Endogenous subclinical hyperthyroidism: Metabolic and cardiac parameters.

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

Iodide organification defect in iodine deficiency endemic goiter.

In 17 goitrous persons in an iodine-deficient area, in 23 nongoitrous inhabitants of the same village, in 10 goitrous persons in Athens, and 8 normal controls the perchlorate discharge test was performed, either in the simple standard form or after pretreatment with either 0.5 or 2.0 mg potassium iodide or 2.5 mg carbimazole. With the simple test or with 0.5 mg potassium iodide, there was no significant discharge in any group studied. With 2.5 mg carbimazole, there was a profound discharge of the trapped iodide in both groups in the iodine-deficient area. With 2.0 mg potassium iodide, however, there was a clear discharge in the two goitrous groups (i.e. the one in the endemic area and the second in Athens), a less pronounced discharge in the controls studied in Athens, and no discharge at all in the nongoitrous inhabitants of the iodine-deficient endemic area. These findings provide evidence for an abnormality present in the patients with endemic goiter, most probably faulty iodine utilization due to impaired organic binding. The nongoitrous persons in the endemic areas, on the other hand, seem to be even more efficient in handling the trapped iodide than the controls studied in Athens. These findings may provide an explanation for previous observations that in endemic areas only part of the population develop a goiter, whereas the others adapt successfully to iodine deficiency without significantly enlarging their glands.

High serum cholesterol levels in persons with 'high-normal' TSH levels: should one extend the definition of subclinical hypothyroidism?

OBJECTIVE: The association between established hypothyroidism and high cholesterol levels is well known. The aim of the present study was to investigate the effect of thyroxine (T4) administration on cholesterol levels in hypercholesterolemic subjects with TSH levels within the normal range ('high-normal' TSH compared with 'low-normal' TSH). DESIGN AND METHODS: We determined TSH levels in 110 consecutive patients referred for hypercholesterolemia (serum cholesterol >7.5 mmol/l). Those with 'high-normal' TSH (2.0-4.0 microU/ml) as well as those with 'low-normal' TSH (0.40-1.99 microU/ml) were randomly assigned to receive either 25 or 50 microg T4 daily for two months. Thus, groups A and B (low-normal TSH) received 25 and 50 microg T4 respectively and groups C and D (high-normal TSH) received 25 and 50 microg T4 respectively. Serum T4, tri-iodothyronine (T3), TSH, free thyroxine index, resin T3 uptake and thyroid autoantibodies (ThAab) as well as total cholesterol, high and low density lipoprotein cholesterol (HDL, LDL), and triglycerides were determined before and at the end of the two-month treatment period. RESULTS: TSH levels were reduced in all groups. The most striking effect was observed in group D (TSH levels before: 2.77+/-0.55, after: 1.41+/-0.85 microU/ml, P < 0.01). Subjects in groups C and D had a higher probability of having positive ThAabs. A significant reduction in total cholesterol (P < 0.01) and LDL (P < 0.01) was observed after treatment only in group D. In those subjects in group D who were ThAab negative, there was no significant effect of thyroxine on cholesterol levels. CONCLUSIONS: Subjects with high-normal TSH levels combined with ThAabs may, in fact, have subclinical hypothyroidism presenting with elevated cholesterol levels. It is possible that these patients might benefit from thyroxine administration.

The predominant form of non-toxic goiter in Greece is now autoimmune thyroiditis.

Endemic non-toxic goiter (NTG) in Greece has been attributed primarily to iodine deficiency. Thirty years ago about 60% of the prepubertal boys and girls examined in endemic goiter regions presented with NTG and among them thyroid autoimmunity was rarely detected. Although iodine supplementation has corrected this deficiency during the past 30 years, new cases of NTG still appear. To evaluate the prevalence and type of NTG and the effect of iodine supplementation on them in Greece at present, we performed two cross-sectional clinical studies and a retrospective pathology one: (i) thyroid gland volume and urinary iodine excretion (UIE) were assessed in a representative sample of 1213 schoolchildren from previously endemic and non-endemic regions; (ii) serum thyroxine, tri-iodothyronine, TSH, thyroid autoantibodies (AAB) (anti-thyroid peroxidase and anti-thyroglobulin antibodies) and UIE (in 60 patients) were measured in 300 consecutive patients with NTG from Athens and Heraklion; and (iii) we compared the prevalence of autoimmunity among fine needle aspiration smears of benign thyroid pathologies performed by the same pathologist between 1985 and 1986 (975 cases) and between 1994 and 1995 (2702 cases). We found that 12. 5% of the schoolchildren examined in regions with a previous history of endemic goiter had NTG, whereas this percentage was only 1.7% in areas without such a history. In Athens (61.6%) and Heraklion (58. 5%) a substantial number of NTG patients were AAB positive and biochemically hypothyroid. UIE in Athens did not differ between patients with autoimmune goiter (ATG) and simple goiter. The prevalence of autoimmune stigmata in pathology smears has increased from 5.94% (years 1985-1986) to 13.91% (years 1994-1995) (P<0.05). We conclude that: (i) the persistence of endemic goiter in regional foci despite iodine deficiency correction suggests a possible role for a naturally occurring goitrogen; (ii) ATG is the predominant form of NTG in Greece nowadays; and (iii) the five-fold decrease in the prevalence of NTG during the past 30 years followed by the increase of ATG may support the relative character of the latter.

