The Impact of Age- and Sex-Specific Reference Ranges for Serum Thyrotropin and Free Thyroxine on the Diagnosis of Subclinical Thyroid Dysfunction: A Multicenter Study from Japan.

Background: Reference ranges for serum thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) established without considering age- and sex-based differences are currently used to evaluate thyroid function. Therefore, we investigated age- and sex-based differences in serum TSH and thyroid hormone levels in euthyroid individuals. Methods: We performed cross-sectional analyses of retrospective data collected from two Japanese institutions. We estimated sex-specific 95% reference ranges for TSH and fT4 according to age strata. Results: We included data from 14,860 participants undergoing screening with a Siemens thyroid testing kit and 8,132 participants undergoing screening with an Abbott kit during annual health check-ups at Takasaki Hidaka Hospital. In addition, 515 participants visiting a specialized thyroid-focused hospital were evaluated using Tosoh kits. The median TSH level of women in their 30s was 1.5 mIU/L (2.5th percentile, 0.5; 97.5th percentile, 4.6) using the Siemens kit, while that of women in their 60s was 1.9 (0.7-7.8) mIU/L. The corresponding levels were lower in men; the age-associated increase was small. The median serum fT4 level of men in their 30s was 1.3 (1.0-1.7) ng/dL and that of men in their 60s was 1.2 (1.0-1.6) ng/dL. These levels gradually but significantly decreased with age. fT4 levels in women were lower than those in men and remained consistent with age. Serum fT3 levels were significantly higher in men than in women and gradually but significantly decreased with age. The Abbott and Tosoh kits showed similar results. When using the Siemens kit, ∼60% (216/358) of women diagnosed with subclinical hypothyroidism using manufacturer-recommended reference ranges had normal results when age- and sex-specific reference ranges were applied, demonstrating the high percentage of overdiagnosis, especially in those aged ≥60 years. Conversely, some middle-aged individuals with normal thyroid function were reassessed and classified as having subclinical hyperthyroidism by age- and sex-specific reference ranges. Conclusions: Age- and sex-specific reference ranges should be used to avoid over- and underdiagnosis of subclinical thyroid dysfunction and appropriate therapies.

Seasonal Variation in Thyroid Function in Over 7,000 Healthy Subjects in an Iodine-sufficient Area and Literature Review.

Context: Seasonal variation in thyroid function, especially serum free triiodothyronine (FT3) and free thyroxine (FT4) levels, in healthy subjects remains unclear. Methods: We examined thyroid function, including serum FT3 and FT4 levels, in healthy Japanese subjects using data of more than 7,000 health check-up participants and applied the analysis of means with transformed ranks (ANOMTR) to compare each month. In addition, we reviewed reports published in the last 2 decades. Results: The median serum thyrotropin (TSH) level was the highest in January (1.61 mIU/L), and the lowest in May (1.16 mIU/L). ANOMTR revealed that serum TSH levels are high in winter and low in summer. Conversely, the median serum FT3 level was higher in July than in other months, and the ANOMTR plot demonstrated serum FT3 levels to be significantly higher in summer and lower in winter. In contrast, serum FT4 levels were more consistent throughout the year, but statistically, those in February and March, October, and November were higher than those in other months. ANOMTR revealed variations in serum FT4 levels to be small through the year but biphasic. Conclusions: Taken together with previous reports, our study demonstrated seasonal changes in the serum TSH levels to be high in winter in the northern hemisphere; however, the serum FT3 differed among countries, and those of Japanese, an iodine-sufficient country, were high in summer. In contrast, FT4 levels were more consistent. These changes should be taken into account to precisely evaluate thyroid function.

Development and preliminary validation of a machine learning system for thyroid dysfunction diagnosis based on routine laboratory tests.

