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Subclinical thyroid disease represents an early stage of thyroid dysfunction, which is usually asymptomatic and biochemically defined; its diagnosis can be performed thanks to the high sensitivity of the hypothalamic-pituitary-thyroid axis. The approach to this disorder requires correct diagnosis, clinical assessment and treatment. Cardiovascular diseases (e.g. atrial fibrillation, heart failure, and coronary heart disease), bone loss and fractures, and dementia represent the main adverse events of severe subclinical hyperthyroidism with undetectable TSH levels. Treatment of patients with subclinical hypothyroidism with a serum TSH level above 10 mIU/L is justified in order to reduce the risks of coronary heart disease and heart failure., (Copyright © 2020. Published by Elsevier Masson SAS.)

Thyroid hormone suppression therapy is designed to lower serum thyrotropin (TSH) levels using doses of thyroid hormone in excess of what would normally be required to maintain a euthyroid state. The basis of this therapy is the knowledge that TSH is a growth factor for thyroid cancer, so that lower serum TSH levels might be associated with decreased disease activity. However, clinical studies have not documented improved outcomes with TSH suppression, except in patients with the most advanced disease. Furthermore, there are a number of negative outcomes related to aggressive thyroid hormone therapy, including osteoporosis, fracture, and cardiovascular disease. Therefore, a graded approach to TSH suppression is recommended by the American Thyroid Association, based on initial risk and ongoing risk assessment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Over the past five years several meta-analyses have evaluated the cardiovascular mortality in patients with hyperthyroidism. They assessed various studies in which different inclusion criteria were used for the analysis of the cardiovascular mortality. More selective criteria have been used in recent meta-analyses. Only prospective cohort studies were included and only cohorts using second and third generation TSH assays were chosen. In addition, only the studies where the TSH evaluation was repeated during the follow-up were selected. The results of these recent meta-analyses provide evidence that overt and subclinical hyperthyroidism, particularly in patients with undetectable serum TSH, may increase the cardiovascular mortality. However, still today, the results remain inconclusive and not sufficient enough to recommend treatment for patients with low-detectable serum TSH. The high cardiovascular risk and mortality in presence of thyroid hormone excess suggest that this dysfunction is an important health problem and requires guidelines for the treatment of patients at high cardiovascular risk. Rigorous studies are necessary to evaluate the effects of the various causes of hyperthyroidism on the clinical outcomes. Randomized controlled clinical trials are needed to assess the benefits of treatment to improve the cardiovascular mortality and morbidity of mild and overt hyperthyroidism.

Subclinical thyroid diseases--subclinical hyperthyroidism and subclinical hypothyroidism--are common clinical entities that encompass mild degrees of thyroid dysfunction. The clinical significance of mild thyroid overactivity and underactivity is uncertain, which has led to controversy over the appropriateness of diagnostic testing and possible treatment. In this Seminar, we discuss the definition, epidemiology, differential diagnoses, risks of progression to overt thyroid disease, potential effects on various health outcomes, and management of subclinical hyperthyroidism and subclinical hypothyroidism. Treatment recommendations are based on the degree to which thyroid-stimulating hormone concentrations have deviated from normal and underlying comorbidities. Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Various clinical disorders can cause hyperthyroidism, the effects of which vary according to the patient's age, severity of clinical presentation and association with other comorbidities. Hyperthyroidism is associated with increased morbidity and mortality from cardiovascular disease, although whether the risk of specific cardiovascular complications is related to the etiology of hyperthyroidism is unknown. This article will focus on patients with Graves disease, toxic adenoma and toxic multinodular goiter, and will compare the cardiovascular risks associated with these diseases. Patients with toxic multinodular goiter have a higher cardiovascular risk than do patients with Graves disease, although cardiovascular complications in both groups are differentially influenced by the patient's age and the cause of hyperthyroidism. Atrial fibrillation, atrial enlargement and congestive heart failure are important cardiac complications of hyperthyroidism and are prevalent in patients aged > or = 60 years with toxic multinodular goiter, particularly in those with underlying cardiac disease. An increased risk of stroke is common in patients > 65 years of age with atrial fibrillation. Graves disease is linked with autoimmune complications, such as cardiac valve involvement, pulmonary arterial hypertension and specific cardiomyopathy. Consequently, the etiology of hyperthyroidism must be established to enable correct treatment of the disease and the cardiovascular complications.

