Low-normal Thyroid Function Research Articles

Low thyroid function is associated with metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is recently introduced to better highlight the pathogenic significance of cardiometabolic dysfunction, as compared with non-alcoholic fatty liver disease. This study aimed to investigate the association between low thyroid function and MASLD in the new context. We recruited 2901 participants for our retrospective cohort study from 2016 to 2021. Participants were divided into strict-normal thyroid function and low thyroid function groups (low-normal thyroid function, subclinical hypothyroidism) based on initial thyroid stimulating hormone (TSH) levels, respectively. Cox regression models were used to estimate the hazard ratios (HRs) and 95% CI. During a median follow-up of 15.6 months, 165 (8.9%) strict-normal thyroid function subjects and 141 (13.4%) low thyroid function subjects developed MASLD; this result was statistically relevant (P < 0.05). Univariate regression analysis showed that low thyroid function and subclinical hypothyroidism were statistically significantly associated with MASLD (low thyroid function: HR1.53; 95% CI 1.22-1.92; subclinical hypothyroidism: HR1.95; 95% CI 1.47-2.60). MASLD is associated with low thyroid function and the relationship between MASLD and low thyroid function is independent.

Associations between cardiovascular health and low thyroid function among US adults: a population-based study.

Higher thyroid-stimulating hormone (TSH) amidst normal thyroid hormone (TH) levels may contribute to a negative impact on cardiovascular health (CVH). We sought to probe the associations between Life's Essential 8 (LE8), a newly revised CVH evaluation, and low thyroid function among US adults. The datasets from the 2007-2012 National Health and Nutrition Examination Survey (NHANES) were applied to the study. Low-normal thyroid function and subclinical hypothyroidism (SCH) were both regarded to be low thyroid function. Multivariable logistic regressions were utilized to inquire about the relationship between LE8 and low thyroid function. Among the 6,315 participants (age ≥20 years), 1,375 (21.77%) were ascertained to be low thyroid function. After adjusting possible confounders, a higher LE8 score was linked to a lower probability of experiencing low thyroid function (Odds ratio [OR] for each 10-point increase: 0.923 [95% CI, 0.884-0.964]). A similar correlation was found between the health factors score and low thyroid function (OR for each 10-point increase: 0.905 [95% CI, 0.876-0.935]). Also, scoring better on physical activity (PA), body mass index (BMI), blood lipid, blood glucose (BG), and blood pressure (BP) may be conducive to reducing the rates of low thyroid function. Furthermore, subgroup and sensitivity analyses indicated that the negative correlations were generally robust. The LE8 score and health factors score were nonlinearly and negatively related to the prevalence concerning low thyroid function. Promoting the regulation of optimum CVH levels could work on mitigating the load of low thyroid function and cardiovascular diseases (CVDs).

Association between low-normal thyroid function and advanced liver fibrosis in metabolic dysfunction-associated fatty liver disease patients: a retrospective cohort study.

Recent studies have found that thyroid function may be associated with the occurrence and development of advanced liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the majority of such research has consisted of cross-sectional studies. This retrospective cohort study aimed to investigate the effect of low-normal thyroid function on advanced liver fibrosis in MAFLD patients over a 5-year period. This retrospective cohort study enrolled 825 outpatients and inpatients with MAFLD who attended the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2011 and December 2018. Based on plasma thyroid hormone and thyroid-stimulating hormone levels, these patients were divided into two groups, namely a low-normal thyroid function group and a strict-normal thyroid function group. The fibrosis-4 score was used to assess advanced liver fibrosis. A chi-square test was conducted to compare the occurrence of advanced fibrosis between the groups. Among the 825 MAFLD patients, 117 and 708 were defined as having low-normal thyroid function and strict-normal thyroid function, respectively. Follow-up data were available for 767 patients (93.0%) during a 5-year period. Eight (7.5%) MAFLD patients with low-normal thyroid function and 26 (3.9%) with strict-normal thyroid function developed advanced liver fibrosis and the cumulative incidence was not significantly different (P = 0.163). Stratification analysis showed that the lean MAFLD patients (body mass index ≤ 23 kg/m2) with low-normal thyroid function had a higher risk of advanced liver fibrosis than the lean MAFLD patients with strict-normal thyroid function (P < 0.05). Low-normal thyroid function is associated with advanced liver fibrosis among lean MAFLD patients.