Background: Approximately 2.4 million patients in Japan would benefit from treatment for thyroid disease, including Graves' disease and Hashimoto's disease. However, only 450,000 of them are receiving treatment, and many patients with thyroid dysfunction remain largely overlooked. In this retrospective study, we aimed to develop and conduct preliminary testing on a machine learning method for screening patients with hyperthyroidism and hypothyroidism who would benefit from prompt medical treatment. Methods: We collected electronic medical records and medical checkup data from four hospitals in Japan. We applied four machine learning algorithms to construct classification models to distinguish patients with hyperthyroidism and hypothyroidism from control subjects using routine laboratory tests. Performance evaluation metrics such as sensitivity, specificity, and the area under receiver operating characteristic (AUROC) were obtained. Techniques such as feature importance were further applied to understand the contribution of each feature to the machine learning output. Results: The results of cross-validation and external evaluation indicated that we achieved high classification accuracies (AUROC = 93.8% for hyperthyroidism model and AUROC = 90.9% for hypothyroidism model). Serum creatinine (S-Cr), mean corpuscular volume (MCV), and total cholesterol were the three features that were most strongly correlated with the hyperthyroidism model, and S-Cr, lactic acid dehydrogenase (LDH), and total cholesterol were correlated with the hypothyroidism model. Conclusions: We demonstrated the potential of machine learning approaches for diagnosing the presence of thyroid dysfunction from routine laboratory tests. Further validation, including prospective clinical studies, is necessary prior to application of our method in the clinic.

Association between high normal-range thyrotropin concentration and carotid intima-media thickness in euthyroid premenopausal, perimenopausal and postmenopausal women.

OBJECTIVE: There are currently no established cutoff levels for thyrotropin (TSH) within the reference intervals associated with carotid atherosclerosis to prevent the onset of cardiovascular diseases. The present study aimed to determine the TSH cutoff level associated with carotid maximum intima-media thickness (max IMT) in euthyroid premenopausal, perimenopausal and postmenopausal women. STUDY DESIGN: We conducted a cross-sectional study of 468 euthyroid women who had not been treated for or diagnosed with cardiovascular diseases and/or metabolic disorders among 1221 Japanese women who participated in a comprehensive medical examination at the Hidaka Hospital, Japan. Participants' weight, blood pressure, plasma glucose, serum lipoprotein, free thyroxine and TSH were measured and an interview about menstruation was conducted. Carotid ultrasonography was performed to determine max IMT. RESULTS: Max IMT significantly increased stepwise as menopausal status progressed (p < 0.001). Serum TSH levels were significantly higher in participants with carotid plaques, defined as max IMT ≥1.1 mm (p = 0.038), and were independently associated with the presence of carotid plaque using multivariate logistic regression analysis (ß =1.218, p = 0.036). In postmenopausal women, significantly higher carotid max IMT values were observed in women with serum TSH ≥2.5 µIU/mL compared with women with concentrations <2.5 µIU/mL (p = 0.018) without elevated total cholesterol and low-density lipoprotein cholesterol concentrations. These differences were not observed in premenopausal women. CONCLUSIONS: Laboratory finding of serum TSH concentration ≥2.5 µIU/mL may be useful to assess risk of atherosclerosis, especially in postmenopausal women.

Influence of Smoking on Thyroid Function in Japanese Subjects: Longitudinal Study for One Year of On-Off Smoking.

