A comparison of serum copper levels in patients with papillary thyroid carcinoma, nodular goiter, and healthy volunteers

A comparison of serum copper levels in patients with papillary thyroid carcinoma, nodular goiter, and healthy volunteers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A comparison of serum copper levels in patients with papillary thyroid carcinoma, nodular goiter, and healthy volunteers Prachya Maneeprasopchoke, Phoupong Phousamran, Warut Pongsapich, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1595959/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Serum copper (Cu) is an essential trace element that plays a key role in thyroid hormone production. An inappropriate level of serum Cu might be related to development of both benign and malignant thyroid neoplasm. Nodular goiter and papillary thyroid carcinoma (PTC) are common benign and malignant tumors of the thyroid, respectively. This study aims to compare the serum Cu levels of healthy women with women with PTC or nodular goiter. A total of 205 Thai women were recruited for this cross-sectional study. The reference group was comprised of 100 healthy volunteers. There were 61 nodular goiter and 41 PTC patients that had been treated with surgery. Serum Cu was measured using an atomic absorption spectrophotometer and the three groups were compared. The serum Cu levels of the PTC, nodular goiter and the reference group were 0.99 ± 0.27 µg/ml, 1.07 ± 0.26 µg/ml and 1.00 ± 0.30 µg/ml, respectively. The results were not statistically different ( P = 0.26). A post hoc subgroup analysis in the PTC group showed serum Cu levels were significantly higher in the blood vessel invasion group ( P = 0.01) and the BRAF V600 E mutation group ( P = 0.04), but no relationships between serum Cu and other aggressive histopathology were observed. The serum Cu levels of patients with PTC and nodular goiter were not different and did not differ significantly from the reference group. Thus, serum Cu cannot be applied to stratify risk in indeterminate thyroid nodules. Nevertheless, higher serum Cu levels were associated with blood vessel invasion and BRAF V600E mutation in PTC. Therefore, this trace element might have a potential role in prognostication of PTC. Serum copper (Cu) Nodular goiter Papillary thyroid carcinoma Thyroid cancer BRAF mutation Figures Figure 1 Introduction Serum Cu is an arbitrary marker for many types of malignancies and is more available and less expensive than genetic testing. Serum Cu levels rise significantly in many types of malignancies, such as esophageal cancer, gynecologic cancer, pancreatic cancer, and melanoma [ 1 – 4 ]. Why serum Cu is elevated in the presence of malignancy is not yet clear. Copper may be a key factor in tumor angiogenesis [ 5 , 6 ]. Ceruloplasmin, the Cu-binding protein, can increase in malignancies due to decreased metabolism or an inflammatory response state [ 7 , 8 ]. Zhu et al. found that Cu transportation in tumor cells increased as a result of elevated expressions of transporter genes[ 9 ]. Coates and coauthors reported that the sensitivity and specificity of high serum copper for the risk of developing a cancer were 40% and 80.4%, respectively, but a cutoff value was not determined [ 10 ]. Serum copper plays a key role in thyroid hormone production [ 11 ]. This trace element controls T4 levels by regulating calcium homeostasis. An inappropriate serum Cu level stimulates the growth of thyroid follicles and the development of thyroid hyperplasia or carcinoma. Furthermore, Cu acts as an antioxidant, eliminating free radicals caused by various tissue damage in the body. However, excessively high Cu levels can cause abnormal cell growth by creating free radicals and damaging DNA [ 12 , 13 ]. Several studies have reported that the serum Cu levels of patients with thyroid carcinoma were higher than those of normal subjects [ 14 – 17 ]. Additionally, Baltaci et al. also found that serum Cu decreased after removal of thyroid tumors [ 18 ]. In contrast, Al-Sayer et al. did not identify a difference between the serum Cu levels of patients with thyroid cancer and healthy controls, and serum Cu increased after thyroidectomy[ 19 ]. Due to insufficient data and inconclusive evidence, the association between serum cop per and thyroid cancer needs further investigation. Therefore, we aimed to compare the serum copper levels of patients with PTC, nodular goiter and healthy Thai women. Methods Study design This cross-sectional study was conducted at the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, from July 2018 to June 2021. Serum Cu was measured by the Clinical Toxicology Laboratory of the Faculty of Medicine Siriraj Hospital. The laboratory has been certified to the ISO 15189 accreditation standard since 2013. This study was approved by the Institutional Review Board, Faculty of Medicine Siriraj Hospital, Mahidol University (approval #250/2560, EC3) and was conducted in accordance with the Declaration of Helsinki. Study population Diseases of the thyroid gland are generally more common in females than males. In the Thai population, the female to male ratio of incidence of thyroid cancer is approximately 4.3:1, and the gender ratio of thyroid surgery was 5.2:1 during 2018–2020 [ 20 ]. Because serum Cu levels can vary by gender [ 21 ], we investigated only female patients. The thyroid disease group consisted of Thai women aged 18 years and older who had thyroid nodules. Fine needle aspiration was performed prior to surgery. All patients with pathological reports of PTC or nodular goiter who needed surgical treatment for thyroid diseases were eligible. Patients with incidental papillary microcarcinoma, thyroid carcinoma other than PTC, or other thyroid or systemic diseases that could alter serum Cu levels (i.e., thyroiditis, Wilson’s disease, pulmonary disease, cardiovascular disease, infectious disease, and other types of cancer) were excluded. Patients with current medications or supplements that would alter serum Cu levels, a history of previous thyroid surgery, or abnormal levels of FT4 or TSH were also excluded. The reference group consisted of healthy female volunteers with normal thyroid glands confirmed by ultrasonography and blood tests showing FT4, TSH, Cr, and eGFR within normal limits. All study subjects were fully informed about the treatment options and study protocol before signing informed-consent forms. Data collection Demographic data and ultrasonographic findings of the thyroid gland were recorded. Blood samples were tested for FT4, TSH, Cr, eGFR, and serum Cu levels. For the cancer group, a pathology-confirmed specimen was sent for detection of the BRAF V600E mutation using the PCR-based Sanger sequencing technique combined with allele-specific, real-time PCR. Adverse features such as multifocality, blood vessel invasion, capsular invasion, extrathyroidal extension and evidence of transformation from coexisting nodular goiter were noted. The maximum diameter of the tumors was recorded in centimeters. The risk of recurrence was classified according to the 2015 guidelines of the American Thyroid Association [ 22 ]. Stage was classified using the 8th edition of the AJCC/TNM staging system of thyroid cancer [ 23 ]. If indicated, post-treatment I-131 total body scans and serum thyroglobulin (Tg) levels were used to detect residual diseases and distant metastases. Serum Cu level analysis Blood samples were collected with the standard method in accordance with the Clinical and Laboratory Standards Institute guidelines for trace element analysis [ 24 ]. Collection and access procedures were performed in the patient ward one day before surgery with talc-free gloves, a 21-gauge