Clinical features and prognosis of patients hospitalized with heart failure and low T3 syndrome

Objective: To investigate the association between triiodothyronine (T3) and inflammatory factors, and its potential effect on long-term outcomes in hospitalized patients with heart failure (HF). Methods: A total of 2 475 patients with HF admitted in Heart Failure Care Unit were consecutively enrolled in this retrospective cohort study from December 2006 to June 2018. Patients were divided into low T3 syndrome group (n=610, 24.6%) and normal thyroid function group (n=1 865, 75.4%). The median follow-up time was 2.9 (1.0, 5.0) years. A total of 1 048 all-cause deaths were recorded at the final follow-up. The effects of free T3 (FT3) and high-sensitivity C-reactive protein (hsCRP) on the risk of all-cause death were evaluated by Cox regression analysis and Kaplan-Meier analysis. Results: The age of the total population was 19-95 (57±16) years, 1 823 cases (73.7%) were male. Compared to those with normal thyroid function, albumin [(36.5±5.4) vs. (40.7±4.7) g/L], hemoglobin [(129.4±25.1) vs. (140.6±20.6) g/L], total cholesterol [3.6 (3.0, 4.4) vs. 4.2 (3.5, 4.9) mmol/L] (all P<0.001) were lower, Whereas age [(60.5±16.0) vs. (55.2±15.4) years], creatinine [105.0 (83.6, 137.0) vs. 87.8 (75.6, 106.3) mmol/L], log N-terminal B-type natriuretic peptide [(8.2±1.3) vs. (7.2±1.4) ng/L] were higher in LT3S patients (all P<0.001). In Kaplan-Meier survival analysis, patients with lower FT3 and higher hsCRP had significantly lower cumulative survival (P<0.001), lower FT3 combined with higher hsCRP subgroup had the highest risk of all-cause death (Ptrend<0.001). In multivariate Cox regression analysis, LT3S was an independent predictor of all-cause mortality (HR=1.40, 95%CI 1.16-1.69, P<0.001). Conclusion: LT3S is an independent predictor of poor prognosis in patients with heart failure. FT3 combined with hsCRP improve the predictive value of all-cause death in hospitalized patients with heart failure.

Low-Normal Thyroid Function Is Not Associated with Either Non-Alcoholic Fatty Liver Disease or with Metabolic Dysfunction-Associated Fatty Liver Disease.

The association of low-normal thyroid function (LNTF) with non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) is controversial; thus, the aim of this study is to determine this association. NAFLD was evaluated by controlled attenuation parameter of transient elastography. Patients were classified by MAFLD criteria. LNTF was defined as TSH levels of 2.5 to 4.5 mIU/L and were divided into three different cut-off points (>4.5 to 5.0, >3.1, and >2.5 mIU/L). Associations between LNTF, NAFLD, and MAFLD were evaluated by univariate and multivariate logistic regression analyses. A total of 3697 patients were included; 59% (n = 2179) were male, and median age and body mass index were 48 (43-55) years and 25.9 (23.6-28.5) kg/m2, respectively, and 44% (n = 1632) were diagnosed with NAFLD. THS levels of 2.5 and 3.1 showed significant associations with the presence of NAFLD and MAFLD; however, LNTF did not show an independent association with the presence of NAFLD or MAFLD in multivariate analysis. According to different cut-off points, patients with LNTF presented similar risks for NAFLD as the general population. LNTF is not associated with NAFLD or MAFLD. Patients with high LNTF are equally at risk for NAFLD as the general population.

Impact of Thyroid Function on the Prevalence and Mortality of Metabolic Dysfunction-Associated Fatty Liver Disease.

Thyroid function variation within the thyroxine reference range has negative metabolic effects. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a recently proposed definition. We aim to explore the effects of thyroid function status on prevalence and mortality of MAFLD. Data of 10 666 participants from the Third National Health and Nutrition Examination Survey (NHANES III) were used. MAFLD was diagnosed based on the new definition. Thyroid function variation within the thyroxine reference range was defined based on thyroid-stimulating hormone (TSH) levels: subclinical hyperthyroidism, <0.39 mIU/L; strict-normal thyroid function, 0.39-2.5 mIU/L; and low thyroid function, >2.5 mIU/L, which comprised low-normal thyroid function (2.5-4.5 mIU/L) and subclinical hypothyroidism (> 4.5 mIU/L). Logistic and Cox regression were used in multivariate analysis. Low thyroid function is independently associated with MAFLD (odds ratio: 1.27). Compared with strict-normal thyroid function, subclinical hypothyroidism was significantly associated with increased risk for all-cause and cardiovascular mortality in the total population (hazard ratio [HR] for all-cause: 1.23; cardiovascular: 1.65) and MAFLD population (HR for all-cause: 1.32; cardiovascular: 1.99); meanwhile, in the low-normal thyroid function group, an increasing trend in mortality risk was observed. Furthermore, low thyroid function also showed significant negative impact on mortality in the total and MAFLD population. Among thyroid function spectrum, mild subclinical hypothyroidism showed the highest HRs on mortality. Low thyroid function is independent risk factor of MAFLD and is associated with increased risk for all-cause and cardiovascular mortality in the MAFLD population. Reevaluation of TSH reference range should be considered.

