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PubMed1986

[Responses of plasma bradykinin and the renin angiotensin axis to angiotensin II in hyperthyroid patients].

The present investigation was undertaken to elucidate the possible interplay between the circulating kinin(s) and the renin angiotensin axis in hyperthyroidism. The responsiveness of plasma aldosterone (p-Ald), kinin (p-BK), plasma renin activity (PRA) and serum angiotensin converting enzyme activity (ACEA) to infusion of angiotensin II at a dose of 4, 8 and 16 ng/kg.min. was asessed in 15 hyperthyroid patients and 10 euthyroid controls. There was impaired angiotensin II induced response of blood pressure in hyperthyroid patients, and basal concentrations of p-Ald were 7.7 +/- 3.8 ng/dl in euthyroid controls and 12.6 +/- 3.1 ng/dl in hyperthyroid patients (p less than 0.05). As compared to the euthyroid controls, the hyperthyroid patients showed a reduced response of plasma aldosterone to angiotensin II infusion. Angiotensin II infusion increased p-BK from basal levels of 19.1 +/- 8.2 pg/ml to 31.0 +/- 7.8 pg/ml (p less than 0.05) only in hyperthyroid patients and did not increase ACEA in either group. Next, the effects of a single administration of captopril (50 mg p.o.) on blood pressure and p-BK in hyperthyroid patients and euthyroid controls were studied. In the two groups blood pressure was not changed by captopril, but p-BK increased significantly. The present results do not support the view that there may be a direct linkage between the kallikrein kinin system and the renin angiotensin axis mediated by kininase II or angiotensin converting enzyme in human peripheral blood. Also it is unlikely that kinin may play a role in the mechanism of reduced responsiveness of aldosterone and blood pressure to angiotensin II in hyperthyroidism.

Adult↗
PubMed1986

Pharmacokinetics of methimazole in normal subjects and hyperthyroid patients.

Serum and urinary concentrations of methimazole (MMI) were measured by high-performance liquid chromatography (HPLC) with an electrochemical detector (ECD) in 10 normal subjects and 43 hyperthyroid patients after intravenous and oral administration of the drug. The pharmacokinetic parameters of MMI were estimated in 5 normal subjects and 15 hyperthyroid patients according to a two-compartment model after intravenous injection of a 10 mg dose. The mean half-life of the distribution phase (T1/2 alpha) was 2.7 +/- 1.0 h (mean +/- SD) and 3.1 +/- 1.4 h and that of the slower-phase (T1/2 beta) was 20.7 +/- 9.6 h and 18.5 +/- 12.9 h in normal subjects and hyperthyroid patients, respectively. There were no significant differences between pharmacokinetic parameters of normal subjects and those of hyperthyroid patients. No correlations between free T4 index (FT4I) and pharmacokinetic parameters were observed. Maximum serum MMI concentrations (Cmax) (213 +/- 84 and 299 +/- 92 ng/ml) were attained 1.8 +/- 1.4 h and 2.3 +/- 0.8 h after a single dose of 10 mg in 5 normal subjects and in 15 hyperthyroid patients, respectively. In hyperthyroid patients the time taken to reach the peak concentration (Tmax) after a single dose of 10 mg was similar to that after a single 15 mg and 30 mg dose. The pharmacokinetic parameters, except Cmax and the area under the curve (AUC), were not affected by the administered dose and those, except Cmax, were not affected by the thyroid function. All urine was collected at intervals of 3 h for the first 12 h and then at 24 h and 48 h after intravenous and oral administration of MMI. In all subjects, MMI rapidly appeared in the urine and the rate of excretion was highest in the first 3 h. The cumulative urinary excretion of MMI was 5.5-8.5% of administered doses in normal subjects and hyperthyroid patients. These findings in the present study are compatible with the assumption that the extent of absorption of MMI is high, if not complete, and hyperthyroidism does not affect the kinetics of MMI, and that interindividual variation is observed in the time taken to reach the peak concentration after oral administration.

Administration, Oral↗
PubMed1991

Diagnostic relevance of suppressed basal concentrations of TSH compared with the negative TRH test in detection and exclusion of hyperthyroidism.