needle, and a BD Vacutainer plastic blood collection tubes for trace element testing (K2EDTA). The tubes were kept upright and either immediately sent to the Clinical Toxicology Laboratory, or stored in a refrigerator at 2º to 8º C for no longer than 24 hours. Before analysis, internal quality assurance for trace elements was routinely performed using ClinCheck Controls. An atomic absorption spectrophotometer was used to heat the analytes and convert them to atoms. Next, the sample was analyzed with a flame atomic absorption spectrophotometer to produce free atoms of Cu in the gaseous state. The absorbance of light with the specific wavelength of Cu was measured. The intensity of the absorbed light wave was proportional to the amount of copper in the sample. Subsequently, a standard calibration curve was plotted with linear regression. Serum Cu levels were reported as mg/dl and converted to µg/ml as a standard unit. Statistical analysis Demographic data are presented using descriptive statistics. One-way analysis of variance was used to compare the three groups (Reference, PTC, and nodular goiter). If the P values were less than 0.05, post hoc analysis was applied. Serum Cu levels (µg/ml) are reported as means ± SD. Subgroup analyses of the serum Cu levels of the PTC group were performed for histopathological aggressiveness and BRAF V600E mutation using the independent samples T-test. Variant of PTC, risk of recurrence and the TNM staging were compared by one-way analysis of variance. Pearson’s correlation was used to test the association between the size of the PTC or nodular goiter and the serum Cu level. A P value of < 0.05 was considered statistically significant. Statistical analyses were carried out using PASW Statistics for Windows (version 18; SPSS Inc., Chicago, IL, USA). Results Two hundred and twenty-two subjects were enrolled and 17 were later excluded. The excluded subjects comprised 10 cases with papillary thyroid microcarcinoma, five cases with follicular thyroid carcinoma, and two cases with thyroiditis. Therefore, the study population was 205 subjects, consisting of 105 patients with thyroid disease (44 with PTC and 61 with nodular goiter), and 100 healthy controls. Serum Cu levels The serum Cu levels of the PTC group, the nodular goiter group and the reference group, were 0.99 ± 0.27 µg/ml, 1.07 ± 0.26 µg/ml and 1.00 ± 0.30 µg/ml, respectively (Fig. 1 ). The results were not statistically different ( P = 0.26). Age, serum creatinine and eGFR were significantly different among the PTC, nodular goiter and reference groups (Table 1 ). After adjustment for age, serum creatinine and eGFR, there was still no statistical difference. Table 1 Demographic data and characteristics of PTC, nodular goiter, and the reference group Patient characteristics (mean ± SD) PTC (n = 44) Nodular goiter (n = 61) Reference (n = 100) P value Age (years) 45.70 ± 13.59 47.62 ± 12.99 39.64 ± 13.85 0.001* ,a,b Weight (kg) 60.38 ± 11.89 59.94 ± 12.99 57.96 ± 12.71 0.47 Height (cm) 156.55 ± 9.40 156.93 ± 6.36 157.29 ± 5.92 0.83 FT4 (ng/dL) 1.23 ± 0.20 1.19 ± 0.15 1.20 ± 0.15 0.42 TSH (uIU/mL) 1.85 ± 1.23 1.58 ± 1.17 1.94 ± 0.99 0.14 Cr (mg/dL) 0.79 ± 0.24 0.70 ± 0.13 0.68 ± 0.10 < 0.001* ,a,c eGFR(L/min/1.73m 2 ) 93.74 ± 21.73 99.74 ± 17.03 108.58 ± 16.28 < 0.001* ,a,b * P values less than .05 considered statistically significant. a P value between reference and PTC was < 0.05 b P value between reference and nodular goiter was < 0.05 c P value between PTC and nodular goiter was < 0.05 Abbreviations: PTC, papillary thyroid carcinoma; FT4, free thyroxine; TSH, thyroid stimulating hormone; Cr, creatinine; eGFR, estimated glomerular filtration rate. PTC group Histopathological aggressiveness Of the 44 PTC cases, the classical variant was found in 88.6% (n = 39) and the follicular variant in 6.8% (n = 3). Two patients (4.5%) had non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NIFTP). Multifocal cancers were identified in 70.5% (n = 31) of cases with no statistical difference ( P = 0.16). The serum Cu in the blood vessel invasion group was significantly higher than those without invasion (Table 2 ). There were no significant differences in serum Cu levels for coexisting nodular goiter, capsular invasion, extrathyroidal extension, high- risk of recurrence and TNM staging. There was no correlation between tumor size and serum Cu levels (r =-0.04; P = 0.81). Four patients (9.1%) had distant metastases detected by I-131 total body scan. Their serum Cu levels were higher than in the no-metastasis group, but the difference was not significant (1.11 ± 0.26 µg/ml, and 0.98 ± 0.27 µg/ml, respectively; P = 0.38). Table 2 Comparison of the histopathological, molecular status, risk of recurrence and staging of 44 PTC cases and their serum copper levels Histopathological aggressiveness n (%) Serum copper level (µg/ml) P value Coexisting nodular goiter Yes 17 (38.6) 0.99 ± 0.20 0.89 No 27 (61.4) 1.00 ± 0.31 Multifocal (Foci > 1) Yes 31 (70.5) 0.97 ± 0.20 0.24 No 13 (29.5) 1.07 ± 0.37 Blood vessel invasion Yes 26 (59.1) 1.08 ± 0.310 0.01* No 18 (40.9) 0.88 ± 0.15 Capsular invasion Yes 25 (56.8) 1.06 ± 0.32 0.11 No 19 (43.2) 0.93 ± 0.16 Extrathyroidal extension Yes 20 (45.5) 1.08 ± 0.35 0.08 No 24 (54.5) 0.93 ± 0.16 Variant Classic 39 (88.6) 1.01 ± 0.32 0.688 Follicular 3 (6.8) 0.99 ± 0.16 NIFTP 2 (4.5) 0.84 ± 0.12 BRAF V600E mutation Yes 20 (45.5) 1.09 ± 0.32 0.04* No 24 (54.5) 0.92 ±0.19 Risk of recurrence Low 11 (25) 0.94 ± 0.12 0.71 Intermediate 23 (52.3) 1.01 ± 0.33 High 10 (22.7) 1.04 ± 0.26 Tumor (T) T1 15 (34.1) 0.98 ± 0.36 0.82 T2 14 (31.8) 1.01 ± 0.22 T3 12 (27.3) 1.03 ± 0.25 T4 3 (6.8) 0.87 ± 0.01 Node (N) N0 21 (47.7) 0.94 ± 0.14 0.25 N1 23 (52.3) 1.04 ± 0.35 Metastasis M0 40 (90.9) 0.98 ± 0.27 0.38 M1 4 (9.1) 1.11 ± 0.26 Stage 1 34 (77.3) 0.98 ±0.29 0.76 2 7 (15.9) 1.03 ±0.15 3 1 (2.3) 1.00 † 4 2 (4.5) 1.19 ± 0.27 * P values less than .05 considered statistically significant. † No min, max as there was only one data item for that category. Abbreviations: NIFTP, Noninvasive follicular thyroid neoplasm with papillary-like nuclear features Molecular testing The BRAF V600E mutation was positive in 20 patients (45.5%) and negative in 24 (54.5%). The serum Cu levels of BRAF-positive cases were significantly higher than in the negative groups. (1.09 ± 0.32 µg/ml, and 0.92 ± 0.19 µg/ml, respectively; P = 0.04). Nevertheless, the results from both groups remained within the reference range. Nodular goiter group The correlation coefficient between the diameters of the nodular goiter and serum Cu levels was ( r = 0.02; P = 0.89). The mean serum Cu level in cases of PTC with nodular goiter was 0.99 ± 0.20 µg/ml (n = 17), while the mean serum Cu level for cases with pure nodular goiter was 1.07 ± 0.26 µg/ml (n = 61) ( P = 0.76). Discussion We compared serum Cu levels of patients with PTC, nodular goiter and normal healthy subjects. Zhang[ 21 ] and Shen[ 25 ] reported that gender and ethnicity influence serum Cu levels and so we investigated Thai women, the gender most often affected by this disease. The mean serum Cu levels of our reference group were comparable to those in other studies (Table 3 ), and very close to the mean value of the biggest dataset in a Chinese population (1.00 ± 0.30 vs 1.01. ± 0.24 µg/ml) [ 21 ]. We did not identify any statistically significant differences in the serum Cu levels of the PTC, nodular goiter, and reference groups. The serum Cu levels were measured using atomic absorption spectrometry, as was done by many previous studies [ 17 , 21 , 26 ]. Moreover, the quality of the measuring techniques used by the Clinical Toxicology Laboratory is also attested by its ISO-accreditation. Table 3 Serum copper levels in healthy subjects Studies Year Country Measurement technique N Sex Serum copper levels (mean ± SD; µg/ml) Maneeprasopchoke et al. 2022 Thailand AAS 100 Female 1.00 ± 0.30 Zhang et al.