The association of endogenous subclinical hyperthyroidism (SHyper) with cardiovascular mortality is controversial. This may reflect the different causes of endogenous SHyper in the population studied due to differences in iodine intake, and different selection criteria, e.g. sex, age, and race, the cutoff for serum TSH level, the duration of follow-up, and the presence of co-morbidities. A small sample size of SHyper patients could have caused a low statistical power in some of these studies. In other studies, the results were not adjusted for relevant confounders. Importantly, various meta-analyses have also given conflicting results. This issue of the European Journal of Endocrinology contains two articles that address the association between endogenous SHyper and cardiovascular and total mortality: one study was conducted in a north-eastern German population and the other in a Japanese-Brazilian population. After adjusting for relevant confounders, there was no association between decreased serum TSH levels and all-cause and cardiovascular mortality in the Pomerania study; on the contrary, all-cause mortality and cardiovascular mortality were significantly higher for individuals with SHyper in the Japanese-Brazilian population. Interestingly, both studies had similar characteristics in terms of selection criteria and duration of follow-up. It remains controversial whether or not to treat middle-aged patients with low serum TSH levels. Large prospective randomized controlled double-blind studies of young and middle-aged patients with SHyper and without underlying cardiac disease are required to assess the potential benefits of treating endogenous SHyper in these age groups.

Subclinical hyperthyroidism appears to be a common disorder. It may be caused by exogenous or endogenous factors: excessive TSH suppressive therapy with L-thyroxine (L-T4) for benign thyroid nodular disease, differentiated thyroid cancer, or hormone over-replacement in patients with hypothyroidism are the most frequent causes. Consistent evidence indicates that 'subclinical' hyperthyroidism reduces the quality of life, affecting both the psycho and somatic components of well-being, and produces relevant signs and symptoms of excessive thyroid hormone action, often mimicking adrenergic overactivity. Subclinical hyperthyroidism exerts many significant effects on the cardiovascular system; it is usually associated with a higher heart rate and a higher risk of supraventricular arrhythmias, and with an increased left ventricular mass, often accompanied by an impaired diastolic function and sometimes by a reduced systolic performance on effort and decreased exercise tolerance. It is well known that these abnormalities usually precede the onset of a more severe cardiovascular disease, thus potentially contributing to the increased cardiovascular morbidity and mortality observed in these patients. In addition, it is becoming increasingly apparent that subclinical hyperthyroidism may accelerate the development of osteoporosis and hence increased bone vulnerability to trauma, particularly in postmenopausal women with a pre-existing predisposition. Subclinical hyperthyroidism and its related clinical manifestations are reversible and may be prevented by timely treatment.

