Lynnda J. N. van Tienhoven-Wind

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

Subclinical 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).

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.

Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: The Lifelines Cohort Study

OBJECTIVE Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects. METHODS The study was conducted in the Lifelines Cohort Study, a population-based cohort study of participants living in the North of the Netherlands. Only euthyroid subjects (thyroid-stimulating hormone (TSH) 0.5-4.0mU/L, free thyroxine (FT4) 11-19.5pmol/L and free triiodothyronine (FT3) 4.4-6.7pmol/L) older than 18years were included. Exclusion criteria were participants with excessive alcohol use, known hepatitis or cirrhosis, liver functions ≥ three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid or glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI≥60 was categorized as NAFLD. A P<0.01 was considered significant. RESULTS FLI≥60 was found in 4274 (21.1%) of 20,289 individuals (62.1% male, median age 46years) with increased prevalence of MetS (P<0.0001). In age- and sex-adjusted analysis FLI≥60 was independently associated with a higher FT3 (OR 1.34, 95% CI 1.29-1.39, per SD increment, P<0.0001) and a lower FT4 (OR 0.73, 95% CI 0.70-0.75, P<0.0001) but not by TSH. The strongest association was found for the FT3/FT4 ratio (OR 1.44, 95% CI 1.39-1.49, P<0.0001). These associations remained similar after additional adjustment for the presence of MetS. In subjects with enlarged waist circumference, TSH and FT4 were lower while FT3 was higher, resulting in an increased FT3/FT4 ratio (P<0.0001). CONCLUSIONS Euthyroid subjects with suspected NAFLD are characterized by higher FT3, lower FT4 and higher FT3/FT4 ratio, probably consequent to central obesity.

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 T4) 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 T4 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 (β=0.196, p=0.039). Large VLDL particles (β=-0.215, p=0.020) and VLDL size were inversely associated with free T4 (β=-0.285, p<0.001). These relationships were not significantly modified by diabetes status (interaction terms: 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.

Pre-β-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-β-high density lipoproteins (pre-β-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-β-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-β-HDL, pre-β-HDL formation (pre-β-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 < 0.05) in T2DM vs. non-diabetic subjects. HDL cholesterol and apoA-I were lower, whereas pre-β-HDL (expressed as % of apoA-I), triglycerides and PLTP activity were higher in T2DM (P < 0.05 to P < 0.001). In T2DM, pre-β-HDL formation (in apoA-I concentration and in % of apoA-I) was positively related to free T4, PLTP activity, total cholesterol and triglycerides (P < 0.05 for each). Multivariable linear regression analyses, adjusted for age, sex, PLTP activity, total cholesterol and triglycerides, demonstrated that pre-β-HDL formation was positively related to free T4 (in apoA-I concentration: β = 0.278, P = 0.014; in % of apoA-I: β = 0.343, P = 0.003) in T2DM, but not in non-diabetic subjects (both P > 0.30; interaction terms: both P < 0.05). CONCLUSIONS Variations in thyroid function within the euthyroid range may influence the metabolism of pre-β-HDL in T2DM.

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).

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.

Glomerular filtration rate is associated with free triiodothyronine in euthyroid subjects: Comparison between various equations to estimate renal function and creatinine clearance

BACKGROUND Effects of variations in thyroid function within the euthyroid range on renal function are unclear. Cystatin C-based equations to estimate glomerular filtration rate (GFR) are currently advocated for mortality and renal risk prediction. However, the applicability of cystatin C-based equations is discouraged in patients with overt thyroid dysfunction, since serum cystatin C and creatinine levels are oppositely affected by thyroid dysfunction. Here, we compared relationships of thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) with various measures of kidney function in euthyroid subjects. METHODS Relationships of eGFR, based on creatinine (eGFRcrea), cystatin C (eGFRcysC), creatinine+cystatin C combined (eGFRcrea-cysC) and creatinine clearance (CrCl) with TSH, FT4 and FT3 were determined in 2180 euthyroid subjects (TSH, FT4 and FT3 all within the reference range; anti-thyroid peroxidase autoantibodies negative) who did not use thyroid hormones, anti-thyroid drugs, amiodarone or lithium carbonate. RESULTS In multivariable models including TSH, FT3 and FT4 together, eGFRcrea, eGFRcysC and eGFRcrea-cysC and CrCl were all positively related to FT3 (P≤0.001), translating into a 2.61 to 2.83mL/min/1.73m2 increase in eGFR measures and a 3.92mL/min increase in CrCl per 1pmol/L increment in FT3. These relationships with FT3 remained taking account of relevant covariates. CONCLUSIONS In euthyroid subjects renal function is associated with thyroid function status, especially by serum FT3, irrespective of the eGFR equation applied. In the euthyroid state, cystatin C-based eGFR equations are appropriate to assess the relationship of renal function with variation in thyroid function status.

The HDL anti-inflammatory function is impaired in the context of low-normal free thyroxine in diabetic and nondiabetic individuals

Differences in thyroid function status within the euthyroid range have been proposed to affect the development of (subclinical) atherosclerosis [1], as evidenced by a greater carotid artery intima media thickness and progression of coronary artery calcification in the context of low normal thyroid function, i.e. a higher thyroid stimulating hormone (TSH) or a lower free thyroxine (FT4) thyroid hormone in the euthyroid range [2,3]. Importantly, with respect to high density lipoproteins (HDL) the concept is emerging that abnormalities in function rather than low concentrations of HDL cholesterol per se may give rise to impaired atheroprotective potential of this lipoprotein fraction. In line, a lower FT4 within the euthyroid range associates with a diminished ability of HDL to protect against LDL oxidation in vitro [4]. This article is protected by copyright. All rights reserved.