[ 21 ] 2009 China AAS 890 Female 1.01 ± 0.24 Baltaci et al. [ 18 ] 2017 Turkey AES 15 Female 0.74 ± 0.24 Przybylik-Mazurek et al.[ 26 ] 2011 Poland AAS 20 All 1.11 ± 0.19 Kosova et al. [ 17 ] 2012 Turkey AAS 37 All 1.06 ± 0.11 Leung et al. [ 16 ] 1996 China AES 50 All 0.74 ± 0.19 Kucharzewski et al.[ 15 ] 2003 Poland TRXRF 50 All 0.69 ± 0.06 Abbreviations: AAS, atomic absorption spectrometry; AES, atomic emission spectrometry; TRXRF, total reflection fluorescence The use of Cu to support the diagnosis of thyroid cancer remains inconclusive. Baltaci et al. [ 18 ] showed that serum Cu levels of women with thyroid cancer were significantly higher than those of healthy controls (0.87 ± 0.33 µg/ml, and 0.74 ± 0.24 µg/ml, respectively; P < 0.05). Additionally, the serum Cu levels of female patients with thyroid cancer significantly decreased to levels close to those of the control group within two weeks after surgery (0.74 ± 0.30 µg/ml). Vesna and colleagues [ 14 ] compared 35 cases of PTC and 13 cases of papillary thyroid microcarcinoma with 82 cases of benign thyroid tumor. The serum Cu levels of patients with PTC and microcarcinoma were significantly higher than patients with benign thyroid tumor. However, because incidental microcarcinoma was included in the PTC group, their findings are challenging to interpret and to compare with our study. In 2015, Shen and colleagues published a meta-analysis of five case-control studies investigating serum Cu levels [ 25 ]. One study was carried out in China (n = 100), three in Poland (n = 71, n = 45, and n = 33), and one in Turkey (n = 84). Overall, patients with thyroid cancer had higher serum Cu levels than healthy controls (standardized mean difference, 2.372; 95% CI, 0.945–3.799; P = 0.001). However, consistent with our results, the Polish studies did not find higher serum Cu levels in patients with thyroid cancer relative to their controls. A 2004 study from Kuwait also reported that serum Cu levels in thyroid cancer patients were not different from healthy controls and rose significantly after thyroidectomy [ 19 ]. Hence, ethnicity can influence serum Cu levels. Normally, Cu is actively recycled in the digestive tract, body fluids and tissues, and is mainly excreted from the body via bile. Copper levels are primarily controlled by recycling and resorption, and dietary Cu represents only a small proportion of total Cu resorption [ 15 ]. Therefore, dietary intake of Cu has an insignificant affect on serum Cu levels and does not need to be controlled. In the post hoc subgroup analysis of PTC, we found significantly higher serum Cu levels in patients with blood vessel invasion. This finding suggests a relationship between serum Cu and the aggressiveness of PTC. Moreover, the mean serum Cu levels were also higher in the presence of adverse features such as positive capsular invasion, extrathyroidal extension, lymph node involvement, distant metastases and high stage. While the difference was not statistically significant, we can infer that high serum Cu may be related to the invasiveness of PTC. The potential relationship between serum Cu levels and gene mutation in humans has not been studied. Since copper regulates the function of follicular cells, aberrant levels of serum Cu may be associated with molecular alterations. Currently, there are several genetic mutations reported in thyroid cancer and the BRAF V600E mutation is the most common biomarker for PTC. Brandy et al. demonstrated that Cu is required for BRAF signaling and tumorigenesis. A reduction in serum Cu levels caused the size of BRAF V600E -driven melanomas to decrease in laboratory animals [ 27 ]. A recent investigation by Baldari et al. also found that Cu-chelating agents reduced the proliferation, survival, and migration of human colon cancer cells carrying the BRAF V600E mutation [ 28 ]. We hypothesized that in thyroid cancer, the BRAF V600E mutation would be associated with increased serum Cu levels, as is seen in melanoma and colon cancer. We did observe a significant elevation of serum Cu levels in PTC with BRAF V600E mutation, suggesting that serum copper may indicate the severity of PTC. The role of Cu-chelating agents as an adjuvant therapy in BRAF V600E mutation positive PTC merits further investigation. To our knowledge, this is the first study to report serum Cu levels in terms of histopathological aggressiveness, risk of recurrence, staging, and molecular status in PTC. In addition, we screened all healthy subjects with ultrasonography of the thyroid gland to avoid unexpected thyroid nodules in the control group. This ensured that the reference serum Cu values of the healthy Thai women were reliable and could be used as a standard for further studies. On the other hand, our analyses suggests that serum Cu levels are not appropriate for diagnostic purposes, but may have value to predict the severity of PTC. Our study has some limitations. Our subjects were Thai women with PTC and nodular goiter. We did not address the role of serum Cu levels in men, other types of thyroid cancer, and in advanced-stage thyroid cancers such as tracheal or recurrent laryngeal nerve invasion. Conclusions The role of serum Cu in the pathogenesis and prognosis of thyroid tumors remains unclear. Serum Cu levels in patients with PTC and nodular goiter were not different, and also were not different from the reference group. However, serum Cu was associated with aggressive histopathology of PTC such as blood vessel invasion and BRAF mutation. Therefore, serum Cu levels are not currently suitable for use as an assistive tool for the diagnosis, but may be useful to establish the prognosis of PTC. Declarations Funding source: Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. The funding source had no role in the study design, conduct, or writing. Authors’ contributions Prachya Maneeprasopchoke: conceptualization, data collection, formal analysis, validation, and manuscript review and editing. Phoupong Phousamran: data collection, formal analysis, and manuscript drafting. Warut Pongsapich: supervision, critical revisions, and final approval. Paveena Pithuksurachai: visualization and validation. Jakrit Worrakulpanit: investigation and formal analysis. Tippanate Keawvijit: determination of serum Cu levels. Naravat Poungvarin: investigation of the BRAF mutations. Kanchana Amornpichetkul: pathological review. Cheerasook Chongkolwatana: conceptualization, methodology, project administration, critical revisions, and final approval. Acknowledgments The authors appreciate the assistance provided by Dr. Saowalak Hunnangkul, PhD, Division of Clinical Epidemiology, Department of Health Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, for her assistance with the sample size calculation and statistical analyses. We also thank Miss Jeerapa Kerdnoppakhun of the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, for secretarial support. The authors also gratefully acknowledge the professional English editing of this paper by Mr. Mark Simmerman. Data Availability The data used to support the findings of this study are available from the corresponding author upon request. Conflicts of Interest The authors declare that they do not have any conflict of interest regarding this research. Funding Statement This work was supported by Faculty of Medicine Siriraj Hospital, Mahidol University [grant number R016133003] References Goyal MM, Kalwar AK, Vyas RK, Bhati A (2006) A study of serum zinc, selenium and copper levels in carcinoma of esophagus patients. Indian Journal of Clinical Biochemistry 21:. https://doi.org/10.1007/BF02913100 Margalioth EJ, Udassin R, Cohen C, et al (1987) Serum copper level in gynecologic malignancies. American Journal of Obstetrics and Gynecology 157:. https://doi.org/10.1016/S0002-9378(87)80353-8 Lener MR, Scott RJ, Wiechowska-Kozłowska A, et al (2016) Serum Concentrations of Selenium and Copper in Patients Diagnosed with Pancreatic Cancer. Cancer Research and Treatment 48:. https://doi.org/10.4143/crt.2015.282 Fisher GL, Spitler LE, McNeill KL, Rosenblatt LS (1981) Serum copper and zinc levels in melanoma patients. 