Association of Helicobacter pylori Infection with Papillary Thyroid Carcinoma: A Case-control Study


avatar Alireza Bakhshipour ORCID 1 , avatar Maryam Amirian ORCID 2 , avatar Zahra Heidari ORCID 2 , *

Department of Gastroenterology, Zahedan University of Medical Sciences, Zahedan, Iran
Department of Endocrinology and Metabolism, Zahedan University of Medical Sciences, Zahedan, Iran

how to cite: Bakhshipour A, Amirian M, Heidari Z. Association of Helicobacter pylori Infection with Papillary Thyroid Carcinoma: A Case-control Study. Int J Cancer Manag. 2022;15(4):e118031.



The thyroid nodules incidence has risen worldwide. Although factors such as increasing the use of imaging techniques and more rapid detection of small thyroid nodules have been implicated in the recent rise in thyroid cancer incidence, some environmental parameters such as infectious agents may be involved. Helicobacter pylori infection is an environmental risk factor, which may mimic the antigenic properties of membranes of thyrocytes.


This study aimed at evaluating the association of H. pylori infection with benign and malignant thyroid nodules in comparison with the control group.


Patients with benign thyroid nodules, papillary thyroid cancer (PTC), and euthyroid healthy controls without thyroid nodules that had just been diagnosed were included in the study. All participants underwent clinical examination. Various biochemical parameters such as serum H. pylori Ab (IgG) and thyroid function tests were measured. Comparisons were made between groups.


Finally, 370 patients with benign thyroid nodules, 364 patients with PTC, and 360 healthy subjects without nodules participated as a control group. In the patients with PTC, the prevalence of H. pylori infection was 89.6%, while in the group of patients with benign thyroid nodules and the control group was 81.1% and 75%, respectively (P < 0.001). Helicobacter pylori antibody (Ab) titer was not significantly associated with any of the anthropometric and biochemical variables.


Helicobacter pylori infection was significantly higher in patients with benign thyroid nodules and PTC than in the control group. Also, the rate of infection was significantly higher in the malignant nodule group than in the benign thyroid nodules group.

1. Background

Thyroid nodules are lesions in the thyroid that are different from the surrounding parenchymal tissue. Thyroid nodules prevalence in ultrasound examinations has been estimated at 60%. The malignancy rate in thyroid nodules is 5 to 10% and most thyroid nodules are benign. Thyroid cancer is the most common endocrine-related malignancy, accounting for 1.3% of all cancers worldwide. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer and accounts for more than 80% of thyroid cancers. An increase in the incidence of thyroid cancer is reported in recent years (1-4). Apart from thyroid ultrasonography and ultrasound-guided fine-needle aspiration biopsy in the early stages of cancer, which have led to an increase in the diagnosis of small thyroid nodules, the role of other unidentified factors in the increased incidence of these malignancies requires further investigations (5, 6).

Currently, the most well-known thyroid cancer risk factors include the history of cancer in first-degree relatives, head and neck radiation in childhood (7), and insufficient or excessive intake of iodine (8). But the recent rise in the incidence of thyroid cancer is not justified by any of these factors. Different risk factors such as metabolic syndrome, diabetes, obesity (9), insulin resistance (10), chemical toxins (11), nutritional factors (12), and infections have been recently suggested as potential risk factors for thyroid cancer. Regarding benign thyroid nodules, risk factors including insulin resistance (13), and infectious agents, such as Helicobacter pylori (14), have been introduced in recent years.

Helicobacter pylori is a microaerophilic, helical-shaped, and Gram-negative bacterium, which colonizes the mucosa of the stomach. This bacterium is involved in gastric diseases, such as peptic ulcers, gastritis, and stomach cancer (15-17). Infection with H. pylori leads to severe infiltration of polymorphonuclear cells into the mucosa of the stomach. If the infection is not effectively cleared, this acute infiltration gradually leads to a chronic infiltration of mononuclear cells through the immune system. On the other hand, chronic infiltration of the mononuclear cells results in the production of local pro-inflammatory cytokines, whose systemic diffusion will affect distant tissues and various systemic organs. Accordingly, H. pylori infection has been associated with some diseases outside the gastrointestinal tract (18, 19).

