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[Analysis of radio-isotope tests "in vivo" and "in vitro" in the diagnosis of hyperthyroidism. Statistical study of parameters obtained from routine investigations in normal and hyperthyroid subjects (author's transl].

Considering recent progress which permits routine direct estimation of circulating iodinated hormones, classical investigations based on plasma iodine fractions (PBI 127, BEI 127, 127 IH) must be considered out of date for the routine diagnosis of hyperthyroidism. The best possible approach for the detection of hyperthyroidism by radio-isotope tests in vitro consists of associating a determination of the free thyroxine index and tri-iodothyronine. Certain types of hyperthyroidism, mainly in the goup of toxic adenomas, escape this detection in vitro, and justify the use of conventional in vivo tests whenever this diagnosis is suspected.

Electronic Data Processing

[Characteristics of the water-electrolyte regulation in experimental hyperthyroidization and hyperthyroidism].

In experiments on rats the effect of hyperthyroidization (induced by thyroidin, 1-thyroxin) and hyperthyrosis (induced by TSH, cold exposure) on volume natriuresis was studied. As revealed, after expansion of extracellular space natriuresis increased under hyperthyroidization and hyperthyrosis, and was much higher than in control rats. Natriuresis elevation in response to increased volume of extracellular fluid in rats under hyperthyroidization resulted from the rise of natriuretic factor in the blood.

Animals

Gonadal steroids and gonadotropins in hyperthyroidism.

Gynecomastia occurs in about 20 to 40 per cent of men with hyperthyroidism. Serum concentrations of total estradiol-17beta, total testosterone, and luteinizing hormone are supranormal in these patients. Serum concentration of SHBG is also high in hyperthyroidism. This can explain the high serum testosterone, essentially completely but not the high serum estradiol-17beta; thus, whereas serum unbound testosterone is normal, serum unbound estradiol-17beta is above normal in hyperthyroid men. This balance in relative concentrations of unbound gonadal steroids is apparently quite favorable to the development of gynecomastia in hyperthyroidism. Increased peripheral tissue metabolism of androgens to estrogens seems to be the major factor responsible for high estradiol-17beta in hyperthyroidism; increased glandular secretion of estradiol-17beta may also be important. The mechanism of hypomenorrhea or amenorrhea in hyperthyroidism remains unclear. Changes in circulating estrogens, androgens, and luteinizing hormone in hyperthyroid women are similar to those in hyperthyroid men. The mid-cycle ovulatory peak of luteinizing hormone may be blunted in patients with scanty periods whereas it may be altogether absent in those with amenorrhea.

Androgens

Development of ketonemia in fasting patients with hyperthyroidism.

Concentrations of ketone bodies, free fatty acids, glycerol, lactate, glucose, insulin, glucagon and cortisol were determined 6-hourly during 36 hours of fasting in 4 hyperthyroid patients and in 4 euthyroid controls. The concentrations of ketone bodies were elevated in hyperthyroid patients from the beginning and increased during fasting more rapidly and to higher values as compared to the controls. After 6 hours of fasting the blood ketone concentrations were 1.1--1.8 mM in hyperthyroid patients and 0.3--0.6 mM in the controls. After 36 hours the concentrations had increased to about 3.5 mM and 1.4 mM in hyperthyroid and control subjects, respectively. The concentrations of free fatty acids were identical in the groups compared postprandially, but increased significantly more in the hyperthyroid patients than in the controls during fasting. The glycerol concentration was higher in the hyperthyroid group throughout the observation period. The concentrations of insulin were slightly higher in the hyperthyroid group than in the control, whereas the concentrations of the "ketogenic" hormones, glucagon and cortisol were identical in the compared groups. It is concluded that hyperthyroidism leads to an increased tendency to ketosis, that is partly explained by increased concentrations of free fatty acids and that might also involve a direct action of long term thyroid hormone excess on enzyme activities (e.g. carnitine acyltransferase in liver).

Adult

Adrenergic binding sites and enzyme activities in the heart of hyperthyroid rats.

