Bernadette Biondi

Subclinical thyroid disease

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.

Effects of Subclinical Thyroid Dysfunction on the Heart

The cardiovascular system is very sensitive to thyroid hormone, and a wide spectrum of cardiac changes has long been recognized in overt thyroid dysfunction (1-5). In contrast, cardiovascular impairment in patients with subclinical thyroid dysfunction has only recently been studied in detail (6-9). This condition, characterized by normal levels of circulating free thyroxine (FT4) and free triiodothyronine (FT3) and elevated (subclinical hypothyroidism) or below-normal (subclinical hyperthyroidism) thyroid-stimulating hormone (TSH) concentrations, is associated with changes in several cardiovascular measures. These changes support the view that subclinical thyroid dysfunction is not a compensated biochemical change sensu strictu. To clarify this process, we reviewed clinical studies of the consequences of subclinical thyroid dysfunction on the heart. Methods Data sources were articles in our collection about the cardiovascular effects of subclinical thyroid dysfunction in humans published between 1970 and September 2001. We checked that articles had not been overlooked by searching the MEDLINE database (keywords were thyroid hormone, heart, subclinical hypothyroidism, subclinical hyperthyroidism, and cardiovascular risk), references of relevant articles, textbooks, and abstracts of presentations at international thyroid meetings. Given the relatively few studies on the effect of subclinical thyroid disease on the cardiovascular system, we are confident that we considered all English-language peer-reviewed reports. All authors assessed the reports and agreed about article content. Subclinical Hypothyroidism Subclinical hypothyroidism, defined as increased serum TSH concentrations associated with normal FT4 and FT3 concentrations, may be caused by exogenous (l-thyroxine under-replacement in hypothyroid patients; medication with lithium, cytokines, iodine, or antithyroid drugs; and iodine 131 therapy or thyroidectomy) or endogenous (Hashimoto thyroiditis and previous subacute or silent thyroiditis) factors (8). Its prevalence ranges from 1.3% to 17.5%, depending on age, sex, and iodine intake (10-14). A large cross-sectional study from Colorado reported a mean prevalence of 9% (15). People with thyroid antibodies caused by Hashimoto thyroiditis are prone to subclinical hypothyroidism. The incidence of subclinical hypothyroidism, derived from a review (14) of three longitudinal studies that included a total of 2956 patients (with 6-, 10-, and 20-year follow-up, respectively) (16-18), is 2.1% to 3.8% per year in thyroid antibodypositive patients and about 0.3% per year in thyroid antibodynegative patients. The annual risk for developing overt hypothyroidism after 20 years is 4.3% in women with increased TSH concentrations and thyroid antibodies and 2.6% in women with subclinical hypothyroidism without thyroid antibodies (18). Cardiac Manifestations Table 1 lists the cardiovascular abnormalities reported in subclinical hypothyroidism (19-33). Resting heart rate was normal in all patients in whom it was evaluated (21, 22, 25, 28-30, 33). Cardiac function, evaluated from systolic time intervals, was also normal in patients with subclinical hypothyroidism (19, 27). In contrast, the preejection period and the interval from Q wave to pulse arrival at the brachial artery were prolonged, and the preejection periodleft ventricular ejection time ratio was higher in 20 patients with subclinical hypothyroidism than in the same patients after l-thyroxine replacement therapy (20). Table 1. Cardiovascular Abnormalities in Subclinical Hypothyroidism In the first double-blind study of the effects of 1 year of l-thyroxine therapy compared with placebo in 17 patients with subclinical hypothyroidism of different origins, the preejection periodleft ventricular ejection time ratio was significantly decreased after l-thyroxine therapy, particularly in patients with the highest ratio (>0.390) (21). In 18 patients, l-thyroxine caused a small but significant increase in left ventricular ejection fraction (evaluated by radionuclide ventriculography) during maximal exercise but caused no change at rest or during moderate exercise (22). In 10 patients evaluated before and after TSH concentrations were normalized with l-thyroxine, the treatment did not affect left ventricular ejection fraction at rest but did enhance the increase in ejection fraction during exercise (23). In the same study, sodium nitroprusside produced similar increases in cardiac output in patients with subclinical hypothyroidism and in euthyroid persons. However, in the former group, enhanced cardiac output was due to a large increase in heart rate and reduced stroke volume, whereas euthyroid persons had a smaller increase in heart rate and no change in stroke volume. Therefore, restoration of euthyroidism by l-thyroxine improves systolic function on effort in patients with subclinical hypothyroidism. This could have resulted from improved myocardial