Some studies have shown an association between H. pylori infection and autoimmune thyroid disease (20-23), but to our knowledge, only one study has examined the association between H. pylori infection and benign nodules. In recent years, insulin resistance has been introduced as one of the mechanisms involved in nodule formation. Helicobacter pylori infection may play a pathogenic role in the evolution of insulin resistance (14, 24).

2. Objectives

Concerning limited data in this field, we conducted this case-control study to investigate the association between H. pylori infection and the presence of benign and malignant thyroid nodules separately in comparison to a healthy euthyroid control group without nodules; in an Iodine sufficient area.

3. Methods

This case-control study was performed between March 2018 and October 2020 on euthyroid patients with thyroid nodules who were referred to endocrinology clinics in Zahedan, southeastern Iran.

Inclusion criteria were: age ≥ 18 years, presence of thyroid ≥ 1 cm, and normal thyroid function tests (TSH: 0.4 - 4.2 mIU/L, FT4: 0.8 - 1.8 ng/dL, and FT3: 2.3 - 4.2 pg/mL) (25). Subjects with previous head and neck radiation, surgery for thyroid disease, thyroid dysfunction, thyroid medications, receiving contrast for imaging during the last 6 months, diabetes mellitus, liver failure, and kidney failure were excluded. Also, women who were pregnant or lactating were not included in the study.

All participants underwent thyroid sonography that was performed by a sonologist. If a nodule larger than or equal to one centimeter was reported on ultrasound, the nodule was examined by fine-needle aspiration biopsy. The cytology was reported, based on the Bethesda system (26). Patients suspected of papillary thyroid cancer based on the cytology result underwent total thyroidectomy. These patients were included in the PTC group if the permanent pathology confirmed the diagnosis of PTC. Patients with benign cytology report were classified as the benign thyroid nodule group. Non-first-degree relatives of the patients and hospital staff without thyroid disease were chosen as the control group after considering the inclusion and exclusion criteria. Patients in the control group underwent thyroid ultrasound. If no nodules with any size were reported on their ultrasound, they were included in the control group. They were apparently healthy and had no evidence of any acute or chronic illness on history or physical examination. Socio-economic level and geographical area of the control group were similar to the case group. Finally, three groups; including the PTC group, benign thyroid nodule group, and control group were recruited for this study.

Height using a stadiometer and weight with minimal clothing using a digital scale was measured. Blood samples were recruited from all subjects. Samples were stored at -70°C until the day of testing. Thyroid function tests and H. pylori Immunoglobulin (Ig) G were measured. TSH, FT3, and FT4, by an automated analyzer using immunochemoluminescent assays were measured. Helicobacter pylori IgG was assessed by the enzyme-linked immunoassay method. Values above 10 IU/mL were considered positive.

This study was approved by the Zahedan University Ethics Committee for Human Studies (ethical code number: IR.ZAUMS.REC.1399.091). The participants provided written, informed consent.

3.1. Statistical Analysis

Continuous variables were presented as mean and standard deviation (SD) and categorical variables as absolute number and percentages. One-way ANOVA test was used to compare a numerical variable in three study groups. An independent t-test or a Mann–Whitney U-test was used to assess significance of differences for continuous variables and a chi-square or Fisher's exact test for categorical variables. Bonferroni correction for continuous variables and chi-square test for categorical variables was used for a Post-hoc pairwise comparison of these three study groups. The correlation between H. pylori antibody (IgG) titers with numerical variables was assessed with the Pearson correlation coefficient, and an important correlation was presented in scatter plots with quadratic fitting and a 95% confidence interval. P-value lower than 0.05 was considered statistically significant. All of the analyses were conducted with Stata statistical software: Release 14. College Station, TX: StataCorp LP.