To evaluate the sensitivity of basal TSH concentrations as determined by an "ultrasensitive" IRMA-assay (RIA-gnost h-TSH-monoclonal, Behring) versus a "negative" TRH test (defined as an increment of TSH less than or equal to 0.2 mU/l 20 min after administration of 400 micrograms TRH iv) in the diagnosis of hyperthyroidism we examined 193 consecutive patients from our thyroid outpatient clinic: 34 patients displayed hyperthyroidism (total T4: 184.4 +/- 26.0 mumol/l, effective thyroxine index: 1.25 +/- 0.08), whereas 12 had isolated T3-hyperthyroidism (total T3: 3.47 +/- 0.48 nmol/l). Employing the producer's definition of subnormal ("suppressed") bTSH concentrations (less than or equal to 0.1 mU/l), only 19 (41.3%) hyperthyroid patients would have been detected; on the other hand, one euthyroid patient would have been recognized false positively as hyperthyroid. Using the TRH test as criterion led to the correct diagnosis in 42 (sensitivity: 91.3%) hyperthyroid patients, whereas two had low bTSH concentrations (less than or equal to 0.5 mU/l), but a normal TSH response to TRH (greater than 2.0 mU/l). Raising the threshold concentration to 0.2 and, subsequently, to 0.4 mU TSH/l increased the number of correct results to 38 (sensitivity: 82.6%) and 43 (93.5%), respectively. This was associated with a concomitant decrease in specificity in the diagnosis of hyperthyroidism from 93.7 (0.1 mU/l) to 27.9% (0.4 mU/l). In conclusion, despite ultrasensitive methods for estimation of low TSH concentrations, the TRH test remains an irreplaceable tool for the correct diagnosis of hyperthyroidism.

Adult↗
PubMed1992

Increased lymphocyte thermogenesis in hyperthyroid patients. Role of Na/K pump function. Evaluation of aerobic/anaerobic metabolism.

The role of the Na/K pump for the increased cell energy expenditure in hyperthyroidism was studied by measuring total lymphocyte heat production rate in samples with and without ouabain inhibition of Na/K ATP-ase. In addition, the relative contribution of aerobic processes to lymphocyte thermogenesis was calculated from oxygen consumption measurements. In 12 patients with clinical and laboratory hyperthyroidism total lymphocyte heat production rate was 3.19 +/- 0.21 pW/cell, significantly higher than in 7 patients with subclinical hyperthyroidism (2.14 +/- 0.11 pW/cell) and in 15 euthyroid subjects (2.26 +/- 0.11 pW/cell) (p less than 0.001). The relative decrease in lymphocyte heat production rate after ouabain, giving a quantitative measure of the activity of the Na/K ATP-ase and reflecting the importance of Na/K pump function for the overall rate of lymphocyte metabolism, was not significantly different between the groups: 19.5 +/- 3.6% in hyperthyroid patients, 14.2 +/- 2.3% in subclinical hyperthyroid patients and 17.8 +/- 3.1% in euthyroid subjects. According to the rate of lymphocyte oxygen consumption, aerobic processes represented 58.4 +/- 6.7% of total lymphocyte energy expenditure in hyperthyroid patients, not significantly different from subclinical hyperthyroidism (62.6 +/- 8.4%) or from euthyroidism (66.6 +/- 2.7%). These data do not support the hypothesis of a specific role of the Na/K pump function for the increased cell thermogenesis in hyperthyroidism and indicate a parallel stimulation of aerobic and anaerobic processes by thyroid hormone excess.

Adult↗
PubMed2000

Serum cytokine levels in autoimmune and non-autoimmune hyperthyroid states.

Although the role of interleukin-2 (IL-2) and interferon gamma (gammaIFN) is still poorly understood in hyperthyroid diseases, it is reasonable to assume that these cytokines may be present at higher levels in Graves' disease (GD) than in other primarily non-autoimmune thyroid diseases. In order to look for an easy method to distinguish GD from primarily non-autoimmune causes of hyperthyroidism, we compared 13 healthy individuals with 21 treated and untreated hyperthyroid GD patients and with 19 patients with hyperthyroidism due to other etiologies: 7 cases of multinodular goiter, 5 cases of excessive hormone replacement and 7 cases of amiodarone-associated hyperthyroidism. All patients presented low TSH levels and a dubious clinical thyroid state. We found a good correlation between TSH and serum IL-2 levels (r = 0.56; P<0.01). Serum IL-2 (P<0.01) and gammaIFN (P<0.01) levels were lower in the hyperthyroid group of patients than in control subjects, suggesting a depressed TH1 pattern in the T-cell subset of hyperthyroid patients. GD had normal IL-2 levels, while patients with other forms of thyrotoxicosis presented decreased IL-2 levels (P<0.05). There was no difference between treated and untreated GD patients. We suggest that the direct measurement of serum IL-2 level may help to confirm hyperthyroidism caused by GD.

