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Background: Evidence is needed on the risks and benefits of combination therapy with levothyroxine (LT4)+liothyronine (LT3) for the treatment of hypothyroidism. Objective and Methods: We performed a randomized, double-blind placebo-controlled study to assess the effects of LT4+LT3 therapy versus LT4+placebo in a homogeneous group of athyreotic patients, without cardiovascular risk factors during long-term replacement monotherapy with LT4. The primary objective of the study was to assess the effects of combination LT4+LT3 therapy on heart rate, cardiac rhythm, and sensitive cardiovascular parameters of cardiac morphology and function by means of electrocardiography and Doppler echocardiography. The secondary objective of the study was to evaluate patient compliance, tolerability, and potential adverse events. Results: Thirty-eight patients with postsurgical hypothyroidism satisfying the inclusion criteria were selected from a group of 300 patients with low-risk thyroid cancer followed for a routine follow-up; they were randomized to receive LT4+LT3 or LT4+placebo. Twenty-four patients were evaluated after 1 year of treatment. All clinical and laboratory parameters were compared with the results obtained from 50 healthy euthyroid volunteers without comorbidities, matched for gender, age, physical activity, and lifestyle. Participants and clinicians remained blinded to the treatment allocation. After 1 year of combination therapy, a significant improvement in the diastolic function, evidenced by a significant reduction in the E/e' ratio ( p  = 0.046) and its positive trend over time, was observed in the LT4+LT3 group versus the LT4+placebo group. In addition, the univariate analyses showed a significant relationship between free triiodothyronine (fT3) levels (in pg/mL) with Δ of variation of the E/e' ratio in the LT4+LT3 group (standardized β coefficient = 0.603 [confidence interval: 0.001-1.248], p  = 0.050) after combination therapy. No adverse events including tachycardia, arrhythmias, atrial fibrillation, or other important events occurred between the first administration and the end of the study. Conclusions: In this preliminary report, combination treatment with LT4+LT3 induced favorable changes in cardiovascular parameters of diastolic function without any adverse cardiovascular events. Trial Registration: EUDRACT number: 2017-001261-25.

Context: General rates of over- and underreplacement in levothyroxine (LT4) users with primary hypothyroidism are variably high. No information on LT4 adequacy exists in obesity., Objective: We explored rates and factors relating to LT4 adequacy in obese patients with primary hypothyroidism., Setting: Tertiary care center., Design: Among 4954 consecutive obese patients admitted between 2011 and 2014, 691 hypothyroid patients receiving LT4 therapy and 691 body mass index (BMI)-, age-, and sex-matched euthyroid controls underwent analysis of thyroid function, glucolipid profile, body composition, and indirect calorimetry. LT4 users were classified into low TSH (<0.27 mU/L), euthyroid (0.27 to 4.2 mU/L), and high TSH (>4.2 mU/L)., Results: LT4 users constituted 13.9% of the incident population. TSH was low in 7.5%, high in 17.2%, and normal in 75.2% of LT4 users. Overtreatment decreased with aging and more LT4 users ≥65 years of age had normal TSH than those <65 years of age (P < 0.05). Compared with the euthyroid obese group, LT4 users showed higher adiposity, similar insulin resistance, but a healthier lipid profile. In multivariable analyses, LT4 dose was predicted by fat-free mass, hypothyroidism cause, and sex (P < 0.0001 to < 0.05). Risk of LT4 overreplacement increased with younger age (OR 0.96; 95% CI 0.94 to 0.99), higher LT4 dose (OR 2.98; 95% CI 1.44 to 6.14), and lower BMI (OR 0.93; 95% CI 0.88 to 0.99). Male sex increased the likelihood of LT4 underreplacement (OR 2.37; 95% CI 1.10 to 5.11)., Conclusions: Obesity is associated with milder rates of inadequate LT4 treatment compared with nonobese populations. LT4 adequacy increases with aging. Age, body composition, and sex are main determinants of LT4 requirements in obesity., (Copyright © 2019 Endocrine Society.)

