BACKGROUND: Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS: The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS: The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.
Lipid Metabolism/genetics* ; Mendelian Randomization Analysis ; Thyroid Function Tests ; Thyroid Gland ; Thyrotropin ; Thyroxine ; Triiodothyronine

BACKGROUND/AIMS: Maternal thyroid dysfunction has been associated with adverse pregnancy outcomes. The purpose of our study was to establish trimester-specific reference intervals for thyroid hormones in pregnant women in Korea, where iodine intake is more than adequate and to examine pregnancy and perinatal outcomes in their offspring. METHODS: Among 459 healthy pregnant women who were screened, we enrolled 417 subjects who had negative results for thyroid autoantibodies. Serum thyroid stimulating hormone (TSH) and free thyroxine were measured using an immunoradiometric assay. Urine iodine concentration was measured using inductively coupled plasma-mass spectrometry in 275 women. Reference ranges of thyroid hormones were determined according to the guidelines of the National Academy of Clinical Biochemistry. Pregnancy and perinatal outcomes were compared according to maternal thyroid function. RESULTS: The reference ranges of serum TSH were 0.03 to 4.24 mIU/L in the first trimester, 0.13 to 4.84 mIU/L in the second trimester, and 0.30 to 5.57 mIU/L in the third trimester. Pregnancy and perinatal outcomes did not vary in mothers with subtle changes in thyroid function. CONCLUSIONS: Trimester-specific thyroid hormone reference intervals in Korean pregnant women differ from those of other countries with different iodine nutrition status and ethnicity. The establishment of population-based, reliable trimester-specific reference intervals is critical for the interpretation of thyroid function in pregnant women to avoid unnecessary tests and treatments.
Autoantibodies ; Biochemistry ; Female ; Humans ; Immunoradiometric Assay ; Iodine ; Korea* ; Mothers ; Nutritional Status ; Pregnancy Outcome ; Pregnancy Trimester, First ; Pregnancy Trimester, Second ; Pregnancy Trimester, Third ; Pregnancy* ; Pregnant Women ; Reference Values ; Republic of Korea ; Spectrum Analysis ; Thyroid Gland* ; Thyroid Hormones* ; Thyrotropin ; Thyroxine

BACKGROUND/AIMS: Although a low triiodothyronine (T3) state is closely associated with heart failure (HF), it is uncertain whether total T3 levels on admission is correlated with the clinical outcomes of acute myocardial infarction (AMI). The aim of this study is to investigate the prognostic value of total T3 levels for major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with AMI undergone percutaneous coronary intervention (PCI). METHODS: A total of 765 PCI-treated AMI patients (65.4 ± 12.6 years old, 215 women) between January 2012 and July 2014 were included and 1-year MACCEs were analyzed. We assessed the correlation of total T3 and free thyroxine (fT4) with prevalence of 1-year MACCEs and the predictive values of total T3, fT4, and the ratio of total T3 to fT4 (T3/fT4), especially for HF requiring re-hospitalization. RESULTS: Thirty patients (3.9%) were re-hospitalized within 12 months to control HF symptoms. Total T3 levels were lower in the HF group than in the non-HF group (84.32 ± 21.04 ng/dL vs. 101.20 ± 20.30 ng/dL, p < 0.001). Receiver operating characteristic curve analysis showed the cut-offs of total T3 levels (≤ 85 ng/dL) and T3/fT4 (≤ 60) for HF (area under curve [AUC] = 0.734, p < 0.001; AUC = 0.774, p < 0.001, respectively). In multivariate analysis, lower T3/fT4 was an independent predictor for 1-year HF in PCI-treated AMI patients (odds ratio, 1.035; 95% confidential interval, 1.007 to 1.064; p = 0.015). CONCLUSIONS: Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to predict HF.
Area Under Curve ; Heart Failure* ; Heart* ; Humans ; Multivariate Analysis ; Myocardial Infarction* ; Percutaneous Coronary Intervention ; Prevalence ; Prognosis ; ROC Curve ; Thyroxine* ; Triiodothyronine*

Familial dysalbuminemic hyperthyroxinemia (FDH) is an inherited disease characterized by increased circulating total thyroxine (T4) levels and normal physiological thyroid function. Heterozygous albumin gene (ALB) variants have been reported to be the underlying cause of FDH. To our knowledge, there have been no confirmed FDH cases in Korea. We recently observed a female patient with mild T4 elevation (1.2 to 1.4-fold) and variable levels of free T4 according to different assay methods. Upon Sanger sequencing of her ALB, a heterozygous c.725G>A (p.Arg242His) variant was identified. The patient's father and eldest son had similar thyroid function test results and were confirmed to have the same variant. Although the prevalence of FDH might be very low in the Korean population, clinical suspicion is important to avoid unnecessary evaluation and treatment.
Adult ; Albumins/*genetics ; Base Sequence ; Female ; Heterozygote ; Humans ; Hyperthyroxinemia, Familial Dysalbuminemic/*genetics ; Pedigree ; Radioimmunoassay ; Sequence Analysis, DNA ; Thyroxine/analysis