4. Results

Baseline characteristics of study participants are presented in Table 1. There was no statistically significant difference in age, sex, and BMI in these groups. Although all participants were euthyroid, levels of TSH were higher in patients with PTC than in patients with benign thyroid nodules and controls. The prevalence of H. pylori infection in PTC patients was 89.6% which was significantly higher than the groups of benign thyroid nodules (81.1%) and the control group (75.0%) as shown in Figure 1.

Table 1.

Baseline Characteristics of Study Participants a, b

VariablesPatients with PTC (n = 364)Patients with Benign Nodule (n = 370)Control Subjects (n = 360)P-Value
Age (y)34.95 ± 11.9434.99 ± 12.8134.63 ± 12.980.855
Sex (female)290 (79.7)296 (80.0)290 (80.6)0.956
Body mass index (Kg/m2)24.61 ± 3.8824.91 ± 3.6624.21 ± 4.310.609
Thyroid stimulating hormone (mIu/L)2.49 ± 1.11 A1.79 ± 1.03 B2.10±1.01 C< 0.001
Free T4 (ng/dL)1.29 ± 0.301.30 ± 0.201.31 ± 0.250.406
Free T3 (pg/mL)3.49 ± 0.593.60 ± 0.663.58 ± 0.590.104
Helicobacterpylori-Ab titer (Iu/mL)49.62 ± 35.75 A42.74 ± 36.54 B37.22 ± 36.84 B< 0.001
Positive H. pylori326 (89.6) A300 (81.1) B270 (75.0) B< 0.001
Helicobacter Pylori antibody (IgG) titer distribution and prevalence of H. Pylori infection by papillary thyroid carcinoma, benign thyroid nodules, and control group.
Helicobacter Pylori antibody (IgG) titer distribution and prevalence of H. Pylori infection by papillary thyroid carcinoma, benign thyroid nodules, and control group.

In patients with PTC; Vascular Invasion in 5.5%, extrathyroid extension in 3.8%, Capsular invasion in 8.8%, and multifocality in 12.1% was observed. The mean of H. pylori antibody and also the prevalence of H. pylori infection in these groups were not significantly different. Although the prevalence of H. pylori infection in different cancer stages and tumor size categories was not significantly different, the mean of H. pylori antibody in lower stages of cancer, as well as small tumors, was lower (Table 2).

Table 2.

Distribution of Helicobacter pylori-Ab and Infection in Various Categories of Papillary Thyroid Carcinom