CONTEXT: We previously identified factors affecting thyroid status, including sex, age, and smoking. OBJECTIVE: In the current study, we increased the number of subjects examined and investigated the effects of these factors, particularly smoking and the thyroid peroxidase antibody (TPO-Ab), in Japanese patients with euthyroxinemia and serum free T4 levels within the normal range. PARTICIPANTS: A total of 12,289 subjects who underwent health checkups were analyzed in a cross-sectional and longitudinal study. RESULTS: The mean age of subjects was 50 ± 10 years (age range: 21 to 88 years). Serum TSH levels and the prevalence of positivity for TPO-Ab increased with age in Japanese subjects with euthyroxinemia. Mean serum TSH levels were significantly lower in the smoking group than in the nonsmoking group except for women older than 50 years. Serum TSH levels were significantly higher in subjects with positivity for TPO-Ab than in those with negativity at all ages and in both sexes; however, smoking did not affect free T4 levels or positivity for TPO-Ab. Among men, the rate of smokers was significantly higher in patients with subclinical hyperthyroidism (25%) than in those with subclinical hypothyroidism (10%; P < 0.05). Furthermore, the results of the longitudinal study revealed a significant decrease in serum TSH levels 1 year after the start of smoking in men (P < 0.05). CONCLUSION: Because smoking appeared to lower serum TSH levels in Japanese subjects with euthyroxinemia, their smoking status warrants careful consideration when evaluating subclinical thyroid function.

Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan.

CONTEXT: In patients with aldosterone-producing adenomas (APAs), adrenalectomy causes a rapid decrease in blood pressure and increase in blood potassium levels; however, the effects of these intensive metabolic changes on kidney function with age have not yet been examined in Japan. OBJECTIVE: To investigate factors related to the progression of kidney dysfunction after adrenalectomy in different age groups. PARTICIPANTS: Fifty Japanese patients with APAs and 27,572 health checkup patients as controls were examined. MAIN OUTCOME MEASURES: We investigated changes in estimated glomerular filtration rate (eGFR) after adrenalectomy and characterized patients who progressed to chronic kidney disease (CKD). RESULTS: The postoperative cutoff age of CKD is 50 years and age is a unique factor for the progression of CKD after adrenalectomy. Among preoperative patients, CKD was 6% for those <50 years old and 40% for those ≥50 years old, indicating a higher prevalence of CKD with APAs than in control subjects. Median eGFR <50 mL/min/1.73 m2 did not significantly change after adrenalectomy but decreased from 67 to 42 mL/min/1.73 m2 in those with APAs ≥50 years old. Patients with APAs ≥50 years old who progressed to CKD showed higher preoperative aldosterone/renin ratios, lower potassium and chloride levels, lower body mass index, and a higher incidence of a history of cardiovascular events and KCNJ5 mutation rates. CONCLUSION: Age is the most important predictor of the progression of kidney dysfunction after adrenalectomy in Japanese patients with APAs, particularly those with a history of cardiovascular events and positivity for KCNJ5 mutations.

Triglyceride content in remnant lipoproteins is significantly increased after food intake and is associated with plasma lipoprotein lipase.

BACKGROUND: Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma. METHODS: TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal. RESULTS: RLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal. CONCLUSIONS: Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma.

Impact of the Visceral Fat Area Measured by Dual Impedance Method on the Diagnostic Components of Metabolic Diseases in a Middle-aged Japanese Population.

Objective The aim of this study was to examine the associations between the visceral fat area (VFA) and the subcutaneous fat area (SFA) as estimated by the dual impedance method with a body composition monitor (BCM) and the diagnostic components of metabolic syndrome in a middle-aged Japanese population. Methods The subjects included 303 men (average age 51.3±9.0 years old) and 345 women (average age 40.0±9.4 years old). The VFA and SFA were estimated by BCM, and the associations among the components of metabolic syndrome (waist circumference, blood pressure and related blood sample tests) were evaluated. Results VFA showed positive correlations with waist circumference, HbA1c, high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol, triglyceride and uric acid level in men, while showing positive correlations with waist circumference, HDL cholesterol, triglyceride and HbA1c in women. The estimated SFA showed positive correlations with systolic blood pressure, HDL/LDL cholesterol and triglyceride in men, and HDL cholesterol and triglyceride in women. A receiver operating characteristic (ROC) analysis showed the estimated VFA to be as effective as WC to identify subject with metabolic syndrome. Conclusion By estimating the VFA using BCM, it may be possible to identify patients at risk of developing metabolic syndrome and hyperuricemia.