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.     

ANALYSIS OF FACTORS IN HYPERTHYROIDISM, WHICH DETERMINE THE DURATION OF SUPPRESSIVE TREATMENT BEFORE RECOVERY OF THYROID STIMULATING HORMONE SECRETION

In twenty-three thyrotoxic patients a prospective study was undertaken to assess the time until restoration of TSH secretion. For several methodological reasons we chose to study a model in which the patients were deliberately continued on full dose treatment until biochemical hypothyroidism was established. The period until reappearance of TSH secretion varied between 42 and 293 days. In this time FTI had become subnormal, while T3 and the clinical index remained in the normal range. The interval until TSH restoration was not correlated with the parameters of thyroid status from the initial evaluation with the exception of a negative correlation with log PB¹³¹I 48 h (r= 0·511; P < 0·02). The average follow up period in our patients was 115 days during which FTI decreased exponentially to 19±7 ± 20±5. The disappearance of T3 followed a biphasic course in which after 2–4 weeks T3 decline practically ceased and concentrations remained normal. Assuming that a FTI between 100 and 65 was the threshold value beneath which hypophyseal TSH synthesis and secretion could be expected, we were able to determine the interval between the corresponding date and the date of returning TSH secretion in twenty-one patients. This latency time was 34 ± 9±7 days and proved completely independent of the total time until TSH reappearance. In contrast there was a highly significant correlation (r= 0·987; P<0·001) between the time to reach the assumed threshold level and the time to recovery of TSH secretion. The disappearance of FTI, although widely variable from patient to patient, showed a constant rate throughout the full scale from elevated to practically absent concentrations. Thus, the initial part of the disappearance curve determines the length of time until restoration of TSH secretion. This is illustrated by the tight relationship (r= 0·92; P < 0·001) between FTI after 28 days of treatment and the time when TSH started to rise. Knowledge of the FTI on day 28 allows treatment to be tailored to the needs of the individual patient.     

THYROID FUNCTION IN CHORIOCARCINOMA: DEMONSTRATION OF A THYROID STIMULATING ACTIVITY IN SERUM USING FRTL-5 and HUMAN THYROID CELLS

Hyperthyroidism is a well recognized complication of gestational trophoblastic tumours (GTT) and may be due to high circulating concentrations of human chorionic gonadotrophin (hCG) or its variants. We have studied 24 clinically euthyroid women with GTT. Eight were biochemically hyperthyroid with low or undetectable serum thyrotrophin (TSH) and had a mean serum hCG of 361.2 x 10(3) IU/l compared to 76.2 x 10(3) IU/l in the other patients (P less than 0.01). Purified hCG stimulated iodide uptake into FRTL-5 cells with 25 x 10(3) IU/l being equivalent in potency to 1 mU/l of thyrotrophin (TSH). Sixteen out of the 24 sera (67%) stimulated iodide uptake when applied to the cells at a 1:10 dilution. Sera from all eight hyperthyroid patients contained thyroid stimulating activity. The mean hCG concentration in the 16 stimulatory sera was 238.2 x 10(3) IU/l compared to 37.1 x 10(3) IU/l in the other eight sera (P less than 0.01). Six men with hCG-secreting testicular tumours were biochemically euthyroid although three of their sera stimulated iodide uptake into FRTL-5 cells. In human thyroid cells the mean cAMP production over 4 h with sera from five healthy controls was 54.2 +/- 1.81 pmol/mg cell protein compared to 67.0 +/- 3.8 pmol/mg protein with sera from five choriocarcinoma patients (P less than 0.02). Serum from patients with gestational trophoblastic tumours contains a thyroid stimulating activity which may be hCG and whose presence correlates with hyperthyroidism.     

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.     

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.     