In present study interactions of some adrenergic drugs with the binding of 3H-norepinephrine (NE) and response of some enzymatic systems in the heart of rats with pharmacological hyperthyroidism have been investigated. Binding of NE to cardiac particles was inhibited by isoproterenol, propranolol and in lower concentrations by another beta-blocking drug trimepranol both in control and hyperthyroid hearts in the same degree. However, after addition of nonradioactive norepinephrine (10(-3) M) the degree of displacement was lower in hyperthyroid than in euthyroid group. Activity of adenylate cyclase was lower in hyperthyroid cardiac particles. This difference remained preserved after stimulation by norepinephrine or NaF. The activities of hormone-sensitive lipase and lipoprotein lipase were increased in preparation of hyperthyroid hearts. The phosphorylase "a" activity was also increased in hyperthyroid cardiac particles. There was no change in cardiac adrenergic binding sites properties in hyperthyroidism with the exception of less displacement of NE by nonlabelled hormone. The results indicate that the increased lipolytic and phosphorylase "a" activities in hyperthyroid hearts are not necessarily linked to elevated activity of adenylate cyclase.

Adenylyl Cyclases

The effect of hyperthyroidism on gastric emptying rates and pancreatic exocrine and biliary secretion in man.

Malabsorption and diarrhea in hyperthyroidism has been attributed in part to an increased rate of gastrointestinal transit as measured with barium sulfate suspension. Data are unavailable on the effect of hyperthyroidism on gastric emptying rates of normal food and pancreatic enzyme secretion. These functions have been studied in 4 hyperthyroid patients and compared to results obtained when treatment achieved euthyroidism. Pancreatic trypsin secretion was half the euthyroid level in the hyperthyroid state. No significant change in bile salts occurred, although there was a tendency for a greater proportion of dihydroxy bile salts while hyperthyroid. Gastric emptying rates of a mixed fat, protein, and carbohydrate liquid meal were normal. Similarly the gastric emptying rate of a beef stew plus chicken liver meal was normal. We conclude that in hyperthyroidism gastric emptying rates of "physiologically active" food is normal. Pancreatic enzyme secretion is depressed in hyperthyroidism and may contribute to maldigestion.

Adolescent

Comparison between serum thyroxine and triiodothyronine estimation and the TRH test in the routine diagnosis of hyperthyroidism.

Serum T3 and T4 levels have been determined by a radioimmunoassay technique and the TRH test has been performed in 50 patients in whom hyperthyroidism could not be ruled out by the first clinical examination alone. Each patient was then further evaluated in order to establish the state of the thyroid function. The extent to which the determination of T3 or T4 could replace the TRH test in the routine diagnosis of hyperthyroisism was evaluated. The results showed that 26 of the 50 patients had normal thyroid function and 24 had hyperthyroidism. No patient in the normal groups and all but one in the hyperthyroid group had T3 levels above the upper normal limit (2 S.D.). Two of the patients in the normal group and 19 in the hyperthyroid group had T4 levels above the upper normal limit (2 S.D.). Twenty of the patients in the normal group showed a normal TSH response to TRH (increment is greater than 3.0 micronU/ml); the remaining 6 showed an impaired or absent response. Twenty of the hyperthyroid patients had no response and four had a slightly positive response to TRH. No hyperthyroid patient had a TSH response exceeding 3.0 micronU/ml. It is concluded that the determination of T3 is superior to both the determination of T4 and the TRH test for the laboratory discrimination between eu- and hyperthyroidism.

Adult

Thyroid function tests in elderly hyperthyroid patients.

Several tests of thyroid function were performed in 35 hyperthyroid patients over the age of 65 (elderly). The results were compared to those of similar tests in 48 hyperthyroid patients under the age of 65 (young). Total serum thyroxine (T4) was within the normal range in 14 percent of the elderly and 11 percent of the young hyperthyroid patients. The free thyroxine index (FTI) was within the normal range in 11 percent of both groups. The triiodothyronine uptake (T3U) proved to be a poor test in both groups. Although elevation of the triiodothyronine (T3) level allowed a diagnosis of "T3-toxicosis" in 2 elderly and 3 young hyperthyroid patients, the T3 level was normal in 34 percent of the elderly and 13 percent of the young subjects. Correction of the T3 range for age reduced the number of normal T3 values to 12.5 percent in the elderly hyperthyroid patients. The 24-hour uptake of radioactive iodine was normal in 12 percent of the young hyperthyroid patients, 27 percent of the elderly patients with Graves' disease, and 70 percent of the elderly patients with toxic nodular goiter, despite recent readjustment of the normal range for the test. It is concluded that the diagnosis of hyperthyroidism in the elderly may be difficult and that no single test can be relied upon to exclude the diagnosis.

