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Hypothyroidism is a common condition, and numerous studies have been published over the last decade to assess the potential risks associated with this disorder when inappropriately treated. The standard of care for treatment of hypothyroidism remains levothyroxine (LT4) at doses to achieve biochemical and clinical euthyroidism. However, about 15% of hypothyroid patients experience residual hypothyroid symptoms. Some population-based studies and international population-based surveys have confirmed dissatisfaction with LT4 treatment in some hypothyroid patients. It is well established that hypothyroid patients treated with LT4 exhibit higher serum thyroxine:triiodothyronine ratios and can have a persistent increase in cardiovascular risk factors. Moreover, variants in deiodinases and thyroid hormone transporter genes have been associated with subnormal T3 concentrations, persistent symptoms in LT4-treated patients, and improvement in response to the addition of liothyronine to LT4 therapy.The American (ATA) and European Thyroid Association (ETA) guidelines have recently evolved in their recognition of the potential limitations of LT4. This shift is reflected in prescribing patterns: Physicians’ use of combination therapy is prevalent and possibly increasing. Randomized clinical trials have recently been published and, while they have found no improvement in treating hypothyroid patients, a number of important limitations did not allow generalizability. Meta-analyses have reported a preference rate for combination therapy in 46.2% hypothyroid patients treated with LT4. To promote discussions about an optimal study design, the ATA, ETA, and British Thyroid Association have recently published a consensus document.Our study provides a useful counterpoint on the controversial benefits of treating hypothyroid patients with combination therapy.

Background: Mounting evidence indicates that subclinical thyroid dysfunction has important clinical effects and prognostic implications, supporting the view that it is not a compensated biochemical change sensu strictu. Purpose: To review clinical information on the effects of subclinical thyroid dysfunction on the heart. Data Sources: English-language articles identified from files and a MEDLINE search (1970-September 2001), references of relevant articles, textbooks, and meeting abstracts. Study Selection: Reports on the effects of subclinical hypothyroidism and subclinical hyperthyroidism on the cardiovascular system in humans. Data Extraction: Data on cardiac structure and performance, arrhythmias, and risk for coronary artery disease were independently assessed by all authors and summarized. Data Synthesis: Subclinical hypothyroidism is associated with impaired left ventricular diastolic function at rest, systolic dysfunction on effort, and enhanced risk for atherosclerosis and myocardial infarction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased left ventricular mass with marginal concentric remodeling, impaired ventricular relaxation, reduced exercise performance, and increased risk for cardiovascular death. All abnormalities were reversed by restoration of euthyroidism (subclinical hypothyroidism) or were blunted by beta-blockade and tailoring of the L-thyroxine dose (subclinical hyperthyroidism). Conclusion: The heart responds to the minimal but persistent changes in circulating thyroid hormone levels typical of subclinical thyroid dysfunction. Thus, the condition is not a compensated biochemical change sensu strictu, and timely treatment should be considered in an attempt to avoid adverse cardiovascular effects.

Subclinical hypothyroidism, which is defined as a thyroid-stimulating hormone concentration higher than the reference range (generally 4·5 mIU/L or higher) with normal free thyroxine concentrations, is frequently found in older individuals. International guidelines differ in recommendations for management of subclinical hypothyroidism in older individuals. We assessed published data during the past decade on the clinical significance and treatment of subclinical hypothyroidism in individuals aged 65 years and older. Meta-analyses, randomised clinical trials, and cohort studies are discussed in this narrative Review. Studies showed no significantly increased incidence in adverse cardiovascular, musculoskeletal, or cognitive outcomes in individuals aged 65 years or older when serum thyroid-stimulating hormone concentration was 4·5–7·0 mIU/L versus a euthyroid group. Moreover, in older individuals with subclinical hypothyroidism, symptoms of hypothyroidism and cardiac and bone parameters did not improve after levothyroxine treatment. These data suggest that treatment with levothyroxine should be considered for individuals aged 65 years or older with subclinical hypothyroidism when thyroid-stimulating hormone concentration is persistently 7 mIU/L or higher and to not initiate treatment with thyroid-stimulating hormone concentrations of less than 7 mIU/L. Levothyroxine doses should be personalised according to age, comorbidities, and life expectancy.

General rates of over- and underreplacement in levothyroxine (LT4) users with primary hypothyroidism are variably high. No information on LT4 adequacy exists in obesity.