This study was aimed at evaluating serum osteoprotegerin (OPG) concentrations in a cohort of patients with hyperthyroidism before and after methimazole (MMI) treatment. One hundred fourteen hyperthyroid patients [93 with Graves disease (GD) and 21 with toxic nodular goitre (TNG)] and 68 matched for sex and age healthy subjects were evaluated for serum free-thyroxine (FT4), free-triiodiothyronine (FT3), thyrotropin (TSH), TSH receptor antibodies (TRAb), bone alkaline phosphatase (BALP), C-telopeptides of type-1 collagen (CrossLaps), OPG levels, and bone mineral density (BMD). In hyperthyroid patients, the biochemical evaluations were performed before and after 6 and 12 months of MMI treatment, whereas BMD was measured at baseline and after 12 months of treatment. Hyperthyroidism was more severe in GD than TNG patients. Serum OPG levels were found to be significantly higher in hyperthyroid patients than in the healthy subjects (4.3 pmol/l, range: 1.6-12.0, vs. 2.2 pmol/l, range: 1.4-6.0; P < 0.001), the values being higher in GD patients than TNG. A significant correlation between serum OPG levels and age was found in the healthy subjects (r: 0.48; P < 0.001) but not in hyperthyroid patients (r: -0.03; P = 0.8). In the healthy subjects, serum OPG levels were also positively correlated with both serum FT4 (r: 0.23; P = 0.03) and FT3 (r: 0.24; P = 0.04) levels. In hyperthyroid patients, however, serum OPG was still correlated with FT3 levels (r: 0.38; P < 0.001), whereas the correlation with serum FT4 was lost (r: 0.19; P = 0.06). In hyperthyroid patients, but not in the healthy subjects, serum OPG levels were correlated positively with CrossLaps (r: 0.20; P = 0.03) and negatively with BALP (r: -0.24; P = 0.01) and BMD (r: -0.33; P = 0.01). After 6 months of MMI treatment, serum OPG concentrations decreased significantly in TNG patients (from 3.5 pmol/l, range: 1.6-8.0, to 2.3 pmol/l, range: 1.0-4.3; P < 0.001), whereas a not significant change in OPG levels occurred in GD patients (from 4.8 pmol/l, range: 1.8-12.0, to 4.2 pmol/l, range: 1.0-14.0; P = 0.7). At Month 12 of treatment, serum OPG concentrations were significantly lower than those measured at baseline in both TNG (2.5 pmol/l, range: 1.0-3.1, vs. 3.5 pmol/l, range: 1.6-8.0; P < 0.001) and GD (2.1 pmol/l, range: 1.0-8.6, vs. 4.8 pmol/l, range: 1.8-12.0; P < 0.001). At this time, no significant differences in serum OPG, CrossLaps, and BALP values were found between patients and control subjects. At the end of follow-up, BMD was higher than those measured at baseline but still significantly lower than those measured in the control subjects. This study shows that hyperthyroid patients have serum OPG concentrations significantly higher in comparison with euthyroid subjects, in relation to thyroid hormone excess and high bone turnover. Medical treatment of hyperthyroidism normalizes serum OPG levels in temporal relationship with the normalization of bone metabolism markers, even in presence of persistent abnormal bone structure as determined by ultrasonography.

Objectives: To ascertain whether myocardial contractility and total arterial stiffness are significantly altered in human thyrotoxicosis, and to what extent they are affected by acute beta(1)-adrenergic blockade., Methods: Doppler-echocardiography was used to assess left ventricular (LV) structure and function, hemodynamics and total arterial stiffness in untreated overt hyperthyroid patients before and 2 h after 5 mg bisoprolol given orally compared with age- and sex-matched healthy euthyroid controls., Results: Compared with controls, untreated patients (n=20) had a higher heart rate (HR) and LV stroke index (SI), which were associated with higher pulse pressure (PP), larger LV end-diastolic volume index (EDVI, an index of preload,+11%, P<0.05), marginally increased stress-corrected LV midwall fractional shortening (MWS, an index of myocardial contractility,+5%; P=0.066), and shorter isovolumic relaxation time (IVRT). These changes resulted in a higher cardiac index (CI) and a lower systemic vascular resistance (SVR), which were associated with fairly normal mean blood pressure (BP) but higher PP/stroke volume (an index of total arterial stiffness,+29%; P<0.01). After bisoprolol, compared with controls, the randomly treated patients (n=10) had comparable HR but additionally increased SI; PP remained enhanced, EDVI was further enlarged (+26%, P<0.001), stress-corrected MWS was substantially unchanged, and IVRT remained shorter. Overall, these effects attenuated the high-output state, which was associated with normalization of PP/stroke volume without changes of mean BP., Conclusions: In human overt hyperthyroidism, myocardial contractility does not play a major role in increasing LV performance, which is instead predominantly sustained by increased preload with enhanced LV diastolic function. In addition, human thyrotoxicosis is associated with increased total arterial stiffness despite fairly normal mean BP. In this scenario, acute beta(1)-adrenergic blockade blunts the cardiovascular hyperkinesia predominantly by slowing HR - a process that is associated with normalization of total arterial stiffness.