Low thyroid function is associated with an increased risk of advanced fibrosis in patients with metabolic dysfunction-associated fatty liver disease

AimsObservational studies showed that low thyroid function may perturb liver function. We aimed to evaluate the association of low thyroid function with both metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced hepatic fibrosis.MethodsParticipants who underwent abdominal ultrasonography and thyroid function test in a Chinese hospital from 2015 to 2021were enrolled. Fibrosis-4 index (FIB-4) > 2.67 and/or non-alcoholic fatty liver disease fibrosis score (NFS) > 0.676 were used to define advanced fibrosis. Descriptive analyses were performed to characterize the epidemiology of MAFLD according to levels of thyroid-stimulating hormone (TSH). The logistic regression model was applied to estimate the association of low thyroid function with MAFLD and advanced fibrosis.ResultsA total of 19,946 participants (52.78% males, mean age: 47.31 years, 27.55% MAFLD) were included, among which 14,789 were strict-normal thyroid function, 4,328 were low-normal thyroid function, 829 were subclinical hypothyroidism. TSH levels were significantly higher in MAFLD patients with a FIB-4 > 2.67 and /or NFS > 0.676 than their counterparts. The logistic regression model adjusted for age and sex showed that low-normal thyroid function increased the risk of MAFLD (odds ratio [OR] = 1.09; 95% confidence interval [CI] 1.01–1.18). Multivariable regression model adjusted for age, sex, body mass index, type 2 diabetes, and hypertension showed low-normal thyroid function increased the risk of advanced fibrosis in patients with MAFLD (FIB-4 > 2.67: OR = 1.41, 95% CI 1.02–1.93; NFS > 0.676: OR = 1.72, 95% CI 1.08–2.72).ConclusionElevated TSH concentrations are associated with advanced hepatic fibrosis, even in the euthyroid state.

Associations of Thyroid Hormones Profile During Normal Pregnancy and Postpartum With Anxiety, Depression, and Obsessive/Compulsive Disorder Scores in Euthyroid Women.

ObjectiveThyroid dysfunction (overt and subclinical) has been consistently linked to pregnancy adversity and abnormal fetal growth and development. Mood disorders such as anxiety, depression, and obsessive-compulsive disorder (OCD) are frequently diagnosed during pregnancy and at postpartum, and emerging evidence suggests association with impaired offspring neurodevelopment and growth. This study aimed to examine potential associations between thyroid function and mood symptoms during pregnancy and postpartum.DesignThis is a prospective study measuring thyroid hormones and assessing mood symptoms by employing specific questionnaires in the same cohort of 93 healthy pregnant women at the 24th (2nd trimester) and 36th (3rd trimester) gestational weeks and at the 1st postpartum week.MethodsSerum thyroid hormones, TSH, anti-TPO, and anti-Tg antibodies were measured at the 24th (2nd trimester) and 36th (3rd trimester) gestational weeks and at the 1st postpartum week. Specific validated questionnaires were employed at the same time-points to assess separately symptoms of anxiety [Generalized Anxiety Disorder Inventory (GADI), Penn State Worry Questionnaire (PSWQ), STAI-State Anxiety inventory (STAI-S), STAI-Trait Anxiety Inventory (STAI-T)], depression [Edinburgh Postnatal Depression Scale (EPDS), Stein’s Blues Scale (BLUES), Beck Depression Inventory (BDI)], and obsessive compulsive disorder (OCD) [Yale-Brown Obsessive Compulsive scale (Y-BOCS)].ResultsAt the 2nd trimester, GADI score correlated negatively with FT3 (p < 0.010, r = −0.545) and positively with TSH (p < 0.050, r = 0.837) concentrations; GADI, PSWQ, EPDS and Y-BOCS scores correlated negatively with FT4 concentrations (p < 0.010, r = −0.768; p < 0.010, r = −0.384; p < 0.050, r = −0.364; p < 0.010, r = −0.544, respectively). At the 3rd trimester, BLUES score correlated positively with rT3 concentrations (p = 0.00, r = 0.89); GADI, EPDS, and Y-BOCS scores correlated negatively with FT4 concentrations (p = 0.001, r = − 0.468; p = 0.036, r = −0.39; p = 0.001, r = −0.625, respectively); GADI, STAI-S, and Y-BOCS scores correlated positively with TSH concentrations (p = 0.015, r = 0.435; p = 0.024, r = 0.409 p = 0.041, r = 0.389, respectively). At postpartum, PSWQ, STAI-T, EPDS, and BDI scores correlated positively with rT3 concentrations (p = 0.024, r = 0.478; p = 0.014, r = 0.527; p = 0.046, r = 0.44; p = 0.021, r = 0.556, respectively, Y-BOCS score correlated positively with TSH (p = 0.045, r = 0.43), and BLUES score correlated positively with anti-TPO antibody concentrations (p = 0.070, r = 0.586).ConclusionThe reported findings demonstrate positive associations between low-normal thyroid function at the 2nd and 3rd trimesters of pregnancy and postpartum with anxiety, depression, and OCD scores.