The effect of iodine administration on the development of thyroid autoimmunity in patients with nontoxic goiter.

OBJECTIVE: Previous studies, mostly performed in iodine-deficient areas, have suggested that the administration of iodine to patients with endemic goiter may be associated with the development of thyroid autoantibodies (ThAbs); however, this has not been a consistent finding. In this study, we evaluated the effect of iodine on thyroid function and on the development of indices of autoimmunity (ThAbs and lymphocytic infiltration) in an iodine replete area. METHODS: Iodized oil (1 mL) was administered intramuscularly to 40 euthyroid patients with nontoxic goiter, adequate iodine intake, and absent or normal levels of ThAbs. Blood and urinary samples were taken at time 0, 3, 6, and 12 months after iodine administration. Thyroid volume was evaluated and fine-needle aspiration (FNA) was performed at 0, 6, and 12 months. RESULTS: Seven patients developed abnormal levels of ThAbs at some time between 3 and 12 months after iodine administration (p = 0.017). Mean anti-thyroglobulin (Tg) antibody levels increased at 6 months without reaching abnormal levels, but did not reach statistical significance (p = 0.062). Lymphocytic infiltration was detected in FNA smears in 10 cases before and in 27 cases after treatment (p = 0.0003). Triiodothyronine (T3) decreased at 12 months of follow-up, while thyroxine (T4) and thyrotropin (TSH) levels did not change significantly. A decrease in the mean levels of thyroglobulin as well as a small reduction in goiter size was observed at 6 and 12 months. CONCLUSION: The administration of iodized oil to patients with small nontoxic goiter in an iodine-replete area was accompanied by the development of abnormal levels of ThAbs in some cases and by an increase in thyroid lymphocytic infiltration.

Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values.

Patients with hypothyroidism are considered to have an increased risk of developing atherosclerosis; because endothelial dysfunction is an early sign of atherosclerosis, we investigated whether endothelial dysfunction is present in patients with hypothyroidism. Thirty-five subjects with various TSH levels were investigated by high-resolution ultrasound imaging of the brachial artery to assess endothelial and smooth muscle responses. Flow-mediated, endothelium-dependent vasodilatation was significantly higher in subjects with TSH 0.4-2 microIU/mL (11.8 +/- 2.7%), compared with subjects with TSH 2.01-4 microIU/mL (6.8 +/- 2.9%), 4.01-10 microIU/mL (5.2 +/- 6.3%) and >10 microIU/mL (4.0 +/- 4.4%); TSH levels correlated inversely to endothelium-dependent dilatation. Thus, flow-mediated vasodilatation, a marker of endothelial function, is impaired not only in patients with mild hypothyroidism but also in subjects with "high-normal" serum TSH levels (ie, 2.01-4.0 microIU/mL) that may be characterized as possibly abnormal.

Mitral valve prolapse in autoimmune thyroid disease: an index of systemic autoimmunity?

