THE SECRETION OF THYROTROPHIN WITH IMPAIRED BIOLOGICAL ACTIVITY IN PATIENTS WITH HYPOTHALAMIC–PITUITARY DISEASE

We describe here two patients with hypothyroidism due to pituitary-hypothalamic disease in whom basal thyrotrophin (TSH) levels measured by radioimmunoassay (RIA) were elevated yet when measured by a cytochemical bioassay (CBA) were found to be normal. This finding and the absence of the normal rise of thyroid hormones in response to thyrotrophin-releasing hormone (TRH) mediated release of TSH confirms for the first time the secretion of TSH with impaired biological activity. Primary thyroid disease as a cause for the elevated immunoreactive TSH was excluded by the absence of circulating thyroid antibodies and by a normal thyroidal radioiodine uptake response to exogenous TSH.     

STUDIES ON THYROTROPHIN RECEPTOR ANTIBODIES IN PATIENTS WITH EUTHYROID GRAVES'' DISEASE

Thyroid stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) were assessed in 30 patients with euthyroid Graves' disease. TSAb were detected in 24 cases (80.0%), the incidence being not significantly different from that in hyperthyroid Graves' disease (29/30, 97.6%). On the other hand, the incidence of TBII in patients with euthyroid Graves' disease (12/30, 40.0%) was significantly lower than that in patients with hyperthyroid Graves' disease (30/30, 100.0%). The mean TSAb and TBII activities in the euthyroid patients were significantly lower than in the hyperthyroid patients (P less than 0.005 and P less than 0.001, respectively). Both TBII and, more closely, TSAb activities correlated with T3-nonsuppressibility and inhibition of serum TSH response to TRH stimulation. The findings supported the stimulation in vivo of the thyroid by these antibodies. Both antithyroglobulin and antimicrosomal antibody titres in euthyroid Graves' disease were significantly lower than in hyperthyroid Graves' disease (P less than 0.05, P less than 0.01, respectively). Goitre size was significantly smaller (P less than 0.001), and 99mTc thyroid uptake was significantly lower (P less than 0.001) in the euthyroid than in the hyperthyroid group. Thus, the reduced mass of thyroid tissues responding to the stimulators was considered to be one of the factors responsible for the euthyroidism despite the presence of TSAb. The high incidence of TSAb and relatively low incidence of TBII in euthyroid Graves' disease indicate that the presence of TSAb does not necessarily lead to hyperthyroidism and that the development of overt thyrotoxicosis may require augmentation of both TSAb and TBII.     

PATIENTS WITH ANKYLOSING SPONDYLITIS SHOW INDIVIDUAL PATTERNS OF VARIATION IN DISEASE ACTIVITY

Disease activity was monitored sequentially over 1 year in 22patients with ankylosing spondylitis (AS) attending regularlythe local NASS group. Assessments, using standard methods, weremade at monthly intervals by the same observer. There was markedheterogeneity such that each patient's profile of disease activitywas virtually unique. All patients experienced at least oneexacerbation and most underwent exacerbations and remissions,reminiscent of the experience of many patients with rheumatoidarthritis. In most instances no reason for changes in diseaseactivity could be discerned clinically. These observations raisethe possibility that the natural history of disease in AS maybe different for each individual patient, which, if true, wouldhave important implications for the design of studies to testthe efficacy of therapy and for approaches to investigatingpathogenic mechanisms in patients with AS. KEY WORDS: Clinical heterogeneity, Chronic arthritis     

THE LOSS OF CIRCADIAN RHYTHM FOR INTACT PARATHYROID HORMONE AND NEPHROGENOUS CYCLIC AMP IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

The measurement of serum intact parathyroid hormone (PTH) (1-84) over a 24-h period has shown the existence of a circadian rhythm in normal males which is absent in patients with primary hyperparathyroidism. The physiological significance of this observation is reflected in the presence of parallel changes in nephrogenous cyclic adenosine monophosphate (N-cAMP) in normals which are also absent in primary hyperparathyroidism. Serum calcium, adjusted for variations in albumin concentrations, showed a transient fall in normal subjects prior to the nocturnal rise in PTH (1-84). A similar transient fall in serum adjusted calcium was observed in the hyperparathyroid patients. Serum phosphate showed a circadian rhythm in normal subjects, and an attenuated rhythm persisted in primary hyperparathyroidism. These data suggest that both ionic factors and higher centres play important roles in the fine control of PTH (1-84) secretion.     

