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Hyperglucagonemia of insulin autoimmune syndrome induced by methimazole in a patient with Graves' disease.

A 47-year-old man with Graves' disease suffered from a feeling of hunger and sweating in the night, polyarthralgia and fever one month after the start of treatment with methimazole. The above symptoms were ascribed to the side effects of methimazole; insulin autoimmune syndrome and lupus-like syndrome. The change in the antithyroid drug to propylthiouracil caused an amelioration of the symptoms. In addition to an anti-insulin antibody with a high binding capacity, hyperglucagonemia (260 pg/ml with a plasma glucose level of 61 mg/dl) was observed, which returned to normal in parallel with the decrease in the insulin binding capacity of the plasma one month after beginning the treatment with propylthiouracil. A normal decrease in the plasma glucagon level due to exogenous insulin (2 mU/kg/min) was observed with the euglycemic clamp. However, the plasma glucagon level was not suppressed by the oral glucose loading and elicited a poor response to the arginine infusion. Taking previous reports into account, this basal hyperglucagonemia seems to be a characteristic finding in the insulin autoimmune syndrome, while a sluggish response of glucagon to oral glucose or arginine infusion might be ascribed to hyperthyroidism. This is the first case report concerning a kinetical study of the glucagon secretion in insulin autoimmune syndrome with Graves' disease.

Arginine↗

Regulation of thymosin beta10 expression by TSH and other mitogenic signals in the thyroid gland and in cultured thyrocytes.

OBJECTIVE: To investigate the expression of thymosin beta10 - a small conserved acidic protein involved in the inhibition of actin polymerization - in human and experimental thyroid goiters as well as the regulation exerted by TSH on thymosin beta10 expression in thyroid follicular cells both in vivo and in vitro. DESIGN: To this aim, we have used 5 bioptic specimens from patients affected by thyroid goiter, a well known experimental model of thyroid goitrogenesis (rat fed with the drug propylthiouracil) and a cultured rat thyroid cell line (PC Cl 3 cells) as a model system. RESULTS: We report that the mRNA expression of thymosin beta10 is markedly enhanced in human goiters compared with normal thyroid. In vivo results showed that the steady-state level of thymosin beta10 mRNA is up-regulated in the thyroid gland of propylthiouracil-fed rats in parallel with follicular cell proliferation: iodide administration to goitrous rats, which induced a marked involution of thyroid hyperplasia, reduced the mRNA level of thymosin beta10. Finally, in vitro studies showed that in cultured rat thyrocytes, the expression of thymosin beta10 mRNA is induced in a time- and dose-dependent manner by the activation of pathways which are mitogenic for thyroid cells (i.e. the protein kinase (PK) A and PKC pathways). CONCLUSION: Taken together, the findings reported here demonstrate that thymosin beta10 expression is regulated by extracellular signals that stimulate growth of thyroid cells both in vitro and in vivo, and suggest a role for this protein in thyroid diseases characterized by proliferation of follicular cells.

Animals↗

Short-term hyperthyroidism followed by transient pituitary hypothyroidism in a very low birth weight infant born to a mother with uncontrolled Graves' disease.