A coexistence of mitral valve prolapse (MVP) with autoimmune thyroid disease (AITD) has been described, but there are not sufficient data to explain this association. The aim of the present study was to investigate the prevalence of MVP in patients with AITD and to evaluate whether any correlation between MVP and certain immunological parameters exists. M-mode, two-dimensional Doppler echocardiography was performed in 29 patients with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 20 with nonautoimmune goiter, and 30 normal controls. Serum samples were examined for antinuclear antibodies (ANA), antibodies against extractable nuclear antigen (ENA), antiphospholipid antibodies (aCL), rheumatoid factor (RF), thyroid autoantibodies (TAAb), immunoglobulins and C3, C4. Eight of 29 GD patients and 8 of 35 HT patients had MVP, while none of the control group and 2 of 20 of the simple goiter group had MVP (p < 0.05). ANA were detected at low titers in 5 of 8 in MVP(+) GD versus 3 of 21 in MVP(-) GD (p < 0.05). In the HT group the MVP(+) patients had a significantly higher incidence of ANA and ENA, 5 of 8 and 2 of 8 versus 5 of 27 and 0 of 27 of MVP(-) patients, respectively, p < 0.05. A statistically significant higher incidence of aCL was found in HT MVP(+) patients. (3/8) versus HT MVP(-) 1/27, p < 0.05. RF levels (immunoglobulin A [IgA]) were significantly higher in MVP(+) patients. The association of MVP with nonorgan-specific autoantibodies indicates that MVP may also be an autoimmune disease. It is possible that patients with AITD who also have MVP may be at an increased risk to develop systemic autoimmunity.

Some epidemiologic studies of HBSAg in Greece.

In an epidemiologic study in 17 villages from different areas of Greece, 2898 persons were examined in order to find possible relations between HBSAg prevalence, altitude and endemic goitre morbidity. A lower prevalence with a significant difference was found in areas with a high altitude as compared with those with a low one, in endemic goitre than non-endemic areas, and in low altitude endemic than in low altitude non-endemic areas. Goitrous subjects had a lower HBSAg prevalence than non-goitrous subjects, but the difference was of borderline significance. The results can probably be explained by the presence of an environmental factor associated with altitude acting together with a host factor predisposing to endemic goitre and favouring the immunity to HBV infection.

Lack of influence of povidone-iodine on tests of thyroid function.

The external application of povidone-iodine, an antiseptic agent, was tested for its influence on thyroid function. Previous workers have described some in vitro changes in thyroid function tests following its use. In the present study topical application of povidone-iodine did not affect thyroid function as measured some days later using both in vivo and radio-active iodine in vitro test methods, despite the fact that the latter are notorious for being influenced by exogenous iodine.

The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement.

OBJECTIVE: To clarify the duration and the extent of the antithyroid effect of iodides in hyperthyroidism, and to investigate whether iodides have an additional peripheral effect on the metabolism of thyroid hormones, as has been reported for some organic iodine compounds. DESIGN: The effect on the peripheral thyroid hormone levels of 150 mg of potassium iodide daily (equivalent to 114 mg of iodide) for 3-7 weeks was compared in 21 hyperthyroid patients and 12 healthy controls. A possible effect of iodide on the peripheral metabolism of thyroid hormones was investigated by assessing the serum levels of thyroid hormone in 12 hypothyroid patients on thyroxine replacement for 2 weeks. PATIENTS: There were 21 thyrotoxic patients, 12 healthy hospital controls, and 12 patients with complete or near-complete hypothyroidism, on thyroxine replacement. MEASUREMENTS: The following were measured before and at weekly intervals after iodide administration: (1) pulse rate, (2) serum T4, (3) serum T3, (4) serum TSH, (5) serum thyroxine-binding capacity (TBC), (6) serum rT3, (7) serum thyroxine-binding globulin (TBG), (8) the free-T4 Index, calculated as T4/TBC. RESULTS: In the hyperthyroid patients serum T4, T3 and rT3 decreased, whereas serum thyroxine-binding globulin and thyroxine binding capacity increased. Serum T3, however, did not become completely normal in all cases. After 21 days, serum T4 and T3 started increasing again in some cases, but other patients remained euthyroid even after 6 weeks. In the normal controls there was a small but significant and consistent decrease in serum T4, T3 and rT3 and an increase in serum TSH. Finally, in the T4-treated hypothyroid patients there was no consistent change, except for an increase of serum T4 at 1 and 14 days and a decrease of serum TSH the first day. CONCLUSION: Iodides in hyperthyroidism have a variable and unpredictable intensity and duration of antithyroid effect. Their antithyroid effect is smaller in normal controls. They have no important effect on the peripheral metabolism of thyroid hormones.

Serial serum calcitonin concentrations to evaluate response to therapy of patients with medullary thyroid carcinoma.