No. (%)Helicobacter pylori-Ab TiterH. pylori (> 10)
Mean ± SDP-ValueNegative (%)Positive (%)P-Value
Multifocality 0.3500.173
Absent320 (87.91)48.97 ± 35.8636 (11.3)284 (88.8)
Present44 (12.09)54.35 ± 34.962 (4.5)42 (95.5)
Extrathyroidal extension0.1510.681
Absent350(96.15)49.08 ± 35.5437 (10.6)313 (89.40
Present14(3.85)63.08 ± 39.701 (7.1)13 (92.9)
Capsular invasion0.8480.417
Absent332 (91.21)49.51 ± 35.7736 (10.8)296 (89.2)
Present32 (8.79)50.78 ± 36.042 (6.3)30 (93.8)
Vascular invasion0.9000.947
Absent344 (94.5)49.68 ± 35.9036 (10.5)308 (89.5)
Present20 (5.5)48.65 ± 33.792 (10.0)18 (90.0)
Nodal involvement0.8930.878
N0308 (84.61)50.00 ± 35.4932 (10.4)276 (89.6)
N1a42 (11.54)47.61 ± 38.135 (11.9)37 (88.1)
N1b14 (3.85)47.29 ± 36.551 (7.1)13 (92.9)
Cancer stage0.0190.377
I320 (87.91)47.52 ± 34.7237 (11.6)283 (88.4)
II22 (6.04)61.62 ± 29.420 (0.0)22 (100.0)
III8(2.20)82.98 ± 59.810 (0.0)8 (100.0)
IVa12 (3.30)59.30 ± 42.411 (8.3)11 (91.7)
IVb2 (0.55)61.78 ± 38.350 (0.0)2 (100.0)
Tumor size category 0.1090.410
T1a116 (31.9)44.43 ± 33.2815 (12.9)101 (87.1)
T1b108 (29.7)50.35 ± 39.0113 (12.0)95 (88.0)
T2110 (30.2)53.16 ± 34.169 (8.2)101 (91.9)
T320 (5.5)43.17 ± 32.500 (0.0)20 (100)
T4a6 (1.6)65.26 ± 40.861 (16.7)5 (83.3)
T4b4 (1.1)82.56 ± 46.890 (0.0)4 (100)
Tumor size: T1 vs >T10.1150.104
T1112 ()53.36 ± 34.8210 (7.1)130 (92.9)
>T170 ()47.28 ± 36.2028 (12.5)196 (87.5)
Histological type0.2580.247
Classic 306 (84.07)50.68 ± 35.5629 (9.5)277 (90.5)
Follicular50 (13.74)45.93 ± 37.187 (14.0)43 (86.0)
Tall cell8 (2.20)32.13 ± 31.752 (25.0)6 (75.0)

Clinical features and biochemical characteristics comparison of H. pylori positive and negative patients in three study groups are shown in Table 3. None of these clinical and laboratory characteristics were significantly different in any of the groups.

Table 3.

Clinical Features and Biochemical Characteristics Comparison of Helicobacter pylori Positive and Negative Patients by Papillary Thyroid Carcinoma, Benign Thyroid Nodule, and Control Group a

Patients with PTC (n = 364)Patients with Benign Nodule (n = 370)Control Group (n = 360)
Negative H. pyloriPositive H. pyloriP-ValueNegative H. pyloriPositive H. pyloriP-ValueNegative H. pyloriPositive H. pyloriP-Value
Female31 (81.6)259 (79.4)55 (78.6)241 (80.3)74 (82.2)216 (80.0)
Male7 (18.4)67 (20.6)15 (21.4)59 (19.7)16 (17.8)54 (20.0)
Age (y)35.61 ± 13.1035.43 ± 11.640.93834.44 ± 12.4135.20 ± 13.090.64936.53 ± 13.4534.43 ± 12.880.196
Body mass index (Kg/m2)24.32 ± 3.7424.59 ± 3.920.67624.58 ± 4.7624.23 ± 3.750.50823.50 ± 3.8824.60 ± 4.140.027
Free T4 (ng/dL)1.33 ± 0.231.29 ± 0.250.3971.27 ± 0.221.29 ± 0.250.4911.33 ± 0.241.30 ± 0.240.385
Free T3 (pg/mL)3.60 ± 0.533.58 ± 0.610.8763.66 ± 0.603.68 ± 0.700.7873.59 ± 0.433.62 ± 0.620.729
Thyroid stimulating hormone (mIu/L)2.38 ± 1.132.53 ± 1.050.3991.81 ± 1.001.89 ± 1.000.5312.03 ± 0.922.07 ± 1.110.705

The correlation between H. pylori antibody titer and anthropometric, biochemical characteristics in study groups are shown in Table 4. Helicobacter pylori antibody was not significantly correlated with any of the anthropometric and biochemical variables.

Table 4.

