Graves' disease: an analysis of thyroid hormone levels and hyperthyroid signs and symptoms

PURPOSE: Assessment of disease severity for patients with hyperthyroidism involves clinical evaluation and laboratory testing. To determine if there is a correlation between symptoms and thyroid function test results, we prospectively studied hyperthyroid patients using a standardized symptom rating scale and serum thyroid function parameters. PATIENTS AND METHODS: We examined 25 patients with untreated, newly diagnosed Graves' disease using the Hyperthyroid Symptom Scale (HSS) and serum levels of thyroxine (T4), triiodothyronine (T3) relative insulin area (RIA), and estimates of free thyroxine index (FTI). In addition, we compared thyroid hormone levels with standard measures of depression and anxiety in these patients. RESULTS: When regression analyses controlling for age were performed, none of these symptom ratings were associated with FTI or T3 RIA. The HSS was correlated with goiter size and anxiety ratings and was inversely correlated with age. CONCLUSION: The present study suggests that there is no relationship between the clinical assessment of disease severity and serum levels of thyroid hormone in untreated Graves' disease.     

Measurement of thyroid hormone in experimental thyroid tumours in rats

Rats treated with 131I and propylthiouracil were shown to develop thyroid tumours 7--9 months after treatment. In this group, the levels of total thyroxine and tri-iodothyronine, and free thyroxine and tri-iodothyronine in the serum were low, and that of TSH was raised. In a group of rats treated with 131I and then propylthiouracil and thyroxine, thyroid tumours were found despite normal concentrations of total and free thyroxine and tri-iodothyronine in the serum. The level of TSH in the serum was significantly raised in this group. Thyroid tumours were not found in the various control groups of rats.     

Opposing effects of chronic alcohol consumption on hepatic gluconeogenesis for female versus male rats

BACKGROUND: The impact of chronic alcohol consumption on hepatic gluconeogenesis (HGN) between males and females is unknown. To determine the effects of chronic alcohol consumption (8 weeks) on HGN, the isolated liver perfusion technique was used on 24-hr-fasted male and female Wistar rats. METHODS: After surgical isolation, livers were perfused (single pass) for 30 min with Krebs-Henseleit bicarbonate buffer and fresh bovine erythrocytes with no added substrate (washout period). After the washout period, livers were perfused with lactate (10 mM) and [U-14C]lactate (15,000 dpm/ml) using the recirculation method. RESULTS: There was no significant difference in HGN between males and females fed the control diet. In contrast, the females chronically fed the ethanol diet (FE) had significantly lower HGN rates (2.73 +/- 0.37 micromol/min x g liver protein(-1)), whereas males fed the ethanol diet (ME) had significantly higher HGN rates (4.99 +/- 0.45 micromol/min x g liver protein(-1)) than controls (3.83 +/- 0.34 micromol/min x g liver protein(-1)). Concomitant decreases were also observed for both 14C-lactate incorporation into 14C-glucose and rates of lactate uptake for FE, while corresponding increases were observed for 14C-lactate incorporation into 14C-glucose for ME. The livers from ME were able to convert a greater percentage of the lactate into glucose, resulting in the elevation in gluconeogenic capacity. CONCLUSION: Chronic alcohol consumption lowers the hepatic gluconeogenic capacity from lactate in females and elevates HGN in males.     

Direct effect of thyroid hormone on intracardiac conduction in acute and chronic hyperthyroid animals.

Studies of intracardiac conduction utilizing His bundle electrograms demonstrate direct thyroid hormone action on the conduction system in both acute and chronic hyperthyroid animals.     

Iodothyronine deiodinases and the control of plasma and tissue thyroid hormone levels in hyperthyroid tilapia (Oreochromis niloticus)