Six female patients with medullary thyroid carcinoma were treated with doxorubicin (50 mg/m2) and cis-diammine dichloroplatinum (70 mg/m2) every three weeks. No patient responded to therapy as was suggested by serial serum calcitonin concentrations before and after treatment.

Treatment of hyperthyroidism with potassium iodide.

Potassium iodide was given to 17 cases of Basedow's disease in comparison to 12 normal controls for 5 weeks. In the thyrotoxic patients, the maximum decrease in serum T3 and T4 levels was observed 2 and 3 weeks, respectively, but in some cases remained normal even at 5 weeks. The euthyroid persons showed a small decrease in T4 and T3 and an increase in serum TSH.

An epidemiologic survey of thyroid enlargement among schoolchildren in a non-endemic area.

In 534 unselected schoolchildren aged 6-14 yr from the greater Athens area the size of the thyroid gland was assessed by palpation, and information was obtained on sex, age, height, weight, skinfold thickness, socioeconomic class, eye colour and urinary iodine excretion. The results were analysed by discriminant analysis. Altogether 14% of these children had a thyroid enlargement (7% had a definite goitre and another 7% a smaller enlargement). The set of variables studied were significantly discriminatory (Wilk's lambda 0.926, p approximately equal to 0.004). Most of the discrimination was accounted for by height (positive association, b coefficient 0.0114, SE 0.0029, t = 3.95) and weight (negative association, b coefficient 0.0107, SE 0.0030, t = 3.61). No other parameter, including iodine excretion, showed a significant difference between goitrous and nongoitrous. It is concluded that the only genuine difference is that goitrous are heavier for a given height or shorter for a given weight, i.e. more obese. The reason for which obesity protects from sporadic nontoxic goitre is not entirely clear, but probably both nutritional and genetic factors are involved.

Increased mean serum thyrotropin in apparently euthyroid hypercholesterolemic patients: does it mean occult hypothyroidism?

Serum thyroid hormones and antithyroid autoantibodies (AAB) were assayed in 87 randomly selected hypercholesterolemic persons compared to 80 controls with normal serum total cholesterol (TC). Of the 87 hypercholesterolemic persons 22 (25%) had positive AAB compared to 5 (6%) controls. Furthermore, 8 of the hypercholesterolemic patients had a serum TSH level above 5 mU/l, i.e. the had subclinical hypothyroidism, not diagnosed before, whereas thyroid function was normal in all normocholesterolemic persons. The new and unexpected finding was that the hypercholesterolemic persons had on average a significantly higher serum TSH than the controls, and this was true even when persons with positive AAB were excluded. There was a significant correlation between TC and serum TSH. It is concluded that hypothyroidism may not be an all-or-none phenomenon, and that many hypercholesterolemic persons with thyroid tests within the conventional normal range may have a slight impairment of their thyroid function.

Comparison of the effect of amiodarone and benziodarone on thyroxine metabolism and surface ECG.

This study examined whether or not the electrophysiological effect of amiodarone on the heart is mediated through its action on thyroxine metabolism. Serum thyroid hormones and ECG were evaluated before and serially during amiodarone (15 subjects) and benziodarone (15 subjects) administration. Both amiodarone and benziodarone shifted the peripheral conversion of thyroxine (P less than 0.001 for amiodarone and P less than 0.001 for benziodarone) towards reverse triiodothyronine and away from triiodothyronine, whilst TSH levels initially fell and then rose with both drugs. After amiodarone the heart rate decreased (P less than 0.025), whilst the PR (P less than 0.005) and the QT interval (P less than 0.005) corrected for the heart rate increased. By contrast with benziodarone only the PR interval decreased (P less than 0.05). Since both drugs had roughly similar effects on thyroid hormone metabolism but different ones on the ECG, our results provide indirect evidence against the hypothesis that the antiarrhythmic effects of amiodarone are mediated through a decrease in the serum T3 presented to the peripheral tissues.

Metabolic insufficiency as a limiting factor in the dietetic treatment of obesity.