Adolescent↗
PubMed1985

Spermatogenesis, seminal characteristics and reproductive hormone levels in mature rams with induced hypothyroidism and hyperthyroidism.

Mature Merino rams were made hypothyroid by daily oral drenching with methylthiouracil or hyperthyroid by daily subcutaneous injections of thyroxine for 8 weeks. Neither hypothyroidism nor hyperthyroidism had any apparent effect on either spermatogenesis or daily sperm production, but motility of ejaculated spermatozoa and circulating testosterone concentrations were reduced in both conditions. The ratio of testosterone concentrations in plasma from the internal spermatic vein to those in peripheral blood plasma was higher in hyperthyroid (21.2 +/- 3.5) than in control (11.1 +/- 4.4) and hypothyroid (7.6 +/- 1.4) rams. The basal secretion rate for testosterone was slightly lower in hypothyroid rams and testosterone responses to human chorionic gonadotrophin and after LH-releasing hormone (LHRH) were very much reduced. Basal serum LH levels were low in both hypothyroid and hyperthyroid rams compared with controls whereas there were no differences in FSH levels. The LH response to exogenous LHRH was reduced in hypothyroid rams but not in hyperthyroid rams. Serum prolactin levels on the other hand were higher than control in both hypothyroid and hyperthyroid rams. Reduced testosterone secretion in hypothyroid rams indicates that the normal function of Leydig cells depends on an adequate level of thyroid hormones. The decrease in circulating testosterone concentrations in hyperthyroid rams with normal secretion rates suggests an increased testosterone clearance rate in these animals. The decreased spermatozoal motility in hypo- and hyperthyroid rams suggests that the lowered testosterone level in these animals has altered the androgen-dependent maturation of spermatozoa in the epididymis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Relationship between the resting metabolic rate and hepatic metabolism in rats: effect of hyperthyroidism and fasting for 24 hours.

We have examined the relationship between the changes in resting metabolic rate (RMR) and those in hepatic metabolism induced by hyperthyroidism and fasting for 24 h. We found that hyperthyroidism induced a significant increase in RMR, while fasting for 24 h reduced RMR in euthyroid but not in hyperthyroid rats. We have also measured oxygen consumption in isolated hepatocytes from euthyroid and hyperthyroid rats, fed or fasted for 24 h. Hyperthyroidism induced an increase in oxygen consumption in rat liver cells; fasting for 24 h increased respiratory rates in isolated liver cells from euthyroid but not from hyperthyroid rats. The findings showed that hyperthyroidism and fasting for 24 h have opposite effects on RMR but similar effects on hepatic metabolism. The results also indicated that the increase in RMR found in hyperthyroid rats is partly due to an increase in hepatic metabolism, while no correlation exists between variations in resting and hepatic metabolism induced by 24-h fasting.

Animals↗
PubMed1998

Hyperthyroidism. Current treatment guidelines.

Hyperthyroidism is common and affects approximately 2% of women and 0.2% of men. The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder associated with circulating immunoglobulins that bind to and stimulate the thyrotropin (TSH) receptor, resulting in sustained thyroid overactivity. Toxic nodular goitres cause hyperthyroidism due to autonomous hyperfunctioning of localised areas of the thyroid. There are 3 recognised modalities of treatment for hyperthyroidism: antithyroid drugs, surgery and radioiodine. All are effective but no single method offers an absolute cure. Patients with Graves' disease may be prescribed antithyroid drugs over a period of 12 to 18 months with a view to inducing a long term remission. These drugs are also often given for a short period to render the patient euthyroid before definitive therapy with radioiodine or thyroidectomy. However, antithyroid drugs will not 'cure' hyperthyroidism associated with a toxic nodular goitre. The use of radioiodine as a first-line therapy for hyperthyroidism is growing. It is well tolerated, with the only long term sequelae being the risk of developing radioiodine-induced hypothyroidism. Radioiodine can be used in all age groups other than children, although it should also be avoided in pregnancy and during lactation. Pregnancy should be avoided for 4 months following its administration. Radioiodine may cause a deterioration in Graves' ophthalmopathy and corticosteroid cover may reduce the risk of this complication. The treatment of choice for toxic nodular goitre hyperthyroidism is radioiodine. Surgery, either subtotal or near-total thyroidectomy, has limited but specific roles to play in the treatment of hyperthyroidism: this approach is rarely used in patients with Graves' disease unless radioiodine has been refused or there is a large goitre causing symptoms of compression in the neck. The goal of surgery is to cure the underlying pathology while leaving residual thyroid tissue to maintain postoperative euthyroidism.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Gastric inhibitory polypeptide (GIP) responses after oral glucose ingestion in hyperthyroidism.

Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone stimulated after oral nutrient ingestion, but not after intravenous nutrient administration. GIP stimulates insulin release in the presence of hyperglycemia and as such is considered a major enteroinsular hormone. Since elevated glucose and insulin levels are found in hyperthyroidism, we compared the GIP responses to oral glucose ingestion in 12 hyperthyroid patients and 10 age-matched controls. Seventy-five grams of oral glucose was ingested after overnight fasting and samples were obtained at 0, 30, 60, 90, 120, and 180 min for serum glucose and immunoreactive insulin (IRI) and GIP (IRGIP). The mean serum glucose levels in hyperthyroid subjects were significantly higher (P less than or equal to 0.05) at every time studied except at 180 min. At 60 min, peak mean glucose was 171 +/- 14 mg/dl versus 128 +/- 7 mg/dl in controls (P less than 0.02). Except for fasting, mean IRI levels were significantly higher (P less than 0.001) in hyperthyroid subjects than in controls at all times studied. At 60 min, IRI rose to a peak of 125 +/- 11 microU/ml in hyperthyroid subjects versus 50 +/- 9 microU/ml in controls (P less than 0.001). Mean fasting, stimulated, and incremental IRGIP levels were slightly higher but not statistically different in the hyperthyroid subjects versus controls. Glucose and IRI responses are exaggerated in hyperthyroidism after oral glucose ingestion. Even though GIP has insulinotropic action, its role in the hyperinsulinism found in hyperthyroid subjects appears to be minimal.

Adult↗
PubMed2000

[Contribution of the renin-angiotensin system to blood pressure variability in hyperthyroid rats].

OBJECTIVES: To produce a chronical thyrotoxicosis model in rat, and to evaluate, using spectral analysis, the involvement of the renin-angiotensin system (RAS) in short-term variability of blood pressure (BP) in experimental hyperthyroidism. DESIGN AND METHODS: Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (T4: 0.1 mg/kg for 15 days) in Wistar rats. Control (euthyroid) rats received i.p. daily injection of the thyroxine solvent. Two series of experiments were performed in conscious and unrestrained rats. In the first series, 10 euthyroid and 14 hyperthyroid rats were surgically prepared with a femoral artery catheter to measure BP and heart rate (HR) and to collect blood samples on the last day of treatment. In the second series of experiments (n = 12 in each group), on the fifteenth day of treatment, BP and HR were recorded by telemetry in control conditions and after a specific blockade of the RAS by the angiotensin type I receptors antagonist: valsartan (10 mg/kg, i.p.). BP recordings were analysed by the Fast Fourier Transform on consecutive 204.8-s stationary periods. RESULTS: The dose and duration of T4 treatment was sufficient to induce a significant degree of hyperthyroidism with characteristic features including: tachycardia, systolic hypertension, myocardial hypertrophy, hyperthermia, and weight loss. In addition, we measured an increase in free fractions of thyroid hormones, and a 3 fold-increase of plasma renin activity. Hyperthyroidism modified systolic BP (SBP) variability profiles. An amplification of low frequency (LF) oscillations (2.37 +/- 0.12 mmHg vs 1.78 +/- 0.11 mmHg, p < 0.01) was observed after T4 treatment. In hyperthyroid rats, valsartan diminished the slow fluctuations of SBP (p < 0.001) and increased the mid-frequency oscillations (2.44 +/- 0.20 mmHg vs 1.32 +/- 0.18 mmHg, p < 0.001). CONCLUSION: The cardiovascular alterations of hyperthyroidism are reproduced with thyroid hormone injections in rats. Activation of the RAS in hyperthyroid rats was accompanied by increased SBP variability in the LF range. Using the angiotensin type I receptors antagonist, valsartan, we demonstrated that the RAS impinged on the LF oscillations of the SBP in our experimental hyperthyroidism model.

Angiotensin I↗
PubMed1992

[Influence of dexamethasone and epinephrine on glycogen content and cytosol glucocorticoid receptors in hyperthyroid rat liver].