Background: Although thyroid hormone (TH) exerts relevant effects on the cardiovascular system, it is unknown whether TH also regulates vascular reactivity in humans. Methods and Results- We studied 8 patients with hyperthyroidism, basally (H) and 6 months after euthyroidism was restored by methimazole (EU). Thirteen healthy subjects served as control subjects (C). We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial graded infusion of acetylcholine, sodium nitroprusside (SNP), norepinephrine, and L-NMMA (inhibitor of NO synthesis). Basal FBF (in mL. dL(-1). min(-1)) was markedly higher in H than in C (5.8+/-1.2 and 1.9+/-0.1, respectively; P<0.001) and was close to normal in EU (2.6+/-0.3, P<0.01 versus H). During acetylcholine infusion, FBF increased much more in H (+33+/-5) than in C (+14+/-3, P<0.01 versus H) and in EU (+20+/-5, P=0.01 versus H and P=NS versus C). In contrast, the response to SNP infusion was comparable in the patients and control subjects. During norepinephrine infusion, the fall in FBF was much more pronounced in H (-6+/-1) than in C (-0.7+/-0.3, P<0.005 versus H) and in EU (-1.5+/-0.3, P<0.01 versus H). Finally, inhibition of NO synthesis by L-NMMA decreased FBF by 2.8+/-0.6, 0.61+/-0.7, and 1.4+/-0.3 in H, C, and EU, respectively (H versus C and EU, P<0.05)., Conclusions: In hyperthyroidism, (1) the marked basal vasodilation is largely accounted for by excessive endothelial NO production, (2) vascular reactivity is exaggerated because of enhanced sensitivity of the endothelial component, (3) the vasoconstrictory response to norepinephrine is potentiated, and (4) this abnormal vascular profile is corrected when euthyroidism is restored by medical therapy. The data demonstrate that vascular endothelium is a specific target of TH.

To determine the clinical impact of endogenous subclinical hyperthyroidism, specific symptoms and signs of thyroid hormone excess and quality of life were assessed in 23 patients (3 males and 20 females; mean age, 43 +/- 9 yr) and 23 age-, sex-, and lifestyle-matched normal subjects by using the Symptoms Rating Scale and the Short Form 36 Health Survey questionnaires. Because the heart is one of the main target organs of the thyroid hormone, cardiac morphology and function were also investigated by means of standard 12-lead electrocardiogram (ECG), 24-h Holter ECG, and complete Doppler echocardiography. Stable endogenous subclinical hyperthyroidism had been diagnosed in all patients at least 6 months before the study (TSH, 0.15 +/- 0.1 mU/L; free T(3), 6.9 +/- 1.1, pmol/L; free T(4), 17.2 +/- 2.3, pmol/L). Fifteen patients were affected by multinodular goiter, and eight patients by autonomously functioning thyroid nodule. The mean Symptoms Rating Scale score (9. 8 +/- 5.5 vs. 4.3 +/- 2.2, P: < 0.001) and both the mental (36.1 +/- 9.5 vs. 50.0 +/- 8.5, P: < 0.001) and physical (42.6 +/- 8.0 vs. 55. 6 +/- 4.1, P: < 0.001) component scores of Short Form 36 Health Survey documented a significant prevalence of specific symptoms and signs of thyroid hormone excess and notable impairment of quality of life in patients. Holter ECG showed a higher prevalence of atrial premature beats in endogenous subclinical hyperthyroid patients than in the controls, but the difference was not statistically significant, although the average heart rate was significantly increased in the patients (P: < 0.001). An increase of left ventricular mass (162 +/- 24 vs. 132 +/- 22 g, P: < 0.001) due to the increase of septal (P: = 0.025) and posterior wall (P: = 0.004) thickness was observed in patients. Systolic function was enhanced in patients as shown by the significant increase of both fractional shortening (P: = 0.005) and mean velocity of heart rate-adjusted circumferential fiber shortening (P: = 0.036). The Doppler parameters of diastolic function were significantly impaired in the patients as documented by the reduced early to late ratio of the transmitral flow velocities (P: < 0.001) and the prolonged isovolumic relaxation time (P: = 0.006). These data indicate that endogenous subclinical hyperthyroidism has a relevant clinical impact and that it affects cardiac morphology and function. Moreover, they suggest that treatment of persistent endogenous subclinical hyperthyroidism should be considered also in young and middle-aged patients to attenuate specific symptoms and signs of thyroid hormone excess, ameliorate the quality of life, and avoid the consequences to the heart of long exposure to a mild excess of thyroid hormone.