Transient hypothyroxinemia in infants born to mothers with poorly controlled Graves' disease was first reported in 1988. We report that short-term hyperthyroidism followed by hypothyroidism with low basal thyroid-stimulating hormone (TSH) levels developed in a very low birth weight infant born at 27 weeks of gestation to a noncompliant mother with thyrotoxicosis attributable to Graves' disease. We performed serial thyrotropin-releasing hormone (TRH) tests in this infant and demonstrated that TSH unresponsiveness to TRH disappeared at 6.5 months of age. The maternal thyroid function was free triiodothyronine (FT(3)), 21.1 pg/mL; free thyroxine (FT(4)), 8.1 ng/dL; TSH, <0.03 microU/mL; thyroid-stimulating hormone receptor antibody, 52% (normal: <15%); thyroid-stimulating antibody, 294% (normal: <180%); and thyroid-stimulation blocking antibody, 9% (normal: <25%) on the day of delivery. A nonstress test revealed fetal tachycardia >200 beats per minute, and a male infant weighing 1152 g was born by emergency cesarean section. Thyroid-stimulating hormone receptor antibody was 16% and thyroid-stimulating antibody was 370% in the cord blood. We administered 10 mg/kg per day of oral propylthiouracil from day 1. Tachycardia along with elevated FT(4) and FT(3) levels in the infant decreased from 200/minute to 170/minute, 4.7 ng/dL to 2.9 ng/dL, 7.0 pg/mL to 4.8 pg/mL, respectively, in the first 33 hours. At 5 days, FT(4) and FT(3) were 1.1 ng/dL and 2.9 pg/mL, respectively, and we stopped propylthiouracil administration. Although FT(4) decreased to 0.4 ng/dL, TSH was quite low and did not respond to intravenous TRH by 14 days of age. We began daily levothyroxine 5-micro/kg supplementation. The responsiveness of TSH to TRH did not become significant until 4 months old and normalized at 6.5 months old. At this time, levothyroxine was stopped. We conclude that placental transfer of thyroid hormones may cause hyperthyroidism in the fetal and early neonatal periods and lead to transient pituitary hypothyroidism in an infant born to a mother with uncontrolled Graves' disease.

Adult↗

Effects of trimethoprim and sulphonamide preparations on the pituitary-thyroid axis of rodents.

The effects on pituitary-thyroid function of the commonly prescribed anti-bacterial preparations co-trimoxazole and co-trifamole, and their component drugs, have been studied in the rat and compared to the changes caused by propylthiouracil. Co-trimoxazole and co-trifamole, in doses 20-fold in excess of a pharmacological dose administered for 10 days, produced marked changes in hormone levels consistent with blocking of hyperplastic goitre formation, were also demonstrated. Propylthiouracil produced less marked changes of thyroid hormone levels but higher levels of thyroid-stimulating hormone. Pharmacological doses of co-trimoxazole and co-trifamole and sulphamoxole, the sulphonamide component of co-trifamole, caused significant changes in thyroid hormone levels consistent with anti-thyroidal activity. In contrast, there was no evidence that trimethoprim, which is common to both preparations, or sulphamethoxazole, the sulphonamide component of co-trimoxazole, had an anti-thyroidal action, indeed, serum thyroxine levels were significantly increased at pharmacological dosage. We have concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.

Animals↗

[Thyrotoxic crisis in a patient with Graves' disease].

A 33-year-old man presented with diarrhoea, dyspnoea, palpitations, fever and shock. One year and a half before admission, Graves'-hyperthyroidism had been diagnosed, for which he was treated with thiamazole and levothyroxine as block-replacement therapy. A diagnosis of thyrotoxic crisis, precipitated by lack of compliance with antithyroid drug therapy and possibly an underlying infection, was made. Euthyroidism was achieved with propylthiouracil, potassium iodide, corticosteroids and propranolol. However, the propylthiouracil had to be stopped due to agranulocytosis, after which hyperthyroidism recurred. An emergency thyroidectomy was then performed; the patient recovered completely. Thyrotoxic crisis is a rare, potentially life-threatening disease in patients with underlying un(der)treated hyperthyroidism. It is characterised by fever, tachycardia, and neurological and gastrointestinal symptoms.

Adult↗

[Two cases of acute hepatitis E in patients with hyperthyroidism].

Acute hepatitis E occur commonly as outbreaks in endemic areas, but can occur sporadically in other part of the world. Acute hepatitis E has been reported rarely in Korea. A case of concurrent acute hepatitis E virus (HEV) infection and hyperthyroidism was reported in an inactive hepatitis B surface antigen carrier. We experienced two cases of concomitant acute HEV infection in patients with hyperthyroidism. The first case had acute HEV infection with subclinical hyperthyroidism while taking propylthiouracil. The second case suffered from acute HEV infection in a patient with Graves' disease intractable to propylthiouracil. Herein, we suggest the possible association between HEV infection and hyperthyroidism.

Acute Disease↗

Congestive heart failure associated with hyperthyroidism in cats.