Importance: Subclinical hypothyroidism, defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT4) affects up to 10% of the adult population., Observations: Subclinical hypothyroidism is most often caused by autoimmune (Hashimoto) thyroiditis. However, serum thyrotropin levels rise as people without thyroid disease age; serum thyrotropin concentrations may surpass the upper limit of the traditional reference range of 4 to 5 mU/L among elderly patients. This phenomenon has likely led to an overestimation of the true prevalence of subclinical hypothyroidism in persons older than 70 years. In patients who have circulating thyroid peroxidase antibodies, there is a greater risk of progression from subclinical to overt hypothyroidism. Subclinical hypothyroidism may be associated with an increased risk of heart failure, coronary artery disease events, and mortality from coronary heart disease. In addition, middle-aged patients with subclinical hypothyroidism may have cognitive impairment, nonspecific symptoms such as fatigue, and altered mood. In the absence of large randomized trials showing benefit from levothyroxine therapy, the rationale for treatment is based on the potential for decreasing the risk of adverse cardiovascular events and the possibility of preventing progression to overt hypothyroidism. However, levothyroxine therapy may be associated with iatrogenic thyrotoxicosis, especially in elderly patients, and there is no evidence that it is beneficial in persons aged 65 years or older., Conclusions and Relevance: Subclinical hypothyroidism is common and most individuals can be observed without treatment. Treatment might be indicated for patients with subclinical hypothyroidism and serum thyrotropin levels of 10 mU/L or higher or for young and middle-aged individuals with subclinical hypothyroidism and symptoms consistent with mild hypothyroidism.

The cardiovascular system is one of the main targets of thyroid hormone action, and triiodothyronine deficiency has crucial consequences on cardiac structure and function. Patients with overt or subclinical hypothyroidism should be treated with levothyroxine to improve their cardiovascular function and the potential risk of heart failure. Even patients with thyroid hormone deficiency and heart failure should receive replacement doses of levothyroxine to improve their prognosis and worsening of the cardiovascular function. An innovative therapeutic multifactorial approach could improve the progression of heart failure. There is a potential beneficial effect of thyroid hormones and their analogs in patients with heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.)

The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST-IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of l-T4 replacement therapy in the frail elderly., (© 2017 European Society of Endocrinology.)

Levothyroxine (L-T4) is recommended as lifelong replacement therapy for hypothyroidism. Recent clinical and experimental data support the addition of levotriiodothyronine (L-T3) treatment in some selected hypothyroid patients when their symptoms persist and their quality of life remains impaired despite adequate L-T4 monotherapy. An increase in L-T3 prescriptions has been recently observed in Italy due to availability of different L-T3 formulations, making it possible to clinicians to prescribe L-T3 alone or in combination with L-T4. The aim of the present position statement was to define the correct clinical indications, schedule, duration of treatment and contraindications of combined treatment with L-T4 and L-T3 in hypothyroid patients in an attempt to guide clinicians and to avoid potential adverse effects of overtreatment.

Context: Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic., Evidence Acquisition: We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action., Evidence Synthesis: The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients., Conclusions: Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

Subclinical hypothyroidism (SH) is a frequent condition affecting millions of people around the world. Defined by increased thyrotropin-stimulating hormone (TSH) and accompanied by normal thyroid hormone levels, SH reflects a mild tissue hypothyroidism that has been associated with metabolic derangements and-although this issue is still contentious-possibly with increased cardiovascular risk. Depending on the degree of TSH elevation, SH has accordingly been associated with hyperlipidemia, arterial hypertension, and cardiovascular disease (CVD), as well as, increasingly, newly emerging CVD risk factors such as serum C-reactive protein and retinol binding protein 4 levels. There have also been reports of abnormalities in glucose metabolism and of hemostatic parameters, mainly underscored by the increased activity of factor VII. This review discusses the results of the latest studies on the various parameters affected by SH while highlighting the need for timely treatment with levothyroxine., (© Thieme Medical Publishers.)

Background: Despite clinical practice guidelines for the management of differentiated thyroid cancer (DTC), there are no recommendations on the optimal serum thyrotropin (TSH) concentration to reduce tumor recurrences and improve survival, while ensuring an optimal quality of life with minimal adverse effects. The aim of this review was to provide a risk-adapted management scheme for levothyroxine (L-T4) therapy in patients with DTC. The objective was to establish which patients require complete suppression of serum TSH levels, given their risk of recurrent or metastatic DTC, and how potential adverse effects on the heart and skeleton, induced by subclinical hyperthyroidism, in concert with advanced age and comorbidities, may influence the degree of TSH suppression., Summary: A risk-stratified approach to predict the rate of recurrence and death from thyroid cancer was based on the recently revised American Thyroid Association guidelines. A stratified approach to predict the risk from the adverse effects of L-T4 was devised, taking into account the age of the patient, as well as the presence of preexisting cardiovascular and skeletal risk factors that might predispose to the development of long-term adverse cardiovascular or skeletal outcomes, particularly increased heart rate and left ventricular mass, atrial fibrillation, and osteoporosis. Nine potential patient categories can be defined, with differing TSH targets for both initial and long-term L-T4 therapy., Conclusion: Before deciding on the degree of TSH suppression during initial and long-term L-T4 treatment in patients with DTC, it is necessary to consider the aggressiveness of DTC, as well as the potential for adverse effects induced by iatrogenic subclinical hyperthyroidism. More aggressive TSH suppression is indicated in patients with high-risk disease or recurrent tumor, whereas less aggressive TSH suppression is reasonable in low-risk patients. In patients with high-risk DTC and an equally high risk of adverse effects, long-term treatment with L-T4 therapy should be individualized and balanced against the potential for adverse effects. In patients with an intermediate risk for thyroid cancer recurrence and a high risk of adverse effects of therapy, the degree of TSH suppression should be reevaluated during the follow-up period. Normalization of serum TSH is advisable for long-term treatment of disease-free elderly patients with DTC and significant comorbidities.

