Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy

To assess whether subclinical hypothyroidism is associated with changes in lipoprotein fractions, 13 patients maintained in a stable state of subclinical hypothyroidism for at least 3 months were studied prior to and 2 and 4 months following restoration of a euthyroid state with incremental levothyroxine sodium therapy. Thyrotropin levels ( +/- SEM) had decreased from 16.6 +/- 3.2 mU/L to 3.1 +/- 0.7 mU/L and 3.2 +/- 0.7 mU/L at 2 months and 4 months. At 2 months, levothyroxine treatment led to a decrease in levels of total cholesterol from 5.5 +/- 0.3 mmol/L (213 +/- 12 mg/dL) to 4.8 +/- 0.3 mmol/L (186 +/- 12 mg/dL), in low-density lipoprotein cholesterol (LDL-C) from 3.7 +/- 0.3 mmol/L (143 +/- 12 mg/dL) to 2.9 +/- 0.3 mmol/L (112 +/- 12 mg/dL), and in apolipoprotein B from 91 +/- 8 mg/dL to 74 +/- 7 mg/dL. At 4 months, levels of LDL-C and apolipoprotein B remained significantly lower than pretreatment values (2.9 +/- 0.2 mmol/L [112 +/- 8 mg/dL] and 75 +/- 6 mg/dL, respectively). While high-density lipoprotein cholesterol (HDL-C), HDL3-C, and apolipoprotein A-I were not significantly affected by levothyroxine therapy, there was a slight trend of increase in HDL2-C during levothyroxine substitution. There was also a tendency for a decrease in triglyceride levels from 1.3 +/- 0.2 mmol/L (115 +/- 18 mg/dL) to 0.9 +/- 0.1 mmol/L (80 +/- 9 mg/dL) at 4 months of levothyroxine therapy. Levels of HDL-C tended to decrease from 4.8 +/- 0.4 mmol/L (186 +/- 15 mg/dL) to 4.5 +/- 0.5 mmol/L (174 +/- 19 mg/dL) at 2 months and to 3.9 +/- 0.4 mmol/L (151 +/- 15 mg/dL) at 4 months. The LDL-C/HDL-C ratio also decreased from 3.3 +/- 0.3 mmol/L (128 +/- 12 mg/dL) to 2.9 +/- 0.5 mmol/L (112 +/- 19 mg/dL) and 2.5 +/- 0.3 mmol/L (97 +/- 12 mg/dL) at 2 months and 4 months, respectively. These results suggest that long-term levothyroxine therapy in patients with subclinical hypothyroidism is associated with a decrease in LDL-C and apolipoprotein B levels that are reflected in a trend of decreases in cholesterol/HDL-C and LDL-C/HDL-C ratios known to have a relationship with coronary artery disease.     

Hemodynamic changes after levothyroxine treatment in subclinical hypothyroidism.

In hypothyroidism, lack of thyroid hormones results in reduced cardiac function (cardiac output [CO]), and an increase of systemic vascular resistance (SVR). We speculated whether hemodynamic regulation in subjects with subclinical hypothyroidism (SH) (defined as mildly elevated thyrotropin [TSH] despite free thyroxine [T(4)] and triiodothyronine [T(3)] estimates within reference range) would benefit from levothyroxine (LT(4)) substitution. CO was measured by impedance cardiography, which is an observer independent method with high precision, and mean arterial pressure (MAP) by oscillometry. SVR was then calculated as MAP/CO. Measurements were performed before and after 60 degrees head-up tilting, and before and after LT(4) substitution. Plasma levels of catecholamines were also measured. In 16 otherwise healthy women with SH (ages 44-74 years; serum TSH in mean 17.1 mU/L (range, 6.8-27), and normal free T(4) and T(3) estimates) LT(4) treatment resulted in 6% reduction in supine MAP (p < 0.01), 14% increase in upright CO (p < 0.05), and 13%-20% decrease in SVR (supine and upright position, respectively) (p < 0.05). Plasma norepinephrine as well as epinephrine decreased during LT(4) treatment (p < 0.05). These changes were qualitatively similar but quantitatively less pronounced than in 15 women with overt hypothyroidism, also studied. Taking the two groups together (n = 31), pretreatment thyroid function (expressed as either TSH or free T(4) estimate) correlated to CO and SVR as well as the changes induced by LT(4) (p < 0.05), i.e., the lower the thyroid function the lower the CO and the higher the SVR, and the greater the response to LT(4). We conclude, that LT(4) treatment in SH results in changes in hemodynamic parameters of potentially beneficial character. SH and overt hypothyroidism should be regarded as a continuum, and our data favor earlier and more aggressive treatment of SH.     

Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study

The relationship between subclinical hypothyroidism (SCH) and an atherogenic lipoprotein profile is still controversial. We measured lipoproteins in 49 SCH patients by comparison with 33 euthyroid controls. Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), apolipoprotein A(1), apolipoprotein B, and lipoprotein (a) [Lp(a)] were measured after an overnight fast. Patients were randomly assigned to levothyroxine therapy or placebo and re-evaluated after 6 months of euthyroidism. SCH patients showed significantly higher TC (P < 0.01), LDLc (P = 0.01), and apolipoprotein B (P = 0.001) levels than controls, positively correlated with baseline TSH levels (P = 0.003, P = 0.01, and P = 0.03, respectively). Elevated Lp(a) levels were significantly more frequent in SCH (P < 0.05) and associated with familial diabetes mellitus and/or coronary heart disease (P < 0.01). Levothyroxine treatment resulted in a significant decrease of both TC and LDLc concentrations (P = 0.003), in direct proportion to the respective baseline values (P < 0.05 and P < 0.01, respectively), whereas no change in Lp(a) level was observed. No changes occurred in the placebo group. In conclusion, only serum LDLc levels are increased specifically and reversibly in association with SCH. Altered Lp(a) values reflect a genetic influence rather than a reduced thyroid hormone action.     

Prolactin dysregulation in women with subclinical hypothyroidism: effect of levothyroxine replacement therapy.

This study investigated the effect of levothyroxine treatment on serum prolactin (PRL) levels in women with subclinical hypothyroidism. Sixty-six women (mean age, 58.5 +/- 1.3 years) with confirmed subclinical hypothyroidism (mean thyrotropin [TSH], 11.7 +/- 0.8 mIU/L) were randomly assigned to receive levothyroxine or placebo for 48 weeks. Based on blinded TSH monitoring, physiologic levothyroxine replacement (85.5 +/- 4.3 microg/d; TSH, 3.1 +/- 0.3 mIU/L) was ascertained throughout the study. PRL levels were measured before and after administration of thyrotropin-releasing hormone (TRH) at baseline, after 24 and 48 weeks. Sixty-three of the 66 women completed the study. At baseline, basal PRL levels were elevated in 19% of the patients. None of the patients reported menstrual disturbances, infertility, or galactorrhea. In the levothyroxine group (n = 31) basal and peak PRL levels were significantly reduced after 24 and 48 weeks (p = 0.03 and p = 0.001). Mean changes in PRL levels differed significantly between the two treatment groups after 24 weeks (p = 0.03 and p = 0.01). The treatment effect was more pronounced in patients with PRL and TSH levels above the median at baseline (i.e., PRL > 16 ng/mL; TSH > 11 mIU/L). Based on this double-blinded, placebo-controlled study we demonstrate that in subclinical hypothyroidism PRL regulation is altered with elevated basal and stimulated PRL levels, and that physiologic levothyroxine treatment restores PRL concentrations.     

The effect of levothyroxine on arterial stiffness and lipid profile in patients with subclinical hypothyroidism