Hyperthyroidism was diagnosed in 4 cats with congestive heart failure. Dyspnea and anorexia were observed in 3 of the 4 cats. In each cat, a holosystolic left and/or right apical heart murmur was auscultated. In 3 cats, a prominent extra heart sound (gallop rhythm) was auscultated. All cats had a palpably large thyroid lobe(s) and weight loss. The laboratory and ECG changes were similar to those reported for feline hyperthyroidism. Moderate-to-severe pleural effusion and cardiomegaly were detected via radiography in all cats. Some cats had radiographic signs of pulmonary venous engorgement and pulmonary edema. Echocardiography revealed cardiac dilatation and low left ventricular shortening fraction (wall motion) in all cats. Three cats responded initially to cardiac drugs and propylthiouracil or thyroidectomy. One of these died later, presumably from an adverse reaction to propylthiouracil, and the others died from recurrent congestive heart failure (1) or postoperative cardiac arrest (1). One cat did not respond to treatment, and died 2 days after diagnosis.

Animals↗

Amiodarone-induced thyroid dysfunction.

Cases of hypothyroidism and hyperthyroidism associated with amiodarone therapy are described, and the mechanisms, clinical appearance, and management of amiodarone-induced thyroid dysfunction are discussed. A 72-year-old man with a history of recurrent ventricular tachycardia unresponsive to conventional antiarrhythmic drugs was started on amiodarone therapy. Initially he responded well, but after three months he began to have fatigue, dry skin, and intolerance of cold. His serum thyroid-stimulating hormone (TSH) concentration had risen from 4.4 microU/mL before amiodarone therapy began to 20 microU/mL, consistent with hypothyroidism. He was started on sodium levothyroxine for thyroid hormone replacement; the dosage was adjusted in accordance with subsequent TSH measurements. His hospital course was complicated by congestive heart failure. The second patient was a 43-year-old man with a history of atrial fibrillation who developed hyperthyroidism when placed on amiodarone therapy. He had persistent sweating, intolerance of heat, restlessness, and tachycardia. Thyroid function tests confirmed the presence of hyperthyroidism. The patient was treated with propylthiouracil and propranolol, and amiodarone was discontinued. He remained unresponsive to the propylthiouracil, which was discontinued, and was scheduled for radioactive iodine treatment. The mechanism of amiodarone-induced thyroid dysfunction may involve the large iodine content of the drug. Amiodarone-induced hypothyroidism may range in severity from mild symptoms to severe myxedema; the skin, hair, and nails are particularly affected. Persons with clinical hyperthyroidism secondary to amiodarone treatment show the signs and symptoms of a hypermetabolic state resulting from thyroid hormone excess. Amiodarone-induced hypothyroidism is treated with levothyroxine and hyperthyroidism with antithyroid drugs. Amiodarone can cause thyroid dysfunction, which can have serious consequences.

Adult↗

Prenatal treatment of fetal hypothyroidism: is there more than one option?

Following the diagnosis of fetal goitre at 22 and 24 weeks' gestation in two hyperthyroid pregnant women who underwent treatment with 400-500 mg of propylthiouracil in the first weeks of pregnancy, a total of seven fetal blood samplings were performed to evaluate thyroid function before and after the initiation of two different treatment regimens. L-Thyroxine (600 micrograms) was injected five times intra-amniotically in one woman and continuous maternal administration of the thyroid analogue 3, 5, 3'-triiodothyroacetic acid (Triac) was attempted in the other. Normalization of fetal thyroid function and reduction of fetal goitre were achieved in both fetuses and transplacental passage of Triac was indirectly demonstrated by high levels of free triiodothyronine in fetal blood. In cases of fetal hypothyroidism, direct or indirect prenatal therapy can be adopted successfully and safely.

Adult↗

Alternating antineutrophil cytoplasmic antibody specificity: drug-induced vasculitis in a patient with Wegener's granulomatosis.