Risk of Liver Fibrosis According to TSH Levels in Euthyroid Subjects.

Alterations in thyroid function may contribute to the development of liver fibrosis especially in subjects with non-alcoholic fatty liver disease. This study aimed to investigate the risk of liver fibrosis according to low-normal thyroid function in the general population. We performed a descriptive cross-sectional study in subjects from 18–75 years randomly selected from 16 primary health care centers from 2017–2019. Each subject underwent clinical evaluation, physical examination, blood analysis and transient hepatic elastography. Descriptive and multivariate logistic regression analyses were used to identify factors associated with fibrosis. We included 1096 subjects (60 ± 11 years; 61% women); 70% had strict-normal thyroid function and 30% had low-normal thyroid function. Low-normal thyroid function was associated with a higher liver stiffness (LS) values: 5.2 vs. 4.8 kPa (p = 0.001) and a greater prevalence of fibrosis: 6.1 vs. 3% (p = 0.016) and 4.3 vs. 2.1% (p = 0.044) for the cut-off points of ≥8.0 kPa and ≥9.2 kPa, respectively. After adjustment for potential confounding factors, the risk of fibrosis in subjects with low-normal thyroid function was OR 1.54 (p = 0.213). In conclusion, low-normal thyroid function is associated with higher LS values and a greater risk of liver fibrosis in the general population, being dependent on other metabolic factors.

Lower free thyroid hormone levels are associated with high blood glucose and insulin resistance; these normalize with metabolic improvement of type 2 diabetes.

This study aimed to explore the relationship of thyroid function and glucose metabolism and to investigate the changes in thyroid function after National Metabolic Management Center (MMC) management in type 2 diabetic mellitus (T2DM). A total of 2000 euthyroid participants from MMC in Shanghai General Hospital and a community physical examination were recruited. They were categorized into four groups: normal glucose tolerance (NGT, n = 132), prediabetes (N = 147), DM well-controlled (T2DM with glycosylated hemoglobin [HbA1c] ≤ 7%, n = 505), and DM uncontrolled (T2DM with HbA1c > 7%, n = 1216). The parameters were compared among the groups and their changes before and after MMC follow-up in DM uncontrolled group were observed. Free triiodothyronine (FT3) and free thyroxine (FT4) levels varied significantly among groups. FT3 and FT4 levels negatively correlated with HbA1c level (P < 0.05), and positively correlated with the estimated glucose disposal rate (eGDR) (P < 0.05). Following MMC management, blood glucose and insulin resistance in the DM uncontrolled group were dramatically improved (P < 0.001). Meanwhile, FT3 was elevated compared to the baseline (from 4.51 ± 0.78 pmol/L to 4.68 ± 0.87 pmol/L, P < 0.05), and reverse triiodothyronine (r-T3) decreased from 1.03 ± 0.24 nmol/L to 0.92 ± 0.25 nmol/L (P < 0.001). Thyroid-stimulating hormone significantly decreased as well (P < 0.001). Decreased free thyroid hormone levels in normal range were associated with high glucose and insulin resistance. After MMC management, improvement of blood glucose and insulin resistance were accompanied by the restoration of low-normal thyroid function.