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Nature 509:. https://doi.org/10.1038/nature13180 Baldari S, di Rocco G, Heffern MC, et al (2019) Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells. Cancers (Basel) 11:. https://doi.org/10.3390/cancers11050659 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1595959","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":101694513,"identity":"4fe6f3d8-f0a6-49ef-ad75-abd73b9e8073","order_by":0,"name":"Prachya Maneeprasopchoke","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Prachya","middleName":"","lastName":"Maneeprasopchoke","suffix":""},{"id":101694514,"identity":"cf88dc80-6f4b-42f5-a4bd-04e5788ccd92","order_by":1,"name":"Phoupong Phousamran","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Phoupong","middleName":"","lastName":"Phousamran","suffix":""},{"id":101694515,"identity":"ffe7387e-aac2-492f-8feb-8b4f57106488","order_by":2,"name":"Warut Pongsapich","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Warut","middleName":"","lastName":"Pongsapich","suffix":""},{"id":101694516,"identity":"751f6bbd-e9af-42d9-8acf-bec20f08a82b","order_by":3,"name":"Paveena Pithuksurachai","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paveena","middleName":"","lastName":"Pithuksurachai","suffix":""},{"id":101694517,"identity":"791ebc41-58bf-413a-a824-e6b7bc5df221","order_by":4,"name":"Jakrit Worrakulpanit","email":"","orcid":"","institution":"Bhumibol Adulyadej Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jakrit","middleName":"","lastName":"Worrakulpanit","suffix":""},{"id":101694518,"identity":"5ff41b08-aa5f-40e9-9990-115a4756be83","order_by":5,"name":"Tippanate Keawvijit","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tippanate","middleName":"","lastName":"Keawvijit","suffix":""},{"id":101694519,"identity":"78c32647-19dd-44e5-8891-22b0d8603f90","order_by":6,"name":"Naravat Poungvarin","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Naravat","middleName":"","lastName":"Poungvarin","suffix":""},{"id":101694520,"identity":"c104b3d0-96d2-4bd8-a1a8-0aa4ba24f09e","order_by":7,"name":"Kanchana Amornpichetkul","email":"","orcid":"","institution":"Mahidol University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kanchana","middleName":"","lastName":"Amornpichetkul","suffix":""},{"id":101694521,"identity":"b2dbf38b-9b5d-4414-acb2-a4237b94aab0","order_by":8,"name":"Cheerasook Chongkolwatana","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIiWNgGAWjYDACCRiDh4GBmYHBBijC2CDBUAAWYyNGSxpUiwFIiJkoLYfBIni18M9uPvi4oqZOjp/nAOPngorz0UCRxhsfDBjk+Rv4jz3AZsmdY8mGZ44dNpbsbWCWnnHmdu6MOwebLWcYMBjOOMDMboBFi4FEjplkA9uBxA3nGdiYedtu5zbcSGyT5jFgYNwAdJgEVi353382/KuDaTmXOx+qxR63lhw2xsY25sQNZxtAWg7kboBqScSlReJGmrFkYx/QLz0Hm6V5ziTnbryRCPKLRPKMw8xm2LTwz0h++LHhGyjEkg9+5qmwy513I/3hjQ8VNrb97Y3PsGlBAowNKNaDo2kUjIJRMApGAXkAAP/PXjkqCZebAAAAAElFTkSuQmCC","orcid":"","institution":"Mahidol University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Cheerasook","middleName":"","lastName":"Chongkolwatana","suffix":""}],"badges":[],"createdAt":"2022-04-26 07:29:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1595959/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1595959/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20888141,"identity":"f8706f99-5213-4c3b-a996-4366d3bb53c3","added_by":"auto","created_at":"2022-04-28 16:50:47","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25080,"visible":true,"origin":"","legend":"\u003cp\u003eThe serum Cu levels of the PTC group, nodular goiter group and the reference group\u0026nbsp;\u003c/p\u003e","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-1595959/v1/47f983e40f803167cf25931f.jpeg"},{"id":23026009,"identity":"f3319888-762b-415e-aacb-69df15859198","added_by":"auto","created_at":"2022-06-24 02:14:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":386591,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1595959/v1/20b2f34b-ff44-4005-9175-1beaf15de2fd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A comparison of serum copper levels in patients with papillary thyroid carcinoma, nodular goiter, and healthy volunteers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSerum Cu is an arbitrary marker for many types of malignancies and is more available and less expensive than genetic testing. Serum Cu levels rise significantly in many types of malignancies, such as esophageal cancer, gynecologic cancer, pancreatic cancer, and melanoma [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Why serum Cu is elevated in the presence of malignancy is not yet clear. Copper may be a key factor in tumor angiogenesis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Ceruloplasmin, the Cu-binding protein, can increase in malignancies due to decreased metabolism or an inflammatory response state [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Zhu et al. found that Cu transportation in tumor cells increased as a result of elevated expressions of transporter genes[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Coates and coauthors reported that the sensitivity and specificity of high serum copper for the risk of developing a cancer were 40% and 80.4%, respectively, but a cutoff value was not determined [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSerum copper plays a key role in thyroid hormone production [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This trace element controls T4 levels by regulating calcium homeostasis. An inappropriate serum Cu level stimulates the growth of thyroid follicles and the development of thyroid hyperplasia or carcinoma. Furthermore, Cu acts as an antioxidant, eliminating free radicals caused by various tissue damage in the body. However, excessively high Cu levels can cause abnormal cell growth by creating free radicals and damaging DNA [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies have reported that the serum Cu levels of patients with thyroid carcinoma were higher than those of normal subjects [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, Baltaci et al. also found that serum Cu decreased after removal of thyroid tumors [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In contrast, Al-Sayer et al. did not identify a difference between the serum Cu levels of patients with thyroid cancer and healthy controls, and serum Cu increased after thyroidectomy[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Due to insufficient data and inconclusive evidence, the association between serum cop per and thyroid cancer needs further investigation. Therefore, we aimed to compare the serum copper levels of patients with PTC, nodular goiter and healthy Thai women.