Cardiovascular assessment of hyperthyroid patients with multinodular goiter before and after radioiodine treatment preceded by stimulation with recombinant human TSH

Treatment of large multinodular goiter (MNG) with radioiodine preceded by recombinant human thyrotropin (0.1 mg rhTSH) has been shown to be a safe alternative for patients with comorbidities that preclude surgery. However, the increase in serum thyroid hormones that follows both treatments may be harmful for some patients, particularly those with underlying cardiovascular disease. In this study, we evaluated cardiac parameters (clinical, ECG, 24-h Holter, Doppler echocardiogram, treadmill stress test) in 27 of 42 patients (ages 42–80 years) with large MNGs who were treated with rhTSH before receiving 30 mCi radioiodine therapy. At baseline, 18 patients had subclinical and six patients had overt iodine-induced hyperthyroidism. All patients had a transient surge in serum levels of free T4 and total T3 into the hyperthyroid range after therapy. However, repeated cardiac evaluation did not show significant changes as compared with baseline evaluation. In conclusion, rhTSH stimulated RAI treatment of MNG did not affect structural and functional parameters of the heart, despite transient high-serum levels of thyroid hormones.     

A case of Plummer disease that appeared in older old age after 10-year course of subclinical hyperthyroidism

A 81-year-old woman with a thyroid tumor and subclinical hyperthyroidism since ten years ago was admitted to our hospital for palpitations and hyperthyroidism (FT(4) 1.75 ng/dl, FT(3) 5.37 pg/ml, TSH<0.03 microIU/ml). Although thyroid stimulating antibody (TSAb) was transiently and mildly positive, anti-TSH receptor antibody (TRAb), microsome test, and thyroid test were negative. Thyroid echogram showed an isoechoic nodule in the left lobe (33 x 42 x 22 mm) and a small nodule (10 x 15 x 9 mm) in right lobe. Thyroid scintiscan showed a hyperfunctional (hot) nodule in left thyroid lobe with suppressed uptake in the remainder of the gland. The uptake rate of thyroidal radioiodine ((123)I) in 24 hours was within the normal range (7.3%). Based on the above findings, a diagnosis of Plummer disease was made. Since she refused invasive surgical or radioiodine treatment, she was treated with 10 mg thiamazole daily. After treatment with propranolol and thiamazole, the thyrotoxic symptoms disappeared and thyroid function returned to normal level. She had osteoporosis but she had neither atrial fibrillation nor cardiac symptoms. This was a rare case of Plummer disease that appeared in extremely old age after a long course of subclinical hyperthyroidism.     

Cardiovascular symptoms and risks of subclinical dysthyroidism

PURPOSE: To clarify the importance of cardiovascular symptoms and risks in subclinical dysthyroidism in order to define the best way of treatment and follow-up. CURRENT KNOWLEDGE AND KEY POINTS: Subclinical dysthyroidism is defined by abnormal circulating TSH values in face and normal free thyroid hormones levels, in asymptomatic individuals. If the cardiovascular effects of overt hyperthyroidism are well documented, the relation between subclinical dysthyroidism and the heart is not well established. Subclinical hyperthyroidism may be caused by the same thyroid disorders that results in overt hyperthyroidism, but the most common cause is excessive dosage in levothyroxine. The most frequent cardias complication of subclinical hyperthyroidism is atrial fibrillation. Recently minimal alterations of myocardial function have also been described. In most patients, one tries to return to euthyroidism in order to prevent cardiovascular complications. Subclinical hypothyroidism is 3 to 10 times more frequent, especially in women after 60 years. Subtle modifications of cardiac function and lipid metabolism and an increased risk of atherosclerosis have been described in this condition. There is still debate about the decision to treat or not to treat these patients. FUTURE PROSPECTS AND PROJECTS: Until now, treatment of subclinical dysthyroidism is mainly based upon experiences and convictions to physicians. Prospective studies are necessary to assess the true benefits and risks of either early treatment or therapeutic abstention with regular clinical and biological follow up. In such studies, patients should be separated according to age and the nature (endogenous or exogenous) of dysthyroidism.     

Thyroid and the Heart

Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension, and cardiovascular disease all increase with advancing age, monitoring of thyroid-stimulating hormone, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions about thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases.     

