Gaetano Lombardi

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

Growth hormone and the heart.

Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in GH deficiency and excess. Experimental and clinical studies have supported the evidence that GH and IGF‐I are implicated in cardiac development. In most patients with acromegaly a specific cardiomyopathy, characterized by myocardial hypertrophy with interstitial fibrosis, lympho‐mononuclear infiltration and areas of monocyte necrosis, results in biventricular concentric hypertrophy. In contrast, patients with childhood or adulthood‐onset GH deficiency (GHD) may suffer both from structural cardiac abnormalities, such as narrowing of cardiac walls, and functional impairment, that combine to reduce diastolic filling and impair left ventricular response to peak exercise. In addition, GHD patients may have an increase in vascular intima‐media thickness and a higher occurrence of atheromatous plaques, that can further aggravate the haemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. However, several lines of evidence have suggested that the cardiovascular abnormalities can be partially reversed by suppressing GH and IGF‐I levels in acromegaly or after GH replacement therapy in GHD patients.

Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury

objective  Acquired hypopituitarism in adults is obviously suspected in patients with primary hypothalamic–pituitary diseases, particularly after neurosurgery and/or radiotherapy. That brain injuries (BI) can cause hypopituitarism is commonly stated and has been recently emphasized but the management of BI patients does not routinely include neuroendocrine evaluations.

The Medical Treatment of Cushing’s Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery

BACKGROUND The role of dopamine agonists in the treatment of Cushings disease (CD) has been previously debated. AIM The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. PATIENTS AND METHODS 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery.

Growth-hormone and prolactin excess

The treatment of acromegaly and hyperprolactinaemia has been improved by the availability of effective and well-tolerated slow-release somatostatin analogues and dopamine agonists with long-lasting activity, such as cabergoline. The use of these drugs has extended the possibility of treatment to patients who would have responded poorly to the previously available compounds, such as octreotide or bromocriptine, and to those who were intolerant to pharmacotherapy. Moreover, the improvement in the management of acromegaly has enabled the reversal, at least partly, of cardiomyopathy and sleep apnoea, two important risk factors for morbidity and mortality in these patients.

Prolactin and Autoimmunity

The interrelationship between prolactin (PRL) and the immune system have been elucitaded in the last decade, opening new important horizons in the field of the immunoendocrinology. PRL is secreted not only by anterior pituitary gland but also by many extrapituitary sites including the immune cells. The endocrine/paracrine PRL has been shown to stimulate the immune cells by binding to PRL receptors. Increased PRL levels, frequently described in autoimmune diseases, could depend on the enhancement of coordinated bi-directional communications between PRL and the immune system observed in these diseases. Hyperprolactinemia has been described in the active phase of some non organ-specific autoimmune diseases, as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and organ-specific autoimmune diseases, as celiac disease, type 1 diabetes mellitus, Addisons disease, autoimmune thyroid diseases. In these diseases PRL increases the syntesis of IFNγ and IL-2 by Th1 lymphocytes. Moreover, PRL activates Th2 lymphocytes with autoantibody production. Of particular interest is the association between hyperprolactinemia and levels of anti DNA antibodies, islet cell antibodies (ICA), thyreoglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb), adrenocortical antibodies (ACA), transglutaminase antibodies (tTGAb) in SLE, in type 1 diabetes mellitus, in Hashimotos thyroiditis, in Addisons disease and in celiac disease, respectively. High levels of PRL have been also frequently detected in patients with lymphocytic hypophysitis (LYH). Several mechanisms have been invoked to explain the hyperprolactinemia in LYH. The PRL increase could be secondary to the inflammatory process of the pituitary gland but, on the other hand, this increase could have a role in enhancing the activity of the immune process in LYH. Moreover, the detection of antipituitary antibodies targeting PRL-secreting cells in some patients with idiopathic hyperprolactinemia suggests the occurrence of a possible silent LYH in these patients. Finally, the role of anti-prolactinemic drugs to inactivate the immune process in LYH is still discussed.

Thyroid Nodules and Related Symptoms Are Stably Controlled Two Years After Radiofrequency Thermal Ablation

BACKGROUND Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs. METHODS Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA. RESULTS All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed. CONCLUSIONS RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

High prevalence of endocrine dysfunction in long‐term survivors after allogeneic bone marrow transplantation for hematologic diseases

The progressively increasing number of long‐term survivors after allogeneic bone marrow transplantation (allo‐BMT) led researchers to focus on the early and late complications of this procedure. Endocrine dysfunction occurred mostly in patients who had undergone total body irradiation (TBI) as part of pretransplantation treatment. The extent to which chemotherapy and immune system derangement affect endocrine function in allo‐BMT recipients is still unclear.

Increased prevalence of tricuspid regurgitation in patients with prolactinomas chronically treated with cabergoline.

BACKGROUND Cabergoline, a dopamine receptor-2 agonist used to treat prolactinomas, was associated with increased risk of cardiac valve disease in Parkinsons disease. OBJECTIVE Our objective was to evaluate prevalence of cardiac valve regurgitation in cabergoline-treated patients with prolactinomas. DESIGN AND SETTING An observational, case-control study was conducted at a university hospital. PATIENTS Fifty treated patients (44 women and six men) and 50 sex- and age-matched control subjects participated; 20 de novo patients were also studied. INTERVENTION In the treated patients, the last cabergoline dose was 1.3 +/- 1.3 mg/wk (<1 mg/wk in 44%, 1-3 mg/wk in 46%, and >3 mg/wk in 10%). Treatment duration was 12-60 months in 32% and more than 60 months in 68%. The cumulative (milligrams x months of treatment) dose of cabergoline ranged from 32-1938 mg (median 280 mg). MEASUREMENTS Valve regurgitation was assessed according to the recommendations of the American Society of Echocardiography. RESULTS In de novo patients, treated patients, and controls, the prevalence of mild regurgitation of mitral (35, 22, and 12%, P = 0.085), aortic (0, 4, and 2%, P = 0.59), tricuspid (55, 30, and 42%, P = 0.13) or pulmonic (20, 12, and 6%, P = 0.22) valves was similar. Conversely, the prevalence of moderate tricuspid regurgitation was higher in the treated patients (54%) than in de novo patients (0%) and controls (18%, P < 0.0001). Moderate tricuspid regurgitation was more frequent in patients receiving a cumulative dose above the median (72%) than in those receiving a lower dose (36%, P = 0.023). A higher systolic (P = 0.03) and diastolic blood pressure (P < 0.0001) was found in patients with than in those without moderate tricuspid regurgitation. CONCLUSION Moderate tricuspid regurgitation is more frequent in patients taking cabergoline (at higher cumulative doses) than in de novo patients and control subjects, but the clinical significance of this finding has not been established. A complete echocardiographic assessment is indicated in patients treated long term with cabergoline, particularly in those requiring elevated doses.

Cushing's Syndrome

Cushings syndrome is a rare endocrine disease characterized by cortisol hypersecretion, induced mainly by a pituitary tumor (Cushings disease) or, rarely, by an adrenal or an ectopic neuroendocine tumor. Cushings syndrome is associated with severe morbidities and an increased mortality. The major systemic complications and the main cause of death are represented by cardiovascular disease. The prognosis of the disease is mainly affected by the difficulties in the diagnosis and treatment of the disease, which remain a considerable challenge.