The Pearson Correlation Coefficient Between Helicobacter pylori Antibody Titer and Anthropometric, Biochemical Characteristics in Papillary Thyroid Carcinoma, Benign Nodules, and Control Group

H. pylori-Ab Titer
PTC GroupBenign Nodule GroupControl Group
Tumor size

5. Discussion

The present study showed a significant association between H. pylori infection and benign or malignant thyroid nodules. The prevalence of H. pylori infection was estimated at 89% in patients with PTC, 81% in patients with benign thyroid nodules, and 75% in the euthyroid control group without nodules. Also, the rate of infection was significantly different between the benign and malignant thyroid nodules. These findings are consistent with a study conducted in China, which demonstrated an association between H. pylori infection and thyroid nodules (14). To our knowledge, no study has been conducted on the relationship between H. pylori infection and thyroid cancer.

Thyroid nodules are characterized by the overgrowth of one or more areas in the thyroid gland. The etiology of thyroid nodules involves interactions between genetic and environmental factors (27). Although factors such as increasing the use of imaging techniques and more rapid detection of small thyroid nodules have been implicated in the recent increase in the incidence of thyroid cancer, but some environmental factors such as infectious agents may be involved (28-30)

Recently, an association has been found between infectious agents and thyroid nodules (14, 31-33). Helicobacter pylori infection is an environmental risk factor, which may mimic the antigenic profile of thyrocyte membranes and can have a considerable role in autoimmune thyroid disease pathogenesis (20-23). Helicobacter pylori is a Gram-negative labyrinthos bacterium, which can be mainly found in the mucous membrane and is responsible for the most common bacterial infection in humans (34). In Iran, the prevalence of H. pylori infection ranges from 36% to 90% in different geographical areas (35). In the present study, despite the high prevalence of this infection in the study population, an association was found between thyroid nodules and this infection. However, the mechanism responsible for this association has not been determined yet.

Thyroid-stimulating hormone (TSH) plays a key role in regulating the growth and differentiation of thyroid cells and acts as a mitogen in cell cultures by reducing apoptosis (35). In the present study, TSH was in the normal range, therefore, the present results cannot be justified by TSH.

Moreover, the insulin-like growth factor (IGF) is an important growth and differentiation factor in different cell types. The IGF system consists of a network of ligands, including IGF-I, IGF-II, and their receptors, with significant homology to insulin and insulin receptors (36). Insulin/IGF-1 signaling pathway is involved in regulating thyroid gene expression, differentiation and proliferation of thyroid cells (37). Previous studies have shown that IGF-1, IGF-2, IGF-1 receptors, and insulin receptor isoforms are abundant in thyroid follicular cell precursors. Therefore, activation of the IGF system and the insulin pathway may explain the present findings. Insulin resistance and abnormal glucose metabolism increase insulin levels, which in turn augment thyroid cell proliferation and thyroid nodule formation. In recent years, insulin resistance has been introduced as one of the mechanisms involved in nodule formation (10, 38). Helicobacter pylori infection may play a pathogenic role in the evolution of insulin resistance (39). Therefore, activation of the insulin pathway may explain the present results, although further investigation is required in this area.

On the contray, previous researches have shown an association between vitamin D and thyroid cancer (39, 40). These studies have shown that vitamin D exerts its anti-cancer effects by increasing apoptosis, ending the cell cycle, increasing differentiation, inhibiting proliferation, and reducing invasion (41, 42).

Molecular modeling has revealed that a type of bacterium produces a substance, which can inactivate vitamin D receptors, resulting in the decreased level of 25-hydroxyvitamin D receptors and the increased level of 1, 25-dihydroxy vitamin D (43). It has been shown that 1, 25-dihydroxy vitamin D has a strong tendency to bind to α- thyroid receptors. If the transcription of α- thyroid receptor is impaired, numerous metabolic dysfunctions will occur (44). However, it is unclear whether this mechanism can be generalized to H. pylori infection.

This study had several limitations. First, it had a cross-sectional design, which could not show the cause-and-effect relationship between H. pylori infection and thyroid nodules. Second, to identify infection, we used IgG antibodies against H. pylori, which could not differentiate between acute and chronic infections. The main strengths of this study were including a nodule-free euthyroid control group, cytological evaluation of nodules, histopathological examination of thyroid nodule outcomes, and adequate sample size.