Previous observations that acute total fasting decreases serum T3 and increase rT3 has prompted the following study. 17 obese women were placed on a 1000 kcal/day weight-reducing diet, and body weight (BW), serum T4, RT3U, T3, rT3, TSH and the Achilles tendon reflex (ATR) were estimated before and after each month for 3 consecutive months of the diet. The results showed a consistent decrease in serum T3, and inconsistent increase in rT3, a consistent prolongation of the ATR and a levelling-off of the BW loss after the second month of the diet. At 3 months there was a negative correlation between the decrease in BW and the increase in ATR, i.e. the more abnormal the ATR became, the less weight the patient lost. It is concluded: 1) Even a moderate hypocaloric diet in ambulatory patients induces a disturbance in the peripheral conversion of T4 to T3 and a secondary state of metabolic insufficiency. 2). This insufficiency is probable related to the observed tendency of the BW loss to level off after two months. 3) A controlled trial of physiologic doses of T3, such as 40 mu g/day, seems indicated, as opposed to pharmacologic dosed of T3 used by previous investigators.

Thyroid autoantibodies in the subsets of lupus erythematosus: correlation with other autoantibodies and thyroid function.

Thirty four sera from: 12 patients with Systemic Lupus Erythematosus (SLE), 9 with Subacute Cutaneous Lupus Erythematosus (SCLE) and 13 with Discoid Lupus Erythematosus (DLE) (disseminatus 3, localised 10) were tested for the presence of: (a) anti-thyroglobulin and anti-microsomal autoantibodies (b) anti-Sm/RNP, anti-doublestranded. DNA (anti-ds. DNA), anti-single-Stranded. DNA (anti-ss. DNA), anti-cardiolipin (anti-Cl), anti-SSA, anti-SSB, Antinuclear Antibodies (ANA). T3, T4, TSH levels were also determined. Five patients with SLE (41.6%), 4 with SCLE (44.4%), and 2 with DLE (15.3%) had thyroid autoantibodies and only three of the 41 controls (7.3%). Five patients (14.7%), especially from SLE and SCLE groups, had biochemical hypothyroidism whereas only one had hyperthyroidism. Statistical evaluation for the possible coexistence of thyroid autoantibodies with a panel of lupus characteristic autoantibodies, revealed highly significant correlations with anti-Sm/RNP, IgG (p = 0.003) and anti-ds. DNA, IgM (p = 0.012). It may be concluded, that not only SLE but also SCLE predisposes to autoimmune thyroid disease and the prevalence of the latter is related to a great extent to the subset of the LE spectrum. From these results and from the inhibition experiments, it seems that some of the specific mono- or polyclonal autoantibodies may be multiple organ reactive.

Thyroid gland neurofibroma in a NF1 patient.

Neurofibromas are a hallmark of neurofibromatosis type 1 (NF1). They are usually benign and rarely present in the thyroid gland region. There is a suspected association between NF1 and intramedullary thyroid carcinoma and there is a well-known association between NF1 and pheochromocytoma. Here, we present a 55-year-old man with typical symptoms of NF1, whose course was complicated by a neurofibroma of the thyroid gland. His clinical spectrum of symptoms included bilateral cataract established before the age of 35 years, quadriparesis and an intrathoracic mass. The patient died because of abdominal carcinomatosis of unknown origin. The rarity of thyroid gland neurofibroma is discussed here, emphasizing the importance of early detection of these and other NF1 complications, also including the risk of malignant transformation with lethal outcome.

The effect of benziodarone on the thyroid hormone levels and the pituitary-thyroid axis.

The effect of benziodarone on the levels of thyroid hormones in the serum has not attracted interest, in spite of the prolific literature on the related drug amiodarone. It is shown here that benziodarone administration has several effects, mainly similar to amiodarone, but some possibly opposite and inappropriate. Nine normal volunteers received benziodarone, 100 mg three times daily for 14 days. Before and 1, 3, 7 and 14 days after continuous administration the following estimates were obtained: serum T4, T3, rT3 and TSH, both basal (TSH0) and 30 min after iv administration of TRH (TSH30), the difference being calculated as delta TSH. Serum T4 remained relatively constant. Serum T3 decreased significantly from the 1st to the 14th day (eg. before 2.15 +/- 0.12 nmol/l, at 3 days 1.45 +/- 0.07). Serum rT3 increased significantly from the 1st to the 14th day (eg. before 0.71 +/- 0.16 nmol/l, at 7 days 2.61 +/- 0.19). Serum TSH0 and TSH30 decreased significantly on the 1st and 3rd day. Later they increased, and TSH0 at 14 days was significantly higher than the pre-treatment value. Our results suggest that benziodarone has an amiodarone-like action in diverting the peripheral metabolism of T4 towards rT3 rather than T3. However, the effects on the pituitary-thyroid axis are not similar to those previously reported by others and ourselves about amiodarone, and these merit further research.