Association of Thyroid-Stimulating Hormone and Thyroid Hormones with Cardiometabolic Risk Factors in Euthyroid Children and Adolescents Aged 10\u201318 Years: A Population-Based Study

Recent evidence indicates that low-normal thyroid function test results within the reference ranges may be related to increased cardiometabolic risk factors. The current study aimed to evaluate the relationship between thyroid function using thyroid-stimulating hormone (TSH) and free thyroxine (FT4) and cardiometabolic risk factors and the clustering of these risk factors (metabolic syndrome) in euthyroid children and adolescents. A total of 250 euthyroid children and adolescents aged 10–18 years were included using data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2015. In the unadjusted correlation analyses, TSH was positively correlated with glucose (r = 0.172, P = 0.006), hemoglobin A1c (HbA1c) (r = 0.149, P = 0.018), insulin (r = 0.144, P = 0.023), homeostatic model assessment for insulin resistance (HOMA-IR) (r = 0.163, P = 0.010), and triglyceride (TG) (r = 0.155, P = 0.014), whereas FT4 was negatively associated with the waist circumference (WC) standard deviation score (SDS) (r = −0.134, P = 0.035), body mass index (BMI) SDS (r = −0.126, P = 0.046), insulin (r = −0.219, P < 0.001), and HOMA-IR (r = −0.211, P < 0.001). In the multiple linear regression analysis, TSH was positively associated with glucose (β = 1.179, P = 0.021), HbA1c (β = 0.044, P = 0.039), and TG (β = 8.158, P = 0.041) after adjustment for possible confounders. FT4 was negatively associated with serum fasting insulin (β = −5.884, P = 0.017) and HOMA-IR (β = −1.364, P = 0.023) in the multiple linear regression analysis. Boys and girls with elevated glucose levels had a higher adjusted mean TSH level compared to those without elevated glucose levels after controlling for confounding factors in the analysis of covariance (2.16 mIU/L vs 3.88 mIU/L, P = 0.004). Our results suggest that higher TSH and/or lower FT4 levels, even within the reference ranges, may be related to increased cardiometabolic risk factors.

Thyroid function and life expectancy with and without noncommunicable diseases: Apopulation-based study.

BackgroundVariations in thyroid function within reference ranges are associated with increased risk of diseases and death. However, the impact of thyroid function on life expectancy (LE) with and without noncommunicable diseases (NCDs) remains unknown. We therefore aimed to investigate the association of thyroid function with total LE and LE with and without NCD among euthyroid individuals.Methods and findingsThe study was embedded in the Rotterdam Study, a prospective population-based study carried out in the Netherlands. In total, 7,644 participants without known thyroid disease and with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels within reference ranges were eligible. NCDs were defined as presence of cardiovascular disease, diabetes mellitus type 2, or cancer. We used the demographic tool of multistate life tables to calculate LE estimates at the age of 50 years, using prevalence, incidence rates, and hazard ratios for three transitions (healthy to NCD, healthy to death, and NCD to death). The total LE and LE with and without NCD among TSH and FT4 tertiles were calculated separately in men and women. Analyses were adjusted for sociodemographic and cardiovascular risk factors. The mean (standard deviation) age of the participants was 64.5 (9.7) years, and 52.3% were women. Over a median follow-up of 8 years (interquartile range 2.7–9.9 years), 1,396 incident NCD events and 1,422 deaths occurred. Compared with those in the lowest TSH tertile, men and women in the highest TSH tertile were expected to live 1.5 years (95% confidence interval [CI] 0.8–2.3, p < 0.001) and 1.5 years (CI 0.8–2.2, p < 0.001) longer, respectively, of which 1.4 years (CI 0.5–2.3, p = 0.002) and 1.3 years (CI 0.3–2.1, p = 0.004) with NCD. Compared with those in the lowest FT4 tertile, the difference in LE for men and women in the highest FT4 tertile was −3.7 years (CI −5.1 to −2.2, p < 0.001) and −3.3 years (CI −4.7 to −1.9, p < 0.001), respectively, of which −1.8 years (CI −3.1 to −0.7, p = 0.003) and −2.0 years (CI −3.4 to −0.7, p = 0.003) without NCD. A limitation of the study is the observational design. Thus, the possibility of residual confounding cannot be entirely ruled out.ConclusionsIn this study, we found that people with low–normal thyroid function (i.e., highest tertile of TSH and lowest tertile of FT4 reference ranges) are expected to live more years with and without NCD than those with high–normal thyroid function (i.e., lowest tertile of TSH and highest tertile of FT4 reference ranges). These findings provide support for a re-evaluation of the current reference ranges of thyroid function.