We describe a patient who presented with Wegener's granulomatosis associated with antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) with a cytoplasmic immunofluorescence pattern (cANCA), whose ANCA type changed to antimyeloperoxidase antibodies with a perinuclear immunofluorescence pattern (pANCA) when treated with propylthiouracil, and changed back to anti-PR3 antibodies with cANCA after the medication was discontinued. The patient developed flares of vasculitis symptoms associated with rises in either type of ANCA. Tests for antimyeloperoxidase ANCA were repeatedly negative before the drug was started, strongly implicating the drug as the cause of the episode. This case demonstrates that patients with idiopathic ANCA-positive vasculitis may quickly develop a superimposed drug-associated ANCA-positive vasculitis. Iatrogenic vasculitis should be suspected when a patient with idiopathic vasculitis with one type of ANCA develops the other type of ANCA.

Adult↗

The thyroid in the spontaneously hypertensive rat: a light and electron microscopic study.

The present study was undertaken to seek ultrastructural changes in the thyroid gland of the spontaneously hypertensive rat which would contribute to the understanding of previously reported abnormalities in thyroid function. Light and electron microscopic observations and measurements of plasma T3 and systolic blood pressure were recorded from a colony of Wistar Kyoto rats (WKY) and of spontaneously hypertensive rats (SHR). The systolic blood pressure of SHR was significantly higher than that of WKY but the plasma T3 levels of the two groups did not differ significantly. After administration of propylthiouracil (PTU), serum T3 levels and systolic pressure of both groups decreased. The size of the thyroid follicles in SHR was highly variable throughout the gland, and the colloid contained unevenly dense areas and cell debris. The follicular cells contained slightly dilated rough surfaced endoplasmic reticulum (ER) and numerous pleomorphic bodies of uneven density. After treatment with PTU, the vessels between the follicles of SHR did not become as dilated as those in WKY but the fine structure of follicular cells in SHR was similar to that of WKY and was characteristic of the typical thyroid response to PTU administration. We suggest that the thyroid in SHR does not respond adequately to the elevated TSH levels reported to be present in these animals, although it can respond to the highly elevated TSH levels which occur with PTU administration. This impairment most probably involves defects in synthesis and/or secretion of thyroid hormones in response to TSH stimulation.

Animals↗

Ontogeny of the pituitary-thyroid system in fetal rats: observations on the fetal thyroid after maternal treatment with goitrogen.

The critical time of onset of the reciprocal relationship between the pituitary and the thyroid in fetal rats was assessed by the appearance of goiters in fetuses after maternal treatment with goitrogen, propylthiouracil (PTU), on various days of gestation. The assessment was based on changes in the weight and histology of the fetal thyroids. The day following overnight mating was regarded as day 1 of gestation. Pregnant rats were treated with 40 mg PTU each day for two days and autopsied on the third day. The various experimental periods were days 16--18, 17--19, 18--20, 19--21, and 20--22. PTU given to pregnant rats on days 16 and 17 did not cause any change in the fetal thyroids. PTU given on days 17 and 18 caused only a slight increase of fetal "thyroid weight/body weight" ratio. In all other experimental periods (days 18--20, 19--21, and 20--22), PTU induced conspicuous goiters in fetuses, which was reflected by an increased weight of thyroids, an increased height of follicular cells, and a decreased amount of colloid stored in follicles. The results suggest that in fetal rats, the reciprocal relationship between the pituitary and the thyroid is established on approximately days 19--20 of gestation.

Animals↗

Neuronal development in the trigeminal mesencephalic nucleus of the duck under normal and hypothyroid states: I. A light microscopic morphometric analysis.

Light microscopic morphometric procedures were used in order to examine the effects of propylthiouracil (PTU) on the development of the mesencephalic nucleus of the trigeminal nerve in the duck. A single vascular injection of a 0.2% solution of PTU was administered at a dosage of 2 microliter/gm embryo weight on embryonic day nine (E9). Control embryos received a similar dose of Ringer's solution. The following parameters of cytodifferentiation of cells of the mesencephalic nucleus of V were studied: somal area profiles, nuclear area, and nuclear cytoplasmic ratios. In addition, the frequency of beak clapping was recorded from E16. Significant differences were observed in somal area profiles in the experimental group at E16 and E18 and in nuclear area profiles from E16 through hatching. Beak activity in the experimental embryos was drastically reduced. It is concluded that PTU induces a retardation in the differentiation of cells of the mesencephalic nucleus of V which may lead to behavior deficits as evidenced by reduction of beak activity. These observations provide a basis for the study of interactions between thyroid hormone and specific neuronal systems in the emergence of an adaptive function.

Animals↗

Role of thyroid hormone in the initiation of EGF (epidermal growth factor) expression in the sublingual gland of the postnatal mouse.

The effect of triiodo-L-thyronine (T3) and propylthiouracil (PTU) on the initiation of epidermal growth factor (EGF) expression in the sublingual glands (SLGs) of postnatal mice was investigated by indirect enzyme-labeled and immunogold antibody methods for light and electron microscopy, respectively. In normal males, EGF immunoreactivity first appeared in a few scattered granular cells of striated ducts (SDs) at 5 weeks of age, and the immunoreactive cells had increased in number at 6 weeks of age. No EGF expression was observed in the glands of females at any ages examined. When T3 (1 mg/kg body weight) was given to males every other day for 2 weeks before examination, EGF expression began earlier; the immunoreactive granular cells were first detected at 4 weeks of age, and at later ages they were markedly increased in number compared to those of normal males. Moreover, T3 was capable of inducing EGF in the female glands. After T3 was administered to females in the same manner as in males, a few immunoreactive cells were first detected at 5 weeks of age, and increased numbers were detected at later ages. By contrast, when PTU (1 mg/kg body weight) was given to male mice every other day for 2 weeks before examination, the EGF-immunoreactive cells were markedly decreased in number compared to those of normal males of the same age. Electron microscopy revealed that many SD cells contained secretory granules, and that these cells constituted the granular striated tubule (GST) in a portion of SDs, but they were undetectable by light microscopy, because their secretory granules were minimal in size and few in number. Gold-labeling of EGF was confined to the secretory granules of scattered granular cells, whose secretory granules were far larger in size and more abundant than those of the GST cells. These results suggest that thyroid hormone is essential to differentiation of the cellular phenotype of GST precursor cells into typical granular cells (detectable by light microscopy) that express EGF in the mouse SLG, showing a close resemblance to the submandibular granular convoluted tubule cells.

Animals↗

Oxidative damage and antioxidant enzyme activities in experimental hypothyroidism.

Free radicals are now well known to damage cellular components. To investigate whether age and thyroid level affect peroxidation speed, we examined the levels of malondialdehyde and antioxidant enzyme activities in different age groups of hypothyroid rats. Hypothyroidism was induced in 30- and 60-day-old Wistar Albino rats by the i.p. administration of propylthiouracil (10 mg kg(-1) body weight) for 15 days. While malondialdehyde levels of 30- or 60-day-old hypothyroid rats were increased in liver, they were decreased in the tissues of the heart and thyroid. While glucose-6-phosphate dehydrogenase activity levels did not change in heart, brain and liver tissues of 30-day-old rats, they increased in brain and heart tissues of 60-day-old experimental groups, but decreased in the liver. Catalase activities decreased in the liver and heart of rats with hypothyroidism, but increased in erythrocytes. In control groups while malondialdehyde levels increased in brain, heart and thymus with regard to age, they decreased in plasma. Glucose-6-phosphate dehydrogenase and catalase activities were not affected by age in tissues of the thymus, thyroid and brain, but they were decreased in the heart tissue. The changes in the levels of lipid peroxidation and antioxidant enzyme activities which were determined in different tissues of hypothyroid rats indicate a cause for functional disorder of these tissues. Moreover, there may be changes depending on age at lipid peroxidation and antioxidant enzyme activity levels.

Aging↗

The effect of taurine supplementation on oxidative stress in experimental hypothyroidism.

