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

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