Thyroid status is one of the most potent regulators of peripheral thyroid hormone metabolism in vertebrates. Despite this, the few papers that have been published concerning the role of thyroid hormones in the regulation of thyroid function in fish often offer conflicting data. We therefore set out to investigate the effects of tetraiodothyronine (thyroxine) (T4) or tri-iodothyronine (T3) supplementation (48 p.p.m.) via the food on plasma and tissue thyroid hormone levels as well as iodothyronine deiodinase (D) activities in the Nile tilapia (Oreochromis niloticus). T4 supplementation did not induce a hyperthyroid state and subsequently had no effects on the thyroid hormone parameters measured, with the liver as the sole notable exception. In T4-fed tilapias, the hepatic T4 levels increased substantially, and this was accompanied by an increase in in vitro type I deiodinase (D1) activity. Although the lack of effect of T4 supplementation could be partially explained by an inefficient uptake of T4 from the gut, our current data suggest that also the increased conversion of T4 into reverse (r)T3 by the D1 present in the liver plays an important role in this respect. In addition, T3 supplementation increased plasma T3 and decreased plasma T4 concentrations. T3 levels were also increased in the liver, brain, kidney, gill and white muscle, but without affecting local T4 concentrations. However, this increase in T3 availability remained without effect on D1 activity in liver and kidney. This observation, together with the 6-n-propylthiouracyl (PTU) insensitivity of the D1 enzyme in fish, sets the D1 in teleost fish clearly apart from its mammalian and avian counterparts. The changes in hepatic deiodinases confirm the role of the liver as an important T3-regulating tissue. However, the very short plasma half-life of exogenously administered T3 implies the existence of an efficient T3 clearing/degradation mechanism other than deiodination.     

Effect of chronic alcohol consumption on total plasma homocysteine level in rats

BACKGROUND: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6. Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS: In the present study, 10 male Sprague Dawley rats were fed ethanol-containing Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/- 4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76 micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion.     

Effect of chronic alcohol consumption on the pregnant mare serum gonadotropin-induced luteinizing hormone surge

The studies reported in this paper were undertaken to investigate the effect of chronic (10 day) alcohol consumption on female pituitary-gonadal function. The immature female rat model treated with pregnant mare serum gonadotropin (PMSG) was used since it results in a highly reproducible luteinizing hormone (LH) surge and ovulation. Twenty-day-old female rats were placed on diets that were either (1) unrestricted (ad libitum); (2) contained 5% ethanol in a liquid diet, or (3) isocalorically pair-fed with the liquid diet to the ethanol group. After 10 days on their respective diets, the groups were subdivided and given either 8 IU of PMSG in 0.1 ml saline or 0.1 ml saline s.c. between 10.00 and 11.00 h. The animals were sacrificed by decapitation at 24, 48, 52, 54, 56, 58, 60 and 62 h after injection. Trunk blood was obtained for serum measurements of LH. The uteri were weighed and prepared for the histological study. In all dietary groups, serum LH levels were significantly higher in the PMSG-treated animals when compared to the saline controls at all time intervals with the exception of the alcohol 58-hour group. In the ad libitum animals, plasma LH concentrations were highest at 52 h following hormone administration. The serum LH concentrations were highest at 56 h after hormone administration in the pair-fed group and were significantly less than the ad libitum group at 52, 54, 56, and 58 h after PMSG stimulation. No significant plasma LH surge was observed in the alcohol group and the LH concentrations were significantly less than the pair-fed rats at 56 and 58 h after PMSG treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heterogeneity of autoantibodies against thyroid peroxidase in autoimmune thyroid disease: evidence against antibodies directly inhibiting peroxidase activity as regulatory factors in thyroid hormone metabolism.

The close relationship between thyroid microsomal antigen and thyroid peroxidase (TPO) is now well established. The present study evaluates the significance of autoantibodies against TPO (anti-TPO-Abs) in the various forms and stages of autoimmune thyroid disease with respect to a possible heterogeneous nature and particularly to their influence on TPO activity. When measured by a RIA using purified human TPO, anti-TPO-Abs were highly correlated with microsomal antibodies determined by enyzme-linked immunosorbant assay (r = 0.96; P less than 0.0001) and with the results of a TPO immunoprecipitation assay using crude microsomal preparations (r = 0.76; P less than 0.001). Relating the results of these assays to the reactivities of patients' sera with thyroid microsomes in immunoblot under nonreducing and reducing conditions, discordant results could be observed in a few cases. Further analysis of these data indicate a heterogeneous nature of anti-TPO-Abs, which react with at least two antigenic domains of the TPO molecule. The comparative analysis of patients with hyperthyroid Graves' disease, patients with Graves' disease in clinical remission, and patients with hypothyroid Hashimoto's thyroiditis revealed no significant differences in the antibody spectrum. When evaluating the direct influence of anti-TPO-Abs on the activity of TPO under a rigorous methodological approach, we found no significant inhibition of the enzymatic activity by any of the sera investigated from patients with autoimmune thyroid disease compared to that in sera from normal controls. In conclusion, the data indicate a heterogeneous nature of anti-TPO-Abs. The spectrum of antigenic epitopes recognized by anti-TPO-Abs seems not to be significantly different in the various forms and stages of autoimmune thyroid disease. The lack of an inhibitory effect of autoantibodies on TPO activity argues against direct binding of autoantibodies to the enzymatic sites of TPO and indicates that they are not important factors in producing thyroid dysfunction in autoimmune thyroid disease.     

