applied neck ultrasound in each visit after thyroidectomy. The follow-up lasted for almost 36 months. The patients are still being monitored. Following overnight fasting, each participant provided a venous blood sample for biochemical evaluation that included routine renal and hepatic function, fasting glucose, insulin, HDL cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels, as well as vitamin B12, folic acid, iron, ferritin, calcium, phosphor, 25-hydroxycholecalciferol 25 (OH) D. Fasting insulin, thyroid function tests including free thyroxin (fT4), thyroid-stimulating hormone (TSH), thyroid autoantibodies including anti-thyroglobulin (anti-TG) and thyroid peroxidase anti-body (anti-TPO) were measured with enzyme chemiluminescence immunoassay method with a commercial kit (Immulite 2000, Bio DPC, Los Angeles, CA, USA). Normal reference ranges for these tests were as follows: TSH, 0.55–4.78 mIU mL-1; FT4, 0.74–1.52 ng dL-1; anti-TPO, 0–57 IU mL-1; TgAb,\64 IU mL-1). Serum 25 (OH) Vitamin D levels were measured using commercially available ELISA kit (Immuno-Biological Laboratories Inc., Minneapolis, MN, USA). Kit’s normal reference range was
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between 11.1 and 42.9 ng/mL. 25(OH) Vitamin D measurements were made between September and March. Tg was measured by an IMA (Access Thyroglobulin assay; Beckman Coulter, Inc., Fullerton CA) (functional sensitivity 0.1 ng/mL). Homeostasis model analysis-insulin resistance (HOMAIR), HOMA-% B, and HOMA-% S were calculated in all patients according to a new model [21]. The cutoff value was taken as 2.7 for HOMA-IR [22]. Thyroid ultrasonography was performed using a 12-MHz linear probe (Hitachi EUB 7000 HV). Thyroid volume was calculated using the following formula; Volume = Right
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(height 9 width 9 depth) cm 9 0.479 ? Left (height 9 width 9 depth) cm 9 0.479. Height, weight, and waist circumference (WC) were measured. WC (cm) was measured on a horizontal plane at the level of the umbilicus. The body mass index (BMI) was calculated by dividing the body weight (kg) by the square of height (cm). Statistical analysis was performed with SPSS Statistics (IBM Corporation, Somers, NY) software, version 20.0). The normality of the distribution of continuous variables was determined using the Kolmogorov–Smirnov test. Only age,
Table 1 Clinical and laboratory characteristics of thyroid cancer patients compared to controls Control group n = 116
Patient group n = 344
p
NS
Age (years)
44.9 ± 8
45.5 ± 11
BMI (kg/m2)
29.6 ± 5.4
29.8 ± 5.6
NS
Waist (cm)
96.3 ± 12.1
96.4 ± 12.8
NS
Waist/hip ratio
0.90 ± 0.04
0.91 ± 0.07
NS
17
55
NS
99 6.99 ± 1.8
289 7.33 ± 2.0
NS
Gender Male Female White blood cell count, (/lL) (WBC) Red blood cell count, RBC (/lL)
4.8 ± 0.5
4.6 ± 0.4
0.007
Hemoglobin (g/dL)
13.7 ± 1.7
13.6 ± 1.6
0.009
Hematocrit (%)
40.0 ± 5.5
38.8 ± 3.8
0.002
Red cell distribution width (RDW) (%)
14.3 ± 0.3
14.7 ± 0.2
\0.0001
Mean platelet volume (MPV) fL
8.76 ± 0.1
8.7 ± 0.2
NS
Erythrocyte sedimentation rate (ESR) (mm/h)
19 ± 6
28 ± 8
\0.0001 \0.0001
Fasting glucose (mg/dL)
86 ± 8.7
96 ± 12
Insulin
10.1 ± 2.3
14 ± 3.6
0.003
HOMA-IR(%)a
2.12 ± 0.9
3.6 ± 1.1
\0.0001
HOMA-B
127 ± 18
128 ± 28
NS
HOMA-S
94.5 ± 14
78.3 ± 12
0.001
HOMA-IR(%)b
1.3 ± 0.3
1.8 ± 0.6
0.002
Total cholesterol (mg/dL)
182 ± 32
204 ± 45
0.002
Plasma triglycerides (mg/dL) High-density lipoprotein cholesterol HDL cholesterol (mg/dL)
121.5 ± 11 74.7 ± 19
143.4 ± 8 52 ± 13
0.142 \0.0001
Low-density lipoprotein cholesterol LDL cholesterol (mg/dL)
90 ± 24
162 ± 34
\0.0001
Calcium (mg/dL)
9.3 ± 0.9
9 ± 0.7
0.013
Serum phosphor (mg/dL)
3.4 ± 0.4