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eMethods\u003c/h2\u003e \u003cdiv id=\"Sec3\" class=\"Section3\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis cross-sectional study was conducted at the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, from July 2018 to June 2021. Serum Cu was measured by the Clinical Toxicology Laboratory of the Faculty of Medicine Siriraj Hospital. The laboratory has been certified to the ISO 15189 accreditation standard since 2013. This study was approved by the Institutional Review Board, Faculty of Medicine Siriraj Hospital, Mahidol University (approval #250/2560, EC3) and was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eDiseases of the thyroid gland are generally more common in females than males. In the Thai population, the female to male ratio of incidence of thyroid cancer is approximately 4.3:1, and the gender ratio of thyroid surgery was 5.2:1 during 2018\u0026ndash;2020 [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Because serum Cu levels can vary by gender [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], we investigated only female patients. The thyroid disease group consisted of Thai women aged 18 years and older who had thyroid nodules. Fine needle aspiration was performed prior to surgery. All patients with pathological reports of PTC or nodular goiter who needed surgical treatment for thyroid diseases were eligible. Patients with incidental papillary microcarcinoma, thyroid carcinoma other than PTC, or other thyroid or systemic diseases that could alter serum Cu levels (i.e., thyroiditis, Wilson\u0026rsquo;s disease, pulmonary disease, cardiovascular disease, infectious disease, and other types of cancer) were excluded. Patients with current medications or supplements that would alter serum Cu levels, a history of previous thyroid surgery, or abnormal levels of FT4 or TSH were also excluded. The reference group consisted of healthy female volunteers with normal thyroid glands confirmed by ultrasonography and blood tests showing FT4, TSH, Cr, and eGFR within normal limits. All study subjects were fully informed about the treatment options and study protocol before signing informed-consent forms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eDemographic data and ultrasonographic findings of the thyroid gland were recorded. Blood samples were tested for FT4, TSH, Cr, eGFR, and serum Cu levels. For the cancer group, a pathology-confirmed specimen was sent for detection of the BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation using the PCR-based Sanger sequencing technique combined with allele-specific, real-time PCR. Adverse features such as multifocality, blood vessel invasion, capsular invasion, extrathyroidal extension and evidence of transformation from coexisting nodular goiter were noted. The maximum diameter of the tumors was recorded in centimeters. The risk of recurrence was classified according to the 2015 guidelines of the American Thyroid Association [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Stage was classified using the 8th edition of the AJCC/TNM staging system of thyroid cancer [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. If indicated, post-treatment I-131 total body scans and serum thyroglobulin (Tg) levels were used to detect residual diseases and distant metastases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eSerum Cu level analysis\u003c/h2\u003e \u003cp\u003eBlood samples were collected with the standard method in accordance with the Clinical and Laboratory Standards Institute guidelines for trace element analysis [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Collection and access procedures were performed in the patient ward one day before surgery with talc-free gloves, a 21-gauge needle, and a BD Vacutainer plastic blood collection tubes for trace element testing (K2EDTA). The tubes were kept upright and either immediately sent to the Clinical Toxicology Laboratory, or stored in a refrigerator at 2\u0026ordm; to 8\u0026ordm; C for no longer than 24 hours. Before analysis, internal quality assurance for trace elements was routinely performed using ClinCheck Controls. An atomic absorption spectrophotometer was used to heat the analytes and convert them to atoms. Next, the sample was analyzed with a flame atomic absorption spectrophotometer to produce free atoms of Cu in the gaseous state. The absorbance of light with the specific wavelength of Cu was measured. The intensity of the absorbed light wave was proportional to the amount of copper in the sample. Subsequently, a standard calibration curve was plotted with linear regression. Serum Cu levels were reported as mg/dl and converted to \u0026micro;g/ml as a standard unit.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDemographic data are presented using descriptive statistics. One-way analysis of variance was used to compare the three groups (Reference, PTC, and nodular goiter). If the \u003cem\u003eP\u003c/em\u003e values were less than 0.05, post hoc analysis was applied. Serum Cu levels (\u0026micro;g/ml) are reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Subgroup analyses of the serum Cu levels of the PTC group were performed for histopathological aggressiveness and BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation using the independent samples T-test. Variant of PTC, risk of recurrence and the TNM staging were compared by one-way analysis of variance. Pearson\u0026rsquo;s correlation was used to test the association between the size of the PTC or nodular goiter and the serum Cu level. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were carried out using PASW Statistics for Windows (version 18; SPSS Inc., Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwo hundred and twenty-two subjects were enrolled and 17 were later excluded. The excluded subjects comprised 10 cases with papillary thyroid microcarcinoma, five cases with follicular thyroid carcinoma, and two cases with thyroiditis. Therefore, the study population was 205 subjects, consisting of 105 patients with thyroid disease (44 with PTC and 61 with nodular goiter), and 100 healthy controls.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSerum Cu levels\u003c/h2\u003e \u003cp\u003eThe serum Cu levels of the PTC group, the nodular goiter group and the reference group, were 0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 \u0026micro;g/ml, 1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 \u0026micro;g/ml and 1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 \u0026micro;g/ml, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The results were not statistically different (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.26). Age, serum creatinine and eGFR were significantly different among the PTC, nodular goiter and reference groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). After adjustment for age, serum creatinine and eGFR, there was still no statistical difference.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic data and characteristics of PTC, nodular goiter, and the reference group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003cp\u003e(mean \u0026plusmn; SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTC\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNodular goiter\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;100)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e45.70 \u0026plusmn; 13.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e47.62 \u0026plusmn; 12.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e39.64 \u0026plusmn; 13.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001*\u003csup\u003e,a,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e60.38 \u0026plusmn; 11.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e59.94 \u0026plusmn; 12.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e57.96 \u0026plusmn; 12.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e156.55 \u0026plusmn; 9.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e156.93 \u0026plusmn; 6.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e157.29 \u0026plusmn; 5.