DIFFERENT EFFECTS OF PROPRANOLOL, ALPRENOLOL, SOTALOL, ATENOLOL AND METOPROLOL ON SERUM T3 AND SERUM rT3 IN HYPERTHYROIDISM

Serum T4, T3, rT3 and T3 resin uptake (T3 RU) were measured before and after 7 days of treatment with either propranolol, alprenolol, sotalol, atenolol or metoprolol in hyperthyroid patients. We found a significant decrease in serum T3 after propranolol, alprenolol, atenolol and metoprolol but no change in the sotalol treated group. A significant increase in rT3 was found in the propranolol and alprenolol treated groups whereas a significant fall in rT3 was found in the atenolol and metoprolol treated groups. No change was found in the sotalol treated group. The changes observed in serum T3 and in rT3 could be explained by an inhibition of the 5'deiodinase enzyme by propranolol and alprenolol and an inhibition of both the 5'deiodinase and 5 deiodinase enzymes caused by atenolol and metoprolol.     

NOCTURNAL NATRIURESIS IN HYPERTHYROIDISM

We measured urine flow and the renal excretion of total solute, sodium, potassium and calcium in eleven patients with hyperthyroidism before and after treatment. Mean nocturnal sodium excretion was significantly greater (P < 0·05) during hyperthyroidism and was unaccompanied by any significant alterations in day time or 24-h values. As a result of this nocturnal natriuresis in hyperthyroidism significant changes were noted in the ratios of day/night sodium excretion (P < 0·005) and urinary flow (P < 0·05). The change in ratio of day/night sodium excretion resulting from treatment of hyperthyroidism was shown to correlate significantly with the change in plasma total triiodothyronine (r=0·73, P < 0·01). Twenty-four hour urinary calcium output was significantly greater (P < 0·02) in hyperthyroidism but there was no significant alteration in the day/night pattern of excretion.     

VITAMIN D METABOLISM IN HYPERTHYROIDISM

The serum concentrations of 25-hydroxycholecalciferol (25 OH D₃), 24,25-dihydroxycholecalciferol [24,25(OH)₂D₃] and 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃] were measured in twenty-one patients with untreated hyperthyroidism. Compared with control subjects, 25 OH D₃ concentrations were not altered, 24,25(OH)₂D₃ concentrations were increased, although not significantly and 1,25(OH)₂D₃ concentrations were decreased (P= 0.01). Following oral carbimazole therapy, 24,25(OH)₂D₃ concentrations fell (P<0.01), 1,25(OH)₂D₃ concentrations increased (P<0.01) and 25 OH D₃ concentrations were unchanged. The altered 1,25(OH)₂D₃ and 24,25(OH)₂D₃ concentrations found in hyperthyroidism are probably due to the effects of thyroid hormone on bone and mineral metabolism. Increased serum calcium and phosphate concentrations with secondary hypoparathyroidism result in stimulation of the renal 24-hydroxylase and suppression of the 1-hydroxylase enzymes. In addition, serum 24,25(OH)₂D₃ concentrations were significantly correlated with serum triiodothyronine levels (T3) (r= 0.66, P<0.002) before treatment. This may indicate a direct stimulatory effect of T3 on 24-hydroxylase activity. No relationship was found between serum 1,25(OH)₂D₃ concentrations before therapy and serum T3.     

HYPERTHYROIDISM IN GESTATIONAL TROPHOBLASTIC NEOPLASIA

The thyroid status of twenty-seven African patients with gestational trophoblastic neoplasia (GTN) was studied. Fifteen patients were found to be biochemically hyperthyroid (eight patients with choriocarcinoma; seven with hydatidiform mole). Of these fifteen patients, nine were clinically thyrotoxic. The most serious complication of thyrotoxicosis was life-threatening acute pulmonary oedema with associated cardiac failure. It was found that when serum levels of the human chorionic gonadotrophin (hCG) reached a level of about 0·1 ± 10⁶ iu/l, thirteen of sixteen patients were biochemically hyper-thyroid; at serum levels of 0·3 ± 10⁶ iu/l of hCG most patients were clinically thyrotoxic. A feature of hyperthyroidism associated with GTN is that whereas T4 is invariably raised the T3:T4 ratio tends to be low (0·015 ± 005); rT3:T3 ratios were high in this group. TSH levels were not increased.     