Acute hypothyroidism induced by thyroid hormone withdrawal in patients with differentiated thyroid cancer during monitoring for remnant or metastatic disease, seriously affects multiple organs and systems, and especially in severe cases can impair quality of life. Indeed, it may induce untoward cardiovascular effects and can be hazardous in patients with underlying cardiovascular disease, particularly in the elderly. Moreover, acute hypothyroidism deranges the lipid profile and exacerbates neuropsychiatric illness. The introduction of recombinant human TSH (rhTSH) as a diagnostic and therapeutic tool in the care of patients with thyroid cancer has widened the scope of disease management. The use of rhTSH prevents derangement of various systems at approximately equivalent societal costs to that of withdrawal and promotes compliance while preserving the patient's normal daily functioning and productivity. Its reliability allied with its safety render this compound a valid alternative in the monitoring of patients with differentiated thyroid carcinoma as well as providing an alternative therapeutic procedure whenever LT4-withdrawal may be hazardous or in cases of patient non-compliance.

Thyroid cancer is the most common endocrine malignancy. More than 90% of primary thyroid cancers are differentiated papillary or follicular types. The treatment of differentiated thyroid carcinoma (DTC) consists of total thyroidectomy and radioactive iodine ablation therapy, followed by L-thyroxine therapy. The extent of initial surgery, the indication for radioiodine ablation therapy and the degree of TSH-suppression are all issues that are still being debated cancers are in relation to the risk of recurrence. Total thyroidectomy reduces the risk of recurrence and facilitates (131)I ablation of thyroid remnants. The aim of radioiodine ablation is to destroy any normal or neoplastic residuals of thyroid tissue. These procedures also improve the sensitivity of thyroglobulin (Tg) as a marker of disease, and increase the sensitivity of (131)I total body scan (TBS) for the detection of persistent or recurrent disease. The aim of TSH-suppressive therapy is to restore euthyroidism and to decrease serum TSH levels, in order to reduce the growth and progression of thyroid cancer. After initial treatment, the objectives of the follow-up of DTC is to maintain adequate thyroxine therapy and to detect persistent or recurrent disease through the combined use of neck ultrasound (US) and serum Tg and (131)I TBS after TSH stimulation. The follow-up protocol should be adapted to the risk of recurrence. Recent advances in the follow-up of DTC are related to the use of recombinant human TSH (rhTSH) in order to stimulate Tg production and the ultrasensitive methods for Tg measurement. Undetectable serum Tg during TSH suppressive therapy with L-T4 does not exclude persistent disease, therefore serum Tg should be measured after TSH stimulation. The results of rhTSH administration and L-thyroxine therapy withdrawal are equivalent in detecting recurrent thyroid cancer, but the use of rhTSH helps to avoid the onset of hypothyroid symptoms and the negative effects of acute hypothyroidism on cardiovascular, hepatic, renal and neurological function. In low-risk DTC patients serum Tg after TSH stimulation, together with ultrasound of the neck, should be used to monitor persistent disease, avoiding diagnostic TBS which has a poor sensitivity. These recommendations do not apply when Tg antibodies are present in the serum, in patients with persistent or recurrent disease or limited thyroid surgery. Low-risk patients may be considered to be in remission when undetectable Tg after TSH stimulation and negative US evaluation of the neck are present. On the contrary, detectable Tg after TSH stimulation is an indicator in selecting patients who are candidates for further diagnostic procedures.