Endogenous subclinical hyperthyroidism: Metabolic and cardiac parameters

BACKGROUND: Subclinical hyperthyroidism (SH) is defined by suppressed TSH and normal levels of thyroid hormones. Endogenous subclinical hyperthyroidism (ESH) is probably less common than exogenous SH. Adverse effects of SH due to exogenous administration of thyroxine have been well studied, while the impact of ESH on the cardiovascular system and metabolic parameters remains controversial. METHODS: In a cross-sectional study, we examined patients with endogenous clinical hyperthyroidism (ECH; n=20), ESH (TSH<0.1 muU/mL, n=25), and mild ESH (TSH=0.1-0.3 muU/mL, n=32), as well as healthy controls (n=50). Biochemical and metabolic parameters influenced by thyroid hormones were assessed and cardiac parameters were studied using echocardiography and 24-hour ECG-blood pressure monitoring. RESULTS: Biochemical and metabolic parameters did not differ significantly between ESH and healthy subjects. The ECH group had significantly higher sex hormone-binding globulin, osteocalcin, and carboxy-terminal telopeptide levels than healthy subjects. No significant differences were noted in echocardiographic parameters between ESH patients and healthy subjects. The ECH group had a significantly higher heart rate, cardiac output, and cardiac index than the control group, as well as end-diastolic and end-systolic diameters of the left ventricle, and end-diastolic and end-systolic volumes of the left ventricle. The 24-hour ECG-blood pressure monitoring parameters did not differ significantly either between SH and healthy subjects while, in the ECH group, mean heart rate, maximum heart rate, and mean tachycardia episodes were significantly increased. CONCLUSION: Only subjects with ECH showed differences in metabolic and cardiac parameters from controls, while no significant effects were noted in the endogenous subclinical forms.     

The early effects of radioiodine therapy for hyperthyroidism on biochemical indices of bone turnover

OBJECTIVE We investigated the early changes following radioiodine therapy for hyperthyroidism, in biochemical indices of bone synthesis and degradation, and their relationship to circulating thyroid hormone concentrations. DESIGN Prospective follow-up over the first 12 weeks after radioiodine therapy. PATIENTS Six women with clinical and biochemical evidence of hyperthyroidism. MEASUREMENTS Serum Concentrations of T4, free T3 and osteocalcin, and urinary excretion of the pyridinium cross-links, pyridinaline and deoxypyridinaline, measured before and weekly for 12 weeks after administration of radioiodine therapy. RESULTS Biochemical indices of bone metabolism were elevated prior to treatment. There was a brisk reduction in circulating thyroid hormones levels paralleled by a similar fall In pyridinlum cross-llnk excretion, which had returned to normal in five patients by the end of the study. There was a positive correlation between pyridinium cross-link excretion and thyroid hormone concentrations. There was no significant change in serum osteocalcin. CONCLUSIONS Treatment of hyperthyroidism results in prompt correction of the associated increased rate of bone collagen degradation suggesting that effective early correction of hyperthyroidism is desirable to limit its detrimental effect on skeletal mass.     

Socio demographic wise risk assessment of thyroid function abnormalities in far western region of Nepal: A hospital based descriptive study

Objective

To know the status of thyroid disorder in population of far western region of Nepal.

Methods

A total of 808 cases (133 men and 675 non pregnant women) were included and study was carried out using data retrieved from the register maintained in the Department of Biochemistry of the Nepalgunj Teaching Hospital between 1st January, 2011 and 28th February, 2012. The variables collected were age, sex, and thyroid function profile including free T3, free T4 and TSH.

Results

The percentage of thyroid disorders was 33.66% in far western region of Nepal. The people were highly affected by overt hyperthyroidism (14.9%) followed by subclinical hyperthyroidism (9.9%). The subclinical hypothyroidism was 7.9% while 1% overt hypothyroidism only in a far western region of Nepal. Females were highly affected by overt hyperthyroidism (17.8%), followed by subclinical hyperthyroidism (11.9%). A total of 5.9% females were affected by subclinical hypothyroidism while only 1.2% by overt hypothyroidism. Males were affected only by subclinical hypothyroidism (18.0%) in this present study. High number of total thyroid dysfunction was observed in 21 to 40 years of age groups, followed by 41 to 60 years of age groups. Less than 40 years people were having 1.03, 0.99, 2.51 and 1.15 times risk of developing overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism and subclinical hyperthyroidism respectively compared to greater than 40. Female were having 0.29 times risk of developing subclinical hyperthyroidism compared to male. But overt hyperthyroidism, subclinical hyperthyroidism and overt hypothyroidism female were having more risk of developing compared to male.

Conclusions

The thyroid disorder, especially overt hyperthyroidism (14.9%) and subclinical hyperthyroidism (9.9%) was high. Further studies are required to characterize the reasons for this high prevalence.     

Subclinical hyperthyroidism.