66例甲状腺功能亢进症患者骨质改变的临床分析

本文对66例甲亢患者测定了桡、尺骨矿物质含量(BMC)、骨密度(BD)、甲状旁腺激素(PTH)以及各种钙磷代谢的指标。50％的患者BMC和BD水平降低,44％的患者PTH水平升高。BMC和BD与病程、甲状腺肿、突眼及应用甲状腺素治疗呈相关关系。我们的初步结果表明BMC和BD的测定是甲亢骨病的一个辅助诊断指标。     

STUDIES OF THE EFFECTS OF SALICYLATE IN HYPERTHYROIDISM

Previous studies in rats have shown that salicylate depresses thyroid function by causing a fall in TSH secretion from the pituitary. This fall in TSH secretion has been correlated with a rise in free thyroxine (T₄) level due to displacement by salicylate from thyroxine-binding proteins in the plasma. There is evidence of similar changes following administration of salicylate to man. In view of these findings, the effects of salicylate have now been studied in hyperthyroidism. Consistent depression of the plasma P.B.I. level was noted in 12 hyperthyroid subjects given 6 grammes of salicylate per day for four days. However, there was no improvement in clinical status. A rise in metabolic rate was observed. There was also a rise in free T₄ (demonstrated with the dialysis procedure of Christensen). This increase in free T₄ was correlated with displacement of T₄ from thyroxine-binding prealbumin (TBPA). The isomer p-hydroxybenzoate was without effect on free T₄ and TBPA. There was a significant depression of three-hour uptake of radioiodine after salicylate administration (5 grammes per day for 48 hours), but no consistent effect on 24-hour uptake. The depression in uptake occurred in the presence or absence of long-acting thyroid stimulator (LATS). A slowing of secretion rate was noted in three of nine hyperthyroid subjects studied after therapeutic doses of ¹³¹I. LATS was demonstrated in one of these three subjects. The significance of these findings is discussed. The persistence of clinical hyperthyroidism has been shown to be correlated with a rise in free T₄ level, in spite of a fall in the plasma P.B.I. (total T₄) concentration. This finding indicates that the free T₄ level determines the clinical state of the patient. The reason for the fall in uptake of radioiodine and slowing of secretion rate is uncertain. The possibility of salicylate affecting the action of LATS on the thyroid gland is suggested.     

MATERNAL HYPERTHYROIDISM AND CONGENITAL MALFORMATION IN THE OFFSPRING

Six hundred and forty-three neonates from mothers with Graves' disease were examined for major malformations of external organs to compare the influence of maternal hyperthyroidism vs. ingestion of methimazole (MMI) during the first trimester on the incidence of congenital malformations. The subjects were divided into four groups according to maternal therapy and thyroid status during the first trimester as follows: (1) infants whose mothers did not receive MMI and were hyperthyroid (Group 1), (2) infants whose mothers did not receive MMI and were euthyroid (Group 2), (3) infants whose mothers received MMI and were hyperthyroid (Group 3) and (4) infants whose mothers received MMI and were euthyroid (Group 4). The prevalence of malformed infants in these four groups was 6.0% (three of 50), 0.3% (one of 350), 1.7% (two of 117) and 0.0% (none of 126), respectively. The incidence in Group 1 was significantly higher than that in Group 2 (P less than 0.01). There was no discernible dose dependency of MMI on the occurrence of malformations. These findings suggest that maternal uncontrolled hyperthyroidism may cause congenital malformations and that the beneficial role of MMI treatment outweighs its teratogenic effect, if any.     

SERUM TRIIODOTHYRONINE CONCENTRATION IN THE DIAGNOSIS OF HYPERTHYROIDISM

The serum triiodothyronine concentration is superior to the serum thyroxine concentration, the resin uptake test and the free thyroxine index in the diagnosis of hyperthyroidism. Over a 14 month period fifty-five patients attending an endocrine clinic with suspected thyrotoxicosis of all degrees of severity had blood taken on initial attendance and the serum was stored for routine thyroid function tests and triiodothyronine estimation. The patients were followed up and forty-six proved to be toxic and seven to be euthyroid; two could not be classified. Analysis of the initial serum showed that the serum triiodothyronine concentration was superior to the serum thyroxine concentration, the resin uptake test and the free thyroxine index in predicting the clinical outcome.     

