Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid Cancer

황보율,박영주 대한내분비학회 2018 Endocrinology and metabolism Vol.33 No.2

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals

Evaluation and Management of Bone Health in Patients with Thyroid Diseases: A Position Statement of the Korean Thyroid Association

홍아람,강호철 대한내분비학회 2023 Endocrinology and metabolism Vol.38 No.2

Thyroid hormones play an important physiological role in maintaining adult bone structure and strength. Consequently, thyroid dysfunction is related to skeletal outcomes. Overt hyperthyroidism is an established cause of high bone turnover with accelerated bone loss, leading to osteoporosis and increased fracture risk. Hyperthyroidism induced by thyroid-stimulating hormone-suppressive therapy in patients with differentiated thyroid cancer is a cause of secondary osteoporosis. In contrast, there is a lack of evidence on the negative impact of hypothyroidism on bone health. Considering the clinical updates on the importance of bone health in thyroid dysfunction, the Task Force from the Clinical Practice Guidelines Development Committee of the Korean Thyroid Association recently developed a position statement on the evaluation and management of bone health of patients with thyroid diseases, particularly focused on endogenous hyperthyroidism and thyroid-stimulating hormone-suppressive therapy-associated hyperthyroidism in patients with differentiated thyroid cancer. Herein, we review the Korean Thyroid Association’s position statement on the evaluation and management of bone health associated with thyroid diseases.

갑상선암 환자에서 진행성 대장 선종 혹은 대장암 발생의 상관관계

김다민 ( Da Min Kim ),김정하 ( Jung Ha Kim ),박준영 ( Jun Young Park ),전병우 ( Byung Woo Jun ),송림화 ( Lim Hwa Song ),정현애 ( Hyun Ae Jung ),김영호 ( Young Ho Kim ) 대한장연구학회 2011 Intestinal Research Vol.9 No.3

Background/Aims: Colorectal cancer and thyroid cancer are common diseases with relatively higher survival rates compared with other cancers. The number of patients identified with colorectal cancer or thyroid cancer who develop multiple primary malignancy during long-term follow-up is increasing with advances in diagnostic techniques and treatment modalities. However, the association between colorectal cancer and thyroid cancer is uncertain, and few data have been reported in Korea. This study examined the association between thyroid cancer and colorectal neoplasm. Methods: We retrospectively investigated 363 patients who underwent a colonoscopy, among patients diagnosed with thyroid cancer between January 2004 and December 2008 at Samsung Medical Center. The control group was comprised of 2,494 patients who underwent screening colonoscopy for the first time within the study period at the center for health promotion at Samsung Medical Center between March 2004 and December 2005. Results: The detection rates in patients with thyroid cancer were 4.7% (17/363) for advanced adenomas and 2.8% (10/363) for colorectal cancer. In the control group, it was 3.2% (79/2,494) for advanced adenomas and 0.3% (7/2,494) for colorectal cancer. A multivariate analysis revealed that the presence of thyroid cancer had an odds ratio of 1.893 (95% confidence interval, 0.868-4.128, P=0.109) in favor of finding at least one advanced colorectal neoplasm. Conclusions: The results indicate that thyroid cancer is not associated with advanced colorectal neoplasm. Survivors of thyroid and colorectal cancer live longer and hence are at risk for second primary cancers. Therefore, further studies that prospectively evaluate the association between thyroid cancer and colorectal advanced neoplasm are needed. (Intest Res 2011;9:206-210)

갑상선 악성종양 및 양성종양에서 Fra - 1 표현에 대한 연구

김용현(Youg Hyun Kim),오정헌(Jeong Heon Oh),김난희(Nan Hee Kim),최경묵(Kyung Muk Choi),김상진(Sang Jin Kim),백세현(Sei Hyun Baik),최동섭(Dong Seop Choi),이응석(Eung Seok Lee) 대한내과학회 2000 대한내과학회지 Vol.59 No.4