Adult

Effect of hypoxia on mechanical properties of hyperthyroid cat papillary muscle.

It has been previously established that hyperthyroid myocardium exhibits increased performance under well-oxygenated conditions. To date, it is not known whether hyperthyroid cardiac muscle can maintain this increased performance during hypoxia. The responses of isolated right ventricular papillary muscles from hyperthyroid and euthyroid kittens to hypoxia were compared under isometric conditions at 31 degrees C. Under well-oxygenated conditions, the hyperthyroid cardiac muscle exhibited both an increased contractility and an accelerated rate of relaxation. A similar degree of acute hypoxic stress for 15 min resulted in a greater decrease in contractility in the hyperthyroid compared with the euthyroid papillary muscle as indicated by a greater fall in both peak tension development (2.2 +/- 0.25 from 4.2 +/- 0.2 vs. 0.9 +/- 0.15 from 3.2 +/- 0.4 g/mm2, P less than 0.01) and +dT/dt (12.9 +/- 2.3 from 25 +/- 3 vs. 4.0 +/- 0.6 from 14 +/- 1 g-s-1-mm-2, P less than 0.01). In addition, compared with the euthyroid data, hypoxia resulted in impaired myocardial relaxation in the hyperthyroid cardiac muscle. Thus, the hyperthyroid compared with the euthyroid papillary muscle exhibits both a greater decrease in contractility and an impairment of myocardial relaxation during hypoxia, indicating a greater susceptibility to a given hypoxic stress.

Animals

The haematology of hyperthyroidism.

In an unselected series of 239 patients with uncomplicated hyperthyroidism the haemoglobin concentration was less than 12.0 g/dl in 37 of 207 women and below 13.0 g/dl in 9 of 32 men. Although some of these patients with a low level of haemoglobin were iron deficient, with a transferrin saturation less than 16 per cent, many were not. On treatment of hyperthyroidism the haemoglobin rose by an average of 0.5 g/dl in patients who had not been anaemic on diagnosis. A small fall in haemoglobin is therefore usual in hyperthyroidism and it may sometimes be sufficient to cause a mild degree of anaemia. The mean corpuscular volume (MCV) was decreased in hyperthyroid patients who had neither anaemia nor a reduced transferrin saturation. After treatment of hyperthyroidism the MCV rose in these patients by an average of 6 fl. A dimunition in MCV, even within the normal range, is an invariable concomitant of hyperthyroidism. The administration of thyroxine to excess does not, however, cause the same change in the MCV. On diagnosis of hyperthyroidism the prevalence of pernicious anaemia in this series of patients was 1.9 per cent. Gastric parietal cell antibodies were present in 15.4 per cent and thyroid microsomal antibodies in 49.5 per cent.

Adolescent

Pitfalls in the laboratory diagnosis of atypical hyperthyroidism.

When hyperthyroidism results from active thyroidal secretion, both serum hormonal levels and the radioactive iodine uptake (RAI) are elevated. Discordant results (increased serum hormone levels and a low RAI) are found either in the usual forms of hyperthyroidism when large quantities of iodide are ingested, or in atypical forms of hyperthyroidism, including spontaneously resolving hyperthyroidism of subacute thyroiditis, thyrotoxicosis factitia, toxic struma ovarii, and functioning metastatic thyroid cancer. Two patients are described who exemplify pitfalls in the interpretation of thyroid function test results in atypical hyperthyroidism. The following guidelines are helpful in avoiding these pitfalls: (1) An RAI should be performed in all thyrotoxic patients to confirm the presence of thyroidal hypersecretion, rather than atypical hyperthyroidism. (2) A positive response to thyroid-stimulating hormone stimulation is an important finding differentiating the other atypical forms of hyperthyroidism listed from subacute thyroiditis.