Recent studies have raised doubts about the efficacy of the postoperative use of levothyroxine (LT4) suppressive doses in patients who underwent thyroid surgery for multinodular goiter. The purpose of this retrospective study was to examine the efficacy of different doses of LT4 in preventing postsurgical recurrences of simple multinodular goiter and to identify a marker that could be useful in discriminating patients with a higher risk of developing recurrence. Two hundred thirty-two patients (57 male, 175 female) operated for nontoxic multinodular goiter were divided into two groups: (I) patients with normal postsurgery thyrotropin (TSH) levels (0.25 to 4.5 mU/L) and (II) patients with elevated postsurgery TSH levels (>4.5 mU/L). All patients were subjected to replacement (1.3 microg LT4/kg/day) or suppressive (1.7 microg LT4/kg/day) doses of LT4, and they were followed for a median period of 6 years (range 2 to 12). No statistical difference was found for sex, age, and postsurgery serum TSH between patients submitted to suppressive and replacement therapy. The ultrasound (US) detection of new postsurgery nodules of at least 0.5 cm maximum diameter was considered a recurrence of disease and was found in 10% of the cases studied. Patients with normal postsurgery serum TSH showed a high recurrence rate (30.4%) when submitted to lower daily doses of LT4. In patients with elevated postsurgery serum TSH, the rate of nodular goiter recurrence did not vary with different types of LT4 therapy. In conclusion, our results suggest that the postsurgical serum TSH is useful for prediction of nodular goiter recurrence, as it reflects the amount of residual functioning thyroid tissue in the cervical area. It may also be indicative of patients who might benefit from LT4 suppressive therapy.

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.

To assess cardiac function and exercise tolerance in patients receiving long term TSH-suppressive therapy with levothyroxine (L-T4), we studied maximal exercise capacity with a bicycle ergometer and left ventricular function at rest and during physical exercise by radionuclide angiography. The evaluation was performed in 10 patients receiving L-T4 therapy (2.31 +/- 0.13 microgram/kg) for 5-9 yr, presenting with effort dyspnea and symptoms of adrenergic overactivity, and 10 matched control subjects. The patients were reassessed after 4 months of administration of the selective beta-adrenergic blocker bisoprolol (4.25 +/- 0.4 mg/day); L-T4 therapy remained unchanged. The results showed that at rest, left ventricular diastolic filling was impaired in the patients (P < 0.05), whereas systolic function was unaltered. During submaximal physical exercise, left ventricular ejection fraction increased in the controls from 58 +/- 2% to 65 +/- 2% (P < 0.001), whereas in the patients it fell from 63 +/- 2% to 53 +/- 2% (P < 0.01), mainly because of increased end-systolic left ventricular volume (P < 0.05). Exercise capacity was markedly reduced in the patients in terms of both peak workload (P < 0.001) and exercise duration (P < 0.001). beta-Adrenergic blockade prevented both the fall in ejection fraction and the increase in end-systolic volume during exercise, and improved exercise tolerance. In conclusion, our data show that long term TSH-suppressive therapy with L-T4 is not as harmless as believed, because it may cause marked impairment of cardiac functional reserve and physical exercise capacity. Administration of a beta-blocking drug for 4 months caused significant improvement of cardiac performance and exercise tolerance.

Thyroid-stimulating hormone (TSH) suppressive therapy with levothyroxine (L-T4) may cause adverse cardiac effects such as rhythm disturbances and ventricular hypertrophy. The latter is a predisposing condition to diastolic dysfunction. Thus, this study was designed to assess the effect of long-term TSH suppressive therapy on cardiac diastolic function. Because beta-blockade is known to reduce ventricular hypertrophy in patients on L-T4 therapy, we also tried to determine whether the addition of a beta-blocker to L-T4 improved diastolic function. Twenty-five patients (21 female and 4 male; mean age 41 +/- 10 yr) on TSH suppressive therapy for 3-9 yr (9 for differentiated carcinoma and 16 for nontoxic goiter) and 20 control subjects were studied. A subgroup of 10 patients, selected for the presence of symptoms and signs of adrenergic overactivity, was treated for 4 months with the beta-blocker bisoprolol (4.25 +/- 1.2 mg/day), and their maintaining L-T4 therapy was unchanged. In the patient group, left ventricular mass was significantly increased (P < 0.001), isovolumic relaxation time was prolonged (P < 0.001), and early diastolic filling velocity was markedly reduced (P < 0.001), whereas late diastolic filling was increased (P < 0.005). Consequently, the early-to-late diastolic flow velocity ratio was markedly decreased (P < 0.001). These alterations were more pronounced in the subgroup of patients with evidence of adrenergic overactivity. In these patients, beta-blockade induced a significant regression of cardiac hypertrophy and improved diastolic dysfunction. In particular, isovolumic relaxation time decreased (P < 0.01) and the early-to-late flow velocity ratio increased significantly (P < 0.01). Both indices reached values after beta-blockade that were no longer different from those of asymptomatic patients. It is concluded that long-term L-T4 therapy increases myocardial mass and causes relevant diastolic dysfunction, particularly in those patients with evidence of mild hyperthyroidism and adrenergic overactivity. Both myocardial hypertrophy and diastolic dysfunction are significantly improved by adrenergic beta-blockade.