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFT4 (ng/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.23 \u0026plusmn; 0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.19 \u0026plusmn; 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.20 \u0026plusmn; 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH (uIU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.85 \u0026plusmn; 1.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.58 \u0026plusmn; 1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.94 \u0026plusmn; 0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCr (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.79 \u0026plusmn; 0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.70 \u0026plusmn; 0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e0.68 \u0026plusmn; 0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003csup\u003e,a,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR(L/min/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e93.74 \u0026plusmn; 21.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e99.74 \u0026plusmn; 17.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e108.58 \u0026plusmn; 16.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003csup\u003e,a,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* \u003cem\u003eP\u003c/em\u003e values less than .05 considered statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e value between reference and PTC was \u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e value between reference and nodular goiter was \u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e value between PTC and nodular goiter was \u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: PTC, papillary thyroid carcinoma; FT4, free thyroxine; TSH, thyroid stimulating hormone; Cr, creatinine; eGFR, estimated glomerular filtration rate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003ePTC group\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section4\"\u003e \u003ch2\u003eHistopathological aggressiveness\u003c/h2\u003e \u003cp\u003eOf the 44 PTC cases, the classical variant was found in 88.6% (n\u0026thinsp;=\u0026thinsp;39) and the follicular variant in 6.8% (n\u0026thinsp;=\u0026thinsp;3). Two patients (4.5%) had non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NIFTP). Multifocal cancers were identified in 70.5% (n\u0026thinsp;=\u0026thinsp;31) of cases with no statistical difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.16). The serum Cu in the blood vessel invasion group was significantly higher than those without invasion (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were no significant differences in serum Cu levels for coexisting nodular goiter, capsular invasion, extrathyroidal extension, high- risk of recurrence and TNM staging. There was no correlation between tumor size and serum Cu levels \u003cem\u003e(r\u003c/em\u003e =-0.04; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.81). Four patients (9.1%) had distant metastases detected by I-131 total body scan. Their serum Cu levels were higher than in the no-metastasis group, but the difference was not significant (1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 \u0026micro;g/ml, and 0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 \u0026micro;g/ml, respectively; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.38).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the histopathological, molecular status, risk of recurrence and staging of 44 PTC cases and their serum copper levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistopathological aggressiveness\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum copper level (\u0026micro;g/ml)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoexisting nodular goiter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (38.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99 \u0026plusmn; 0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (61.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00 \u0026plusmn; 0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal (Foci\u0026thinsp;\u0026gt;\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (70.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood vessel invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (59.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08 \u0026plusmn; 0.310\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (40.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88 \u0026plusmn; 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCapsular invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (56.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.06 \u0026plusmn; 0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (43.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.93 \u0026plusmn; 0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrathyroidal extension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08 \u0026plusmn; 0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.93 \u0026plusmn; 0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClassic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (88.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 \u0026plusmn; 0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFollicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99 \u0026plusmn; 0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNIFTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84 \u0026plusmn; 0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.09 \u0026plusmn; 0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92 \u0026plusmn;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk of recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.94 \u0026plusmn; 0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (52.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 \u0026plusmn; 0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.04 \u0026plusmn; 0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor (T)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98 \u0026plusmn; 0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 \u0026plusmn; 0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.03 \u0026plusmn; 0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.87 \u0026plusmn; 0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNode (N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (47.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.94 \u0026plusmn; 0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (52.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.04 \u0026plusmn; 0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (90.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98 \u0026plusmn; 0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.11 \u0026plusmn; 0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (77.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98 \u0026plusmn;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.03 \u0026plusmn;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19 \u0026plusmn; 0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* \u003cem\u003eP\u003c/em\u003e values less than .05 considered statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e No min, max as there was only one data item for that category.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: NIFTP, Noninvasive follicular thyroid neoplasm with papillary-like nuclear features\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section4\"\u003e \u003ch2\u003eMolecular testing\u003c/h2\u003e \u003cp\u003eThe BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation was positive in 20 patients (45.5%) and negative in 24 (54.5%). The serum Cu levels of BRAF-positive cases were significantly higher than in the negative groups. (1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32 \u0026micro;g/ml, and 0.