P3414Differences in total life expectancy and life expectancy with and without non-communicable diseases within the reference range of thyroid function

Abstract Background Variations in thyroid function within the reference ranges are associated with an increased risk of diseases and death. However, the impact of thyroid function on life expectancy (LE) and the number of years lived with and without non-communicable diseases (NCD) remains unknown. Purpose We aimed to investigate the association of thyroid function with total LE and LE with and without NCD among euthyroid subjects. Methods Participants of the Rotterdam Study without known thyroid disease and with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels within the reference ranges were eligible. NCD were defined as the presence of cardiovascular disease, diabetes mellitus type 2, or cancer. We used multistate life tables to calculate the total LE and LE with and without NCD among TSH and FT4 tertiles, in men and women. LE estimates were obtained using prevalence, incidence rates and hazard ratios for three transitions (healthy to NCD, healthy to death and NCD to death). Analyses were adjusted for sociodemographic and cardiovascular risk factors. Results The mean (standard deviation) age of 7644 participants was 64.5 (9.7) years and 52.2% were women. Over a median follow-up of 8 years, we observed 1396 incident NCD events and 1422 deaths. Compared with those in the lowest tertile, men and women in the highest TSH tertile lived 1.5 (95% confidence interval [CI], 0.8; 2.3) and 1.5 (95% CI, 0.8; 2.2) years longer, respectively; of which 1.4 (95% CI, 0.5; 2.3) and 1.3 (95% CI, 0.3; 2.1) years with NCD. Compared with those in the lowest tertile, the difference in LE for men and women in the highest FT4 tertile was −3.7 (95% CI, −5.1 to −2.2) and −3.3 (95% CI, −4.7; −1.9), respectively; of which −1.8 (95% CI, −3.1 to −0.7) and −2.0 (95% CI, −3.4 to −0.7) years without NCD. Life expectancy in TSH and FT4 tertiles Conclusions There are meaningful differences in total LE, LE with and without NCD within the reference ranges of thyroid function. People with low-normal thyroid function live more years with and without NCD than those with high-normal thyroid function. These findings support a reevaluation of the current reference ranges of thyroid function.

Low-Normal Thyroid Function Predicts Incident Anemia in the General Population With Euthyroid Status.

Thyroid hormones (THs) have direct and indirect effects on hematopoiesis. However, few studies have directly evaluated the effect of THs on incident anemia among euthyroid subjects. This cohort study aimed to explore whether THs under physiological conditions can affect the development of anemia in the general population. A total of 12,310 participants were enrolled in the cohort study (∼5-year follow-up period; mean, 3.1 years). A chemiluminescence immunoassay was used to measure free T3 (FT3), free T4 (FT4), and TSH, and anemia was defined according to the World Health Organization recommendation. THs, TSH, and Hb were assessed yearly during follow-up. Multivariable Cox proportional hazards regression models were used to assess the association between THs, TSH, and incident anemia. The fully adjusted hazards ratios (95% CI) of anemia per 1-unit change in FT3, FT4, and TSH concentrations were 0.70 (0.56, 0.87), 0.93 (0.88, 0.98), and 1.19 (0.94, 1.50) (P < 0.01, P < 0.01, and P = 0.14, respectively). Moreover, a significant and positive association between FT3, FT4, and annual changes in Hb (standard regression coefficients of 0.056 and 0.028, respectively; both P < 0.01) was observed. Similar associations were observed when the participants who had thyroid dysfunction upon follow-up were excluded. The current study demonstrated that THs significantly predict future anemia and annual changes in Hb, even in the euthyroid population.

1504-P: Low Normal Free Thyroxine Levels Are Associated with Prediabetes in Euthyroid Subjects

Background: Although the association between low-normal thyroid function and metabolic syndrome was well documented, little is known about the effect of thyroid hormone within the physiological range on carbohydrate metabolism. This study aimed to determine whether free thyroxine (FT4) influences serum glucose concentration and the prevalence of prediabetes in euthyroid subjects. Methods: This was a cross-sectional survey derived from the Korea National Health and Nutrition Examination Survey, conducted between 2013 and 2015. We studied 4,767 participants of &amp;gt;20 years of age who were euthyroid and nondiabetic. Results: Prediabetic participants had lower FT4 concentrations than those without prediabetes, but thyrotropin concentrations were similar. We stratified the population into tertiles according to FT4 concentration. After adjusting for multiple confounding factors, HbA1c levels significantly decreased with FT4 tertile, whereas FBG was not associated with FT4 both in men and in women. The prevalence of prediabetes was significantly higher in T1 than in T3. Conclusion: Subjects with low-normal serum FT4 had high HbA1c and were more likely to have the prediabetes. These results suggest that low FT4 concentration is a risk factor for prediabetes, even though thyroid function is within the normal range. Thus, screening for prediabetes in subjects with low-normal FT4 should involve the measurement of HbA1c. Disclosure S. Kim: None. E. Jeon: None. J. Lee: None. H. Shon: None. K. Park: None.