The influence of hyperthyroidism on the action of drugs affecting rat liver glycogen content and its mechanism were investigated. The thyroid-induced hyperthyroidism of rat served as the model. In normal rats, dexamethasone (5 mg.kg-1, ip) increased the content of liver glycogen and decreased the Bmax of glucocorticoid receptors (GCR) in liver cytosol. These effects were minimized or even disappeared in hyperthyroid rat models. On the other hand, in normal rats, epinephrine (0.20 mg.kg-1, ip) decreased the content of liver glycogen. This effect was potentiated in hyperthyroid rat models. Epinephrine did not affect the Bmax of GCR in liver cytosol of normal and hyperthyroid rats. These results suggested that hyperthyroidism may be one of the causes effecting the individual differences of drug action, and that the influence of hyperthyroidism on the glycogen-increasing action of dexamethasone correlated well with the changes in glucocorticoid receptor. The mechanism of the influence of hyperthyroidism on the glycogen-decreasing action of epinephrine is to be further explored.

Animals↗
PubMed1990

Diagnosis of occult hyperthyroidism in cats.

As expertise among small animal practitioners grows, feline hyperthyroidism is being diagnosed earlier in the course of the disease. There are, in fact, a growing number of cats with clinical signs of hyperthyroidism and palpably large thyroid glands whose serum total thyroxine (T4) and triiodothyronine (T3) concentrations are within the normal or borderline range. This condition can be referred to as "occult" hyperthyroidism. Early detection and treatment of feline hyperthyroidism presents an obvious advantage in avoiding some of the deleterious effects of chronic thyroid hormone excess (eg, cardiomyopathy). Recent advances have been made in the diagnosis of occult hyperthyroidism in cats. It has been found, for instance, that serum thyroid hormone concentrations can fluctuate in and out of the normal range in some cats with hyperthyroidism. Recent work also has laid the groundwork for use of a T3 suppression test as an aid in the diagnosis of early, mild, or occult hyperthyroidism in cats. The purpose of this chapter is to discuss these and other developments, as well as to discuss some of the problems confronted in diagnosing occult hyperthyroidism in cats.

Animals↗
PubMed1975

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↗
PubMed1995

[Clinical aspects, diagnosis and drug therapy of hyperthyroidism].

Graves' disease and toxic uni- or multinodular goiter are the most frequent causes of hyperthyroidism. Graves' disease is caused by thyroid stimulating immunoglobulins which are directed against the TSH receptor of thyroid follicular cells. Graves' disease affects more females than males and is associated with diffuse goiter and a rapid appearance of symptoms and signs of hyperthyroidism. Patients with Graves' disease are on average younger than patients with toxic nodular goiter. The diagnosis of Graves' disease is usually easy, particularly if signs of endocrine opthalmopathy are present. Toxic nodular goiter is seen more often in older patients with pre-existing goiters. Symptoms and signs of hyperthyroidism often appear only slowly. Hyperthyroidism in these older patients can be oligosymptomatic. Older patients should therefore be investigated for the presence of hyperthyroidism, even if they present only a few symptoms or signs which could suggest this diagnosis. The development of ultrasensitive TSH assays has simplified the diagnosis of hyperthyroidism and made the TRH-test, often used in the past, almost superfluous. At the present time, it is practically always possible to differentiate between Graves' disease and toxic nodular goiter as the cause of hyperthyroidism on the basis of clinical and laboratory findings alone, and in many cases thyroid scintiscans are therefore no longer necessary. A patient with newly diagnosed Graves' disease is treated with antithyroid drugs (carbimazole or PTU) for one year. If hyperthyroidism persists after this one year of antithyroid drug treatment, or if it recurs, another year of therapy with carbimazole or PTU is indicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Serum thyroxine and triiodothyronine responses of hyperthyroid cats to thyrotropin.

OBJECTIVE: To document circulating total thyroxine (T4) and triiodothyronine (T3) responses after administration of thyrotropin (thyroid-stimulating hormone [TSH]) to hyperthyroid and healthy cats and assess the value of these responses as an additional diagnostic test for hyperthyroidism. DESIGN: Prospective case series. ANIMALS: 21 healthy and 40 hyperthyroid cats. PROCEDURES: Serum total T4 and T3 concentrations were measured by radioimmunoassay before and 6 hours after administration of 0.5 IU of bovine TSH/kg of body weight. RESULTS: In healthy cats, serum total T4 concentration increased after administration of TSH (mean +/- SD, 114.0 +/- 36.4 nmol/L) representing a mean increment 3 times baseline concentration (mean +/- SD, 33.7 +/- 7.6 nmol/L). In hyperthyroid cats, the relative increase in serum total T4 concentration was significantly (P < 0.001) different; baseline values (mean +/- SD, 236.2 +/- 146.0 nmol/L) increased minimally after TSH administration (mean +/- SD, 308.1 +/- 178.9 nmol/L) There was a significant negative correlation (rs = -0.366) between relative increase in serum total T4 concentration after TSH administration and baseline concentration in hyperthyroid cats. In 3 cats with equivocal baseline serum total T4 concentration, the T4 response to TSH administration was indistinguishable from that in healthy cats. Serum total T3 response to TSH administration was significantly (P < 0.001) lower in hyperthyroid, compared with healthy, cats but the T3 response in healthy cats was more variable than that for T4 CONCLUSIONS: Thyrotoxic cats with high baseline serum total T4 concentration have a limited T4 response to TSH stimulation. Hyperthyroid cats with equivocal baseline serum total T4 concentrations have T4 response after TSH stimulation similar to those of healthy cats. Measurement of serum total T3 concentration provides no additional information. CLINICAL RELEVANCE: The TSH response test is of limited value in diagnosing hyperthyroidism in cats.