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 \u0026micro;g/ml, respectively; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Nevertheless, the results from both groups remained within the reference range.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eNodular goiter group\u003c/h2\u003e \u003cp\u003eThe correlation coefficient between the diameters of the nodular goiter and serum Cu levels was (\u003cem\u003er\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.02; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.89). The mean serum Cu level in cases of PTC with nodular goiter was 0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20 \u0026micro;g/ml (n\u0026thinsp;=\u0026thinsp;17), while the mean serum Cu level for cases with pure nodular goiter was 1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 \u0026micro;g/ml (n\u0026thinsp;=\u0026thinsp;61) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.76).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe compared serum Cu levels of patients with PTC, nodular goiter and normal healthy subjects. Zhang[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and Shen[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] reported that gender and ethnicity influence serum Cu levels and so we investigated Thai women, the gender most often affected by this disease. The mean serum Cu levels of our reference group were comparable to those in other studies (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), and very close to the mean value of the biggest dataset in a Chinese population (1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 vs 1.01. \u0026plusmn; 0.24 \u0026micro;g/ml) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We did not identify any statistically significant differences in the serum Cu levels of the PTC, nodular goiter, and reference groups. The serum Cu levels were measured using atomic absorption spectrometry, as was done by many previous studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Moreover, the quality of the measuring techniques used by the Clinical Toxicology Laboratory is also attested by its ISO-accreditation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum copper levels in healthy subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMeasurement\u003c/p\u003e \u003cp\u003etechnique\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSerum copper levels (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; \u0026micro;g/ml)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eManeeprasopchoke et al.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThailand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhang et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e1.01 \u0026plusmn; 0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaltaci et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e0.74 \u0026plusmn; 0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrzybylik-Mazurek et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e1.11 \u0026plusmn; 0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKosova et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e1.06 \u0026plusmn; 0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeung et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e0.74 \u0026plusmn; 0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKucharzewski et al.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTRXRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e0.69 \u0026plusmn; 0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: AAS, atomic absorption spectrometry; AES, atomic emission spectrometry; TRXRF, total reflection fluorescence\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe use of Cu to support the diagnosis of thyroid cancer remains inconclusive. Baltaci et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] showed that serum Cu levels of women with thyroid cancer were significantly higher than those of healthy controls (0.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 \u0026micro;g/ml, and 0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24 \u0026micro;g/ml, respectively; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, the serum Cu levels of female patients with thyroid cancer significantly decreased to levels close to those of the control group within two weeks after surgery (0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 \u0026micro;g/ml). Vesna and colleagues [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] compared 35 cases of PTC and 13 cases of papillary thyroid microcarcinoma with 82 cases of benign thyroid tumor. The serum Cu levels of patients with PTC and microcarcinoma were significantly higher than patients with benign thyroid tumor. However, because incidental microcarcinoma was included in the PTC group, their findings are challenging to interpret and to compare with our study.\u003c/p\u003e \u003cp\u003eIn 2015, Shen and colleagues published a meta-analysis of five case-control studies investigating serum Cu levels [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. One study was carried out in China (n\u0026thinsp;=\u0026thinsp;100), three in Poland (n\u0026thinsp;=\u0026thinsp;71, n\u0026thinsp;=\u0026thinsp;45, and n\u0026thinsp;=\u0026thinsp;33), and one in Turkey (n\u0026thinsp;=\u0026thinsp;84). Overall, patients with thyroid cancer had higher serum Cu levels than healthy controls (standardized mean difference, 2.372; 95% CI, 0.945\u0026ndash;3.799; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). However, consistent with our results, the Polish studies did not find higher serum Cu levels in patients with thyroid cancer relative to their controls. A 2004 study from Kuwait also reported that serum Cu levels in thyroid cancer patients were not different from healthy controls and rose significantly after thyroidectomy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Hence, ethnicity can influence serum Cu levels. Normally, Cu is actively recycled in the digestive tract, body fluids and tissues, and is mainly excreted from the body via bile. Copper levels are primarily controlled by recycling and resorption, and dietary Cu represents only a small proportion of total Cu resorption [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, dietary intake of Cu has an insignificant affect on serum Cu levels and does not need to be controlled.\u003c/p\u003e \u003cp\u003eIn the post hoc subgroup analysis of PTC, we found significantly higher serum Cu levels in patients with blood vessel invasion. This finding suggests a relationship between serum Cu and the aggressiveness of PTC. Moreover, the mean serum Cu levels were also higher in the presence of adverse features such as positive capsular invasion, extrathyroidal extension, lymph node involvement, distant metastases and high stage. While the difference was not statistically significant, we can infer that high serum Cu may be related to the invasiveness of PTC.