THYROTROPHIN RESPONSES TO INTRAVENOUS THYROTROPHIN-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMIC AND PITUITARY DISEASE

Plasma immunoreactive thyrotrophin (TSH) responses to synthetic thyrotrophin releasing hormone (TRH) have been measured in forty-five patients with pituitary or hypothalamic disease (largely non-functioning and functioning pituitary tumours) tested before and/or after ablative treatment. Subnormal TSH responses usually indicated impaired pituitary function but were less sensitive indices than those of human growth hormone (HGH) after hypoglycaemia. High basal TSH values with exaggerated rises after TRH were occasionally found with hypothyroidism and impaired HGH and cortisol secretion. Delayed TSH responses were indicative of hypothalamic disease in some cases, but in others were associated with pituitary tumours without overt hypothalamic disease. Normal TRH tests were found with hypothyroidism, while five abnormal tests (four delayed) were found in euthyroid patients. Patterns of TSH response to TRH in hypothalamic-pituitary disease are complex and their significance is not always clear.     

THYROTROPHIN RELEASING HORMONE INDUCED CALCITONIN SECRETION IN PATIENTS WITH MEDULLARY CARCINOMA OF THE THYROID

An i.v. bolus injection of 500 μg TRH caused a prompt increase in plasma calcitonin (CT) in two patients with medullary thyroid carcinoma (MTC). In case 1 with a sporadic MTC, plasma CT increased from 0.32 ng/ml to 0.70 ng/ml 2 min after TRH. In the second case with multiple endocrine neoplasia (MEN) type II, plasma CT increased from 0.39 ng/ml to 4.7 ng/ml 2 min after the injection. None of five normal healthy subjects and a patient with thyroid follicular adenocarcinoma had significant changes in plasma CT levels after TRH. Studies with monolayer cultures of MTC cells derived from one patient revealed that TRH stimulated CT release. Incubation of the cells with TRH of 10⁻⁶ m or 10⁻⁵ m for 1 h increased CT concentration in the medium to 140% or 182% of the control level, respectively. Under the same conditions, pentagastin (10⁻⁶ m ) increased CT concentration in the medium to 156%. These results indicate the direct stimulatory effect of TRH on CT secretion in the patients with MTC.     

CIRCADIAN RHYTHMS IN PATIENTS WITH ABDOMINAL PAIN SYNDROMES

:Circadian rhythms for Cortisol, 6-sulphatoxy melatonin and core body temperature were compared in control subjects and patients with functional abdominal pain. There were 20 patients with biliary pain after cholecystectomy, ten with biliary pain without cholecystectomy and 14 with irritable bowel syndrome. Rhythms were determined by urine collections at intervals of 4 h for 48 h and by overnight monitoring of core body temperature using the Vitalog system. Data were fitted to a sine curve to yield the time of maximal urinary excretion/lowest temperature and the amplitude of each rhythm. Urinary excretion of free Cortisol was similar in patients and control subjects. For urinary 6-sulphatoxy melatonin, the timing (phase) of rhythms was similar in patients and controls but those with pain had a lower urinary excretion of 6-sulphatoxy melatonin (p<0.05) and a rhythm of lower amplitude (p<0.02). The amplitude of the temperature rhythm was also lower in patients with biliary pain with and without prior cholecystectomy (p<0.05). Functional abdominal pain is associated with 6-sulphatoxy melatonin and temperature rhythms of low amplitude, presumably because of suppression of circadian oscillators.     

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).     

CONSISTENCY AND VARIABILITY IN THE CHARACTER OF THYROTROPHIN RECEPTOR ANTIBODIES IN GRAVEs'' DISEASE

At diagnosis there was no correlation between the uptake of pertechnetate by the thyroid and thyrotrophin receptor antibodies (TRAb) measured as TSH binding inhibitory immunoglobulins in a series of 27 patients with Graves' disease. TRAb were detectable initially in 19 patients, in 11 of these there was a significant positive correlation (P less than 0.05) between serial measurements of pertechnetate uptake and TRAb made during 2 years following diagnosis. In five patients pertechnetate uptake fell with time whilst TRAb levels were maintained or fluctuated. In the remaining three of the 19 patients both measurements were low and did not change during treatment. We conclude that TRAb in any individual patient are a mixture of immunoglobulins of variable effectiveness as thyroid stimulators. In a majority of patients the composition of this mixture remains constant during the course of the illness and the clinical state reflects the levels of TRAb in the blood. In a minority, however, the character of these antibodies may alter with time or there is a change in the responsiveness of the thyroid gland. The general lack of correlation between measurements of thyroid stimulating activity and TSH binding inhibitory immunoglobulins in groups of patients is due to differences between patients in the composition of TRAb.     

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.     

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.     

ANOMALIES IN THE ASSAY OF PARATHYROID HORMONE IN NORMOCALCAEMIC PATIENTS WITH RENAL STONE DISEASE

A group of 22 normocalcaemic patients with renal stone disease were retrospectively studied using seven different immunoassays for parathyroid hormone (PTH). N-terminal immunoradiometric assays and an intact hormone immunochemiluminometric assay sometimes gave results which fell above the normal range. These results were at variance with values obtained in three region-specific radioimmunoassays and an immunoradiometric assay for the intact hormone. Since these atypical samples contained normal levels of biologically active PTH the elevated immunoassay results were not thought to relate to the normal circulating hormone but rather to interference in the immunometric assays. The interfering substance was thought to be a large molecule which could not be removed by charcoal and did not dilute out in parallel to the PTH standard curve.     

TREATMENT OF REFRACTORY ASCITES IN PATIENTS WITH LIVER DISEASE

"When the liver is full of fluid and this overflows into the peritoneal cavity so that the belly becomes full of fluid, death occurs" - Hippocrates.     

大骨节病人骺板软骨超微结构的观察

本文用透射电镜观察5例大骨节病人指(趾)骨的骺板软骨。看到未见明显坏死的增殖细胞已出现致密化和空泡化。在明显坏变的增殖层细胞周围,基质胶原纤维间距增宽,蛋白多糖颗粒减少,以及下部增殖层细胞间纵隔基质检见带有最早的磷灰盐结晶的基质小泡,显示了钙化增强现象。     

血浆纤维蛋白原、血脂水平和冠心病的关系

目的探讨血浆纤维蛋白原(Fib)、血脂水平与冠心病的关系。方法收集59例经冠状动脉造影证实为冠心病的患者,22例经冠状动脉造影证实无冠状动脉病变的对照者,测定其血浆Fib和血清胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)。根据冠状动脉造影结果将冠心病组分为1支、2支和3支病变组,观察其Fib及TC、TG、LDL-C、HDL-C的水平及与冠状动脉病变程度的关系。血浆Fib水平与血脂进行回归分析。结果冠心病组的血浆Fib及TC、LDL-C明显高于对照组(P<0.05),HDL-C低于对照组(P<0.05),Fib、TC和LDL-C水平随冠状动脉病变支数增加而升高(P<0.05)。Fib、TC和LDL-C冠状动脉狭窄分数相关(r=0.666、0.378和0.429P<0.001)。Fib和LDL-C相关(r=0.534P<0.01)。结论血浆Fib水平的升高及血脂异常和冠心病有密切关系,并且和冠状动脉病变程度相关。血浆Fib水平和LDL-C相关。