Background: Thyroid hormones greatly affect the cardiovascular system. Although the effects of overt hyperthyroidism on the cardiovascular system have been diffusely studied, only in the last years the effects of subclinical hyperthyroidism on the heart have been investigated. Subclinical hyperthyroidism is a symptomatic or asymptomatic condition with an absent response of thyrotropin (TSH) to thyrotropin-releasing hormone in the presence of normal serum levels of thyroid hormones for the general population, though supraoptimal for the individual. The more frequent causes of endogenous subclinical hyperthyroidism are multinodular goiter, toxic, adenoma and Graves's disease, whereas the exogenous causes are induced by levothyroxine (LT4) therapy used to suppress TSH in patients with nontoxic goiter and differentiated thyroid cancer. This paper reports our experience derived from the study of 60 patients with subclinical hyperthyroidism due to TSH-suppressive therapy with LT4 compared to normal subjects., Methods: Patients (9 males and 51 females, mean age 39 +/- 10 years) were studied by complete Doppler echocardiography, standard and 24 hour ECG Holter monitoring, exercise test with cycloergometer, and radionuclide ventriculography at rest and during fixed workload (75 W)., Results: Holter monitoring showed a significant increase in mean 24 hour heart rate (80 +/- 10 vs 70 +/- 9 b/min, p < 0.001) and supraventricular arrhythmias (42 vs 12 patients, p < 0.003). Echocardiography showed an increase in left ventricular mass index (94 +/- 13 vs 80 +/- 18 g/m2, p < 0.001) due to increased septal and posterior wall thickness. At rest, echocardiographic indices of systolic function (fractional shortening and mean corrected velocity of circumferential fiber shortening) were higher in patients than in controls (fractional shortening 40 +/- 6 vs 34 +/- 4%, p < 0.001; mean corrected velocity of circumferential fiber shortening 1.23 +/- 0.17 vs 1.05 +/- 0.14 circ/s, p < 0.001), while the Doppler indices of diastolic function were significantly impaired as documented by the reduced E/A ratio (1.18 +/- 0.3 vs 1.8 +/- 0.5, p < 0.001) and the prolonged isovolumic relaxation time (94 +/- 13 vs 78 +/- 12 ms, p < 0.001). Exercise tolerance was also significantly impaired in patients with subclinical hyperthyroidism: maximal exercise time (6.4 +/- 0.7 vs 9.4 +/- 1.4 min, p < 0.001) and peak workload (81 +/- 11 vs 121 +/- 17 W, p < 0.001) were significantly reduced and radionuclide ventriculography showed a decrease in ejection fraction during exercise (from 62 +/- 7 to 53 +/- 8%, p < 0.002)., Conclusions: Persistent subclinical hyperthyroidism by TSH-suppressive doses of LT4 significantly affects heart morphology and function. Thus, we suggest that a complete suppression of TSH must be recommended only in patients with differentiated thyroid cancer, while in patients with begin thyroid disease it could be sufficient to maintain subnormal TSH levels.