PURPOSE: Delayed treatment of congenital hypothyroidism (CH) is a common cause of mental retardation. The aim of the present study was to evaluate intellectual outcomes in preschool children with treated CH. METHODS: We retrospectively reviewed the clinical records of 43 children (age range: 13 to 60 days of life; 22 girls and 21 boys) diagnosed with CH. Children aged 5 to 7 years were examined using the Korean Wechsler Intelligence Scale for Children or the Korean Wechsler Preschool and Primary Scale of Intelligence. RESULTS: The patients started treatment between 13 and 60 days of age. The mean intelligence quotient (IQ) of patients tested at age 5 to 7 years was 103.14±11.68 (IQ range: 76–126). None had intellectual disability (defined as an IQ <70). Twenty-one subjects were treated with a low dose (6.0–9.9 µg/kg/day) and 22 with a high dose of levothyroxine (10.0–16.0 µg/kg/day). There was no significant difference in the mean full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) scores between the 2 groups. FSIQ, PIQ, and VIQ scores were not significantly correlated with initial dose of L-T4, initial fT4, age at treatment in multivariate analysis. CONCLUSION: IQ scores of subjects with early treated CH diagnosed through a neonatal screening test were within normal range, regardless of etiology, thyroid function, initial dose of levothyroxine, and age at start of treatment.
Child ; Child, Preschool* ; Congenital Hypothyroidism* ; Female ; Humans ; Hypothyroidism ; Infant, Newborn ; Intellectual Disability ; Intelligence ; Multivariate Analysis ; Neonatal Screening ; Reference Values ; Retrospective Studies ; Thyroid Gland ; Thyroxine

PURPOSE: The measurement of serum thyroglobulin (Tg) of papillary thyroid carcinoma patients, 12 months after total thyroidectomy and radioactive iodine (RAI) ablation following thyroxine hormone withdrawal (T4-off Tg) or recombinant human thyroid-stimulating hormone stimulation (rhTSH-Tg), is standard method for monitoring disease status. The aim of this study was to find predictive factors for detectable T4-off Tg during follow-up. METHODS: A retrospective review was conducted of 329 patients who underwent total thyroidectomy and RAI ablation between October 2008 and August 2012. Subjects were assigned to high (>1 ng/mL, n = 53) and low (≤1 ng/mL, n = 276) groups, based on T4-off Tg measured 12 months postoperatively. Demographic and clinicopathological characteristics at diagnosis and follow-up were compared between the 2 groups. RESULTS: The low and high T4-off Tg groups differed with respect to tumor size, preoperative Tg, ablative Tg, cervical lymph node metastasis, thyroglobulinemia out of proportion to results of diagnostic whole body scan, and American Thyroid Association 3-level stratification and restratification. Multivariate analysis confirmed that ablative Tg > 1.0 ng/mL (odds ratio [OR], 10.801; P = 0.001), more than 5 cervical lymph node metastasis (OR, 6.491; P = 0.003), and thyroglobulinemia out of proportion (OR, 9.221; P = 0.000) were risk factors. CONCLUSION: Ablative Tg >1.0 ng/mL, more than 5 cervical lymph node metastasis, and thyroglobulinemia out of proportion were independent factors for T4-off Tg >1 ng/mL 12 months postoperative. In low-risk patients without these risk factors, the possible omission of Tg measurements could be considered during follow-up.
Diagnosis ; Follow-Up Studies ; Humans ; Iodine* ; Lymph Nodes ; Methods ; Multivariate Analysis ; Neoplasm Metastasis ; Retrospective Studies ; Risk Factors* ; Thyroglobulin* ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy ; Thyrotropin ; Thyroxine ; Whole Body Imaging

Subclinical hyperthyroidism and subclinical hypothyroidism are characterized by abnormal thyroid stimulating hormone (TSH) with normal free thyroxine. Subclinical thyroid diseases, to date, have received less attention compared with other thyroid diseases since they are asymptomatic. This study aimed to verify the association between subclinical thyroid diseases and cardiovascular diseases (CVDs) risk score in the Korean population. This was a population-based cohort study using data collected from 3,722 subjects (aged ≥ 30 years) during the 6th Korea National Health and Nutrition Examination Survey (KNHANES VI; 2013–2015). Gender-specific Framingham risk scores were calculated to identify the association between subclinical thyroid diseases and 10-year CVD risk score. Complex survey, with consideration of sampling weight, was analyzed using generalized linear models after stratification by gender. The TSH reference range was between 0.61 and 6.91 mIU/L in this study. TSH showed a positive association with the 10-year CVD risk score only in the female population (P = 0.001). There were significant differences in the least squares means of 10-year CVD risk score by the effect of subclinical hypothyroidism compared with euthyroidism (normal group) in females, after adjusting for body mass index, white blood cell, and urine iodine (P = 0.006 and Bonferroni corrected P = 0.012). In conclusion, subclinical hypothyroidism is associated with increased 10-year CVD risk score in the female Korean population aged 30 years or more. Therefore, we recommend to clinically checkup major CVD risk factors in female patients with subclinical hypothyroidism aged 30 years or more.
Body Mass Index ; Cardiovascular Diseases* ; Cohort Studies ; Female ; Humans ; Hyperthyroidism ; Hypothyroidism ; Iodine ; Korea ; Least-Squares Analysis ; Leukocytes ; Linear Models ; Nutrition Surveys ; Reference Values ; Risk Factors ; Thyroid Diseases* ; Thyroid Gland* ; Thyrotropin ; Thyroxine