Effects of chronic alcohol consumption and alcohol withdrawal on blood pressure in stroke-prone spontaneously hypertensive rats

The development of blood pressure was monitored by the tail-cuff method in normotensive (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) receiving ethanol (alcohol) in drinking water from weaning (approximately 1 month of age). Alcohol administration over a 3-month period attenuated the development of hypertension in SHRSP and also caused a small reduction of the initial blood pressure rise in WKY. This was accompanied by a reduction of fluid intake and an increase of circulating antidiuretic hormone (arginine vasopressin; AVP). Circulatory volume remained constant. Direct measurement of arterial blood pressure in conscious rats before and after autonomic blockade confirmed the antihypertensive effect of alcohol in SHRSP and indicated that it is at least partly dependent on altered activity of neural mechanisms. Sudden withdrawal of alcohol caused an immediate increase of fluid intake followed by a rise of blood pressure lasting several days in both WKY and SHRSP. This withdrawal hypertension could not be attributed to changes in plasma catecholamines or AVP.     

Mitochondrial glutathione in hypermetabolic rats following burn injury and thyroid hormone administration: evidence of a selective effect on brain glutathione by burn injury.

Cerebral cortex, heart, skeletal muscle, and liver mitochondrial glutathione (GSH) levels in severely burned rats are decreased to between approximately 50% to 70% of sham-operated, normally fed controls. In semistarved rats, weight-matched with burned rats, mitochondrial GSH levels in these tissues are decreased to between approximately 70% to 91% of those in sham-operated rats. Total GSH levels in peripheral tissues and brain are decreased to approximately 60% to 65% of control levels in rats with burn injury and food restriction, suggesting a higher mitochondrial GSH turnover in burned rats than in semistarved rats, probably because of higher "stress hormone" levels in burned rats than in semistarved rats. Cerebral cortex mitochondrial GSH levels are unaffected by variations in thyroid hormone status, but liver mitochondrial GSH levels are decreased by triiodothyronine and increased by propylthiouracil. The present results suggest that mitochondrial GSH is not only regulated by the rate of GSH synthesis in the cytosol, but seems to be under hormonal influence as well; stress hormones and triiodothyronine may decrease mitochondrial GSH by increasing mitochondrial oxygen consumption with increased reactive oxygen species formation or by increasing GSH exchange between mitochondria and the cytosol. These findings may be of importance therapeutically in increasing antioxidative defenses to limit oxidative stress injury in hypermetabolic patients.     

Effect of moderate alcohol consumption on hypertriglyceridemia: a study in the fasting state.

BACKGROUND: Patients with hypertriglyceridemia (HTG) are generally advised to avoid alcohol, even though moderate alcohol consumption is cardioprotective. Alcohol increases plasma triglyceride concentration transiently in normolipidemic subjects, but whether alcohol consumption per se increases triglyceride concentrations in patients with HTG is unclear. OBJECTIVE: To assess whether baseline fasting triglyceride concentration determines plasma triglyceride concentration after acute oral alcohol intake. METHODS: Twelve persons with fasting triglyceride concentrations of 2.3 to 8.5 mmol/L (200-750 mg/dL) and 12 persons as a non-HTG group were enrolled. Obesity, current smoking, and history of hypertension, diabetes, or excessive alcohol use were exclusionary. Fasted subjects consumed 38 mL of ethanol in water (equivalent, 2 alcoholic drinks); blood samples were collected at baseline and at intervals thereafter for 10 hours. No less than 1 week later, the subjects consumed water alone in a control test. RESULTS: Mean triglyceride values were 4.04+/-0.41 mmol/L (358+/-36.9 mg/dL) and 1.00+/-0.11 mmol/L (89+/-10.2 mg/dL) for the HTG and non-HTG groups, respectively. Despite similar changes with alcohol feeding in plasma ethanol, nonesterified fatty acid, and acetate concentrations, the groups differed in triglyceride response. At 6 hours (peak) compared with baseline, triglyceride concentration increased only 3% in the HTG group but 53% in the non-HTG group. The former change was not significantly different from the effect with water alone (-9.2% from baseline; P = .43), whereas the latter was (-8.0%; P = .003). CONCLUSIONS: Acute alcohol intake alone is not an important determinant of plasma triglyceride concentration in individuals with HTG. Other factors, such as the contemporaneous consumption of fat and alcohol, known to increase triglyceride concentrations synergistically in non-HTG individuals, may be more important.     