5.1. Conclusions

In summary, our results showed that the rate of H. pylori infection was higher in patients with malignant and benign thyroid nodules compared to the control group. Further studies are needed to establish such an association and to identify the mechanisms that cause it to take steps to prevent the occurrence of such nodules.



  • 1.

    Olson E, Wintheiser G, Wolfe KM, Droessler J, Silberstein PT. Epidemiology of Thyroid Cancer: A Review of the National Cancer Database, 2000-2013. Cureus. 2019;11(2). e4127.

  • 2.

    Panato C, Serraino D, De Santis E, Forgiarini O, Angelin T, Bidoli E, et al. Thyroid cancer in Friuli Venezia Giulia, northeastern Italy: incidence, overdiagnosis, and impact of type of surgery on survival. Tumori. 2019;105(4):296-303. [PubMed ID: 30917766].

  • 3.

    Colonna M, Uhry Z, Guizard AV, Delafosse P, Schvartz C, Belot A, et al. Recent trends in incidence, geographical distribution, and survival of papillary thyroid cancer in France. Cancer Epidemiol. 2015;39(4):511-8. [PubMed ID: 26003877].

  • 4.

    Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH, et al. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2014. Cancer Res Treat. 2017;49(2):292-305. [PubMed ID: 28279062]. [PubMed Central ID: PMC5398380].

  • 5.

    Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol. 2016;12(11):646-53. [PubMed ID: 27418023].

  • 6.

    Morris LG, Myssiorek D. Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: a population-based analysis. Am J Surg. 2010;200(4):454-61. [PubMed ID: 20561605]. [PubMed Central ID: PMC2943969].

  • 7.

    Dom G, Tarabichi M, Unger K, Thomas G, Oczko-Wojciechowska M, Bogdanova T, et al. A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas. Br J Cancer. 2012;107(6):994-1000. [PubMed ID: 22828612]. [PubMed Central ID: PMC3464765].

  • 8.

    Meinhold CL, Ron E, Schonfeld SJ, Alexander BH, Freedman DM, Linet MS, et al. Nonradiation risk factors for thyroid cancer in the US Radiologic Technologists Study. Am J Epidemiol. 2010;171(2):242-52. [PubMed ID: 19951937]. [PubMed Central ID: PMC3290908].

  • 9.

    Borena W, Stocks T, Jonsson H, Strohmaier S, Nagel G, Bjorge T, et al. Serum triglycerides and cancer risk in the metabolic syndrome and cancer (Me-Can) collaborative study. Cancer Causes Control. 2011;22(2):291-9. [PubMed ID: 21140204].

  • 10.

    Heidari Z, Abdani M, Mansournia MA. Insulin Resistance Associated With Differentiated Thyroid Carcinoma: Penalized Conditional Logistic Regression Analysis of a Matched Case-Control Study Data. Int J Endocrinol Metab. 2018;16(1). e14545. [PubMed ID: 29696038]. [PubMed Central ID: PMC5903382].

  • 11.

    Biondi B, Arpaia D, Montuori P, Ciancia G, Ippolito S, Pettinato G, et al. Under the shadow of vesuvius: a risk for thyroid cancer? Thyroid. 2012;22(12):1296-7. [PubMed ID: 23083444].

  • 12.

    Jung SK, Kim K, Tae K, Kong G, Kim MK. The effect of raw vegetable and fruit intake on thyroid cancer risk among women: a case-control study in South Korea. Br J Nutr. 2013;109(1):118-28. [PubMed ID: 22455656].

  • 13.

    Heidari Z, Mashhadi MA, Nosratzehi S. Insulin Resistance in Patients with Benign Thyroid Nodules. Arch Iran Med. 2015;18(9):572-6. [PubMed ID: 26317597].

  • 14.