3.7 ± 0.9
0.011 0.004
Vitamin D3 (ng/mL)
19.11 ± 8
17 ± 16
TSH (uIU/mL)
2.1 ± 0.2
10 ± 1.8
0.04
Free T4 (ng/dL)
1.0 ± 0.15
1.4 ± 0.3
\0.0001
Anti-TPO (IU/mL)
26.4 ± 14.9
141 ± 25
\0.0001
Anti-tg (IU/mL)
35.9 ± 20
52.1 ± 28
NS
Thyroid volume (mL)
11.3 ± 6
23.6 ± 9
\0.0001
BMI Body mass index, Anti-tg Antithyroglobulin, Antithyroid peroxidase, TSH thyroid-stimulating hormone T4 thyroxine, HOMA-IR homeostasis model assessment for insulin resistance a
HOMA-IR was calculated by multiplying fasting insulin (U/mL) by fasting glucose (mmol/L) and dividing by 22.5
b
HOMA-IR was calculated by new method of Matthews [21]
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hematocrits levels, sedimentation, iron levels, and iron binding capacity were normally distributed. The results are expressed as mean ± SD (standard deviation) for continuous variables. Categorical variables are interpreted by frequency tables. The Mann–Whitney test was used to compare the variables that were not normally distributed. On the other hand, Student’s t test was used to compare the variables with normal distribution. Categorical features and relationships between groups were assessed using an appropriate chisquare test. The level of the statistical significance was set at p \ 0.05.
Results There are no significant difference between control group and patient group in age (control mean age 44.9 ± 8 and patient mean age 45.5 ± 11), body mass index (control group 29, 6 ± 5, 4 and in patient group 29, 8 ± 5, 6), waist circumference (control group 96.3 ± 12.1 and in patient group 96.4 ± 12.8) and sex (289 female, 55 male in patient group; 99 female, 17 male in control) (p [ 0.05) (Table 1). Glucose (control group 86 ± 8.7 and patient group 96 ± 12; p \ 0.0001), insulin (control group 10.1 ± 2.3 and patient group 14 ± 3.6; p = 0.003), HOMA-IR (control group 2.12 ± 0.9 and patient group 3.6 ± 1.1 p \ 0.0001), and LDL (control group 90 ± 24 and patient group 162 ± 34 p \ 0.0001) were significantly higher. HOMA-S (control group 94, 5 ± 14 and patient group 78, 3 ± 12; p = 0.001) was significantly lower in the patient group. Vitamin D3 levels were similar in both groups (control group 19.11 ± 8 and patient group 17 ± 16 p = 0.004) (Table 1). There was no significant difference between liver and renal function tests. Tumor diameter is significantly correlated with the age (r = 0,122; p = 0.034) and log-vitamin D3 (r = 0.141; p = 0.041) level, capsule invasion (r = 0,308; p \ 0,0001), cervical lymph node involvement (r = 0,213; p \ 0,0001), and tumor in surgery border (r = 0,122;p = 0,034). After regression analysis, tumor diameter is associated with logHOMA-IR (b = 0.227;p = 0.065), and log-vitamin D3 (b = 0.265; p = 0.029) is significant. Cancer with a diameter of 10 mm or more is only correlated with log-glucose (r = 0.127; p = 0.041) and log-free T4 (r = 0.293; p \ 0.0001). After regression analysis of macropapillary, thyroid cancer is correlated with log-thyroglobulin (B = 0.386; p = 0.047), log-anti-TPO (B = -0.521; p = 0.076), and log-cholesterol (B = 0.352; p = 0.046). Receiver operating characteristic curve was built between capsule invasion and tumor diameter area. Area under the curve was 0.767; for tumor diameter 0.75 cm, the sensitivity was 83.3 % and the specificity was 60.4 % for detecting capsule invasion. Area under the curve was
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Med Oncol (2013) 30:589 Table 2 Vitamin D deficiency frequencies in patients and controls No vitamin D deficiency (C20 g/mL)
Vitamin D deficiency (\20 g/mL)
Controls
44
64
Patients
69
166
p 0.016