Subclinical hyperthyroidism is defined as a situation where the levels of the peripheral thyroid hormones are normal but serum thyrotropin (TSH) is low. It is not a rare finding; rates between 0.2% and 11.8% have been reported in different groups, according to age, sex, etc. The etiology is usually the same as that of overt hyperthyroidism. The health implications include general symptoms, effects on the cardiovascular system, and decreased bone density. The increased frequency of atrial fibrillation and the increased mortality reported are especially serious. It is not clear whether subclinical hyperthyroidism should be treated or not. Most authors conclude that treatment is required in selected cases or in special circumstances.     

Hyperthyroidism and cardiovascular morbidity and mortality.

Hyperthyroidism is a common disorder affecting multiple systems in the body. The cardiovascular effects are among the most striking. The availability of effective treatments for hyperthyroidism has led to the widespread perception that it is a reversible disorder without any long-term consequences. Recent evidence suggests, however, that there may be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine, as well as those with subclinical hyperthyroidism. Thyroid hormones are known to exert direct effects on the myocardium, as well as the systemic vasculature and predispose to dysrhythmias, especially supraventricular. Atrial fibrillation (AF) is a recognized complication of overt hyperthyroidism, and subclinical hyperthyroidism is also known to be a risk factor for development of AF. Supraventricular dysrhythmias, particularly atrial fibrillation, in older patients may account for some of the excess cardiovascular and cerebrovascular mortality described, especially because AF is known to predispose to embolic phenomena.     

An Analysis of the Natural Course of Subclinical Hyperthyroidism

BackgroundOur aim was to evaluate the incidence rate of overt hyperthyroidism in a cohort of patients with subclinical hyperthyroidism and to assess the potential risk factors for the development of overt thyroid hyperfunction.MethodsWe performed a retrospective analysis in 75 patients (68 women, mean age 62.2 ± 14.2 years) with subclinical hyperthyroidism and different grades of serum thyrotropin (TSH) suppression. Incidence rate of overt hyperthyroidism and survival time, ie, time without requiring therapy for overt hyperthyroidism, were studied.ResultsThirty-four patients (45.3%) developed overt hyperthyroidism and 15 (20.0%) reverted to normal TSH values. The incidence rate of overt hyperthyroidism was 9.69 cases per 100 patient-year in the whole population and 4.12, 7.41, and 29.63 cases per 100 patient-year in subjects with initial TSH values of 0.30 to 0.49, 0.10 to 0.29, and <0.10 mU/L, respectively. Kaplan-Meier analysis of survival time curves showed that the development of overt thyroid hyperfunction was significantly related to the presence of symptoms of hyperthyroidism (P < 0.05) and low (<0.10 mU/L) TSH concentrations (P < 0.001). A stepwise multivariate Cox regression analysis showed that both symptoms and low TSH values were significant factors for progression to overt thyrotoxicosis.ConclusionsTSH concentration is the most powerful predictor in the outcome of patients with subclinical hyperthyroidism. Our results suggest that patients with values under 0.10 mU/L have the highest probability to develop overt thyroid hyperfunction. In patients with TSH values higher than this value, the risk of progression is notably lower.     

Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment

Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.     

Clinical review 142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace?

Thyrotoxicosis is often perceived as a reversible disorder without long-term consequences, perhaps because of the availability of effective treatments, but recent evidence suggests that there may, in fact, be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine as well as in those with subclinical hyperthyroidism indicated by a low serum TSH concentration. Thyroid hormones exert direct effects on the myocardium as well as the systemic vasculature predisposing to dysrhythmias, especially supraventricular. Effects of thyroid hormones on the autonomic nervous system may also contribute to arrhythmogenesis. Atrial fibrillation is a recognized complication of hyperthyroidism that predisposes to embolic events. Development of atrial fibrillation, together with other supraventricular dysrhythmias (both clinically obvious and those detected only by Holter monitoring) in those with hyperthyroidism may account for increased vascular mortality. Improved detection of supraventricular dysrhythmias and therapeutic intervention (e.g. anticoagulants, antiarrhythmics) may improve the long-term vascular prognosis, but their role remains to be established in large therapeutic trials.     

Alterations of cognitive functions induced by exogenous application of thyroid hormones in healthy men: a double-blind cross-over study using event-related brain potentials.