    Shen Z, Qin Y, Liu Y, Lu Y, Munker S, Chen L, et al. Helicobacter pylori infection is associated with the presence of thyroid nodules in the euthyroid population. PLoS One. 2013;8(11). e80042. [PubMed ID: 24244604]. [PubMed Central ID: PMC3823768].

  • 15.

    Wroblewski LE, Peek RJ. Helicobacter pylori, Cancer, and the Gastric Microbiota. Adv Exp Med Biol. 2016;908:393-408. [PubMed ID: 27573782].

  • 16.

    Chmiela M, Karwowska Z, Gonciarz W, Allushi B, Staczek P. Host pathogen interactions in Helicobacter pylori related gastric cancer. World J Gastroenterol. 2017;23(9):1521-40. [PubMed ID: 28321154]. [PubMed Central ID: PMC5340805].

  • 17.

    Negovan A, Iancu M, Fulop E, Banescu C. Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions. World J Gastroenterol. 2019;25(30):4105-24. [PubMed ID: 31435167]. [PubMed Central ID: PMC6700706].

  • 18.

    Camilo V, Sugiyama T, Touati E. Pathogenesis of Helicobacter pylori infection. Helicobacter. 2017;22 Suppl 1. [PubMed ID: 28891130].

  • 19.

    Mejias-Luque R, Gerhard M. Immune Evasion Strategies and Persistence of Helicobacter pylori. Curr Top Microbiol Immunol. 2017;400:53-71. [PubMed ID: 28124149].

  • 20.

    Bassi V, Marino G, Iengo A, Fattoruso O, Santinelli C. Autoimmune thyroid diseases and Helicobacter pylori: the correlation is present only in Graves's disease. World J Gastroenterol. 2012;18(10):1093-7. [PubMed ID: 22416184]. [PubMed Central ID: PMC3296983].

  • 21.

    Aghili R, Jafarzadeh F, Ghorbani R, Khamseh ME, Salami MA, Malek M. The association of Helicobacter pylori infection with Hashimoto's thyroiditis. Acta Med Iran. 2013;51(5):293-6.

  • 22.

    Hou Y, Sun W, Zhang C, Wang T, Guo X, Wu L, et al. Meta-analysis of the correlation between Helicobacter pylori infection and autoimmune thyroid diseases. Oncotarget. 2017;8(70):115691-700. [PubMed ID: 29383192]. [PubMed Central ID: PMC5777804].

  • 23.

    Shi WJ, Liu W, Zhou XY, Ye F, Zhang GX. Associations of Helicobacter pylori infection and cytotoxin-associated gene A status with autoimmune thyroid diseases: a meta-analysis. Thyroid. 2013;23(10):1294-300. [PubMed ID: 23544831].

  • 24.

    Xu F, Tang L, Yuan H, Liu J, Huang G, Song S. Iodine-131 in Helicobacter pylori-positive patients: preliminary accidental finding and in differentiated thyroid cancer. Nucl Med Commun. 2016;37(11):1136-8. [PubMed ID: 27337594].

  • 25.

    Kratzsch J, Fiedler GM, Leichtle A, Brugel M, Buchbinder S, Otto L, et al. New reference intervals for thyrotropin and thyroid hormones based on National Academy of Clinical Biochemistry criteria and regular ultrasonography of the thyroid. Clin Chem. 2005;51(8):1480-6. [PubMed ID: 15961550].

  • 26.

    Cibas ES, Ali SZ. The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2017;27(11):1341-6. [PubMed ID: 29091573].

  • 27.

    Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev. 2003;24(1):102-32. [PubMed ID: 12588812].

  • 28.

    Haggar FA, Preen DB, Pereira G, Holman CD, Einarsdottir K. Cancer incidence and mortality trends in Australian adolescents and young adults, 1982-2007. BMC Cancer. 2012;12:151. [PubMed ID: 22520938]. [PubMed Central ID: PMC3404933].

  • 29.