BACKGROUND AND OBJECTIVES: Abnormal thyroid function influences the cardiovascular system. In particular, brief thyroid functional change due to levothyroxine (LT4) suppression therapy and withdrawal in papillary thyroid cancer (PTC) patients can affect cardiovascular system and other biochemical markers. However, the effect of brief thyroid functional change on arterial stiffness has not been evaluated. Therefore, we evaluated the changes in arterial stiffness according to short-term thyroid hormone levels in patients who underwent total thyroidectomy and radioactive iodine (RAI) therapy for PTC. MATERIALS AND METHODS: Patients with PTC (n=17; 15 females, mean age 52 years) who underwent total thyroidectomy and RAI therapy were enrolled in this study. The arterial stiffness was evaluated using the corrected augmentation index for heart rate (AI@75) and brachial-ankle pulse wave velocity (BaPWV). Serum thyroid hormone levels and arterial stiffness parameters were checked three times consecutively: the day before thyroidectomy (Visit 1; baseline euthyroid state), after LT4 withdrawal (Visit 2; pre-RAI hypothyroid state) and 4 weeks after RAI (Visit 3; post-RAI thyrotoxic state). Biochemical markers, which can influence the arterial stiffness, were also measured. RESULTS: The heart rate, AI@75 and serum thyroid hormone levels changed significantly at each visit. BaPWV was not significantly changed. Changes in AI@75 correlated with systolic blood pressure (SBP), serum thyroid hormone levels, total cholesterol and high density lipoprotein cholesterol in univariate analysis. In multivariate analysis, SBP was the independent factor for AI@75 changes. CONCLUSION: These results suggest that brief thyroid functional changes can influence AI@75. And SBP was important factor for AI@75 change.
Biomarkers ; Blood Pressure ; Cardiovascular System ; Cholesterol ; Cholesterol, HDL ; Female ; Heart Rate ; Humans ; Iodine* ; Multivariate Analysis ; Pulse Wave Analysis ; Thyroid Function Tests ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroidectomy ; Thyroxine ; Vascular Stiffness*

BACKGROUND: Establishment of trimester- and assay-specific reference intervals for every population is recommended. The aim of this study was to establish a trimester- and assay-specific reference interval for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in Korean pregnant women. METHODS: From April 2012 to December 2012, 531 pregnant women receiving prenatal care and 238 age-matched, non-pregnant women were enrolled in this study. After excluding patients with pregnancy-associated complications or thyroid-specific autoantibody, 465 pregnant and 206 non-pregnant women were included. Non-parametric analysis (2.5-97.5th percentile) was performed to determine the reference interval. Levels of TSH and FT4 were determined by electrochemiluminescence immunoassay (Elecsys thyroid tests, Roche Diagnostics, Germany). RESULTS: The TSH reference intervals were 0.01-4.10, 0.01-4.26, and 0.15-4.57 mIU/L for the first, second, and third trimester, respectively. From the first trimester to the third trimester, the median TSH levels showed a significantly increasing trend (P<0.0001). The FT4 reference intervals were 0.83-1.65, 0.71-1.22, and 0.65-1.13 ng/dL for the first, second, and third trimester, respectively, showing a significantly decreasing trend (P<0.0001). CONCLUSIONS: Establishing trimester-specific reference intervals in pregnant women is essential for accurate assessment of thyroid function. Our population-specific and method-specific reference intervals will be useful for screening Korean pregnant women for thyroid disease.
Adult ; Asian Continental Ancestry Group ; Case-Control Studies ; Female ; Humans ; *Immunoassay/standards ; Luminescent Measurements ; Pregnancy ; Pregnancy Trimesters ; Prenatal Care ; Reference Values ; Republic of Korea ; Thyroid Hormones/*analysis/standards ; Thyroxine/*analysis/standards

BACKGROUND/AIMS: Hypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects. METHODS: Apparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings. RESULTS: NAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814-1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28). CONCLUSIONS: Our results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD.
Adult ; Aged ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Hypothyroidism/*complications/*diagnosis ; Incidence ; Kaplan-Meier Estimate ; Liver/ultrasonography ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*complications/*diagnosis/epidemiology ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Thyrotropin/analysis ; Thyroxine/analysis