The influence of experimentally induced subclinical hyperthyroidism on cognitive functions was tested using exogenous thyroxine or placebo. In a double-blind cross-over design, 24 healthy young men received either 300 microg of levothyroxine or placebo for two consecutive 3-week periods. Determination of thyrotropin (TSH), total triiodothyronine (T3), thyroxine (T4), and sex hormone binding globulin (SHBG) confirmed the induction of subclinical hyperthyroidism. Three weeks after treatment with placebo or T4, subjects were tested in two visual search tasks, one requiring the serial scanning of a stimulus array of eight items in order to detect a missing feature (serial task), while the other task allowed the parallel processing of eight items in order to detect an extra feature. Reaction times varied greatly between the tasks while no effect of T4 medication was revealed on overt search behavior. The late cognitive components of the event-related brain potentials (ERP) were registered during the tasks using a multichannel recording. The late positive component (P300) to target stimuli showed a significant reduction in amplitude in the parallel search task in hyperthyroidism, while for the serial search task a significant frontal negativity was revealed for target stimuli, both suggesting an increased effort to be exerted for the execution of visual search tasks. Thus, short periods of subclinical hyperthyroidism in the range commonly induced in the treatment of thyroid cancer patients induce distinct alterations in brain-electric activity.     

Studies on the mechanism of goitrogenic action of diphenylthiohydantoin.

Diphenylthiohydantoin (DPTH) is a potent goitrogenic compound and produces goiters in rats. Like methimazole, DPTH depresses plasma T4 and T3 concentrations and elevates plasma T4 and T3 concentrations and elevates plasma TSH concentration. Unlike methimazole, however, DPTH does not suppress thyroidal radioiodine uptake and thyroid hormone synthesis, although the monoiodotyrosine to diiodotyrosine ration is elevated by DPTH. DPTH does not inhibit thyroidal radioiodine release or augment the degradation of thyroid hormone. DPTH depresses an increase of plasma T4 and T3 in thyroidectomized rats maintained on T4 or T3 by augmenting fecal excretion of hormones. In addition, DPTH decreases conversion of T4 to T3 in vitro. It is suggested that DPTH is a unique goitrogen which acts at two different extrahyroidal sites, viz. fecal loss of thyroid hormone and conversion of T4 to T3.     

THE SECRETION OF THYROTROPHIN WITH IMPAIRED BIOLOGICAL ACTIVITY IN PATIENTS WITH HYPOTHALAMIC–PITUITARY DISEASE

We describe here two patients with hypothyroidism due to pituitary-hypothalamic disease in whom basal thyrotrophin (TSH) levels measured by radioimmunoassay (RIA) were elevated yet when measured by a cytochemical bioassay (CBA) were found to be normal. This finding and the absence of the normal rise of thyroid hormones in response to thyrotrophin-releasing hormone (TRH) mediated release of TSH confirms for the first time the secretion of TSH with impaired biological activity. Primary thyroid disease as a cause for the elevated immunoreactive TSH was excluded by the absence of circulating thyroid antibodies and by a normal thyroidal radioiodine uptake response to exogenous TSH.     

Prevention and multimodal therapy of hyperthyroidism

Subclinical and overt hyperthyroidism have been associated with various negative clinical outcomes as for example an increased risk of atrial fibrillation or increased cardiovascular mortality, especially in old age. In order to avoid hyperthyroidism it is strongly recommended not to start any iodine containing drug therapy or to avoid application of contrast agents unless the patient presents with an unremarkable clinical course. TSH suppressive therapy for the treatment of endemic goiter or differentiated low risk thyroid carcinoma is unnecessary, since it favours the development of subclinical hyperthyroidism. Overt hyperthyroidism is treated with antithyroid drugs and/or radioiodine therapy or surgery according to the underlying disease (toxic nodular goiter, Graves' disease).     

Incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in thyrotropin receptor antibodies after radioiodine therapy for autonomous thyroid disease.