Background : Differential diagnosis of thyroid nodule is important in deciding treatment modality and fine needle aspiration is a good method to do so. But, sometimes, it has limitation in use because of inadequate test material and difficulty in interpreting it. Among the study of oncogene and tumor suppresor gene on the origin of thyroid tumor, expression of Fra-1, one of AP-1 system, is increased in thyroid neoplasm. So there is a possibility that it would be used as a method for differential diagnosis of thyroid nodule. We tried to know whether presence or absence of Fra-1 expression can be used as a diagnostic method in differential diagnosis of thyroid nodule using immuno- histochemical(IHC) staining method.Methods : In 4 types of thyroid tumor that was confirmed by histologic diagnosis after operation(30 cases of papillary cancer, 10 cases of follicular cancer, 16 cases of follicular adenoma, 18 cases of adenomatous goiter), IHC staining method was performed to evaluate the expression of Fra-1.Results : In papillary and follicular thyroid cancer, the expression of Fra-1 was stronger than benign thyroid tumor, but there was no difference in Fra-1 expression between two types of carcinoma. Weak expression of Fra-1 was observed in all cases of follicular adenoma, and it was also weakly expressed in 6 out 18 cases of adenomatous goiter. Conclusion : The expression of Fra-1 was stronger in thyroid cancer than in benign thyroid adenoma, but it was impossible to differentiate thyroid cancer from benign thyroid adenoma by the presence or absence of Fra-1 expression using IHC staining method.(Korean J Med 59:398-403, 2000)

갑상선 질환이 없던 여성에서 우연히 발견된 갑상선 결절의 의의

김은경,박정수,정웅윤,오기근,이종태,유형식 대한영상의학회 2002 대한영상의학회지 Vol.46 No.4

Purpose: To determine the prevalence of thyroid nodules discovered incidentally at ultrasonography and to reassess their significance. Materials and Methods: During a six-month period and using a high-frequency transducer, 1033 subjects with suspected breast disease underwent a prospective study of the thyroid. We determined the prevalence of thyroid nodules according to age, and the malignancy rate. Results: Focal thyroid nodules were detected in 291 women (28.2%), their prevalence increasing with age (p< 0.01). The nodules, totalling 337, were single in 260 cases (89.3%) and multiple in 31 (10.7%); 271 were less than 1 cm in diameter, 53 were 1-2 cm, and 13 were more than 2 cm [mean, 7.1(range, 2-34) mm]; 126 (37.4%) were pure cysts, 62 (18.4%) were mixed, and 149 (44.2%) were solid. Of the 149 solid nodules, 139 were hypoechoic. Eighty women (with 106 nodules) underwent fine-needle aspiration bipsy, and 35 (with 45 nodules) underwent surgery. It was discovered, finally, that 29 women (2.8%) had 35 malignancies, of which 33 were papillary carcinomas and two were carcinomas which had metastasized from a breast malignancy. Eleven women (37.9%) had extrathyroidal invasion and 6 (20.7%) had cervical lymph node metastasis despite incidentaloma. Conclusion: The prevalence of incidentally found thyroid nodules was 28.2%. Since the malignancy rate of these was relatively high, at 10.4%, the clinical significance of this finding should be reassessed. 목적: 갑상선 초음파 검사로 우연히 발견되는 갑상선 결절의 빈도를 알아보고, 이의 의의를 평가하고자 한다. 대상과 방법: 6개월 동안 유방암 검진을 위해 내원한 1033명을 대상으로 갑상선 초음파 검사를 시행하였다. 나이에 따른 갑상선 결절의 비율과 악성율을 알아보았다. 결과: 291명(28.2%)에서 갑상선 결절이 발견되었으며 나이가 증가할수록 많이 관찰되었다(p<0.01). 갑상선 결절은 단일인 경우가 260예(89.3%), 다발성인 경우가 31예(10.7%)로 발견된 결절은 모두 337개였다. 271개는 1 cm이하였고 1-2 cm이 53개, 2 cm이상은 13개였다. 초음파 소견상 126예(37.4%)는 낭성, 62예(18.4%)는 혼합형, 149예(44.2%)는 고형이었다. 고형 중 139예는 저에코 결절이었다. 80명의 106개의 병변에서 세침흡인검사를, 35명의 45개 결절에 대해서는 수술을 시행하였다. 29명(2.8%)의 35개 결절에서 악성으로 확인되었고 33개는 유두상암이었고, 2개의 병변은 유방암으로부터 전이된 병변이였다. 29명 중11예(37.9%)에서 피막외침윤이 있었고, 6예(20.7%)에서 경부임파절 전이가 관찰되었다. 결론: 갑상선 초음파 검사를 통해 발견된 우연종의 빈도는 28.2%였고 이중 악성율은 10.4%로 높았기 때문에 임상적 중요성은 재평가되어야 한다.