老年人甲状腺功能亢进的临床特点

目的探讨老年人甲状腺功能亢进(甲亢)的临床特点。方法对1994年6月～2001年12月期间住我院的44例≥60岁老年甲亢患者的临床资料进行回顾性分析,并与随机抽取的同期住院50例中青年甲亢患者进行对比研究。结果老年甲亢患者临床症状不典型者较中青年组多;淡漠、嗜睡、精神症状、呕吐和粘液性水肿仅见于老年组;老年组中有消化系统症状者较中青年组多;心血管系统症状老年组以房颤等心律失常、心衰、心脏增大为主,心率>90次/分者较中青年组少;老年组中突眼者较中青年组少,而贫血、糖代谢异常者较之多见。以上结果,两组比较均有显著性差异(P<0.05)。老年组的血清FT3值明显低于中青年组(P<0.01);而两组血清FT4值、TSH值比较无显著性差异(P>0.05)。结论老年人甲亢的临床特点:(1)临床症状不典型者多,尤以淡漠、精神症状、嗜睡、呕吐、粘液性水肿为特殊;(2)消化系统症状以食欲减退等为多;(3)房颤等心律失常、心衰、心脏增大者多,而心率>90次/分者较中青年少;(4)突眼者少;(5)贫血者多;(6)糖代谢异常者多;(7)血清FT4值、TSH值变化近似中青年组,而FT3值虽升高,但幅度较中青年组明显低。     

HYPERTHYROIDISM INDUCED BY SECONDARY CARCINOMA IN THE THYROID

A young women presenting with hyperthyroidism proved to have diffuse infiltration of the thyroid with carcinoma probably from a primary breast adenocarcinoma. The gland was diffusely infiltrated with tumour although the thyroid follicles were intact. Blood thyroid hormone levels were raised but thyroid uptake of iodine was undetectable. It is suggested that the tumour released a locally active agent which stimulated hormone release but not iodine uptake, the latter being very low due to suppression of TSH.     

SKIN COLLAGEN AND THICKNESS IN HYPERTHYROIDISM AND MYXOEDEMA

Skin thickness, collagen content and density have been measured in patients with thyrotoxicosis and myxoedema. In hyperthyroidism the skin was of normal thickness but the absolute collagen content and density of collagen were both increased as was the percentage collagen content. In myxoedema both absolute percentage collagen content and density remained normal but the skin thickness was significantly increased and this correlated well with the severity of hypothyroidism and response to treatment.     

甲状腺功能亢进症患者的骨密度改变

对24例甲状腺功能亢进症的血钙(Ca)、磷(P)、碱性磷酸酶(AKP)、25(OH)D、1-25(OH)_2D,24小时尿Ca、P及骨密度进行了测定。结果显示骨密度降低占58.3％(±2s)。骨密度降低组T_3浓度高于骨密度正常组(P<0.05),病程长、病情重者骨密度降低更显著。两组血Ca、P、AKP、25(OH)D、1-25(OH)_2D及尿Ca、P等差异均无显著性,但1-25(OH)_2D比正常人低。     

THE CLINICAL SIGNIFICANCE OF PLASMA THYROID-STIMULATING ACTIVITY IN HYPERTHYROIDISM

The long-acting thyroid stimulator (LATS) measured by the method of McKenzie was detected in 36 of 60 cases of untreated hyperthyroidism—a figure comparable with that in other reported series. An association was found between LATS and several clinical features. There was a definite correlation between LATS and the occurrence of exophthalmos. The mean LATS level of 433% in 13 exophthalmic patients was significantly greater than the mean of 230% in 50 patients without exophthalmos (P<0·02. There was also a significantly higher level of LATS (P<0·05) in 34 patients who had a visible goitre (323%) than in 24 without visible goitre (184%). Sixteen patients who eventually had a recurrence of hyperthyroidism after therapy were found to have a significantly higher mean LATS level (411%) than 34 subjects who remained well (182%) (P<0·01). No correlation could be found between plasma LATS level and (a) thyroid ¹³¹I turnover, (b) the plasma level of protein-bound iodine and (c) the presence of a significant titre of antibodies to thyroglobulin in the patient's blood (Tanned red-cell titre 1/2500). The association between LATS and pretibial myx?dema was demonstrated by two patients who both had elevated plasma levels of LATS and unequivocal pretibial myx?dema when first examined. Follow-up studies over the ensuing three years demonstrated resolution of the pretibial myx?dema concurrently with disappearance of LATS from the plasma of one patient, and increasingly severe pretibial myx?dema associated with an increasing plasma level of LATS in the other. It is concluded that there is a significant relation between the plasma LATS level and various clinical features of hyperthyroidism. These data indicate the importance of LATS in relation to the pathogenesis of the disease. Recent chemical studies indicate that LATS belongs to the 7S globulins. These findings indicate that thyrotoxicosis, exophthalmos and pretibial myx?dema may result from disordered immunological mechanisms.     