BACKGROUND: The aim of the study was to analyze retrospectively the incidence of postradioiodine immunogenic hyperthyroidism/Graves' disease in relation to a temporary increase in TSH-receptor antibodies without overt hyperthyroidism after radioiodine therapy for autonomous thyroid disease. PATIENTS AND METHODS: Between May 2000 and May 2003 all patients (n = 1,357) who had undergone radioiodine therapy for autonomous thyroid disease were retrospectively analyzed for development of postradioiodine immunogenic hyperthyroidism. On pretreatment evaluation 565 of 1,357 patients (41.6%) had unifocal autonomous thyroid disease (UFA), 693 of 1,357 patients (51.1%) had multifocal autonomous thyroid disease (MFA), and 99 of 1,357 patients (7.3%) had diffuse thyroid disease (DISS). Free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyrotropin (TSH), and thyroid antibodies were measured. Ultrasound examinations and thyroid scintigraphy were performed before and after radioiodine therapy. A sensitive assay with the human TSH receptor as antigen was chosen for measurement of the TSH receptor antibody and the study was limited to analysis of data obtained since introduction of this assay. RESULTS: Fifteen of 1,357 patients (1.1%) (UFA, 8/565 = 1.4%; MFA, 6/693 = 0.9%; DISS 1/99 = 1.0%) developed postradioiodine hyperthyroidism between 1 and 13 months after radioiodine therapy with clinically overt hyperthyroidism and an elevation of TSH receptor antibodies. Patients with elevated thyroid peroxidase (TPO) antibodies before radioiodine therapy had an almost 10-fold (6/57 patients =10.5%) higher risk of developing postradioiodine immunogenic hyperthyroidism. Thirteen of 999 patients (1.3%) with antibody measurements after radioiodine therapy (UFA, 2/421 = 0.5%; MFA, 9/494 = 1.8%, DISS, 2/84 = 2.4%) had increased levels of TSH receptor antibodies and, to some extent, TPO antibodies without development of clinically overt hyperthyroidism. CONCLUSIONS: There is an estimated 1.1% risk of developing postradioiodine immunogenic hyperthyroidism/Graves' disease in patients undergoing radioiodine therapy for autonomous thyroid disease and this increases approximately 10-fold when TPO antibody levels are elevated before radioiodine therapy. Furthermore, there is an estimated 1.3% risk of a temporary increase of TSH receptor antibodies after radioiodine therapy for autonomous thyroid disease without development of clinically overt hyperthyroidism.     

Diagnostic algorithm for atrial fibrillation caused by occult hyperthyroidism

Occult hyperthyroidism, a subclinical thyrotoxic state, is not readily identifiable clinically or through routine thyroid function tests. "Idiopathic" atrial fibrillation may be a manifestation of occult hyperthyroidism in the elderly. A normal response on a TRH stimulation test excludes this diagnosis. A blunted TSH response, coupled with elevation of free thyroid hormones and a high radioactive iodine uptake, will settle the diagnosis. Patients with occult hyperthyroidism frequently have toxic adenomas or nonpalpable nodular goiters, and treatment is best achieved with radioactive iodine ablation.     

Prävention und multimodale Therapie der Hyperthyreose

Subclinical and overt hyperthyroidism have been associated with various negative clinical outcomes as for example an increased risk of atrial fibrillation or increased cardiovascular mortality, especially in old age. In order to avoid hyperthyroidism it is strongly recommended not to start any iodine containing drug therapy or to avoid application of contrast agents unless the patient presents with an unremarkable clinical course. TSH suppressive therapy for the treatment of endemic goiter or differentiated low risk thyroid carcinoma is unnecessary, since it favours the development of subclinical hyperthyroidism. Overt hyperthyroidism is treated with antithyroid drugs and/or radioiodine therapy or surgery according to the underlying disease (toxic nodular goiter, Graves’ disease).     

Evaluation of thyroid functions with respect to iodine status and TRH test in chronic autoimmune thyroiditis

Objective: Chronic autoimmune thyroiditis (CAT) is the most common form of thyroiditis in childhood and a frequent cause of acquired hypothyroidism. The objective of this study was to evaluate the thyroid status of childrenand adolescents with CAT with respect to iodine status and diagnostic values of thyrotropin-releasing hormone (TRH) test. Methods: Seventy-one children (mean age: 11.6 years) were studied in a retrospective analysis. Free thyroxine (T4), thyrotropin (TSH), TSH response to TRH test, thyroid autoantibodies, thyroid sonography, and urinary iodine excretion (UIE) were evaluated. Results: At diagnosis, 8.5% of patients had overt hypothyroidisim and 36.6% subclinical hypothyroidism; 5.6% had overt hyperthyroidisim and 8.5% had subclinical hyperthyroidism. Of them, 40.8% were euthyroid. Median UIE was 51 mg/L in overt hypothyroidism and 84 mg/L in subclinical hypothyroidism. The values were 316 mg/L and 221 mg/L in overt and subclinical hyperthyroidism, respectively. Basal TSH showed a strong correlation with peak TSH level on TRH test. Thirty-four percent of patients with normal basal TSH level showed an exaggerated TSH response. Conclusion: Iodine deficiency was seen more in cases with hypothyroidism, while excess of iodine was observed to be more frequent in hyperthyroid patients. Iodine status was a strong predictorof the thyroid status in CAT. TRH test may be helpful in further delineating patients with subclinical hypothyroidism. Conflict of interest:None declared.