Circulating thyroid hormone levels in young pregnant rats and their fetuses: effect of malnutrition

In order to evaluate some factors likely to be involved in the maternal and fetal growth impairment due to alimentary protein deficiency, the circulating levels of triiodothyronine (T3) and thyroxine (T4) were studied in 4 young (45-day-old) female rat groups: control and malnourished, both nonpregnant and pregnant; similarly scheduled groups were studied using adult (100-day-old) rats. Circulating levels of T4 were higher in nonpregnant, malnourished young rats than in their corresponding controls. T3 levels were higher in young malnourished animals and lower in adult malnourished animals, nonpregnant or pregnant, as compared to controls. Pups from young malnourished mothers showed significantly lower birth weights than those from controls. The present results suggest that there are age differences in thyroid function, as affected by protein-calorie malnutrition in pregnant and nonpregnant rats. On the other hand, the circulating thyroid hormone levels were not importantly affected by the mother dietary protein restriction under our experimental conditions.     

Pattern of adenohypophyseal hormone changes in male rats following chronic stress

To delineate the pattern of adenohypophyseal hormone secretion following chronic stress, adult male rats were exposed daily to 6 h of cold, forced exercise or immobilization for 3, 6, 10, 15, 28 or 42 consecutive days. Groups of these animals were sacrificed at the end of the last stress sessions, and plasma growth hormone (GH), luteinizing hormone (LH), prolactin (Prl) and follicle-stimulating hormone (FSH) levels were measured by radioimmunoassay (RIA). Irresspective of the different stimuli used, long-term stress induced a morphologic and hormonal response characterized by decreased ponderal growth, adrenal enlargement, thymus involution and significant diminutions in GH, Prl and LH levels with no modifications in FSH titers. The magnitude and duration of these changes varied with the severity of the stressors.     

An increase in calcitonin levels in the thyroid gland of infant rats following parathyroidectomy

It is well known that serum calcitonin (CT) levels in infantile rats are higher than those in adult rats. In the present experiment, the effects of parathyroidectomy or calcium administration on serum calcitonin levels were observed in suckling rats. Bilateral parathyroidectomy (Px) on 3-, 5-, 7-, 8- or 14-day-old Wistar-Imamichi female rats was performed surgically under a dissecting microscope. Ether anesthesia was used. In the first experiment, the Px rats of various age groups were killed 1 week after the operation. In the second experiment, time course effects of Px on one-week-old rats were observed 1, 2 or 3 weeks after the operation. CT in the serum and thyroid extracts (0.001N HCl) was measured using radioimmunoassay kits for human CT. Serum Ca was measured by the OCPC method and serum inorganic phosphates was measured by the Takahashi method. Serum calcium levels showed a significant decrease 1 week after Px in all age groups. In these rats, serum CT levels showed a slight increase or no changes, and a significant increase in CT concentrations in the thyroid gland was observed in all age groups. Moreover, the increase in CT contents in the thyroid gland became larger 3 weeks after Px in rats operated on at one week of age. Thyroid extract containing 70 pg immunoreactive CT was effective in decreasing 1.22 mg/100 ml serum calcium at 15 min after i.v. injection in a bioassay system in which a dose response curve of human calcitonin was used as standards. Acute s.c. injection of CaCl2 solution resulted in a significant increase in serum CT levels 15 and 30 min later in intact 2- and 3-week-old rats, whereas no significant change in serum CT levels was observed in one-week-old intact rats. Three and 15 min after s.c. injection of Na2EDTA, serum Ca levels decreased markedly, but thyroidal CT contents tended to increase 3 and 5 min after the injection. The results indicated that parathyroidectomy in infantile rats induces a marked increase in biologically active calcitonin in the thyroid gland, inspite of the significant decrease of serum Ca levels.     

