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Experimental hyperthyroidism IV. Myocardial muscle mechanics and oxygen consumption in euand hyperthyroidism.

Myocardial mechanics and oxygen consumption were studied in right ventricular papillary muscles taken from cats pretreated with cristalline L-thyroxine (1 mg/kg/day, i.p.) 8-18 days prior to the examination. Isotonic afterloaded and isometric contractions were employed. Oxygen consumption was determined polarographically. Data obtained were compared with control studies on papillary muscles taken from euthyroid cats. In isotonic afterloaded contractions the extent of shortening was nearly identical in both groups. However, maximum rate of isometric tension development and velocity of isotonic shortening were considerably increased in hyperthyroid myocardium. Myocardial oxygen consumption was significantly increased in hyperthyroidism, primarily due to an increased maximum rate of isometric tension development and-to a lesser extent-to increased isotonic contraction velocity. In isometric contractions maximum tension development (preload near Lmax) was similar in both groups. However, maximum rate of isometric tension development was markedly increased in hyperthyroidism. A close and linear relationship was found between maximum rate of isometric tension development (isometric contraction) and myocardial oxygen consumption. The results demonstrate increases of velocity factors of myocardial performance in experimental hyperthyroidism. Myocardial oxygen consumption is significantly increased. This increase in oxygen consumption quantitatively has its mechanical equivalent in increased isometric contraction velocity and, to a small amount, in increased isotonic contraction velocity.

Animals

DNA-synthesis of lymphocytes in hyperthyroid and euthyroid subjects. Effect of 131I therapy on hyperthyroidism.

The DNA-synthesis of human lymphoid cells as estimated by the measurement of thymidine incorporation in vitro was investigated in healthy controls and in patients with various thyroid disorders before and after therapy. Hyperthyroid patients treated with 131I and surgery (euthyroid at initial blood sampling before surgery), patients with atoxic nodular goitre treated by surgery and healthy untreated control individuals comprised the material. The synthesis of DNA in lymphocytes was higher in hyperthyroid patients in comparison with euthyroid individuals, and decreased subsequent to 131I therapy in the hyperthyroid patients. No decrease was recorded in the other groups of patients. No evidence suggesting a change in the lymphocyte reactivity to thyroglobulin was found in any of the patient groups.

Adult

[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

Metabolic clearance and blood production rates of estradiol in hyperthyroidism.

The metabolic clearance rate of 17beta-estradiol (MCR2), the plasma levels of 17beta-estradiol (E2)1, sex-steroid binding globulin (SSBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in 10 hyperthyroid subjects (7 men and 3 women). The blood production rate of 17beta-estradiol (PB2) was calculated for all subjects. Nine of the 10 hyperthyroid subjects had a decreased MCR2 which returned towards normal in 5 of the 6 subjects restudied following therapy. In all 10 subjects the levels of SSBG were increased when they were hyperthyroid and returned toward normal with therapy. It is concluded that the decrease in MCR2 is largely due to the increased binding of 17beta-estradiol to SSBG. In 7 of the 10 hyperthyroid the plasma E2 concentrations were normal whereas 3 had slightly elevated levels. In 8 of the 10 hyperthyroid the PB2 was within the normal range. Only 2 hyperthyroid subjects had slightly elevated PB2. In the 6 subjects who were restudied after therapy, there was no consistent change in PB2 which remained in the normal range in all cases. It is concluded that the MCR2 is decreased in most subjects with hyperthyroidism in association with an increase of SSBG. Despite this change in MCR2 there is no significant change in PB2. The increase in SSBG levels in hyperthyroidism appears to be a direct effect of the elevation of thyroid hormone activity and is not mediated through estrogen.

Estradiol

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

Effect of arginine on the GHRH-stimulated GH secretion in patients with hyperthyroidism.

Patients with hyperthyroidism have reduced GH responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of arginine on GH secretion has been suggested to depend on a decrease in hypothalamic somatostatin tone. The aim of our study was to evaluate the effects of arginine on the GH-releasing hormone (GHRH)-stimulated GH secretion in patients with hyperthyroidism. Six hyperthyroid patients with recent diagnosis of Graves' disease [mean age +/- SEM, 39.2 +/- 1.4 years; body mass index (BMI) 22 +/- 0.4 kg/m2] and 6 healthy nonobese volunteers (4 males, 2 females; mean age +/- SEM, 35 +/- 3.5 years) underwent two experimental trials at no less than 7-day intervals: GHRH (100 micrograms, i.v.)-induced GH secretion was evaluated after 30 min i.v. infusion of saline (100 ml) or arginine (30 g) in 100 ml of saline. Hyperthyroid patients showed blunted GH peaks after GHRH (13.2 +/- 2.9 micrograms/l) as compared with normal subjects (23.8 +/- 3.9 micrograms/l, p < 0.05). GH peaks after GHRH were only slightly enhanced by arginine in hyperthyroid subjects (17.6 +/- 2.9 micrograms/l), whereas, in normal subjects, the enhancement was clear cut (36.6 +/- 4.4 micrograms/l; p < 0.05). GH values after arginine + GHRH were still lower in hyperthyroid patients with respect to normal subjects. Our data demonstrate that arginine enhances but does not normalize the GH response to GHRH in patients with hyperthyroidism when compared with normal subjects. We hypothesize that hyperthyroxinemia may decrease GH secretion, both increasing somatostatin tone and acting directly at the pituitary level.

Adult

[Cardiac and plasma catecholamine response to dynamic exercise in hyperthyroidism].

To investigate cardiac and sympathoadrenal responses to dynamic exercise, heart rate, systolic blood pressure, serial plasma norepinephrine (NE) and epinephrine (E) concentrations during multistage treadmill exercise were measured in 24 hyperthyroid patients (mean age; 42 +/- 16) and 24 age-sex matched control subjects. Eleven patients were re-examined in the euthyroid state after antithyroid therapy. Exercise duration was shorter in patient with hyperthyroidism. Also, the heart rates and systolic blood pressures at rest and in the early stage of exercise were significantly higher in hyperthyroidism. NE at rest (normal vs hyperthyroid: 124 +/- 10 vs 80 +/- 7 pg/ml, p < 0.01) and NE at peak exercise (475 +/- 38 vs 310 +/- 38 pg/ml, p < 0.01) were lower in hyperthyroidism. E at rest (22 +/- 2 vs 29 +/- 4 pg/ml, n.s.) did not differ, however, E during the first stage of exercise (30 +/- 3 vs 69 +/- 12 pg/ml, p < 0.01) was higher in hyperthyroidism. Re-examination for the euthyroid state revealed the decreases in the heart rates and systolic blood pressures at rest and in the early stage of exercise, and the normalization of the NE and E response. Thus, patients with hyperthyroidism was in the hyperdynamic cardiac state at rest and during dynamic exercise, which was accounted for by decreased sympathetic nervous activity and increased adrenomedullary responses. These modifications of sympathoadrenal response seemed reversible when patients were controlled by antithyroid therapy.

Adolescent

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