Adult

[Thyroid cancers masked by hyperthyroidism. 12 cases].

The main object of this report was to attract again attention to the fact that obvious hyperthyroidism does not exclude the possibility of associated thyroid carcinoma, although this is an exceptional association. The 12 cases presented here may be added to about 30 cases found in the world literature. They were observed over a period of 13 years by the same surgical team and correspond to 0,3 p. 100 of all thyroid operations, 1 p. 100 of operated cases of hyperthyroidism and 3,6 p. 100 of cases of thyroid carcinoma. Contrary to most published cases, 11 or these cases out of 12, presented, clinically, mainly as hyperthyroidism the carcinotous lesion was either palpabale clinically in the form of a very small nodule (6 cases) or totally latent and discovered operation or even on histology as in 5 cases. Hyperthyroidism produced in 3 cases the classical picture of Graves' disease, in 6 cases that of toxic nodular goiter and, in 2 cases, that of a solitary toxic adenoma. The hyperplasia and the carcinoma were always in anatomically different areas. There is no apparent physiopahtological link and the classical notion of para-neoplastic hyperthyroidism seems debatable in most cases presented here, even in the cases of diffuse hyperfunctional hyperplasia. In any case, whatever the pathogenesis of this association, its possibility should be brought to mind in a case of hyperthyroidism. Surgery should always be advised in cases of toxic adenoma and in Graves' disease when the goiter is irregular and, especially, when a nodule is found. The course and prognosis seem to be mainly dictated by the histological type and the local spread or distant spread of the carcinoma, hyperthyroidism does not aggravate seriously the prognosis.

Adult

Evidence for an active immune response in acute hyperthyroidism (Graves' disease).

Activated lymphocytes, identified by an autoradiographic labeling method, were found to be present in the peripheral blood of the majority of 20 patients with acute hyperthyroidism (Graves' disease). The number of such cells in the blood was significantly greater than that found in 30 healthy controls (p less than 0.00001), and in 13 patients who had previously suffered from acute hyperthyroidism, and who were judged to be euthyroid following therapy (p less than 0.025). This latter group included two patients in whom such activated lymphocytes had been found in the blood during the acute phase of their illness. Furthermore, there were significant differences between the number of such activated circulating lymphocytes in the group of patients with acute hyperthyroidism and five patients suffering from hyperthyroidism due to a toxic thyroid nodule (p less than 0.001), five patients suffering from primary myxedema (p less than 0.001), or in 14 patients with a nontoxic multinodular goiter (p less than 0.05). Identification and counting of circulating T and B lymphocytes by fluorescent immunolabeling and rosette-forming techniques in a small number of the patients with acute hyperthyroidism failed to reveal significant differences from the normal. The results suggest that in acute hyperthyroidism there is active stimulation of the cellular immune system, and that this effect is specific to the early, untreated phase of the disease. This response is different to other thyroid diseases, including hyperthyroidism due to a toxic thyroid nodule.

Adolescent

Digoxin in hyperthyroidism.

A patient with chronic atrial fibrillation developed hyperthyroidism. Increasing doses of digoxin were required to maintain satisfactor ventricular rate control. The systemic availability of oral digoxin was decreased in this patient. The metabolism of digoxin was studied in the hyperthyroid rats. The plasma digoxin concentrations were significantly decreased in the hyperthyroid rats. A threefold increase in digoxin excretion in the bile of the hyperthyroid rats was associated with these changes in plasma digoxin concentrations. Conversely, hypothyroid rats excreted less digoxin in the bile when compared with control and hyperthyroid rats. Thus, changes in digoxin absorption and its biliary excretion result, in part, in a decreased therapeutic effect of digoxin based on dose in hyperthyroidism.

Animals

Hormonal pattern of relapse in hyperthyroidism.

