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

BACKGROUND: 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 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). MATERIALS AND METHODS: Serum PON-1 activity (arylesterase activity), TSH, free T4 , free T3 , lipids and apoA-I were measured in 2206 euthyroid subjects (aged 28 to75 years; 1138 men (age 49 ± 13 years) and 1068 women (age 46 ± 12 years), recruited from the general population (PREVEND cohort). RESULTS: In age- and sex-adjusted analysis, PON-1 activity (divided into tertiles) was positively related to TSH (β=-0.045, P=0.036) and inversely to free T4 (β=-0.042, P=0.050), but not to free T3 (β=-0.027, P=0.20). PON-1 activity was positively related to total cholesterol, non-HDL cholesterol and triglycerides, as well as to HDL cholesterol and apoA-I (P<0.01 to <0.001). The inverse relationship of PON-1 activity with free T4 remained present after adjustment for lipids and other potential confounders (β=-0.066, P=0.002), but the positive relationship with TSH lost significance (β=0.034, P=0.11). The inverse relationship of PON-1 activity with free T4 was not different in subjects with vs. without MetS (P=0.94), nor modified by the presence of its individual components (P≥0.22 for each). CONCLUSIONS: Serum PON-1 activity is inversely associated with free T4 in euthyroid subjects, suggesting that low-normal thyroid function may affect PON-1 regulation

Low-Normal Thyroid Function and Novel Cardiometabolic Biomarkers

The concept is emerging that low-normal thyroid function, i.e., either higher thyroid-stimulating hormone or lower free thyroxine levels within the euthyroid reference range, could contribute to the development of atherosclerotic cardiovascular disease. It is possible that adverse effects of low-normal thyroid function on cardiovascular outcome may be particularly relevant for specific populations, such as younger people and subjects with high cardiovascular risk. Low-normal thyroid function probably relates to modest increases in plasma total cholesterol, low density lipoprotein cholesterol, triglycerides and insulin resistance, but effects on high density lipoprotein (HDL) cholesterol and non-alcoholic fatty liver disease are inconsistent. Low-normal thyroid function may enhance plasma cholesteryl ester transfer, and contribute to an impaired ability of HDL to inhibit oxidative modification of LDL, reflecting pro-atherogenic alterations in lipoprotein metabolism and HDL function, respectively. Low-normal thyroid function also confers lower levels of bilirubin, a strong natural anti-oxidant. Remarkably, all these effects of low-normal thyroid functional status appear to be more outspoken in the context of chronic hyperglycemia and/or insulin resistance. Collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures

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

Abstract Background Low-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. Methods Relationships of thyroid stimulating hormone (TSH) and free thyroxine (free T 4 ) 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 T 4 levels within the institutional reference range). Results Neither plasma leptin nor adiponectin was significantly correlated with TSH or free T 4 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 \u2009=\u20090.485, P \u2009<\u20090.001). Notably, the L/A ratio was positively correlated with TSH in subjects with MetS ( r \u2009=\u20090.252, P \u2009=\u20090.040) but not in subjects without MetS ( r \u2009= \u22120.068, P \u2009=\u20090.54; interaction term, P \u2009=\u20090.027). 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 (\u3b2\u2009=\u20090.283, P \u2009=\u20090.018), as well as after adjustment for individual MetS components (\u3b2\u2009=\u20090.294, P \u2009=\u20090.020). Conclusions In 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

Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

Objectives: Low-normal thyroid function may relate to increases in plasma cholesterol and triglycerides, but effects on lipoprotein subfractions are largely unknown. Associations of alterations in lipoprotein metabolism and functionality with low-normal thyroid function could be more pronounced in Type 2 diabetes mellitus (T2DM). We determined relationships of plasma lipids and lipoprotein subfractions with thyroid-stimulating hormone (TSH) and free thyroxine (free T-4) in euthyroid subjects, and assessed whether such relationships are modified in the context of T2DM. Design and methods: TSH, free T4, (apo) lipoproteins and lipoprotein subfractions (nuclear magnetic resonance spectroscopy) were measured after an overnight fast in 61 T2DM subjects and 52 non-diabetic subjects. Results: TSH and free T-4 were similar in T2DM and non-diabetic subjects. Plasma triglycerides, large very low density (VLDL) particles, VLDL size and small low density lipoprotein (LDL) particles were increased, whereas high density lipoprotein (HDL) cholesterol was decreased in T2DM subjects (p = 0.05 for each). Age-, sex-, and diabetes status-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were associated positively with TSH (beta = 0.196, p = 0.039). Large VLDL particles (beta = - 0.215, p = 0.020) and VLDL size were inversely associated with free T4 (beta = - 0.285, p 0.10 for each). In all subjects combined, LDL and HDL subfraction characteristics were not significantly related to thyroid function status. Conclusions: Low-normal thyroid function may confer increased plasma triglycerides, large VLDL particles and increased VLDL particle size. These relationships are not to a major extent modified in the context of T2DM. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved

Low-Normal Thyroid Function and Novel Cardiometabolic Biomarkers

The concept is emerging that low-normal thyroid function, i.e., either higher thyroid-stimulating hormone or lower free thyroxine levels within the euthyroid reference range, could contribute to the development of atherosclerotic cardiovascular disease. It is possible that adverse effects of low-normal thyroid function on cardiovascular outcome may be particularly relevant for specific populations, such as younger people and subjects with high cardiovascular risk. Low-normal thyroid function probably relates to modest increases in plasma total cholesterol, low density lipoprotein cholesterol, triglycerides and insulin resistance, but effects on high density lipoprotein (HDL) cholesterol and non-alcoholic fatty liver disease are inconsistent. Low-normal thyroid function may enhance plasma cholesteryl ester transfer, and contribute to an impaired ability of HDL to inhibit oxidative modification of LDL, reflecting pro-atherogenic alterations in lipoprotein metabolism and HDL function, respectively. Low-normal thyroid function also confers lower levels of bilirubin, a strong natural anti-oxidant. Remarkably, all these effects of low-normal thyroid functional status appear to be more outspoken in the context of chronic hyperglycemia and/or insulin resistance. Collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures

Low-normal thyroid function and the pathogenesis of common cardio-metabolic disorders

BackgroundSubclinical hypothyroidism may adversely affect the development of cardiovascular disease (CVD). Less is known about the role of low-normal thyroid function, that is higher thyroid-stimulating hormone and/or lower free thyroxine levels within the euthyroid reference range, in the development of cardio-metabolic disorders. This review is focused on the relationship of low-normal thyroid function with CVD, plasma lipids and lipoprotein function, as well as with metabolic syndrome (MetS), chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD).Materials and methodsThis narrative review, which includes results from previously published systematic reviews and meta-analyses, is based on clinical and basic research papers, obtained via MEDLINE and PubMed up to November 2014.ResultsLow-normal thyroid function could adversely affect the development of (subclinical) atherosclerotic manifestations. It is likely that low-normal thyroid function relates to modest increases in plasma total cholesterol, LDL cholesterol and triglycerides, and may convey pro-atherogenic changes in lipoprotein metabolism and in HDL function. Most available data support the concept that low-normal thyroid function is associated with MetS, insulin resistance and CKD, but not with high blood pressure. Inconsistent effects of low-normal thyroid function on NAFLD have been reported so far.ConclusionsObservational studies suggest that low-normal thyroid function may be implicated in the pathogenesis of CVD. Low-normal thyroid function could also play a role in the development of MetS, insulin resistance and CKD, but the relationship with NAFLD is uncertain. The extent to which low-normal thyroid function prospectively predicts cardio-metabolic disorders has been insufficiently established so far.</p

Tumor Necrosis Factor-alpha is Inversely Related to Free Thyroxine in Euthyroid Subjects Without Diabetes

Lower thyroid functional status within the euthyroid range may confer increased atherosclerosis susceptibility, as evidenced by increased intima media thickness and coronary artery calcification. Associations of lower thyroid functional status with pro-atherogenic (inflammatory) biomarkers may also extend into the euthyroid range. Here we established relationships of plasma tumor necrosis factor-alpha (TNF-alpha) with thyroid stimulating hormone (TSH) and free thyroxine (free T-4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). Fasting TSH, free T-4, and TNF-alpha were measured in 81 nondiabetic subjects and in 73 T2DM subjects with Type 2 diabetes mellitus (T2DM; insulin using subjects were excluded) with TSH and free T-4 levels each within the institutional reference ranges. TSH was similar and free T-4 was slightly higher in T2DM (p <0.016). Plasma TNF-alpha was increased in T2DM (p = 0.007). In nondiabetic subjects, TNF-alpha was correlated inversely with free T-4 (r = -0.254, p = 0.022), whereas such a relationship was absent in T2DM subjects (r = 0.058, p = 0.63). Multivariable linear regression analysis showed that in nondiabetic subjects TNF-alpha remained inversely associated with free T-4 after adjustment for age and sex (beta = -0.243, p = 0.032) and additionally for thyroid autoantibodies (beta = -0.251, p = 0.027), contrasting the lack of relationship in T2DM subjects (interaction: p = 0.053). In T2DM subjects, TNF-alpha was also unrelated to free T-4 taking account of possible confounders, as well as after exclusion of subjects using metformin or antihypertensive medication. In conclusion, higher levels of TNF-alpha relate to lower free T-4. Low-normal thyroid function could influence pro-inflammatory pathways. This relationship appears to be disturbed in T2DM

Pre-beta-HDL formation relates to high-normal free thyroxine in type 2 diabetes mellitus

Objectives: Low-normal thyroid function within the euthyroid range may influence plasma lipoprotein levels. Associations between variation in thyroid function and pre-beta-high density lipoproteins (pre-beta-HDL), i.e. lipid-poor or lipid free HDL particles that act as initial acceptor of cell-derived cholesterol, are unknown. We determined relationships of plasma pre-beta-HDL with thyroid function in euthyroid subjects with and without type 2 diabetes mellitus (T2DM). Design and Subjects: TSH, free T4, plasma (apo)lipoproteins, pre-beta-HDL, pre-beta-HDL formation (pre-beta-HDL generation during incubation with lecithin:cholesterol acyltransferase being inhibited) and phospholipid transfer protein (PLTP) activity were measured in fasting plasma from 72 T2DM and 82 non-diabetic subjects. Results: TSH was similar and free T4 was slightly higher (P 0.30; interaction terms: both P<0.05). Conclusions: Variations in thyroid function within the euthyroid range may influence the metabolism of pre-beta-HDL in T2DM. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved