THYROID FUNCTION AND THYROID REGULATION IN EUTHYROID MEN WITH CHRONIC LIVER DISEASE: EVIDENCE OF MULTIPLE ABNORMALITIES

Total and free serum thyroxine (T4) and triiodothyronine (T3), basal serum thyrotrophin (TSH) and the serum TSH response to a standard intravenous dose of thyrotrophin releasing hormone (TRH) have been measured in fifteen men with liver cirrhosis and in eight alcoholic men with fatty liver change. All the patients studied were clinically euthyroid. In cirrhotics, total T4 and free T4 (FT4) concentrations were normal as were free T3 (FT3) concentrations but total T3 concentrations were significantly reduced and basal TSH concentrations were significantly higher than normal. Alcoholics with fatty liver change had normal basal TSH concentrations and normal total and free thyroid hormone concentrations apart from reduced FT4. Correlation of thyroid function tests with liver function (serum albumin concentration) showed significant positive correlations for serum albumin with both total T3 and FT3 and significant negative correlations with both FT4 and basal TSH. Nine of fifteen cirrhotics had an abnormal serum TSH response to TRH, the commonest abnormal pattern being a delayed response (seven patients). Three of eight alcoholics with fatty liver change also had an abnormal TSH response to TRH. These findings not only show complex disturbances in hypothalamic-pituitary-thyroid relationships in chronic liver disease but also provide indirect evidence of reduced extra-thyroidal conversion of T4 to T3.     

男性Graves病患者唾液睾酮及血清性激素水平的变化

本文观察了20例男性Graves病患者抗甲状腺药物治疗前后的唾液睾酮及血清中几种性激素水平的变化,并与年龄、性别相配对的20例健康者进行了比较分析。患者治疗前唾液睾酮水平明显低于正常,治疗后显著上升,与血T_3、T_4的变化呈负相关;治疗前血总睾酮、雌二醇、LH及FSH显著高于正常,治疗2个月后除雌二醇外均随T_3、T_4的下降而下降。本文结果支持唾液睾酮不受SHBG的影响,提示Graves病患者游离睾酮减低。     

MALE GONADAL FUNCTION IN COELIAC DISEASE: III. PITUITARY REGULATION

Pituitary regulation of gonadal function was investigated in 39 consecutive men with treated and untreated coeliac disease and in an intestinal disease control group of 19 men with Crohn's disease of similar age and general nutritional status. Basal serum FSH concentration was increased in 10 of the coeliacs (26%) compared to only two of 19 men with Crohn's disease (11%). This abnormality was observed with equal frequency in both treated and untreated coeliacs, and was not associated with oligospermia. Serum LH concentration was increased in eight of 15 untreated coeliacs (53%) with sub-total villous atrophy, an abnormality which unlike the elevation of serum FSH, appears to return towards normal after gluten withdrawal. Serum LH was high in coeliacs despite marked elevation of the free testosterone index. Exaggerated responses of FSH and LH to LHRH were found in 89% and 45% respectively, of coeliacs with sub-total villous atrophy. However, exaggerated responses of LH alone were found more frequently in coeliacs than in men with Crohn's disease (P less than 0.02) and unlike the exaggerated FSH responses, LH responses were closely related to jejunal morphology. Exaggerated responses of FSH and LH in coeliacs were commonly found when basal gonadotrophin concentrations were normal. The occurrence of exaggerated gonadotrophin responses could not be related to plasma concentration of testosterone, dihydrotestosterone, oestradiol or the free testosterone index. Serum prolactin was modestly raised in 25% of untreated and partially treated coeliacs and in the same proportion of men with Crohn's disease. Elevated serum prolactin concentrations never exceeded 809 mU/l and were not associated with impotence or infertility. This study provides further evidence that in men with coeliac disease there is a derangement of pituitary regulation of gonadal function. This would seem to be part of a wider disturbance of central regulatory mechanisms of endocrine function in coeliac disease.     

THE REGULATION AND INTEGRATION OF THYROID FOLLICULAR DIFFERENTIATION AND FUNCTION

As in a number of other endocrine tissues in which expression of differentiated function is dependent upon a stable cellular architecture, the control of differentiation of the thyroid follicle requires a coordination between the ultrastructural and morphological responses to a number of endocrine growth factors, which may ultimately involve autocrine or paracrine-mediated effects within the immediate follicular microenvironment. Through analogy with other cell types, expression of appropriate differentiation characteristics within the thyroid follicle may involve the activation of specific c-oncogenes within each of the component cells. With the recent development and application of oncogene transfection technology, application of such procedures to the thyroid follicular cell should prove to be a particularly fruitful area for future research within the thyroid gland, leading to elucidation of the mechanisms whereby the cellular responses to growth and tissue-differentiating factors are mediated. Clearly however, further consideration must also be made of the roles played in maintaining follicular stability by both physical and chemical interactions between the component cells and the immediate extracellular environment. The contributory roles played by basement membrane and cell-surface components in cellular recognition, together with the physical effects imposed upon the apical surfaces of the follicle by luminal thyroglobulin have already been identified as fundamental factors in this respect. It is also readily apparent that morphological differentiation of the follicle bears critically upon the chemical characteristics of the microenvironment through the ability of the latter to promote expression of specific apical/basal recognition characteristics of the component cells, and thus maintain the unidirectional polarity upon which the functional capacity of the thyroid follicle is so critically-dependent.     

THE THYROID FUNCTION IN YOUNG MEN DURING PROLONGED EXERCISE AND THE EFFECT OF ENERGY AND SLEEP DEPRIVATION

Thyroid function has been investigated in 24 young military cadets participating in a 5 d ranger training course with heavy physical exercise, calorie deficiency and deprivation of sleep. The cadets were divided into three groups, each differing in the amount of sleep and food consumption. The serum levels of thyroid hormones (T4, FT4, T3, rT3) and TBG showed a biphasic pattern during the course. Initially there was an increased secretion concomitant with an increased deiodination of T4 to T3 and rT3 mainly due to physical exercise. When the activities lasted for several days without sufficient food supply the thyroid secretion decreased simultaneously with an alteration of the peripheral conversion of T4 to rT3 instead of T3. A significant correlation was found between the changes in total and free thyroxine (r = 0.9) and between the increase in rT3 and decrease in T3 (r = 0.6). TSH decreased during the first day of activities and remained low throughout the course. The TSH response to TRH stimulation was greatly reduced during the course due to physical exercise and calorie deficiency. The present investigation demonstrates that the thyroid function is strongly affected by prolonged physical exercise and a negative energy balance, whereas sleep deprivation does not have any significant influence. The results indicate that the alteration observed is not regulated just by the hypothalamo-pituitary-thyroid-axis alone.     

DECREASED SERUM THYROID HORMONE LEVELS AND INCREASED TSH RESPONSE TO TRH IN INFANTS WITH COELIAC DISEASE

Plasma levels of thyrotrophin before and after the intravenous administration of 200 microgram of thyrotrophin releasing hormone have been studied in eleven patients with active gluten-induced enteropathy and in a group of twenty-one normal prepubertal children. In nine out of eleven coeliac patients an exaggerated and/or sustained response of plasma thyrotrophin is observed. Basal plasma thyrotrophin level is not significantly different from the value observed in normal children. However, plasma levels recorded 20 and 60 min after injection of the releasing hormone are significantly higher than in control children (at 20 min: P less than 0.01; at 60 min: P less than 0.001). Serum levels of dialysed triiodothyronine and thyroxine and of triiodothyronine are significantly lower in coeliac patients than in normal infants (P less than 0.01). These data support the evidence of an endocrine dysfunction in coeliac disease. It is not clear whether it is due to malnutrition and/or to some direct action of circulating gluten-peptides on the hypothalamus.     

EFFECT OF THE COMBINATION OF DEXAMETHASONE AND SODIUM IPODATE ON SERUM THYROID HORMONES IN GRAVES'' DISEASE

To investigate the effect of the combination of dexamethasone (Dex) and sodium ipodate (SI) on hyperthyroidism, we studied 24 patients with typical Graves' disease, divided into four groups of six persons each. Three groups (Study I) were studied acutely (24 h) to determine the effects of Dex (5 mg every 12 h intramuscularly), SI (one oral dose of 3 g) and both drugs at the same doses, upon T4, T3, and rT3 at 0900 h before therapy was started and 24 h later. The group on Dex and that on SI had a similar T3 decrement of 25.9 +/- 4.0% and 35.8 +/- 5.0%, respectively, (P less than 0.05), whereas the effect of both drugs combined was greater (64.2 +/- 3.6%; P less than 0.01, Dex, and P less than 0.01, SI, respectively). The increment of rT3 was markedly greater in those patients on SI than in those on Dex (561.3 +/- 149.2% and 58.9 +/- 11%, respectively, P less than 0.025). A fourth group (Study II) was studied for seven days while receiving both Dex (1 mg orally three times per day) and SI (500 mg orally three times per day). Both T4 (from 18.8 +/- 1.1 to 13.1 +/- 1.1 micrograms/dl, P less than 0.02) and T3 (from 593 +/- 41 to 136.3 +/- 12.7 ng/dl, P less than 0.001) decreased at day 8. The initial brisk increment of rT3 at 24 h (808 +/- 149%, P less than 0.005) then diminished concomitantly with the fall of its precursor, T4.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF HEROIN ADDICTION ON THYROTROPHIN, THYROID HORMONES AND PROLACTIN SECRETION IN MEN

Pituitary-thyroid function in male heroin addicts and addicts after abstinence (ex-addicts) was studied and compared with that of healthy euthyroid men. In heroin addicts the increases in circulating total thyroxine and triiodothyronine levels were accompanied by an increase in the thyroid hormone uptake test. These changes may reflect a quantitative increase in thyroxine binding globulin. Reverse triiodothyronine concentrations in heroin addicts were normal. The thyrotrophin-releasing hormone elicited a diminished thyrotrophin response in heroin addicts which was significantly different from that in control subjects and ex-addicts. An elevation of serum prolactin was noted in heroin addicts, while ex-addicts had normal levels. Gradual recovery of pituitary-thyroid function occurred after heroin withdrawal.     

LONG-ACTING THYROID STIMULATOR AND THYROID FUNCTION IN RELATIVES OF PATIENTS WITH GRAVES''DISEASE

In ten families, fifty relatives and seven husbands of ten patients with untreated Graves’disease were submitted to clinical examination, biological and immunological investigations. They were compared with fifty control subjects. In the relatives, thyroid diseases were found in 26%, positive LATS-IgG responses in 30%, thyroid antibodies in 23% and abnormal NBEI in 30%. The mean LATS response was significantly greater than in controls. With one exception no overt hyperthyroidism was found in the relatives on the basis of serum PBI, T₃ resin uptake test, total T₄ and TSH level. From the analysis of the pedigrees, no definite mode of inheritance can be found for LATS and NBEI. These data suggest the existence of a thyroid metabolic anomaly in the families of patients with thyrotoxicosis and argue against LATS as the cause of the hyperthyroidism of Graves’disease.     

男性慢性肝病患者下丘脑－垂体－性腺轴功能的研究

用放射免疫法检测６１例男性慢性肝病患者血清睾酮（Ｔ）、雌二醇（Ｅ２）、泌乳素（ＰＲＬ）、促黄体生成素（ＬＨ）和卵泡刺激素（ＦＳＨ）的浓度，并对部分病例进行促黄体生成素释放激素（ＬＲＨ）垂体兴奋试验和绒毛膜促性腺激素（ＨＣＧ）刺激试验。结果示，肝硬化基础血清Ｔ显著降低（Ｐ＜０．０１）；对ＬＲＨ垂体兴奋试验ＬＨ多数呈正常反应，部分呈延迟反应或低反应；而对ＨＣＧ刺激试验均呈正常反应。提示肝硬化患者有下丘脑－垂体－性腺轴功能障碍。     

THE BEHAVIOUR OF THYROID HORMONES IN AN INFANT WITH UNTREATED NEONATAL THYROTOXICOSIS

The clinical course from birth and serial measurements of serum T3, T4 and TSH in an infant with untreated neonatal thyrotoxicosis are reported. The thyroid hormone levels fell exponentially with time at rates very much slower than those previously reported for the maternally-transmitted thyroid stimulating antibody generally thought to cause the disorder. Steady physiological levels of thyroid hormones were achieved after 110 days (serum T3 = 3.4 nmol/1, T4 = 118 nmol/1). TSH first rose to a measurable level after about 90 days.     

THE EFFECT OF PROPRANOLOL ON THYROID HORMONES AND OXYGEN CONSUMPTION IN THYROTOXICOSIS

The possibility that propranolol may exert its beneficial actions in thyrotoxicosis by an effect on thyroid hormone concentrations has been investigated by measuring these and oxygen consumption in a group of thyrotoxic patients before and after treatment with propranolol. Following treatment a significant fall in plasma T3 concentration and oxygen consumption occurred and a direct correlation was found between these two variables. Propranolol may, therefore, exert some of its beneficial effects in thyrotoxicosis by an action on T3 metabolism.     

IDDM儿童和青少年甲状旁腺和甲状腺功能测定及其临床价值

测定32例胰岛素依赖性糖尿病(IDDM)儿童和青少年血Ca、P、AKP、iPTH、CT、T_3和T_4浓度,与正常对照组相比,血Ca、AKP、iPTH和CT水平均明显升高,血T_3水平则明显降低。IDDM儿童和青少年患者钙磷代谢和骨代谢发生了明显异常变化,可以认为是糖尿病性骨质疏松发病的开始。作者认为,糖尿病性骨质疏松的发病可能有一个从继发性甲旁亢到甲旁低的连续变化过程。而IDDM儿童和青少年患者亚临床甲状腺功能减低对缓解钙磷代谢紊乱可能具有重要作用。     

THE INFLUENCE OF CARBAMAZEPINE ON THYROID HORMONES AND THYROXINE BINDING GLOBULIN IN HYPOTHYROID PATIENTS SUBSTITUTED WITH THYROXINE

Carbamazepine (CBZ) decreases the serum concentration of thyroid hormones. It is proposed that CBZ increases the extra-thyroidal metabolism of thyroid hormones. In order to test this hypothesis CBZ was given to nine hypothyroid patients substituted with thyroxine (T4). A significant decrease in serum concentrations of T4, calculated free T4 (FT4), triiodothyronine (T3), and calculated free T3 (FT3) was found after 3 weeks of CBZ medication. The serum concentrations of TSH and the T4:T3 ratios were unaltered, while the serum concentrations of T4-binding globulin (TBG) increased markedly in eight of the nine patients. These findings support the hypothesis of a CBZ induced increase in the extra-thyroidal metabolism of thyroid hormones.     

自身免疫甲状腺病循环和甲状腺内细胞毒性T细胞(T_8/S_6F_1)的实验研究

应用新型单克隆抗体T_8/S_6F_1和流体细胞测定仪双色荧光程序检测了15例Graves病和8例Hashimoto甲状腺炎患者循环和甲状腺内的细胞毒性T细胞(cytotoxic T ceils,Tc)的分布。传统的单克隆抗体CD_8(OKT_8或Leu_2)仅能检测含有两个次亚群——抑制性T细胞(Ts)和细胞毒性T细胞(Tc)的Ts/TcT细胞亚群,不能将它们区别开来。本文应用的单克隆抗体T_8/S-6F_1首次能够单独测定Tc亚群。Graves病和Hashimoto甲状腺炎患者的循环Tc亚群分别为27.6±11.2％和27.5％±12.2％,与正常对照组差异无显著性。两组患者甲状腺内的Tc亚群数目也未见增加。Graves病患者甲状腺内Te细胞为16.45±4.7％。本文结果提示:AITD患者循环内和甲状腺内的细胞毒性T细胞亚群的数目未见增加。     

THE ADRENOCORTICAL STATUS OF PATIENTS WITH THYROID DISEASE

Plasma cortisol, cortisol resin uptake ratio and free cortisol index was measured in twenty-seven euthyroid, ten hypothyroid and fifteen hyperthyroid subjects. No difference was observed between euthyroid subjects and patients with thyroid disease for any of the three parameters tested. The significance of these findings is discussed in the light of earlier reports linking thyroid activity with the levels of corticosteroid binding globulin.     

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.