THE TRH TEST IN THE COURSE OF TREATMENT OF HYPERTHYROIDISM

In nine patients with thyrotoxicosis (three patients with ophthalmopathy, one patient with T₃ thyrotoxicosis) we followed plasma levels of triiodothyronine (T₃) and thyrotoxine (T₄) and the TRH induced TSH release before and under treatment with propythiouracil (PTU), carbimazole or methimazol. The patients were observed for 2-8 months and did not receive any thyroid hormones during this time. Before treatment the TSH responses to TRH were absent in all patients. After commencement of antithyroid drug therapy the T₃ and T₄ plasma values decreased to normal (T₃) or subnormal levels (T₄) within 1-5 weeks and the patients became euthyroid, but at that time the TRH test was still negative in all patients. Moreover, there was a lag of between 2 weeks and 4 months in five of the patient before the TRH test became positive. The duration of this lag could not be correlated with any data of the history or the clinical signs. Several possible explanations for this observation are discussed. Our results suggest that the TRH-test is not suited for the control of the therapeutic effect of antithyroid drug therapy.     

SERUM CALCIUM CONCENTRATION IN HYPERTHYROIDISM AT DIAGNOSIS AND AFTER TREATMENT

In a large, mainly outpatient, series of hyperthyroid patients who attended a district general hospital the serum concentrations of calcium and albumin were measured before and in many cases after treatment. The calcium level (mean +/- SD) before treatment (2.41 +/- 0.21 mmol/l, n = 437) was significantly higher (P less than 0.01) than afterwards (2.36 +/- 0.15 mmol/l, n = 232) and the albumin level rose when the patients became euthyroid (from 40.5 +/- 3.1 g/l to 44.0 +/- 2.4 g/l; P less than 0.01). After treatment neither value differed from those of an unselected group of out-patients. The usual relation between the serum concentrations of calcium and albumin did not hold in the hyperthyroid subjects but reverted to normal on treatment; the variation, probably due to an increase in ionized calcium, leads to an overestimate of the 'corrected calcium' when conventional methods are used to calculate this figure. Thus, using a conventional formula 8.5% of our hyperthyroid patients would appear to have a calcium greater than 2.65 mmol/l (normal mean plus 2 standard deviations) whereas using a correction factor specific for the hyperthyroid situation the figure is reduced to 5.7% which is only twice the expected proportion. The calcium level was significantly greater (P less than 0.001) in those patients in whom initial T3 concentration was high (greater than 7.2 nmol/l). There was no effect of T4 upon serum calcium which could not be accounted for by the action of T3. In this series of 437 patients there was no case of symptomatic hypercalcaemia. The maximum value was 2.80 mmol/l in a patient with coincident primary hyperparathyroidism. Significant hypercalcaemia is rare in hyperthyroidism.     

SERUM TRIIODOTHYRONINE AND HYPERTHYROIDISM IN A POPULATION SAMPLE OF WOMEN

The serum T3 assay has been regarded as the most sensitive single test for hyperthyroidism although impaired conversion of T4 to T3 in non-thyroidal illness (NTI) might decrease its diagnostic sensitivity. The present report gives experience from the T3 assay in middle-aged females under conditions similar to those in a general health survey. The assays were performed during two periods with an interval of six years. In 1974–75 we studied a representative sample (n= 1283) of women of ages 44, 52, 56, 60 and 66 years in Göteborg, Sweden. Individuals with serum T3 concentration > mean + 2·5 SD were selected for a follow-up study (n= 21). Of 16 individuals with no previous thyroid disease and no present treatment with thyroid hormones or oestrogens, 14 were subjected to a TRH-stimulation test giving a normal TSH response in 10 cases having T3 concentrations up to mean + 3·5 SD. Four women with serum T3 concentration ≥ mean + 3·5 SD had previously unrecognized autonomous function thyroid function, of whom two developed hyperthyroidism after two years. The original population sample was reinvestigated after six years in 1980-81 (n= 1138) together with an additional sample of women giving a total sample of 1422 women of ages 26, 38, 50, 58, 62, 66 and 72 years. Of the females studied in 1974–75 eight had developed hyperthyroidism between the two studies; three of these had raised serum T3 at the investigation in 1974–75. No case of hyperthyroidism had been missed by the T3 assay in the 1974–75 study. Of individuals with serum T3≥mean + 2·5 SD selected for a follow-up (n= 29) at least five were found to have previously unrecognized thyroid autonomy. We found a raised serum T3 to be associated with hyperthyroid (n= 2) and euthyroid GRAVES' disease, autonomously functioning thyroid adenoma(s), possible painless subacute thyroiditis, possible thyrotoxicosis factitia, diminished thyroid reserve and thyroid substitution therapy. Since we did not correct for variations in protein binders a number of individuals with oestrogen-associated rise of total T3 were identified, but the rises were usually modest. The incidence of hyperthyroidism for the original sample as calculated for the six-year period was 1.3 cases/1000 women/year whereas the prevalence by 1980-81 was 13 cases/1000 women. We conclude that a single T3 determination will in most cases be sufficient for the diagnosis of clinical hyperthyroidism in a non-hospitalized population. Our study indicates some of the problems associated with the follow-up of a general screening for hyperthyroidism, the possible benefit of which remains to be studied.     