0.584; for tumor diameter 0.65 cm, multifocality observed with the sensitivity of 57.6 % and the specificity of 52 %. Area under the curve was 0.652; for tumor diameter 0.65 cm, lymph node involvement observed with the sensitivity of 81.2 % and the specificity of 52 %. Area under the curve was 0.715; for tumor diameter 0.75 cm, involvement border of surgery observed with the sensitivity of 50 % and the specificity of 56.1 %. Area under the curve was 0.715; for tumor diameter 0.65 cm, involvement border of surgery observed with the sensitivity of 50 % and the specificity of 56.1 %. Thyroglobulin levels were correlated with the thyroid volume (r = 0.161; p = 0.043), the recurrence or the persistence disease (r = 0.284; p \ 0.0001), TSH (r = 0.213; p = 0.04), free T4 (r = -0.231; p = 0.003), iron (r = 122; p = 0.034), insulin resistance (r = 0.212; p = 0.013), and HOMA-S (r = -0.175;p = 0.042). After regression analysis, thyroglobulin levels were correlated with log-TSH (B = 0.414; p = 0.01), log-free T4 (B = 0.839; p = 0.08). Vitamin D3 levels are significantly lower according to the controls, and the vitamin D deficiency is more frequent in papillary thyroid cancer patients (64/108 in controls vs 166/235) (p = 0.026) (Table 2). There are no significant difference in vitamin D3 levels between microcarcinoma and macrocarcinomas. Vitamin D deficiency and insulin resistance frequencies are not different between micro- and macropapillary thyroid cancers. Insulin resistance is more frequent in papillary thyroid cancer patients p \ 0.0001 (24/108; 115/235) (Table 3). All the recurrent and the persistent patients have insulin resistance. Involvement of the surgery border is correlated with the age (r = 0.132; p = 0.022), log-tumor diameter (r = -0.122, p = 0.034), log-TSH (r = 0.126; p = 0.047), and log-glucose (r = 0.140; p = 0.024). Lymph node involvement was correlated with the age (r = 0.148; p = 0.011), log-tumor diameter (r = -0.12, p = 0.039), log-tg (r = 0.209; p = 0.006), log-folate (r = 0.280; p \ 0.001), and log-HOMA-B (r = 0.199 p = 0.011). After the regression analysis, only log-MPV Table 3 Insulin resistance frequencies in patients and controls HOMA-IR index \ 2.7
HOMA-IR index C 2.7
Controls
84
24
Patients
120
115
p \0.0001
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was showed to be correlated with the lymph node involvement (B = 4.595; p = 0.056). None of the factors were related with the insulin resistance or the vitamin D deficiency significantly after the regression analysis. There are 71 follicular types and 151 classical types of papillary thyroid carcinoma. There is no difference between these two groups according to the age, sex, thyroglobulin, antithyroglobulin, vitamin D3, HOMA-IR, and other laboratory parameters. There is no difference between these two groups according to the capsular invasion, involvement of the surgery border or the multifocality. There is less lymph node involvement in the follicular type 4/71 according to 22/151 classical type (p = 0.025). Smoking cigarette, thyroiditis, insulin resistance, and vitamin D deficiency frequencies are not different between these two groups. Vitamin B12 and irons are not found to be related with the tumor size, capsule invasion, lymph node involvement, and tumor at surgery border. Folic acid level is associated with the lymph node involvement. Patients’ selection of ear side while using mobile phone is not correlated significantly with the tumor side or other parameters. As a result, thyroid cancer patients are more insulin resistant and vitamin D3 deficient. Vitamin D3 levels and HOMA-IR index may affect the tumor diameter. Tumor size that is lower than 1 cm (0.65–0.75 cm) may be related to the capsular invasion, lymph node involvement.