BACKGROUND: The influence of treatment for subclinical hypothyroidism (SCH) on cardiovascular morbidity and mortality, arterial stiffness, and lipid profile has not been elucidated yet. The aim of this study was to evaluate the effect of levothyroxine on arterial stiffness, lipid profile, and inflammation. METHODS: The study included 30 patients with SCH. Patients were treated with levothyroxine and were assessed at baseline and at 1, 4, and 7 months. Blood samples were taken for lipid profile and highly sensitive C-reactive protein (hs-CRP). Arterial stiffness was evaluated by augmentation index (AIx). In conditions that cause arterial stiffness, the pulse wave traveling from the periphery to the heart reaches the heart during systole, resulting in augmentation of the central pressure. This increase, calculated as the AIx, is a good expression of central aortic pressure. RESULTS: After accomplishing euthyroidism, the AIx decreased from 17.2 +/- 8.3 to 14.3 +/- 6.5 (p < 0.01) and AIx percentage decreased from 36.2 +/- 11.5 to 33.2 +/- 9.1 (p = 0.03). Systolic blood pressure (SBP) decreased from 134.7 +/- 20 to 127.6 +/- 13.7 mmHg (p < 0.01). In those patients whose AIx decreased, low-density lipoprotein (LDL) levels decreased by 0.4 +/- 0.96 mmol/L compared to the patients whose AIx did not decrease and LDL increased by 0.62 +/- 1.48 mmol/L (p = 0.057). Total cholesterol decreased by 0.72 +/- 1.64 mmol/L in the patients whose AIx decreased and increased by 1 +/- 2.53 mg/dL in the patients whose AIx did not improve (p = 0.06). CONCLUSIONS: In patients with SCH, treatment with levothyroxine had a significant beneficial effect on arterial stiffness and SBP, and no effect on lipid profile or hs-CRP.     

左旋甲状腺素治疗对亚临床甲状腺功能减退患者血脂和症状影响

各种原因所致亚临床甲状腺功能减退 (甲减 )患者 3 6例 ,经左旋甲状腺素治疗后 ,血清总胆固醇 ,低密度脂蛋白和甘油三酯较治疗前明显降低 (P <0 .0 5或P <0 .0 1) ,有甲减症状的部分患者症状缓解。     

Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy

Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 +/- 41 mg/dl (5.6 +/- 0.9 mM)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 +/- 19 mg/dl (4.4 +/- 0.5 mM) and 217 +/- 21 mg/dl (5.6 +/- 0.5 mM), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 +/- 29% vs. +503 +/- 19%, P = 0.0003) and group A (663 +/- 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 +/- 6.3% and 42.7 +/- 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 +/- 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.     

Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment.

The aim of this prospective, follow-up study was to examine the influence of overt hypothyroidism (OHP) and subclinical (SHP), before and during thyroxine (T4) treatment, on lipoprotein(a) [Lp(a)], other lipoproteins, and apolipoproteins. Twenty-four patients (17 females, 7 males) with OHP, aged 54 +/- 11.1 years (group A) and 23 patients (females) with SHP aged 50.1 +/- 13.2 years (group B) were evaluated and compared to 34 and 38 controls, respectively. All patients received T4 therapy in a stepwise fashion until euthyroidism was reached. Thyrotropin (TSH), free thyroxine (FT4), and total triiodothyronine (TT3) levels were measured before T4 therapy and repeatedly every 4 weeks after the initiation of treatment until the euthyroid state was reached. Levels of Lp(a), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured before and 4 months after the achievement of euthyroidism. Additionally, body mass index (BMI) was also evaluated. We found that in OHP patients, levels of TC, LDLc, and apoB were elevated before treatment and decreased significantly after the return to the euthyroid state. BMI and levels of triglycerides also decreased significantly; Lp(a) was higher in OHP patients in comparison with controls and decreased significantly by 14.56% (25.29% in men and 10.34% in women) during T4 treatment. In SHP patients, levels of all common lipoproteins, apolipoproteins, and Lp(a) did not differ significantly from controls before treatment and did not change after the euthyroid stage was reached. It is concluded that in overt hypothyroidism, Lp(a) levels and most of the lipoproteins were elevated before treatment and decreased significantly. In subclinical hypothyroidism, lipoproteins and Lp(a) levels were normal at baseline and did not change during treatment.     

左旋甲状腺素治疗对亚临床甲状腺功能减退症患者血脂的影响

目的 通过对47例亚临床甲状腺功能减退症(简称亚临床甲减)合并高脂血症患者使用左旋甲状腺素钠片治疗,观察治疗前后血脂变化.方法 治疗前记录各病例促甲状腺素(TSH)、血总胆固醇、甘油三脂、低密度脂蛋白胆固醇检查结果,给予左旋甲状腺素钠片,以TSH调整在正常范围为合适剂量,平均50～75 μg/d,治疗三个月后复查TSH及血脂结果并进行统计分析.结果 治疗后血脂明显下降,与治疗前存在显著差异(P<0.01).结论 用左旋甲状腺素钠片治疗亚临床甲减对改善血脂有临床意义.     