The purpose of this article will be to review the basics of thyroid hormone therapy, including various thyroid hormone formulations, the institution and monitoring of thyroid hormone therapy, adverse effects of overtreatment, the management of patients with persistent symptoms despite normal thyroid function tests, and potential new innovations in thyroid hormone therapy. The conclusions support the necessity to personalize thyroid hormone replacement therapy in hypothyroid patients.

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.

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.

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.

The aim was to retrospectively analyse the clinical–histopathological characteristics of patients with newly diagnosis of differentiated thyroid cancer (DTC) referred to two Italian centres, one in Northern and the other in Southern Italy, between 2000 and 2013. 1081 patients were included and subdivided into two groups: group A (474 patients from Novara) and group B (607 patients from Naples). The group A came from the industrial area of Novara, while the Group B came from the areas around Vesuvius and Campi Flegrei. The two groups were comparable for iodine levels, body mass index, diagnostic timing and clinical procedures. For all patients, demographic and clinical data were collected. No difference was found in gender, whereas the age at diagnosis was later in the group A (group A 53.1 ± 15.16 years, group B 41.9 ± 14.25 years, p< 0.001). In both groups, the most frequent histotype was papillary thyroid cancer (PTC) with prevalence of follicular variant in group A (p< 0.0001) and classical variant in group B (p< 0.0001). Aggressive histological features were mainly seen in group A (bilaterality p< 0.0001, multifocality p< 0.0001 and thyroid capsular invasion p< 0.0001). Microcarcinomas were more frequent in group A (p< 0.0001) but mostly characterized by bilaterality (p< 0.001) and multifocality (p< 0.04). In both groups, tumour-associated thyroiditis showed a significant increase over the years (group A p< 0.05, group B p< 0.04). Environmental factors could justify the differences found in our study. These preliminary data should stimulate the need for an Italian Cancer Registry of DTC in order to allow an epidemiological characterization, allowing the identification of specific etiological factors and an improvement in the management of the disease.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland. An algorithm for the diagnosis and treatment of SETTLE has yet to be established. The aim of this study was to identify all case reports of SETTLE and to compare the clinical-pathological features and therapy of the cases identified. We performed a PubMed search for case reports of SETTLE in English published up to November 2014 in which “SETTLE” and “Spindle epithelial tumor with thymus-like differentiation” were keywords. We identified 35 articles for a total of 42 cases. We found that SETTLE usually occurs in children and adolescents as an asymptomatic neck mass. Thyroid function tests and tumor markers are invariably within normal range in all patients, and fine needle aspiration biopsy is rarely diagnostic for SETTLE. All 42 patients had undergone thyroidectomy. After surgical resection, chemotherapy (adjuvant or first/second-line treatment) and/or radiotherapy were administered to control tumor growth in cases with metastatic involvement. Although SETTLE presents a low-grade malignancy, it can metastasize to lymph nodes, the mediastinum, lung, vertebrae, and kidney even many years after the initial diagnosis. SETTLE may have a good prognosis if appropriately treated at initial presentation and if patients undergo long-term monitoring with regular clinical and morphological evaluations.

Endogenous subclinical hyperthyroidism (SHyper) is caused by Graves' disease, autonomously functioning thyroid nodules and multinodular goitre. Its diagnosis is based on a persistently subnormal serum thyroid-stimulating hormone (TSH) level with free thyroid hormone levels within their respective reference intervals. In 2014 the European Thyroid Association Executive Committee, given the controversies regarding the treatment of Endo SHyper, formed a task force to develop clinical practice guidelines based on the principles of evidence-based medicine. The task force recognized that recent meta-analyses, including those based on large prospective cohort studies, indicate that SHyper is associated with increased risk of coronary heart disease mortality, incident atrial fibrillation, heart failure, fractures and excess mortality in patients with serum TSH levels <0.1 mIU/l (grade 2 SHyper). Therefore, despite the absence of randomized prospective trials, there is evidence that treatment is indicated in patients older than 65 years with grade 2 SHyper to potentially avoid these serious cardiovascular events, fractures and the risk of progression to overt hyperthyroidism. Treatment could be considered in patients older than 65 years with TSH levels 0.1-0.39 mIU/l (grade 1 SHyper) because of their increased risk of atrial fibrillation, and might also be reasonable in younger (<65 years) symptomatic patients with grade 2 SHyper because of the risk of progression, especially in the presence of symptoms and/or underlying risk factors or co-morbidity. Finally, the task force concluded that there are no data to support treating SHyper in younger asymptomatic patients with grade 1 SHyper. These patients should be followed without treatment due to the low risk of progression to overt hyperthyroidism and the weaker evidence for adverse health outcomes.