contractility and, perhaps, lusitropic function. The preejection period was prolonged in only 5 of 17 patients with subclinical hypothyroidism compared with 50 euthyroid controls, whereas the mean left ventricular ejection fraction was reduced both at rest and during isometric exercise (24). In the first double-blind, crossover study of women with subclinical hypothyroidism due to Hashimoto thyroiditis, 20 randomly selected women with primary subclinical hypothyroidism received l-thyroxine and placebo for 6 months each (25). Left ventricular systolic function was assessed from systolic time intervals before and after l-thyroxine. Heart ratecorrected preejection period and the preejection periodleft ventricular ejection time ratio decreased significantly after treatment. In another study, left ventricular function, evaluated by echocardiography-derived systolic time intervals, was unchanged in 22 patients with subclinical hypothyroidism compared with normal controls (26). In eight subclinical hypothyroid patients evaluated at rest and during bicycle-ergometer exercise testing before and after l-thyroxine treatment, Doppler-derived systolic time intervals showed a more prolonged preejection period and a higher preejection periodleft ventricular ejection time ratio during pretreatment maximum exercise (28). Echocardiographic left ventricular end-diastolic dimension was slightly but significantly lower before l-thyroxine treatment. Left ventricular structure and function at rest were evaluated by using Doppler echocardiography in 26 selected patients with stable subclinical hypothyroidism due to Hashimoto thyroiditis and in 30 normal controls (29). In 10 randomly selected patients, the evaluation was repeated after 6 months of l-thyroxine therapy (daily dose, 68 g). No significant abnormality in left ventricular structure was seen, whereas Doppler-derived mean aortic acceleration, a reliable index of left ventricular systolic function, was significantly lower in patients than in controls. This acceleration normalized after l-thyroxine therapy. Furthermore, isovolumic relaxation time was prolonged, and the earlylate ratio of Doppler-derived transmitral peak flow velocities was lower in patients than in controls. Both measures of diastolic function returned to normal after l-thyroxine replacement. Doppler echocardiography and ultrasonic myocardial textural analysis confirmed these findings in 16 patients with subclinical hypothyroidism (30). They had a significantly increased left ventricular mass and lower cyclic variation measures (percentage systolic/diastolic change in mean gray levels) in both the interventricular septum and the left ventricular posterior wall (30). Radionuclide ventriculography revealed a longer time to peak filling rate in 10 patients with subclinical hypothyroidism than in 10 normal controls (32). This index of diastolic function normalized after l-thyroxine replacement. Using stress Doppler echocardiography and cardiopulmonary exercise testing, Kahaly (31) studied 20 patients with subclinical hypothyroidism before and after l-thyroxine therapy and 20 normal controls. At rest, the cardiac measures recorded in untreated patients approximated those obtained in controls and in euthyroid patients. However, patients had significantly lower stroke volume, cardiac index, and peak aortic flow velocity and significantly prolonged preejection period during exercise. All measures normalized after a euthyroid state was achieved. Furthermore, the oxygen pulse (oxygen uptake per heartbeat), an index of stroke volume, was significantly decreased both at the anaerobic threshold and at maximal work capacity, and work rate was reduced at the anaerobic threshold in patients versus controls. These measures normalized after replacement therapy. Finally, in a double-blind, placebo-controlled study of the effects of l-thyroxine replacement therapy on cardiac structure and function in subclinical hypothyroidism, cardiac measures, evaluated by Doppler echocardiography and videodensitometry, were almost normal after l-thyroxine therapy (33). Coronary Artery Disease Overt hypothyroidism increases serum cholesterol levels (15, 27, 34-36), but it is not known whether subclinical hypothyroidism affects serum lipid profiles. Serum cholesterol levels have been significantly higher in patients with subclinical hypothyroidism than in normal controls (31, 37-40). In other studies, levels were only marginally increased (41-43). In three studies, the prevalence of subclinical or overt hypothyroidism was higher in hypercholesterolemic patients (44-46), a finding not confirmed in a subsequent study (47). Other markers of atherosclerotic risk described in overt hypothyroidism (enhanced low-density lipoprotein oxidation, elevated lipoprotein[a] levels, and hyperhomocysteinemia) may also be responsible for an association between subclinical hypothyroidism and coronary artery disease (48-50). Of interest, a recent quantitative review of patients with s

Hypothyroidism as a risk factor for cardiovascular disease

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.

Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas

PURPOSE The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. DESIGN We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. RESULTS Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). CONCLUSIONS The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

Thyroid-hormone therapy and thyroid cancer: a reassessment.

Experimental studies and clinical data have demonstrated that thyroid-cell proliferation is dependent on thyroid-stimulating hormone (TSH), thereby providing the rationale for TSH suppression as a treatment for differentiated thyroid cancer. Several reports have shown that hormone-suppressive treatment with the L-enantiomer of tetraiodothyronine (L-T4) benefits high-risk thyroid cancer patients by decreasing progression and recurrence rates, and cancer-related mortality. Evidence suggests, however, that complex regulatory mechanisms (including both TSH-dependent and TSH-independent pathways) are involved in thyroid-cell regulation. Indeed, no significant improvement has been obtained by suppressing TSH in patients with low-risk thyroid cancer. Moreover, TSH suppression implies a state of subclinical thyrotoxicosis. In low-risk patients, the goal of L-T4 treatment is therefore to obtain a TSH level in the normal range (0.5–2.5 mU/l). Only selected patients with high-risk papillary and follicular thyroid cancer require long-term TSH-suppressive doses of L-T4. In these patients, careful monitoring is necessary to avoid undesirable effects on bone and heart.

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

CONTEXT Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.

Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer.

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.

Thyroid and Obesity: An Intriguing Relationship

Obesity is one of the most important health risks of our time. The prevalence of obesity has increased worldwide since the mid 1970s. According to the National Health and Nutrition Examination Survey, obesity affected 32.2% of adults in 2003–2004 and reached a peak in subjects in the fifth decade of life (1). Obesity is associated with an increased risk of diabetes, dyslipidemia, kidney disease, cardiovascular disease, all-cause mortality, and cancer (1). Thus, severe obesity is an important cause of premature mortality among middle-aged adults (2). Moreover, obesity, especially central obesity, is linked to many endocrine abnormalities (3), including thyroid dysfunction (4). This is not surprising because T3 regulates energy metabolism and thermogenesis and plays a critical role in glucose and lipid metabolism, food intake, and the oxidation of fatty acids (4).

MECHANISMS IN ENDOCRINOLOGY: Heart failure and thyroid dysfunction

CONTEXT Heart failure (HF) is a major cause of morbidity and mortality in Europe and in the United States. The aim of this review article was to assess the results of the prospective studies that evaluated the risk of HF in patients with overt and subclinical thyroid disease and discuss the mechanism of this dysfunction. EVIDENCE ACQUISITION Reports published with the following search terms were searched:, thyroid, hypothyroidism, hyperthyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, levothyroxine, triiodothyronine, antithyroid drugs, radioiodine, deiodinases, clinical symptoms, heart rate, HF, systolic function, diastolic function, systemic vascular resistance, endothelial function, amiodarone and atrial fibrillation. The investigation was restricted to reports published in English. EVIDENCE SYNTHESIS The outcome of this analysis suggests that patients with untreated overt thyroid dysfunction are at increased risk of HF. Moreover, persistent subclinical thyroid dysfunction is associated with the development of HF in patients with serum TSH <0.1 or > 10 mU/l. CONCLUSIONS The timely recognition and effective treatment of cardiac symptoms in patients with thyroid dysfunction is mandatory because the prognosis of HF may be improved with the appropriate treatment of thyroid dysfunction.

Recombinant Human TSH Modulates In Vivo C‐Telopeptides of Type‐1 Collagen and Bone Alkaline Phosphatase, but Not Osteoprotegerin Production in Postmenopausal Women Monitored for Differentiated Thyroid Carcinoma

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.