Low-Normal Thyroid Function Is Associated With Advanced Fibrosis Among Adults in the United States

The pathogenetic pathways leading to increasing prevalence of advanced fibrosis in the setting of nonalcoholic fatty liver disease (NAFLD) and resulting in higher rates of liver-related and cardiovascular morbidity and mortality in the United States are multifactorial.1 The negative health impact of "low-normal" thyroid function, which is defined as a higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range, may be comparable with overt and subclinical hypothyroidism.2-4 We reported a strong association between biopsy-proven advanced fibrosis in NAFLD with increasing TSH levels in a dose-dependent manner even within the euthyroid reference range.5 To generalize our findings across all ethnicities, we examined the association of both low-normal thyroid function and subclinical hypothyroidism with advanced fibrosis in the US general population.

Serum paraoxonase-1 activity is inversely related to free thyroxine in euthyroid subjects: The PREVEND Cohort Study.

Low-normal thyroid function within the euthyroid range has been suggested to enhance atherosclerosis susceptibility. Paraoxonase-1 (PON-1) may protect against atherosclerotic cardiovascular disease development by attenuating oxidative stress. We evaluated relationships of PON-1 with thyroid stimulating hormone (TSH), free T4 , free T3 , lipids and apolipoprotein (apo)A-I in euthyroid subjects, and assessed whether such relationships are modified in the context of the metabolic syndrome (MetS). Serum PON-1 activity (arylesterase activity), TSH, free T4 , free T3 , lipids and apoA-I was measured in 2206 euthyroid subjects (aged 28-75years; 1138 men (age 49±13years) and 1068 women (age 46±12years), recruited from the general population (PREVEND cohort). In age- and sex-adjusted analysis, PON-1 activity (divided into tertiles) was positively related to TSH (β=-0.045, P=.036) and inversely to free T4 (β=-0.042, P=.050) but not to free T3 (β=-0.027, P=.20). PON-1 activity was positively related to total cholesterol, non-HDL cholesterol and triglycerides, as well as to HDL cholesterol and apoA-I (P<.01 to <.001). The inverse relationship of PON-1 activity with free T4 remained present after adjustment for lipids and other potential confounders (β=-0.066, P=.002), but the positive relationship with TSH lost significance (β=0.034, P=.11). The inverse relationship of PON-1 activity with free T4 was not different in subjects with vs without MetS (P=.94), nor modified by the presence of its individual components (P≥.22 for each). Serum PON-1 activity is inversely associated with free T4 in euthyroid subjects, suggesting that low-normal thyroid function may affect PON-1 regulation.

Association of Thyroid Function With Life Expectancy With and Without Cardiovascular Disease

Variations in thyroid function within reference ranges are associated with an increased risk of cardiovascular disease (CVD) and mortality. However, the impact of thyroid function on life expectancy (LE) and the number of years lived with and without CVD remains unknown. To investigate the association of thyroid function with total LE and LE with and without CVD among euthyroid individuals. The Rotterdam Study, a population-based, prospective cohort study. We included participants without known thyroid disease and with thyrotropin and free thyroxine (FT4) levels within the reference ranges. Multistate life tables were used to calculate total LE and LE with and without CVD among thyrotropin and FT4 tertiles. Life expectancy estimates in men and women aged 50 years and older were obtained using prevalence, incidence rates, and hazard ratios for 3 transitions (healthy to CVD, healthy to death, and CVD to death), adjusting for sociodemographic and cardiovascular risk factors. The mean (SD) age of the 7785 participants was 64.7 (9.8) years, and 52.5% were women. Over a median follow-up of 8.1 (interquartile range, 2.7-9.9) years, we observed 789 incident CVD events and 1357 deaths. Compared with those in the lowest tertile, men and women in the highest thyrotropin tertile lived 2.0 (95% CI, 1.0 to 2.8) and 1.4 (95% CI, 0.2 to 2.4) years longer, respectively, of which, 1.5 (95% CI, 0.2 to 2.6) and 0.9 (95% CI, -0.2 to 2.0) years longer without CVD. Compared with those in the lowest tertile, the difference in life expectancy for men and women in the highest FT4 tertile was -3.2 (95% CI, -5.0 to -1.4) and -3.5 (95% CI, -5.6 to -1.5) years, respectively, of which, -3.1 (95% CI, -4.9 to -1.4) and -2.5 (95% CI, -4.4 to -0.7) years without CVD. At the age of 50 years, participants with low-normal thyroid function live up to 3.5 years longer overall and up to 3.1 years longer without CVD than participants with high-normal thyroid function. These findings provide supporting evidence for a reevaluation of the current reference ranges of thyroid function and can help inform preventive and clinical care.