The purpose of this study was to investigate the oxidative status in experimental hypothyroidism and the antioxidant effect of taurine supplementation. Forty male Sprague Dawley rats were randomly divided into four groups (group 1, control; group 2, control + taurine; group 3, propylthiouracil (PTU); group 4, PTU + taurine). Hypothyroidism was induced by giving 0.05% PTU in drinking water for 8 weeks. Taurine was supplemented in drinking water at a concentration of 1% for 5 weeks. Plasma (p < 0.05), red blood cell (p < 0.01), liver (p < 0.001) and kidney tissue (p > 0.05) malondialdehyde levels were increased in the PTU group compared with those of the control rats and were decreased in the PTU + taurine group compared with the PTU alone group. No significant changes were observed in glutathione levels of kidney and liver in the PTU group, but taurine supplementation significantly increased the glutathione levels of these tissues. Paraoxonase and arylesterase activities were decreased in the PTU group while taurine supplementation caused no significant changes in paraoxonase and arylesterase activities. These findings suggest that taurine supplementation may play a protective role against the increased oxidative stress resulting from hypothyroidism.

Animals↗

Protective effects of melatonin and indole-3-propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney.

Potassium bromate (KBrO(3)) is classified as a carcinogenic agent. KBrO(3) induces tumors and pro-oxidative effects in kidneys. Melatonin is a well known antioxidant and free radical scavenger. Indole-3-propionic acid (IPA), an indole substance, also reveals antioxidative properties. Recently, some antioxidative effects of propylthiouracil (PTU)-an antithyroid drug-have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the kidneys and blood serum and, additionally, in the livers and the lungs, collected from rats, pretreated with KBrO(3). Male Wistar rats were administered KBrO(3) (110 mg/kg b.w., i.p., on the 10th day of the experiment) and/or melatonin, or IPA (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days), or PTU (0.025% solution in drinking water, for 10 days). The level of lipid peroxidation products-malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA)-was measured spectrophotometrically in thyroid homogenates. KBrO(3), when injected to rats, significantly increased lipid peroxidation in the kidney homogenates and blood serum, but not in the liver and the lung homogenates. Co-treatment with either melatonin or with IPA, but not with PTU, decreased KBrO(3)-induced oxidative damage to lipids in the rat kidneys and serum. In conclusion, melatonin and IPA, which prevent KBrO(3)-induced lipid peroxidation in rat kidneys, may be of great value as protective agents under conditions of exposure to KBrO(3).

Administration, Oral↗

The developing caudate nucleus in the euthyroid and hypothyroid rat.

The basal ganglia are presently implicated in learning, and thyroid deficiency induced neonatally is known to affect mentation. The effects of such a deficiency on the developing causate nucleus might be used to provide insight into structure and function of the normal subcortical brain, as well as possible influences of these extrapyramidal structures on mental retardation. Propylthiouracil was added to the diet of lactating rat dams and observations of the developing caudate nuclei of normal hypothyroid rats were made at 8, 14, 20, 30 and 42 days by using various tissue stains and Golgi-Cox preparations. Seven different types of neurons were distinguished in the caudate nucleus. Differences in the size of cell somata and the varying morphology of axons and dendrites were criteria used to make distinctions. Normally, the nucleus acquires cytoarchitectural complexity during the first three postnatal weeks. Within this period, neuron incidence increases in the caudate neuropil with age while the germinal matrix density decreases. Neuron accumulation reaches a plateau after the third week and cell migration is essentially complete at the end of the first postnatal month as shown by computer analysis of Nissl stained cell counts. Branching of cellular processes, attainment of receptor spines and complexity of the fiber network also appeared during this period. Retardation of structural development with thyroid hormone deficiency was shown by decreased numbers of neurons, inhibition of dendritic arborization, decreased numbers of dendritic spines and a reduced complexity of axonal plexuses. Thyroid deficiency delays cell migration during the first three weeks when compared to age-matched normal controls. The lack of thyroid hormone does not appear to influence the size of neuron somata, and the extent of related dendritic fields, nor does hypothyroidism affect a specific cell type population. Generalized disturbances of caudate nuclear morphological maturation are caused by the deficiency. An apparent compensatory process, including a spurt of neural growth and differentiation, takes place in the period between days 14 and 30 in the deficient animals and a seemingly "normal" caudate cytoarchitecture is seen after the third postnatal week. Quantitative data, however, show that this rapid "catch up" process is inadequate. The developmental imperfection of the caudate nucleus which persists might be a part of the underlying substrate for the mental retardation, disturbed motor performance and perceptual handicaps which are found in the human patient.

Animals↗