Lipoprotein (a) levels, apolipoprotein (a) phenotypes and thyroid autoimmunity

It has been reported that euthyroid normolipidemic males and postmenopausal females exhibit significantly higher serum lipoprotein (a) (Lp(a)) levels compared with age- and sex-matched normolipidemic controls. However, it is well known that there is an inverse correlation between Lp(a) concentration and apolipoprotein (a) (apo(a)) isoform size. Thus, it is imperative to exclude differences in apo(a) isoform frequencies between subjects with or without thyroid autoimmunity in order to verify if there is an association between thyroid autoimmunity and increased Lp(a) concentration. To exclude such an effect of different apo(a) isoform frequencies, we determined apo(a) phenotypes in 22 patients (9 males and 13 postmenopausal females) with thyroid autoimmunity and in 64 (29 males and 35 females) age- and sex-matched individuals without thyroid autoimmunity (control group). There were no significant differences in the values of lipid parameters between the two groups, including Lp(a). We did not detect any significant differences in the apo(a) phenotype frequencies between the two groups. Additionally, in neither of the subgroups formed according to the presence of low molecular vs high molecular weight apo(a) isoforms were there any significant differences in median serum Lp(a) levels between patients with and without thyroid autoimmunity. Thus, our results contradict the previously reported association between thyroid autoimmunity and Lp(a) concentrations.     

Lipoprotein alterations, hepatic lipase activity, and insulin sensitivity in subclinical hypothyroidism: response to L-T(4) treatment.

Subclinical hypothyroidism (sH) has been associated with atherosclerotic cardiovascular disease even in the absence of hypercholesterolemia. OBJECTIVE: Our study was designed to assess the hypothesis that other pro-atherogenic parameters, such as qualitative lipoprotein changes and insulin resistance, might be present in sH. DESIGN AND METHODS: Twenty-one sH women were compared to 11 female controls matched for body mass index, menopausal status, and age. Before and after 6 months of levothyroxine (L-T(4)) treatment, we determined total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apoB levels, hepatic lipase (HL) activity in postheparin plasma samples, the chemical composition and copper-induced oxidation in isolated LDL and homeostasis model assessment (HOMA), quantitative insulin sensitivity check index, and insulinogenic index. MAIN OUTCOME: Lipid profiles were similar between the two groups. No differences in LDL oxidability or the insulin sensitivity assessment parameters were found. HL activity was significantly lower in the sH patients: median (range), 13.1 (2.5-26.7) vs. 18.7 (7.9-28.1) micromol free fatty acids/mL, p < 0.04. The LDL-cholesterol/LDL-TG ratio was decreased in sH: 3.9 (1.8-5.5) vs. 4.7 (3.5-6.8), p < 0.02. HL negatively correlated with thyroid-stimulating hormone (TSH) levels (r = - 0.504, p < 0.01) and positively with LDL-cholesterol/LDL-TG (r = 0.46, p < 0.02). Posttreatment results for all these parameters did not differ significantly compared to baseline. CONCLUSIONS: Increased levels of TSH are associated to a decrease in HL activity, explaining our findings of an LDL particle rich in TG. This qualitative lipoprotein alteration suggests a pro-atherogenic pattern in sH. Treatment with L-T(4), however, did not correct the basal lipid derangement.     

Serum lipoprotein(a) levels and apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in elderly individuals

In a population-based case-control study, we investigated the association of acute ischaemic stroke with lipoprotein(a) (Lp(a)) levels and apolipoprotein (Apo) (a) isoform size in subjects aged older than 70 years. A total of 163 patients with a first-ever-in-a-lifetime acute ischaemic/nonembolic stroke and 166 controls were included. Compared to controls, stroke patients exhibited higher Lp(a) concentrations (median value, 12.2 mg/dl versus 6.4 mg/dl, p < 0.001) and a higher frequency of small Apo(a) isoforms (44.2% versus 29.5%, p < 0.01). Multivariate logistic regression analysis showed a significant association of acute ischaemic stroke with Lp(a) levels [adjusted odds ratio (OR), 1.37, 95% CI (1.12-1.67); p = 0.002], and small Apo(a) isoform size [OR, 1.74 (1.10-3.03); p = 0.04]. Compared to subjects with Lp(a) levels in the lowest quintile, those within the highest quintile had a 3.2-times adjusted risk to suffer an acute ischaemic/nonembolic stroke (1.60-6.62, 95% CI; p < 0.001). Furthermore, analysis of interaction between lipid variables revealed that in the presence of elevated Lp(a) levels the inverse relationship between HDL-cholesterol levels and ischaemic stroke was negated [OR, 1.01 (1.00-1.03); p = 0.015]. Our study suggests that determination of Lp(a) levels and Apo(a) isoform size may be important in identifying elderly individuals at risk of ischaemic stroke independently of other risk factors and concurrent metabolic derangements.     