Subclinical Hypothyroidism and Low-Normal Thyroid Function Are Associated With Nonalcoholic Steatohepatitis and Fibrosis

Variations in level of thyroid-stimulating hormone (TSH) within the reference range of thyroid hormone could have negative health effects. We evaluated the effect of plasma TSH levels within the euthyroid range on the severity of histological damage associated with nonalcoholic fatty liver disease (NAFLD). We performed a cross-sectional study of 425 subjects with biopsy-proven NAFLD (mean age, 53 years; 52% male) who participated in the Boramae NAFLD study from January 2013 to January 2017. Each subject underwent an anthropometric assessment and laboratory and clinical evaluations. Of the subjects, 282 were assigned to a strict-normal thyroid function group (plasma level of TSH, 0.4 to 2.5 mIU/L). Patients with low thyroid function were assigned to groups of subclinical hypothyroidism (plasma level of TSH above 4.5 mIU/L with a normal thyroid hormone level; n = 59) or low-normal thyroid function (higher plasma TSH level [2.5 to 4.5 mIU/L] with a normal thyroid hormone level; n = 84). Multivariate logistic regression analysis was used to identify factors independently associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. NASH and advanced fibrosis were found in higher percentages of subjects with low thyroid function vs strict-normal thyroid function (52.4% vs 37.2% for NASH and 21.0% vs 10.6% for advanced fibrosis; P < .01). Among subjects with low thyroid function, a higher proportion of patients with subclinical hypothyroidism had NASH and associated advanced fibrosis vs patients with low-normal thyroid function (57.6% vs 48.8% for NASH and 25.4% vs 17.9% for advanced fibrosis; P < .01). Subjects with low thyroid function had more extensive hepatic steatosis with greater severity of balloon degeneration and fibrosis. In multivariate analyses, low thyroid function was significantly associated with NASH (odds ratio, 1.61; 95% CI, 1.04-2.50; P = .035) and advanced fibrosis (odds ratio, 2.23; 95% CI, 1.18-4.23; P = .014). Risks of NASH and advanced fibrosis increased significantly with plasma concentration of TSH (Ptrend <.05 for each). Subclinical hypothyroidism and low-normal thyroid function are independent predictors of NASH and advanced fibrosis, confirming the relationship between these diseases. ClinicalTrials.gov, Number: NCT02206841.

Increased leptin/adiponectin ratio relates to low-normal thyroid function in metabolic syndrome

BackgroundLow-normal thyroid function within the euthyroid range may contribute to increased atherosclerosis susceptibility. The leptin/adiponectin (L/A) ratio is associated with cardiovascular disease and reflects adipose tissue dysfunction. Relationships of the L/A ratio with low-normal thyroid function are unknown.MethodsRelationships of thyroid stimulating hormone (TSH) and free thyroxine (free T4) with leptin, adiponectin and the L/A ratio in euthyroid subjects were documented in 67 fasting subjects with metabolic syndrome (Mets) and 86 euthyroid subjects without MetS (TSH and free T4 levels within the institutional reference range).ResultsNeither plasma leptin nor adiponectin was significantly correlated with TSH or free T4 in subjects with and without MetS. In the whole group, high sensitivity C-reactive protein (hs-CRP) was positively correlated with the L/A ratio (r = 0.485, P < 0.001). Notably, the L/A ratio was positively correlated with TSH in subjects with MetS (r = 0.252, P = 0.040) but not in subjects without MetS (r = −0.068, P = 0.54; interaction term, P = 0.027). In MetS subjects, the L/A ratio remained positively related with TSH after adjustment for age, sex, diabetes status, hs-CRP and the use of antihypertensive and glucose lowering medication (β = 0.283, P = 0.018), as well as after adjustment for individual MetS components (β = 0.294, P = 0.020).ConclusionsIn the context of MetS, a higher TSH within the euthyroid range confers an increased L/A ratio, a proposed marker of atherosclerosis susceptibility and adipocyte dysfunction.