Bone Mineral Density in Thyroid Cancer Patients: Data from the Korea National Health and Nutrition Examination Survey

Myung Chul Chang 대한갑상선-내분비외과학회 2017 The Koreran journal of Endocrine Surgery Vol.17 No.4

Purpose: There are conflicting results about bone mineral density (BMD) after thyroid-stimulating hormone (TSH) suppression in thyroid cancer treatment. This study used the Korea National Health and Nutrition Examination Survey (KNHANES) data to investigate BMD of thyroid cancer patients in Korea. Methods: The data were collected from 2008 to 2011 of the KNHANES IV-V. Among a total of 37,753 participants, 18,618 subjects were included. Osteopenia and osteoporosis were evaluated according the past history of thyroid cancer. Subgroups of women and post-menopausal women were analyzed using the same method. Results: Among the 18,618 subjects, 80 thyroid cancer cases were observed. There was no significant difference in osteopenia and osteoporosis with or without thyroid cancer history (P=0.783). In the subgroup analyses of women, no difference was observed in BMD according thyroid cancer history (P=0.685). In the post-menopausal women, osteopenia and osteoporosis were less frequent in thyroid cancer cases in univariate analysis (P=0.003), but that was not significant in multivariate analysis (P=0.095). Conclusion: Although the KNHANES had a small number of thyroid cancer cases, no data about TSH suppression, and short follow-up periods, no significant difference in BMD with or without thyroid cancer was observed. The subgroup analyses of women and post-menopausal women showed similar results.

Postoperative Thyroid-Stimulating Hormone Levels Did Not Affect Recurrence after Thyroid Lobectomy in Patients with Papillary Thyroid Cancer

이명철,김민주,최훈성,조선욱,이국행,박영주,박도준 대한내분비학회 2019 Endocrinology and metabolism Vol.34 No.2

Background: Thyroid-stimulating hormone (TSH) suppression is recommended for patients who undergo thyroidectomy for differentiated thyroid cancer (DTC). However, the impact of TSH suppression on clinical outcomes in low-risk DTC remains uncertain. Therefore, we investigated the effects of postoperative TSH levels on recurrence in patients with low-risk DTC after thyroid lobectomy. Methods: Patients (n=1,528) who underwent thyroid lobectomy for papillary thyroid carcinoma between 2000 and 2012 were included in this study. According to the mean and dominant TSH values during the entire follow-up period or 5 years, patients were divided into four groups (<0.5, 0.5 to 1.9, 2.0 to 4.4, and ≥4.5 mIU/L). Recurrence-free survival was compared among the groups. Results: During the 5.6 years of follow-up, 21 patients (1.4%) experienced recurrence. Mean TSH levels were within the recommended low-normal range (0.5 to 1.9 mIU/L) during the total follow-up period or 5 years in 38.1% or 36.0% of patients. The meanand dominant TSH values did not affect recurrence-free survival. Adjustment for other risk factors did not alter the results. Conclusion: Serum TSH levels did not affect short-term recurrence in patients with low-risk DTC after thyroid lobectomy. TSHsuppression should be conducted more selectively