Morbid obesity is associated with a high rate of raised serum TSH associated with normal free thyroid hormones. The body repercussions of this thyroid abnormality, suggesting subclinical hypothyroidism, are still debated. In particular, it is unclear whether the raised serum TSH of obesity results in changes of circulating lipids typically observed in hypothyroidism. Aim of this study was to evaluate the impact of a raised serum TSH on the lipid profile in morbid-obese and non-obese patients. Serum TSH, FT4, FT3, Tg-Ab, TPO-Ab and lipids were measured in 55 morbid-obese (BMI > 40 kg/m2) and 55 non-obese (BMI < 30 kg/m2) patients with a raised serum TSH. Despite similar serum levels of TSH, FT4 and FT3, morbid-obese patients displayed significantly lower mean levels of total cholesterol (200.8 ± 35.6 vs. 226.9 ± 41.4 mg/dl, p< 0.001) and a significantly lower prevalence of hypercholesterolemia (50.9 vs. 72.7 %, p< 0.01) when compared with non-obese patients. Morbid-obese patients also had lower mean serum HDL cholesterol and higher serum triglycerides. The impact of a raised serum TSH on the lipid profile differs in morbid-obese compared to non-obese patients, suggesting that obese patients might not be truly hypothyroid. Measuring total cholesterol could be a helpful tool for deciding whether a morbid-obese patient with a raised serum TSH should be given levothyroxine treatment.

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.

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.

Graves disease, toxic adenoma and toxic multinodular goiter differ in their clinical presentation and cardiovascular implications. In this Review, establishing the etiology of hyperthyroidism is highlighted as a prerequisite for correct treatment of both the disease and the associated cardiovascular complications.

Thyroid-cell proliferation depends on TSH; suppression of TSH with levothyroxine decreases progression and recurrence rates for thyroid cancer. Long-term TSH suppression benefits patients at high risk of cancer recurrence but not low-risk patients, so TSH levels should be targeted accordingly.

L’ipotiroidismo subclinico è una condizione caratterizzata da un incremento del TSH con ormoni tiroidei normali. Benché la secrezione di ormoni tiroidei sia apparentemente normale, i soggetti con tale pattern ormonale possono essere sintomatici e presentare alterazioni a carico dei loro organi e tessuti bersaglio, che, se non corrette, possono indurre spesso complicanze in grado di modificare la qualità e le aspettative di vita. L’ipotiroidismo subclinico è relativamente frequente nella popolazione generale e, specie negli anziani determina un elevato rischio cardiovascolare per la possibilità di alterazione di vari parametri cardiovascolari e per l’aumentato rischio di aterosclerosi. Tra i fattori di rischio per aterosclerosi un ruolo importante sembra essere svolto dall’ipertensione, dalla disfunzione endoteliale, dalla dislipidemia e dalle alterazioni dei parametri di coagulazione. La terapia con T4 riesce a prevenire o a correggere l’aumentato rischio cardiovascolare associato all’ipotiroidismo subclinico, nonché a migliorare la qualità di vita, i disturbi psichici, cognitivi e muscolari che pure possono essere presenti. Il trattamento dell’ipotiroidismo subclinico è imperativo in gravidanza per le gravi alterazioni che può indurre nel nascituro.

In women monitored for thyroid carcinoma, short‐term stimulation with rhTSH induced an acute decrease in serum C‐telopeptides of type‐1 collagen and an increase in serum BALP levels without any effect on OPG production. The inhibitory effect of TSH on bone resorption occurred only in postmenopausal women who showed low BMD and a high bone turnover rate as an effect of L‐thyroxine suppressive therapy.

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 supra-ventricular 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.

Abstract: The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH>10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels<10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of l-thyroxine outweigh the risk.

The cardiovascular system is sensitive to the action of thyroid hormone. However, although a wide spectrum of cardiac abnormalities has long been recognized in patients with overt thyroid dysfunction, the question of cardiac involvement in patients with subclinical thyroid dysfunction has been investigated only in the last two to three decades. Most clinical studies have shown that subclinical hypothyroidism or hyperthyroidism is associated with changes in several cardiac parameters. More specifically, the literature on cardiac involvement in subclinical hypothyroidism consistently shows that patients have resting left ventricular diastolic dysfunction evidenced by delayed relaxation, and impaired systolic dysfunction on effort that results in poor exercise capacity. Whether or not subclinical hypothyroidism also affects left ventricular systolic function at rest remains controversial. Studies of subclinical hypothyroid patients before and after euthyroidism was achieved with levothyroxine replacement provided evidence of impaired resting left ventricular systolic function. Indeed, at-rest left ventricular systolic function was substantially normal in most studies of subclinical hypothyroid patients compared to normal control subjects. Drawing on these data, it appears that subclinical hypothyroidism should be considered a mild form of thyroid failure, associated with initial signs of cardiovascular hypothyroidism. Therefore, it would seem appropriate to initiate timely treatment of patients with mild thyroid failure to prevent cardiac involvement.