    Ellison LF, Wilkins K. Canadian trends in cancer prevalence. Health Reports. 2012;23(1):716.

  • 30.

    Dal Maso L, Lise M, Zambon P, Falcini F, Crocetti E, Serraino D, et al. Incidence of thyroid cancer in Italy, 1991-2005: time trends and age-period-cohort effects. Ann Oncol. 2011;22(4):957-63. [PubMed ID: 20952599].

  • 31.

    Wang JH, Zhang WP, Liu HX, Wang D, Li YF, Wang WQ, et al. Detection of human parvovirus B19 in papillary thyroid carcinoma. Br J Cancer. 2008;98(3):611-8. [PubMed ID: 18212749]. [PubMed Central ID: PMC2243166].

  • 32.

    Etemadi A, Mostafaei S, Yari K, Ghasemi A, Minaei Chenar H, Moghoofei M. Detection and a possible link between parvovirus B19 and thyroid cancer. Tumour Biol. 2017;39(6):1010428317703630. [PubMed ID: 28618936].

  • 33.

    Adamson LA, Fowler LJ, Clare-Salzler MJ, Hobbs JA. Parvovirus B19 infection in Hashimoto's thyroiditis, papillary thyroid carcinoma, and anaplastic thyroid carcinoma. Thyroid. 2011;21(4):411-7. [PubMed ID: 21190433].

  • 34.

    Narayanan M, Reddy KM, Marsicano E. Peptic Ulcer Disease and Helicobacter pylori infection. Mo Med. 2018;115(3):219-24. [PubMed ID: 30228726]. [PubMed Central ID: PMC6140150].

  • 35.

    Fakheri H, Saberi Firoozi M, Bari Z. Eradication of Helicobacter Pylori in Iran: A Review. Middle East J Dig Dis. 2018;10(1):5-17. [PubMed ID: 29682242]. [PubMed Central ID: PMC5903928].

  • 36.

    Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr Relat Cancer. 2006;13 Suppl 1:S33-43. [PubMed ID: 17259557].

  • 37.

    Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE, Roger PP. Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocr Rev. 2001;22(5):631-56. [PubMed ID: 11588145].

  • 38.

    Rezzonico JN, Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H. Increased prevalence of insulin resistance in patients with differentiated thyroid carcinoma. Metab Syndr Relat Disord. 2009;7(4):375-80. [PubMed ID: 19320560].

  • 39.

    Polyzos SA, Kountouras J, Zavos C, Deretzi G. The association between Helicobacter pylori infection and insulin resistance: a systematic review. Helicobacter. 2011;16(2):79-88. [PubMed ID: 21435084].

  • 40.

    Heidari Z, Nikbakht M, Mashhadi MA, Jahantigh M, Mansournia N, Sheikhi V, et al. Vitamin D Deficiency Associated with Differentiated Thyroid Carcinoma: A Case- Control Study. Asian Pac J Cancer Prev. 2017;18(12):3419-22. [PubMed ID: 29286613]. [PubMed Central ID: PMC5980904].

  • 41.

    Laney N, Meza J, Lyden E, Erickson J, Treude K, Goldner W. The Prevalence of Vitamin D Deficiency Is Similar between Thyroid Nodule and Thyroid Cancer Patients. Int J Endocrinol. 2010;2010:805716. [PubMed ID: 20016683]. [PubMed Central ID: PMC2779458].

  • 42.

    Hansen CM, Binderup L, Hamberg KJ, Carlberg C. Vitamin D and cancer effects of 1 25 OH 2D3 and its analogs on growth control and tumorigenesis. Front Biosci. 2001;6(3):d820-48.

  • 43.

    Marshall TG. Vitamin D discovery outpaces FDA decision making. Bioessays. 2008;30(2):173-82. [PubMed ID: 18200565].

  • 44.

    Proal AD, Albert PJ, Marshall TG. Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women. Ann N Y Acad Sci. 2009;1173:252-9. [PubMed ID: 19758159].