Insulin sensitivity, plasma adiponectin and sICAM-1 concentrations in patients with subclinical hypothyroidism: response to levothyroxine therapy

Subclinical hypothyroidism is associated with an increased risk of atherosclerosis. The aim of this study was to investigate the concentration of plasma soluble intercellular adhesion molecule-1 and adiponectin in relation to insulin sensitivity in patients with subclinical hypothyroidism and to estimate if L-thyroxine treatment had an influence on these parameters. 13 women with subclinical hypothyroidism and 14 euthyroid controls were included in the study. A physical examination was conducted, hyperinsulinemic euglycemic clamp and plasma soluble intercellular adhesion molecule-1, adiponectin and lipids profiles were measured at baseline in both groups and in the group with subclinical hypothyroidism the above procedures were performed after L-thyroxine therapy (mean time of treatment 5.0 months) in stable euthyroid state. Insulin sensitivity and adiponectin were not different at baseline in the two studied groups. Plasma soluble intercellular adhesion molecule-1 concentration was significantly higher in the patients with subclinical hypothyroidism (P = 0.011). The comparison of lipids profiles revealed that only LDL-cholesterol concentration was higher (P = 0.011) in the group with subclinical hypothyroidism. After therapy, we observed an improvement of insulin sensitivity (P = 0.012) and a decrease of plasma glucose (P = 0.019) and soluble intercellular adhesion molecule-1 (P = 0.01), whereas adiponectin concentration remained unchanged. We concluded that L-thyroxine treatment in patients with subclinical hypothyroidism might exert a beneficial effect by reducing cardiovascular risk factors.     

亚临床甲减患者甲状腺激素治疗后血浆脂蛋白(a)水平的变化

40例亚临床甲状腺功能减退症患者以甲状腺激素 (左旋甲状腺素或甲状腺片 )治疗。经治疗后 ,这些患者的血浆脂蛋白 (a)水平由 ( 3 .0 2± 0 .80 )mmol/L降至 ( 2 .74± 0 .75 )mmol/L(P <0 .0 5 )。     

Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism

OBJECTIVE: The aims of the study were to evaluate the disturbances in the coagulation system in patients with overt hypothyroidism (OH), to assess the effects of levothyroxine (LT4) on the coagulation parameters, and to determine whether subclinical hypothyroidism (SH) affects concentrations of coagulation markers and several biochemical parameters, thereby supporting early substitution. DESIGN: The study included 15 patients with SH (TSH levels 5-10 mU/l), 15 patients with OH and 15 euthyroid controls. METHODS: Blood urea nitrogen, creatinine, creatine phosphokinase, aspartate aminotransferase, lactate dehydrogenase, total-cholesterol, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol and triglyceride levels, and bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), factor VIII activity, von Willebrand factor activity (vWF), platelet count and clotting time were evaluated just before and three months after the maintenance of euthyroidism with LT4 treatment. RESULTS: Factor VIII and vWF activities were lower in patients with SH than in controls (P < 0.01). Increased bleeding time, PT, APTT and clotting time and decreased factor VIII activity and vWF activity were observed in patients with OH when compared with controls. Bleeding time, PT, APTT and clotting time decreased and factor VIII activity, vWF and platelet count increased after LT4 in patients with OH. Increases in factor VIII activity and vWF (P < 0.01) were detected also in the SH group with treatment. CONCLUSIONS: OH is associated with significant abnormalities in clotting parameters which are reversed by LT4. In contrast, SH is associated with minor changes in factor VIII activity and vWF which are reversible by LT4. Serum lipids and other measured parameters are not improved by LT4 in patients with TSH < 10 mU/l and these data fail to demonstrate a need to treat such patients.