DISTURBED MINERAL METABOLISM IN HYPERTHYROIDISM: GOOD CORRELATION WITH TRMODOTHYRONINE

Mineral metabolism is frequently disturbed in hyperthyroidism. In a group of seventy-two patients with hyperthyroidism, we observed an increase in serum diffusible calcium in 50% of the cases, elevated inorganic phosphorus in 30% and elevated alkaline phosphatase in 44% of the cases. Correlations existed between the values of diffusible calcium, inorganic phosphorus, alkaline phosphatase and certain indices of thyroid function (T4, FT41, T3, FT3I), of which that with T3 was the best (P less than 0.001). Our results suggest that the magnitude of the disturbances of mineral metabolism depends on the severity of the hyperthyroidism and that it is the T3 level that constitutes the best index of that severity.     

PLASMA INSULIN DISAPPEARANCE CURVE AFTER INTRAVENOUS INSULIN INJECTION IN HUMAN HYPERTHYROIDISM

The disappearance curves of plasma insulin after intravenous injection of unlabelled pork insulin was studied in nine young female hyperthyroid subjects with Graves' disease and eleven young female normal subjects, who served as controls. Comparison of the curves by analysis of variance did not reveal statistical differences between them (F obtained = 2.8, F F 0.05 = 4.41), implying that there was no significant differences in the transference of injected insulin from plasma to the extra-vascular space between hyper- and euthyroid subjects. The results may suggest that the metabolism of insulin is not appreciably affected in hyperthyroidism.     

胺碘酮、索他洛尔与d-索他洛尔对犬心室肌细胞电生理作用的实验研究

目的分析胺碘酮、索他洛尔与d-索他洛尔对犬心室肌细胞电生理作用.方法采用标准玻璃微电极技术,观察胺碘酮、d,l-索他洛尔(即索他洛尔)与d-索他洛尔对犬心室肌细胞动作电位时程(APD)及跨壁复极离散(TDR)的作用,以研究三种药物不同的促心律失常发生率的机制.结果胺碘酮(5μM)对心室壁三层细胞APD作用不一,使M细胞的APD90缩短,而内、外膜的APD90延长,TDR降低.索他洛尔(100μM)使心室壁三层细胞APD90均延长,对M细胞APD延长更明显,使TDR增加.d-索他洛尔(100μM)使心室壁三层细胞APD90均增加,但以M细胞APD90增加最为显著,而且随着d-索他洛尔诱发早期后除极、APD交替变异发生,而在心室肌内、外膜细胞则未见上述变化.结论胺碘酮、索他洛尔及d-索他洛尔三种药物的不同促心律失常作用与其对心室TDR的作用不同有关.     

INSULIN SENSITIVITY IN HYPERTHYROIDISM: MEASUREMENT BY THE GLUCOSE CLAMP TECHNIQUE

Sensitivity to porcine insulin has been compared in overnight fasted hyperthyroid and control subjects using a euglycaemic clamp technique. Basal values for blood glucose, lactate, pyruvate, alanine, serum insulin and C-peptide were similar in the two groups, whilst blood glycerol (hyperthyroid 0.11 +/- 0.02 (mean +/- S.E.) vs. control 0.06 +/- 0.01 mmol/l, P less than 0.01) and blood 3-hydroxybutyrate (0.28 [0.03-0.79, range ]vs 0.09 [0.01-0.29 ]mmol/l, P less than 0.05) were increased in hyperthyroidism. During the 2 hour insulin infusion (0.05 U/kg/h), serum insulin plateaued at the same level (44 +/- 4 vs 44 +/- 1 mU/l) and insulin metabolic clearance rates were similar (1.21 +/- 0.10 vs 1.25 +/- 0.03 l/min). Serum C-peptide levels also decreased by similar amounts (40 +/- 8 vs 47 +/- 6%). The amount of glucose infused to maintain euglycaemia was identical during the second hour of insulin infusion (290 +/- 50 vs 330 +/- 30 mg/kg) as were the increments in lactate and pyruvate concentrations. Blood glycerol values decreased in both groups although values in hyperthyroid patients remained significantly higher than in controls. 3-Hydroxybutyrate concentrations fell to similar values in the two groups. These findings suggest that insulin-stimulated glucose metabolism and inhibition of ketogenesis are normal in hyperthyroidism.