HYPERTHYROIDISM AND THE IMPALPABLE THYROID GLAND

A retrospective analysis of 594 unselected cases of hyperthyroidism from one district was made to determine whether the thyroid gland had been palpable on presentation. The thyroid had been diffusely palpable in 374 patients (63%), nodular in 110 (19%) and impalpable in 96 (16%); there was no clinical record in 14 (2%) cases. Under 40 years of age a diffuse gland was usual, being present in 86% of cases. The proportion of nodular and impalpable glands both increased progressively with age comprising 30% and 48% respectively in patients older than 70 years. Grave's ophthalmopathy was present in 13% of hyperthyroid patients with diffuse glands, in 12% of those with impalpable glands, but in only 1.5% of those with nodular thyroids. Thyroid autoantibodies were found with a similar frequency in all three groups. There was a very good correspondence between clinical assessment of shape and nodularity of thyroid and the results of isotope scanning; the majority of patients with impalpable glands (86%) had a diffuse uptake of isotope. In the elderly hyperthyroid patient an impalpable thyroid gland is common and is not a factor to weight against the diagnosis.     

THE INACTIVATION OF THYROTROPHIN RELEASING HORMONE BY PLASMA IN THYROID DISEASE

The inactivation of immunoreactive TRH in vitro by human plasma has been investigated. In a preliminary study, 2.5 ng TRH was destroyed by 50 μl plasma at a mean rate of 1.7%/min in eight subjects. The per cent inactivation of the same amount of TRH at three plasma dose levels was measured after 60 min in seventy unselected patients attending a thyroid clinic. There was no significant difference in the results obtained in those subsequently shown to be euthyroid (forty-three patients), hyperthyroid (eighteen patients) or hypothyroid (nine subjects).     

地方性甲状腺肿过氧化物酶活性的改变

本文采用生化方法测定地方性甲状腺肿组织甲状腺过氧化物酶(TPO)活性,同时采用免疫组化方法原位观察TPO的改变。结果发现:地甲肿组织TPO活性变化范围很大,胶质结节TPO活性减低,而胶质结节伴增生及实质结节TPO活性明显增高。增生的甲状腺滤泡细胞(如乳头状增生),小滤泡及胎儿型滤泡多为TPO阳性或强阳性,而复旧扁平的滤泡细胞多为TPO阴性。地甲肿组织TPO活性的极不均一性主要受TSH水平的影响。把地甲肿组织结节性变化主要分为胶质结节和实质结节,比较好地反映了地甲肿组织功能状态。     

CHARACTERIZATION OF TSH ANTAGONIST ACTIVITY IN THE SERUM OF PATIENTS WITH THYROID DISEASE

The ability of sera from patients with thyroid disease to block TSH stimulation of cyclic AMP release from isolated porcine thyroid cells has been assessed and the blocking activity characterized. TSH receptor binding activity was also measured. No blocking or receptor binding activity was detectable in patients with primary myxoedema (n = 23), Hashimoto's disease (n = 11), multinodular goitre (n = 6), or rheumatoid arthritis (n = 10). However, analysis of sera from 23 patients (out of an initial screen of 110 patients) with treated Graves' disease which did not stimulate cyclic AMP production in the bioassay showed that two of these sera contained powerful blocking and receptor binding activity. Both these patients had been treated with 131I. Analysis of the two sera by gel filtration on Sephadex G-200 indicated that blocking and TSH receptor binding activity were associated only with the IgG fraction. Digestion of the IgG with pepsin followed by reduction showed that both (Fab)2 and Fab fragments contained high levels of blocking and binding activity. Antibody divalency was not necessary therefore for TSH antagonist activity. However, our studies suggest that autoantibodies of this type with TSH antagonist activity do not occur frequently in patients from the Cardiff region with primary myxoedema, Hashimoto's or treated Graves' disease.     