Several symptoms and signs of hyperthyroidism are frequently shared by patients receiving L-T4 suppressive therapy. The aim of this study was to evaluate whether a beta-adrenergic blocking drug could reduce the severity of these symptoms and signs in these patients, as previously reported in patients with hyperthyroidism. Eleven patients (mean age, 42 +/- 11 yr; 10 females and one male) affected with differentiated thyroid carcinoma or nontoxic goiter were selected from a more numerous group of patients receiving suppressive therapy based on the presence of palpitations, increased heart rate, left ventricular systolic function, and other symptoms mimicking exaggerated beta-adrenergic activity. In these patients the cardioselective beta-blocking drug bisoprolol was added to the L-T4 suppressive therapy at a dose of 2.5-5 mg/day. Blood samples were collected for the determination of thyroid hormones and TSH concentration during L-T4 therapy and after 3 and 6 months of associated L-T4 plus bisoprolol therapy. Cardiac function was assessed by clinical evaluation, standard and Holter electrocardiogram, as well as one- and two-dimensional echocardiography. Furthermore, we applied the symptom-rating scale previously used by Klein et al. in hyperthyroid patients to assess the quality of life in our group of patients. Our findings show that the addition of bisoprolol to L-T4 suppressive therapy produces a normalization of heart rate, which was significantly increased during TSH suppressive therapy, and the disappearance of atrial arrhythmias with considerable reduction of palpitations. Furthermore, bisoprolol produced an effective improvement in measures of the hyperthyroid symptom scale, with significant reduction of the mean score. The echocardiographic data showed an increased left ventricular mass index with significantly enhanced systolic function at the basal evaluation. After 6 months of combined L-T4 plus bisoprolol therapy, left ventricular mass index normalized, and the indices of left ventricular systolic function were reduced, with a tendency to normalize. Further studies conducted on a larger series of patients are required to verify the long term implications of cardiac parameter variations on cardiovascular morbidity and mortality. Our results, however, show that the addition of bisoprolol to L-T4 suppressive therapy improves the quality of life in those patients with clinical features of enhanced adrenergic activity.

To investigate the effects of long term thyroid hormone suppressive therapy on the heart, 20 patients were evaluated by noninvasive techniques. Of them, 10 were athyreotic after surgery for differentiated thyroid cancer, and 10 had diffuse or nodular goiter. The mean age of the group was 39 +/- 11 yr. Twenty age- and sex-matched subjects served as controls. The mean dose of levothyroxine was 163 +/- 34 micrograms daily. Plasma TSH was undetectable in all patients. Mean serum T4, free T4, and sex hormone-binding globulin were significantly higher (P < 0.001), whereas mean serum T3, free T3, and osteocalcin did not differ from control levels. Cardiac evaluation consisted of a standard 12-lead electrocardiogram, an ambulatory electrocardiographic monitoring (Holter), and an echocardiographic study. Two patients showed abnormal electrocardiograms for left ventricular hypertrophy. Holter demonstrated an increase in average heart rate (84 +/- 7 vs. 70 +/- 6 beats/min; P < 0.01). Prevalence of atrial premature beats was higher in the patient group than in the control group (100% vs. 60%; P < 0.006). The echocardiogram showed an increased left ventricular mass index in the patient group (97 +/- 24 vs. 80 +/- 18 g/m2; P < 0.02). Furthermore, left ventricular systolic function was enhanced, with higher values of fractional shortening (38 +/- 7% vs. 34 +/- 4%; P < 0.05) and rate-adjusted velocity of shortening (1.2 +/- 0.13 vs. 1.05 +/- 0.14 circumferences/sec; P < 0.01). These findings indicate that long term levothyroxine therapy at suppressive doses markedly affects cardiac function.

The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST-IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of L-T4 replacement therapy in the frail elderly. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]