갑상선암의 분자표지자들에 관한 고찰

한재준,홍기숙 이화여자대학교 의과학연구소 2012 EMJ (Ewha medical journal) Vol.35 No.1

The incidence of thyroid cancer has been rapidly increased in Korea. Although fine needle aspiration cytology is recommended for diagnosis of cancer, there are some limitations. Patients with indeterminate or suspicious cytology category in which malignancy cannot be ruled out usually undergone a thyroidectomy, however, only 10∼25% of them finally diagnosed as cancer. According to the progress in understanding molecular mechanism, some mutations or other molecular alterations have been studied for the diagnostic and prognostic markers for thyroid cancer. The majority of papillary thyroid cancers have BRAF and RAS mutations or RET/PTC rearrangement, and approximately 80% of follicular thyroid cancers harbor a RAS mutation or PAX8/PPARg rearrangement. These genetic alterations are mostly studied and current clinical guidelines suggested that these molecular markers may help management for patients with indeterminate cytology. In addition, recent studies demonstrated the high sensitivity and specificity of thyroid-stimulating hormone receptor mRNA in diagnosing cancer in patients with indeterminate cytology. For the detection of recurrent or residual thyroid cancer, serum thyroglobulin is the only circulating marker in clinical practice. However, it lacks sensitivity and is unreliable specifically in the presence of antibodies to thyroglobulin. Recent studies demonstrated a significant role of measuring the mRNA of thyroglobulin, thyroid peroxidase, thyroid-stimulating hormone receptor, and sodium/iodine symporter in peripheral blood for monitoring of the recurrence of thyroid cancer.

Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification

Yanhua Bai,Kennichi Kakudo,정찬권 대한내분비학회 2020 Endocrinology and metabolism Vol.35 No.4

Advances in medical sciences and evidence-based medicine have led to momentous changes in classification and management of thyroid neoplasms. Much progress has been made toward avoiding overdiagnosis and overtreatment of thyroid cancers. The new 2017 World Health Organization (WHO) classification of thyroid neoplasms updated the diagnostic criteria and molecular and genetic characteristics reflecting the biology and behavior of the tumors, and newly introduced the category of borderline malignancy or uncertain malignant potential. Some neoplasms were subclassified, renamed, or redefined as a specific entity. This review introduces changes in the fourth edition WHO classification of thyroid tumors and updates the contemporary diagnosis and classification of thyroid tumors. We also discuss several challenges with the proposal of new diagnostic entities, since they have unique histopathologic and molecular features and clinical relevance.

Survival Comparison of Incidentally Found versus Clinically Detected Thyroid Cancers: An Analysis of a Nationwide Cohort Study

문신제,박영주,이은경,최훈성,Sue K. Park 대한내분비학회 2023 Endocrinology and metabolism Vol.38 No.1

Background: The true benefit of thyroid cancer screening is incompletely understood. This study investigated the impact of ultrasound screening on thyroid cancer outcomes through a comparison with symptomatic thyroid cancer using data from a nationwidecohort study in Korea. Methods: Cox regression analysis was performed to assess the hazard ratios (HRs) for all-cause and thyroid cancer-specific mortality. Considering the possible bias arising from age, sex, year of thyroid cancer registration, and confounding factors for mortality (including smoking/drinking status, diabetes, and hypertension), all analyses were conducted with stabilized inverse probability of treatment weighting (IPTW) according to the route of detection. Results: Of 5,796 patients with thyroid cancer, 4,145 were included and 1,651 were excluded due to insufficient data. In comparison with the screening group, the clinical suspicion group was associated with large tumors (17.2±14.6 mm vs. 10.4±7.9 mm), advanced T stage (3–4) (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.09 to 1.41), extrathyroidal extension (OR, 1.16; 95% CI, 1.02 to 1.32), and advanced stage (III–IV) (OR, 1.16; 95% CI, 1.00 to 1.35). In IPTW-adjusted Cox regression analysis, the clinical suspicion group had significantly higher risks of all-cause mortality (HR, 1.43; 95% CI, 1.14 to 1.80) and thyroid cancer-specific mortality (HR, 3.07; 95% CI, 1.77 to 5.29). Mediation analysis showed that the presence of thyroid-specific symptoms was directly associated with a higher risk of cancer-specific mortality. Thyroid-specific symptoms also indirectly affected thyroid cancer-specific mortality, mediated by tumor size and advanced clinicopathologic status. Conclusion: Our findings provide important evidence for the survival benefit of early detection of thyroid cancer compared to symptomatic thyroid cancer.