Mounting evidence suggests that increased circulating aldosterone levels, despite angiotensin-converting-enzyme inhibitors therapy, may exert deleterious cardiovascular effects in heart failure, leading to clinical deterioration and poor prognosis. In the past decades, a number of experimental investigations have provided major insight into the mechanism(s) of action and the biological effects of aldosterone on the cardiovascular system, indicating that aldosterone participates in the structural and functional remodeling of cardiac and vascular tissue. In particular, it has emerged that aldosterone plays a key role in the regulation of myocardial extracellular matrix composition and endothelial function with important pathophysiological implications. Such evidence, coupled with the recent beneficial effects of spironolactone, a competitive aldosterone receptor antagonist, in reducing cardiac mortality and morbidity in patients with severe chronic heart failure treated with angiotensin-converting-enzyme inhibitors and loop diuretics, highlights the importance of aldosterone in the pathophysiology of human heart failure. The purpose of this review is to provide an overview of the regulation of aldosterone production and metabolism in heart failure, the basic mechanism of aldosterone action, and the pathophysiological implications of aldosterone in heart failure, and to discuss recent evidence supporting the efficacy of aldosterone receptor blockade in the treatment of chronic heart failure in humans.

Merola B, Sofia M, Longobardi S, Fazio S, Micco A, Esposito V, Colao A, Biondi B, Lombardi G. Impairment of lung volumes and respiratory muscle strength in adult patients with growth hormone deficiency. Eur J Endocrinol 1995;133:680–5. ISSN 0804–4643Little is known of the respiratory function in patients with growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient in childhood. Ten patients diagnosed as GH deficient in childhood and ten healthy subjects entered the study. For each subject the evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, recording of flowvolume curves, measurement of static lung volumes and lung diffusing capacity. Both maximal inspiratory and expiratory mouth pressures were decreased in GH deficiency. Vital capacity, N2functional residual capacity and total lung capacity were significantly reduced when compared to healthy subjects. Conversely, the residual volume and diffusing lung capacity to CO did not show any significant change. No significant change of percentage forced expiratory volume in 1 s/forced vital capacity ratio was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. In conclusion, the results of this study show that adult patients affected with childhood onset GH deficiency suffer from impairment of ventilatory function and a decrease of respiratory muscle pressures, probably due to reduction of respiratory muscle strength.Gaetano Lombardi, Via G Santacroce 40/1, 80 129 Naples, Italy

Fifteen patients with medullary carcinoma of the thyroid (MCT), who had persistently elevated levels of serum calcitonin (CT) and carcinoembryonic antigen (CEA) after total thyroidectomy, were studied in order to localize the sites of the recurrent disease. Routine diagnostic examinations, including ultrasonography (US) and computed axial tomography (CAT), were carried out in all the cases. Scintigraphy with radio-iodinated meta-iodobenzylguanidine ((131I)-MIBG) was performed in 13 cases; selective venous catheterization (SVC) to reveal a gradient of CT levels was performed in 12 cases. Ten patients underwent both (l31I)-MIBG scintigraphy and SVC. US and CAT revealed the sites of recurrent tumor in only 4 out of the total 15 patients. SVC in basal conditions showed the presence of small metastases in 2 cases, and after intravenous stimulus with pentagastrin in 4 others. The MIBG scan showed metastatic foci of sporadic MCT in 2 patients, residual medullary thyroid tissue in 4 others, and a pheochromocytoma in a previously undiagnosed patient with Sipple’s syndrome. More particularly, MIBG scan and SVC showed the localization of residual or metastatic tumor in 10 cases. In all 10 cases, results of the MIBG scan and SVC were confirmed as true positive by subsequent surgery and histopathologic examination. The conclusions of this study were twofold: (1) in the follow-up of MCT patients with persistently elevated CT and CEA levels, positive US and CAT findings make the MIBG scan useful, if positive, only to determine the nature of the lesion; (2) the association of the two approaches (MIBG scan and SVC) in patients with increased levels of CT and CEA but negative results of routine diagnostic examination can be useful to detect occult rnicrometastases, thus permitting an accurate clinicopathologic staging of the disease.