Changes of serum thyroid hormone levels induce malformations on early embryogenesis in rats

The incidence of malformation is increased in infants of hyperthyroid or hypothyroid woman. Although many papers reported that the fetus is insulted from maternal thyroid hormone, the placenta (maternal-fetal barrier) is not yet fully developed before 11.5 days of gestation in rat embryos, suggesting the effect of thyroid hormone on early rat embryogenesis. This study was, therefore, undertaken to investigate whether excess or lack of thyroid hormones would affect early embryogenesis in rat embryo culture. Malformations including open neuropore and microencephaly were observed in 10 of 30 embryos incubated in hyperthyroid serum, and in 12 of 42 cultured in T3-enriched normal serum. Similar malformations were observed on 14 of 42 embryos cultured in hypothyroid serum and in 10 of 30 cultured in hypothyroid serum supplemented with T3. The frequencies of these malformations were significantly higher than in the control embryos (0 in 72 embryos) cultured with normal rat serum. These results suggest that the maternal thyroid status might play an important role for the complication of fetal malformations during early gestational period.     

Histochemical and immunohistochemical evidence for hepatic zone 3 distribution of alcohol dehydrogenase in rats

The distribution of alcohol dehydrogenase in the hepatic acinus was examined by both histochemical and immunohistochemical approaches. The immunohistochemical method using anti-alcohol dehydrogenase antibody indicated zone 3 predominance of this enzyme in the hepatic acinus, whereas a conventional histochemical method showed slight zone 1 predominance. However, when the histochemical technique was improved by using 2% glutaraldehyde instead of formalin for fixation and by adding phenazine methosulfate (0.33 mmol/L) to the staining incubation mixture, this method also supported zone 3 predominance of alcohol dehydrogenase. Evidence for zone 3 distribution of alcohol dehydrogenase may be of value in elucidating the mechanism of zone 3 liver damage by alcohol.     

Calcitropic hormone levels in polynesians: evidence against their role in interracial differences in bone mass

Blacks are known to have a higher bone mass than whites and have recently been found to have significantly different levels of calcitropic hormones and other biochemical indices of calcium metabolism. To assess the possible significance of these biochemical differences to interracial differences in bone mass, we have undertaken an assessment of indices of calcium metabolism in Polynesian subjects, since they also have a higher bone mass than whites. Serum concentrations of 25-hydroxyvitamin D were slightly lower in Polynesians than in whites (65 +/- 5 vs. 95 +/- 10 nmol/L; P less than 0.02), but there were no differences between the groups in serum levels of calcium (total and ionized), phosphate, magnesium, 1,25-dihydroxyvitamin D, PTH, calcitonin, alkaline phosphatase activity, and bone gla-protein. Furthermore, urinary excretion of hydroxyproline, calcium, phosphate, magnesium, sodium, and potassium and the tubular maximum for the reabsorption of phosphate were not different between whites and Polynesians. Intestinal strontium absorption was similar in the two groups. In contrast, distal forearm bone mineral content was higher in Polynesians (P less than 0.01) and midupper arm muscle area was also increased in this group (P less than 0.005). It is concluded that the higher bone mass of Polynesians cannot be attributed to alterations in the basal levels of calcitropic hormones, but may be related to their greater muscle mass. It is probable that the previously observed black-white differences in the vitamin D endocrine system are secondary to the effects of skin color on vitamin D synthesis and are not contributory to the lower bone mass of whites.     

Deceptively high thyroid hormone levels in a neonate due to autoantibodies against thyroid hormones transferred from a mother with Graves' disease.

At birth, a clinically euthyroid male neonate was found to have unexpectedly high levels of free T3 and T4 concurrent with a high TSH level. The mother was treated with propylthiouracil for Graves' disease during and after pregnancy. The neonate also had an extremely high titer of TSH receptor antibodies. He soon became clinically thyrotoxic as TSH levels were suppressed and thyroid hormone levels rose. After instituting antithyroid therapy, TSH levels became elevated again, while thyroid hormone levels decreased but were still above normal. Around 3 months after birth, both TSH receptor antibodies and discordance, between the levels of thyroid hormones and TSH, disappeared. Because of high maternal TSH levels in conjunction with an elevated free T3 level at 7 months postpartum, we suspected the presence of autoantibodies against thyroid hormones (AAb). Maternal and infant blood samples were then examined retrospectively for AAb and were detected in all the samples except those of the infant taken more than 3 months after birth. The authors, therefore, suggest that physicians be aware of the presence of AAb in pregnant women with Graves' disease, in order to avoid inappropriate treatment which could lead to fetal and neonatal hypothyroidism.