Animals↗
PubMed1997

Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene.

Congenital hyperthyroidism is usually caused by maternal-to-fetal transfer of thyroid-stimulating antibodies from a mother with autoimmune thyroid disease. Very recently, activating thyrotropin (TSH) receptor germline mutations were detected in a few patients with sporadic nonautoimmune congenital hyperthyroidism, as well as in familial forms of nonautoimmune hyperthyroidism defining a new pathophysiological entity of hyperthyroidism. In this report, we describe a nonidentical twin girl with severe congenital hyperthyroidism. The twin brother and the mother were euthyroid. Skull radiographs revealed premature synostosis of the sagittal sutures. Hyperthyroidism was inadequately controlled with antithyroid drugs and radioiodine therapy. After a near-total thyroidectomy performed at age 3, the patient became hypothyroid and required thyroid hormone replacement. At age 14, hyperthyroidism recurred. A hyperplastic remnant of the right upper lobe was removed surgically, resulting in euthyroidism. Over the following years, thyroid hormone levels increased gradually and at age 19 she was again hyperthyroid. There was no clinical or biochemical evidence of an autoimmune process. The patient's neurologic development was impaired and her intelligence is subnormal. Direct sequencing of the TSH receptor gene revealed a heterozygous mutation resulting in a substitution of threonine632 by isoleucine in the sixth transmembrane segment, an amino acid change known to result in constitutive activation of the cyclic adenosine monophosphate (cAMP) pathway. The mutation was absent in the parents and the twin brother, indicating a de novo germline mutation. Early recognition of this disorder is important because of the resistance to standard treatment, special therapeutic implications, and the possibility of familial transmission.

Child↗
PubMed1999

Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism.

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

Adult↗
PubMed2002

A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor.

In this work we report a novel method to efficiently induce a murine model of Graves' hyperthyroidism. Inbred mice of different strains were immunized by i.m. injection with adenovirus expressing thyrotropin receptor (TSHR) or beta-galactosidase (1 x 10(11) particles/mouse, three times at 3-wk intervals) and followed up to 8 wk after the third immunization. Fifty-five percent of female and 33% of male BALB/c (H-2(d)) and 25% of female C57BL/6 (H-2(b)) mice developed Graves'-like hyperthyroidism with elevated serum thyroxine (T(4)) levels and positive anti-TSHR autoantibodies with thyroid-stimulating Ig (TSI) and TSH-binding inhibiting Ig (TBII) activities. In contrast, none of female CBA/J (H-2(k)), DBA/1J (H-2(q)), or SJL/J (H-2(s)) mice developed Graves' hyperthyroidism or anti-TSHR autoantibodies except SJL/J, which showed strong TBII activities. There was a significant positive correlation between TSI values and T(4) levels, but the correlations between T(4) and TBII and between TSI and TBII were very weak. TSI activities in sera from hyperthyroid mice measured with some chimeric TSH/lutropin receptors suggested that their epitope(s) on TSHR appeared similar to those in patients with Graves' disease. The thyroid glands from hyperthyroid mice displayed diffuse enlargement with hypertrophy and hypercellularity of follicular epithelia with occasional protrusion into the follicular lumen, characteristics of Graves' hyperthyroidism. Decreased amounts of colloid were also observed. However, there was no inflammatory cell infiltration. Furthermore, extraocular muscles from hyperthyroid mice were normal. Thus, the highly efficient means that we now report to induce Graves' hyperthyroidism in mice will be very useful for studying the pathogenesis of autoimmunity in Graves' disease.

Adenoviridae↗