\u003c/p\u003e \u003cp\u003eThe potential relationship between serum Cu levels and gene mutation in humans has not been studied. Since copper regulates the function of follicular cells, aberrant levels of serum Cu may be associated with molecular alterations. Currently, there are several genetic mutations reported in thyroid cancer and the BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation is the most common biomarker for PTC. Brandy et al. demonstrated that Cu is required for BRAF signaling and tumorigenesis. A reduction in serum Cu levels caused the size of BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e-driven melanomas to decrease in laboratory animals [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. A recent investigation by Baldari et al. also found that Cu-chelating agents reduced the proliferation, survival, and migration of human colon cancer cells carrying the BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. We hypothesized that in thyroid cancer, the BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation would be associated with increased serum Cu levels, as is seen in melanoma and colon cancer. We did observe a significant elevation of serum Cu levels in PTC with BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation, suggesting that serum copper may indicate the severity of PTC. The role of Cu-chelating agents as an adjuvant therapy in BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation positive PTC merits further investigation.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to report serum Cu levels in terms of histopathological aggressiveness, risk of recurrence, staging, and molecular status in PTC. In addition, we screened all healthy subjects with ultrasonography of the thyroid gland to avoid unexpected thyroid nodules in the control group. This ensured that the reference serum Cu values of the healthy Thai women were reliable and could be used as a standard for further studies. On the other hand, our analyses suggests that serum Cu levels are not appropriate for diagnostic purposes, but may have value to predict the severity of PTC.\u003c/p\u003e \u003cp\u003eOur study has some limitations. Our subjects were Thai women with PTC and nodular goiter. We did not address the role of serum Cu levels in men, other types of thyroid cancer, and in advanced-stage thyroid cancers such as tracheal or recurrent laryngeal nerve invasion.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe role of serum Cu in the pathogenesis and prognosis of thyroid tumors remains unclear. Serum Cu levels in patients with PTC and nodular goiter were not different, and also were not different from the reference group. However, serum Cu was associated with aggressive histopathology of PTC such as blood vessel invasion and BRAF mutation. Therefore, serum Cu levels are not currently suitable for use as an assistive tool for the diagnosis, but may be useful to establish the prognosis of PTC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding source:\u003c/strong\u003e Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. The funding source had no role in the study design, conduct, or writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrachya Maneeprasopchoke: conceptualization, data collection, formal analysis, validation, and manuscript review and editing. Phoupong Phousamran: data collection, formal analysis, and manuscript drafting. Warut Pongsapich: supervision, critical revisions, and final approval. Paveena Pithuksurachai: visualization and validation. Jakrit Worrakulpanit: investigation and formal analysis. Tippanate Keawvijit: determination of serum Cu levels. Naravat Poungvarin: investigation of the BRAF mutations.\u0026nbsp;Kanchana Amornpichetkul: pathological review. Cheerasook Chongkolwatana: conceptualization, methodology, project administration, critical revisions, and final approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors appreciate the assistance provided by Dr.\u0026nbsp;Saowalak\u0026nbsp;Hunnangkul, PhD, Division of Clinical Epidemiology, Department of Health Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, for her assistance with the sample size calculation and statistical analyses. We also thank Miss Jeerapa Kerdnoppakhun of the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, for secretarial support.\u0026nbsp;The authors also gratefully acknowledge the professional English editing of this paper by Mr. Mark Simmerman.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they do not have any conflict of interest regarding this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Faculty of Medicine Siriraj Hospital, Mahidol University [grant number R016133003]\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGoyal MM, Kalwar AK, Vyas RK, Bhati A (2006) A study of serum zinc, selenium and copper levels in carcinoma of esophagus patients. 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Cancers (Basel) 11:. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cancers11050659\u003c/span\u003e\u003cspan address=\"10.3390/cancers11050659\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Serum copper (Cu), Nodular goiter, Papillary thyroid carcinoma, Thyroid cancer, BRAF mutation\t ","lastPublishedDoi":"10.21203/rs.3.rs-1595959/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1595959/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSerum copper (Cu) is an essential trace element that plays a key role in thyroid hormone production. An inappropriate level of serum Cu might be related to development of both benign and malignant thyroid neoplasm. Nodular goiter and papillary thyroid carcinoma (PTC) are common benign and malignant tumors of the thyroid, respectively. This study aims to compare the serum Cu levels of healthy women with women with PTC or nodular goiter. A total of 205 Thai women were recruited for this cross-sectional study. The reference group was comprised of 100 healthy volunteers. There were 61 nodular goiter and 41 PTC patients that had been treated with surgery. Serum Cu was measured using an atomic absorption spectrophotometer and the three groups were compared. The serum Cu levels of the PTC, nodular goiter and the reference group were 0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 \u0026micro;g/ml, 1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 \u0026micro;g/ml and 1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 \u0026micro;g/ml, respectively. The results were not statistically different (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.26). A post hoc subgroup analysis in the PTC group showed serum Cu levels were significantly higher in the blood vessel invasion group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) and the BRAF\u003csup\u003e\u003cem\u003eV600\u003c/em\u003eE\u003c/sup\u003e mutation group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04), but no relationships between serum Cu and other aggressive histopathology were observed. The serum Cu levels of patients with PTC and nodular goiter were not different and did not differ significantly from the reference group. Thus, serum Cu cannot be applied to stratify risk in indeterminate thyroid nodules. Nevertheless, higher serum Cu levels were associated with blood vessel invasion and BRAF\u003csup\u003e\u003cem\u003eV600E\u003c/em\u003e\u003c/sup\u003e mutation in PTC. Therefore, this trace element might have a potential role in prognostication of PTC.\u003c/p\u003e","manuscriptTitle":"A comparison of serum copper levels in patients with papillary thyroid carcinoma, nodular goiter, and healthy volunteers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-28 16:50:45","doi":"10.21203/rs.3.rs-1595959/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82dc2ff2-cbdf-4e84-9918-b408f2042b86","owner":[],"postedDate":"April 28th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-06-24T02:14:10+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-28 16:50:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1595959","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1595959","identity":"rs-1595959","version":["v1"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}