STUDIES OF DIURNAL CHANGES IN PLASMA RENIN ACTIVITY, AND PLASMA NORADRENALINE, ALDOSTERONE AND CORTISOL CONCENTRATIONS IN MAN

Diurnal studies were performed on ten normal volunteers taking a normal sodium diet. Half-hourly blood samples were taken throughout 25 h and assayed for plasma renin activity (PRA) and the plasma concentrations of noradrenaline, aldosterone and cortisol. Sleep was recorded polygraphically and scored by standard criteria. Circadian rhythms were demonstrated for plasma cortisol, aldosterone and noradrenaline concentrations, but not for plasma renin activity. The nadir of the rhythm for the noradrenaline concentration appeared to be related to sleep itself rather than to any chronological index. Only PRA was effected by the stage of sleep, falling sharply during periods of REM sleep. Plasma cortisol and aldosterone concentrations showed a positive correlation over the 24 h. There was, however, no correlation between PRA and plasma aldosterone concentrations, except when the subjects arose after their night's recumbency. Plasma noradrenaline concentration did not correlate with the concentration of any of the other hormones measured.     

THE ASSAY FOR THYROID STIMULATING IMMUNOGLOBULINS USING CULTURED HUMAN THYROID CELLS

Recent reports have shown that thyroid-stimulating immunoglobulins (TSI) may be detected by measuring cyclic AMP increases in cultures of isolated thyroid cells in response to added patient immunoglobulins (Ig). We have compared the frequency that TSI may be detected in the Ig fraction of 114 sera from 112 patients with a variety of thyroid disorders, to the presence of thyrotrophin binding inhibitor Ig (TBII). Whereas the sera of 46 out of 48 (95.6%) patients with untreated thyrotoxic Graves' disease had detectable TSI, only 26 out of 48 (54.2%) had detectable TBII. We did not find any significant correlation between TSI and TBII for these patients but there was a significant correlation between TSI and both serum T3 (r = +0.55, P less than 0.01) and T4 (r = +0.50, P less than 0.01). Twelve patients were studied at the time of relapse of thyrotoxicosis due to Graves' disease. All sera contained detectable TSI whereas only one contained detectable TBII. Of the sera from 20 patients in remission after antithyroid drug therapy three were positive for TSI. One of these samples as well as two others had detectable TBII. The two samples with TBII in the absence of TSI came from patients who had developed hypothyroidism. TSI were detected in the serum of one out of nine patients with Hashimoto's thyroiditis but not in the sera of 20 other patients with a variety of non-autoimmune thyroid disorders including five patients with thyrotoxicosis not due to Graves' disease. However TSI was found in the sera of three out of five patients with exophthalmos and no history of hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

THYROID STIMULATING ANTIBODIES (TSAb) IN PATIENTS WITH GRAVES' DISEASE UNDERGOING ANTITHYROID DRUG TREATMENT: INDICATORS OF ACTIVITY OF DISEASE

Thyroid-stimulating antibodies (TSAb) were studied in patients with Graves' disease using a method based on cAMP production in isolated human thyroid membranes. Stimulation was detected in forty-one (82%) of fifty patients with untreated Graves' disease. In these subjects, the TSAb levels were correlated with the thyroid hormone levels. Among twenty patients treated for 1–2 months with carbimazole, 16 (80%) had positive TSAb. During prolonged treatment TSAb gradually diminished and finally normalized. In fifteen patients, it was possible to compare TSAb levels after cessation of previous medical therapy with TSAb levels at relapse. In nine of these patients, an increase of the TSAb level within the normal range at the time of relapse was found, in four the litres were positive. The results indicate that positive TSAb litres are markers of active Graves' disease and suggest that in such patients antithyroid therapy should be continued. A normal TSAb titre after anti-thyroid therapy does not exclude the possibility of relapse.     