22 patients with Grave's disease were followed up for up to a year after antithyroid drug therapy was discontinued. Clinical assessment and serum T3, T4, and thyroid-stimulating-hormone (T.S.H.) estimations were done serially and simultaneously. Serum T3 or T4 concentrations may be elevated briefly in the first few weeks after antithyroid drugs are stopped, as a rebound effect not necessarily indicative of subsequent relapsf. Clinical relapse of hyperthyroidism with subsequent improvement on antithyroid drugs occurred in 13 patients. Of these 13, serum T3 concentrations became elevated before serum T4 concentrations in 5, thus predicting the subsequent development of clinical hyperthyroidism. In the remaining 8 patients who relapsed, serum T4 was elevated a month before the serum T3. Hyperthyroidism was diagnosed clinically after elevated serum T3 concentrations in 11 patients and at the same time in 2 patients. The mean period of "biochemical hyperthyroidism" in these 11 patients was 12 weeks, with a range of 1 to 56 weeks. During this period 9 of the 11 had minor clinical changes attributable to hyperthyroidism. It is concluded that serial estimations of serum T3 provide the most reliable method of monitoring relapse in hyperthyroidism.

Carbimazole

Influence of hyperthyroidism on glycerol-extracted cardiac muscle from rabbits.

The mechanism responsible for the enhancement of myocardial contractility in hyperthyroidism is unclear. The possibility that this mechanism may involve a direct effect on the contractile proteins was investigated using the glycerol-extracted muscle strip from right ventricular papillary muscles of euthyroid rabbits and rabbits made hyperthyroid by the intraperitoneal injection of 0.25 mg/kg 1-thyroxine for 10 d. Intact papillary muscles from the hyperthyroid rabbits had an enhanced rate of tension development, a decreased time to peak tension, and a slight though insignificant increase in active tension compared to control animals. Maximal isometric contractions were induced in glycerol-extracted cardiac muscle strips from the two animal groups by the addition of 5 mmol/litre ATP and 5 mmol/litre MgCl in a buffer solution containing 0.15 mol/litre Tris-HCl (pH 7.1) at 26 degrees C. Peak isometric tension was increased in glycerinated muscle strips from hyperthyroid rabbits (1.52+/-0.10 vs 1.26 +/-0.13g/mm2), but the differences did not reach statistical significance. However, there was a marked increase in the rate of tension development in the hyperthyroid group (62.5+/-5.4 vs 41.8+/-4.7 mg/mm-2/s, P less than 0.01). This increase in the rate of isometric tension development in both intact and glycerinated muscles from hyperthyroid rabbits may be related to changes in the intrinsic turnover of actomyosin cross-bridge links in this condition. Thus, these findings suggest that thyroid hormone may influence cardiac muscle function by a direct effect on the contractile proteins.

Adenosine Triphosphate

The influence of hyperthyroidism and hypothyroidism on the beta-adrenergic responsiveness of the turkey erythrocyte.

The mechanisms responsible for altered adrenergic tone in hyperthyroidism and hypothyroidism are not fully understood. To investigate these mechanisms, the beta-adrenergic receptor-cyclic AMP complex of the turkey erythrocyte was studied among groups of normal, hyperthyroid, and hypothyroid turkeys. In erythrocytes obtained from hypothyroid turkeys, there were fewer beta-adrenergic receptors than in normal cells as determined by the specific binding of [(125)I]iodohydroxybenzylpindolol, as well as associated decreases both in catecholamine-responsive adenylate cyclase activity and in cellular cyclic AMP content. In contrast, erythrocytes obtained from hyperthyroid turkeys contained the same number of beta-receptors and had the same catecholamine-responsive adenylate cyclase activity as cells from normal birds. Other characteristics of the beta-receptors in cells from hyperthyroid birds were indistinguishable from those present in normal erythrocytes. However, within the range of circulating catecholamine concentrations, 5-50 nM, the erythrocytes of the hyperthyroid turkeys generated substantially more cyclic AMP after exposure to isoproterenol than did normal cells. These results suggest that thyroid hormone affects beta-receptor-cyclic AMP interrelationships in the turkey erythrocyte by two distinct mechanisms: (a) In hypothyroidism, both beta-receptors and catecholamine-dependent cyclic AMP formation are coordinately decreased; (b) in hyperthyroidism, beta-receptors are unchanged but there is an amplification of the hormonal signal so that occupation of a given number of receptors at physiological concentrations of catecholamines leads to increased levels of cyclic AMP.

Adenylyl Cyclases