Discussion Active vitamin D (1, 25 (OH)2 D3) have antineoplastic activity in several cancer types [6, 23]. Vitamin D deficiency which is diagnosed by measuring the 25 (OH) Vitamin D3 levels is reported to be associated with the increased risk for several cancers [24]. Unlike previous studies in the thyroid cancer patients, we observed decreased vitamin D levels and more vitamin D deficiency frequency in the thyroid cancer patients according to the healthy controls. Our patient number is the largest among these studies. Also we use healthy individuals for the control group. Vitamin D levels were also found to be associated with the tumor size. Ethnicity and geographic situations also may affect these relations. We have reported low vitamin D levels in autoimmune thyroid diseases [12, 13]. Here, we did not find the correlation of vitamin D levels with thyroid autoantibodies. Vitamin D status is not found to be related with the insulin resistance. Vitamin D deficiency may affect the quality of life in thyroid cancer patients. We found previously increased prevalence of insulin resistance in nodular thyroid disease [17]. In a previous study, in a small number of thyroid cancer patients, they discovered that patients are more insulin resistance than the
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control ones [18]. Our study confirmed this result in 344 papillary thyroid cancer patients in iodine sufficient area, Ankara. In the study, we also observed the beta cell function; HOMA-S is found to be significantly decreased in thyroid cancer patients. Insulin resistance is also correlated with the tumor size in our study. Insulin may have mitogenic contributing factor in thyroid tumor genesis. Vitamin D3 deficiency and insulin resistance seem to be related with the increased risk of thyroid cancer. Whether they are coexisting or contributing factors is still obscure. We do not know whether vitamin D3 supplementation affects the prognosis or the incidence of thyroid cancers. Drugs that decrease insulin resistance or physical activity and diet may have effect on thyroid cancer prognosis and incidence. Thyroglobulin levels are not affected by vitamin D3 deficiency and insulin resistance after the regression analysis. Preoperative TSH levels were higher in thyroid cancer patients according to the TSH levels in healthy controls compatible to previous studies [25]. But TSH is not found to be associated with vitamin D3 levels or insulin resistance state in our study. There was no significant difference in the frequencies of insulin resistance or vitamin D deficiency between micro- and macropapillary thyroid cancers. ROC curve analysis shows tumor size between 0.65 and 0.75 cm may be related to the capsular invasion, lymph node involvement. Radioiodine treatment may be more appropriate for tumors greater than 0.65 cm and more. Cell phone usage may not be an important risk factor for thyroid cancer. Vitamin D3 levels and HOMA-IR levels seem to be similar between follicular and classical type of thyroid carcinoma. In thyroid cancer patients, there were increased fasting glucose, increased HOMA-IR levels, increased LDL cholesterol, and decreased HDL cholesterol despite comparable age, BMI, and waist circumferences. So, cardiovascular risk seems to be increased in these patients. In addition to the risks of TSH suppression on heart [26], these increased cardiovascular risks may aggravate the situation. Cardiovascular risk factors in thyroid cancer patients are generally ignored. More attention should be given to these patients from this aspect. Thyroid cancer patients have low vitamin D3 levels and increased HOMA-IR levels. New prospective studies are needed to look at the effects of Vitamin D3 supplement and physical activity or diet on thyroid cancer risk and thyroid cancer prognosis. One cm is not a good cutoff for making therapeutic decision. Better cutoff may be between 6.5 and 7.5 mm in order to differentiate the clinical important cancer and incidental carcinoma. Conflict of interest
None.
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