PLATELET AGGREGATING ACTIVITY IN THE PLASMA OF PATIENTS WITH ESTABLISHED THROMBOSIS

This study examines the incidence and significance of novel plasma derived platelet aggregating activity (PAA) in 190 consecutive patients admitted to the medical wards of a general hospital. Seventy five patients (39%) demonstrated this activity. The incidence was highest in patients with a history of thrombosis (52%) or in those with a heightened thrombotic tendency, for example, patients with diabetes or hypertension. In contrast, platelet aggregating activity was observed in six out of 62 patients (approximately 10%) in whom a current or past medical history of thrombosis could not be elicited and in only two out of 72 healthy volunteers examined (3%). A high frequency of PAA was also noted in a small group of patients with idiopathic thrombocytopenia and patients who had previously received, platelet transfusions. In these patients, this activity presumably reflects the presence of antiplatelet antibodies. A good correlation between the presence of plasma derived platelet aggregating activity and the phenomenon of spontaneous platelet aggregation was observed. The platelet aggregating activity was not heparin dependent, but was completely abolished by EDTA (5 mM) and benzamidine (8 mM), or by pretreating the platelets with aspirin. A synergistic response was observed with subaggregatory concentrations of thrombin and adrenalin. Our results suggest that the presence of this platelet aggregating activity may provide a marker for vascular thrombosis. Furthermore we postulate that this plasma derived activity may be partly responsible for platelet hyperactivity previously observed in patients with thromboembolic disorders.     

THE RELATIONSHIPS BETWEEN SERUM T3 INDEX, THYROID VOLUME, AND THYROID STIMULATING, TSH RECEPTOR BINDING AND THYROID GROWTH STIMULATING ANTIBODIES IN UNTREATED GRAVES'' DISEASE

High plasma concentrations of neuropeptide Y (NPY) were found in a patient with bilateral adrenal phaeochromocytomas and medullary thyroid carcinoma associated with MEN IIa (32 pmol/l, normal less than 3.5 pmol/l). Both adrenal tumours contained and secreted NPY. Manipulation at operation produced a remarkable increase in plasma NPY concentrations (peak = 1631 pmol/l) coinciding with increases in plasma levels of catecholamines and arterial pressure. NPY was also shown to be present in thyroid tumour tissue: the concentration of NPY in tumour was 50-fold higher (0.9 nmol/g vs 0.004 nmol/g) than in adjacent normal thyroid tissue. It is possible that NPY from some phaeochromocytomas may contribute to hypertension during surgery.     

IMPAIRED DOPAMINERGIC CONTROL OF THYROID STIMULATING HORMONE SECRETION IN CHRONIC RENAL FAILURE

After administration of intravenous metoclopramide, a dopaminergic receptor blocking agent, no rise in thyroid stimulating hormone (TSH) could be found in patients with chronic renal failure, in contrast to non-uraemic controls. Basal TSH values were normal in the uraemic patients but the TSH response to thyrotrophin-releasing hormone (TRH) was significantly reduced. These results suggest that a discrete abnormality in the hypothalamo—pituitary axis exists in uraemia which may in part be due to interference with central dopaminergic control by a uraemic toxin.     

ULTRASENSITIVE ASSAY OF THYROID STIMULATING HORMONE IN PATIENTS WITH ACUTE NON-THYROIDAL ILLNESS

Serum TSH in critically ill euthyroid patients is generally within the normal range when measured with conventional radioimmunoassays. Sensitive immunoradiometric assays allow detection of low levels of serum TSH. We assessed this method in a prospective study of 34 euthyroid patients admitted to our critical care unit. Serum TSH ranged from 0.12 to 3.60 mU/1 and was significantly lower for the whole group than in the controls ( P < 0-001), as also were serum total T4 and T3 values ( P <0.001). However, 21 patients had a serum TSH within the normal range (group 1) and 13 patients (33%) had a serum TSH < 0.40 mU/1 (group 2). The two groups did not differ in age, sex, type and severity of illness, outcome, and serum T4 and T3 levels. However, the magnitude of TSH increase from the baseline value after the i.v. injection of 200 μg of TRH, assessed by the 30 min TSH/basal TSH ratio was significantly higher in group 2 ( P < 005). These results suggest that a substantial proportion of patients with acute illness have a clearly low serum TSH, unaccounted for by age, sex, type or quantified severity of illness, serum T4 and T3 levels. In addition, the secretory capacity of the pituitary to exogeneous TRH is significantly enhanced in those patients with low basal TSH.     

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。