Ophthalmic Graves's disease: natural history and detailed thyroid function studies

Of 27 patients with ophthalmic Graves's disease (OGD) who had been clinically euthyroid three years previously, one became clinically hyperthyroid and seven overtly hypothyroid. Improvement in eye signs was associated with a return to normal of thyroidal suppression by triiodothyronine (T3) and of the response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). Of a further 30 patients with OGD who had not been studied previously, three were overtly hypothyroid. Of the combined series, 46 patients were euthyroid, 18 (40%) of whom had an impaired or absent TSH response to TRH, and 3(6-7%) an exaggerated response. Eleven out of 37 patients (29-7%) had abnormal results in the T3 suppression test. There was a significant correlation between thyroidal suppression by T3 and the TSH response to TRH. Total serum concentrations of both T3 and thyroxine (T4) were closely correlated with T3 suppressibility and TRH responsiveness. Free T4 and T3 (fT3) concentrations were normal in all but three patients, in whom raised fT3 was accompanied by abnormal TSH responses and thyroidal suppression. The presence of normal free thyroid hormone concentrations in patients with impaired or absent TSH responses to TRH is interesting and challenges the concept that free thyroid hormones are the major controlling factors in the feedback control of TSH.     

Measurement of free thyroid hormones in patients on long-term phenytoin therapy

Summary Total thyroxine and triiodothyronine levels are often reduced in long-term phenytoin therapy, a finding at variance with the euthyroid clinical state of these subjects. We have measured free (biologically active) thyroid hormone levels in 31 patients on phenytoin therapy and have found a significant reduction in measurements of both free thyroxine and free triiodothyronine. In contrast, addition of phenytoin to normal serum in vitro resulted in an increase in free thyroxine and free triiodothyronine concentrations. The findings in vitro are consistent with displacement of thyroid hormones from thyroxine binding globulin while the reduced free hormone levels in vivo confirm that the effects of phenytoin are not confined to binding inhibition and suggest that phenytoin has induced a change in the cellular metabolism of thyroid hormones.     

Drug therapy reviews: management of hypothyroidism.

The therapeutic management of hypothyroidism caused by deficient thyroid hormone production is discussed. The therapeutic use of the following thyroid agents is reviewed: levothyroxine sodium, Thyroid USP, thyroglobulin, liotrix, and liothyronine sodium. Myxedema coma, neonatal hypothyroidism, primary hypothyroidism, and secondary and tertiary hypothyroidism are specific hypothyroid states for which drug therapy is discussed. Levothyroxine sodium is the preferred agent because of consistent potency, restoration of normal, constant serum levels of thyroxine (T4) and triiodothyronine (T3) and ease of interpretation of thyroid hormone levels. Other agents, because they contain T3, result in postabsorptive elevated T3 serum concentrations that may cause thyrotoxic symptoms and reduction of T4 levels. This, in turn, may give rise to misleading estimates of thyroid dosage. Patients with the sick euthyroid or low T3 syndromes are not candidates for thyroid hormone therapy.     

Effect of phenytoin therapy on thyroid function

1 Serum total and free fraction of thyroxine and triiodothyronine and urinary losses of unconjugated hormones in normal subjects and in patients treated long-term with therapeutic doses of phenytoin have been measured.

2 Decreases in serum total hormone concentrations with increased free fractions and resultant significant increase in the concentration of free thyroxine but not triiodothyronine were apparent in phenytoin-treated subjects. However, serum free hormone concentrations remained within the euthyroid range.

3 These changes in serum free hormone concentration were reflected by an increased urinary loss of unconjugated thyroxine, but normal excretion of unconjugated triiodothyronine.

4 Phenytoin in therapeutic doses displaces thyroxine and to a lesser extent, triiodothyronine from binding proteins in serum and thus increases peripheral clearance of thyroid hormones.

     

Dietary calcium induced cytological and biochemical changes in thyroid

Certain epidemiological studies revealed correlation between hard water consumption (with high calcium) and thyroid size of the population, though the possible alterations in thyroid physiology upon calcium exposure are still inconclusive. Adult male Wistar strain rats were subjected to calcium treatment at the doses of 0.5g%, 1.0g% and 1.5g% calcium chloride (CaCl(2)) for 60 days. The parameters studied were - thyroid gland weight, histopathology, histomorphometry; thyroid peroxidase (TPO), 5'-deiodinase I (DI), sodium-potassium adenosine triphosphatase (Na(+)-K(+)-ATPase) activities; serum total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), thyroid stimulating hormone (TSH) levels. Enlargement of thyroid with hypertrophic and hyperplastic changes, retarded TPO and 5'-DI but enhanced Na(+)-K(+)-ATPase activities, augmented serum total and free T4 and TSH but decreased total and free T3 levels and low T3/T4 ratio (T3:T4) were observed in the treated groups. All these findings indicate development of goitrogenesis upon exposure to excessive dietary calcium.     

Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers

Induction of hepatic UDP-glucuronyltransferase(s) (hUDP-GT(s] activity toward thyroid hormones and the relationship between the activity and the serum thyroid hormones or the thyroid stimulating hormone (TSH) level were examined in male Sprague-Dawley rats after four consecutive ip doses of various hepatic enzyme inducers at 75-150 mg/kg/day. hUDP-GT activity toward thyroxine (T4; hUDP-GT-T4) was induced by treatment with beta-naphthoflavone, 3-methylcholanthrene (3-MC), polychlorinated biphenyls, or pregnenolone-16 alpha-carbonitrile. However, no significant induction was observed for isosafrole administration and in the cases of phenobarbital and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane slight decreases were found. The induction profile of hUDP-GT-T4 for these inducers was approximately the same as that of hUDP-GT activity toward triiodothyronine (T3; hUDP-GT-T3), indicating that these two thyroid hormones (T4 and T3) are glucuronidated by the same hUDP-GT(s). Moreover, the induction profile of both hUDP-GT-T4 and hUDP-GT-T3 was similar to that of hUDP-GT toward 1-naphthol, but not chloramphenicol, suggesting that T4 and T3 belong to the so-called group-1 substrates which are preferentially glucuronidated by hUDP-GT(s) inducible by treatment with 3-MC. Decreases in serum T4 levels clearly correlated with an increase in hUDP-GT-T4 activity, indicating that serum T4 levels are directly affected by hUDP-GT-T4 activity. However, no direct correlation between decrease in thyroid hormone levels and compensatory increase in TSH levels was found.     

Anticonvulsants and thyroid function

Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3.     

Drug therapy for hyperthyroidism in pregnancy: safety issues for mother and fetus.

Hyperthyroidism (thyrotoxicosis) in pregnancy and the child bearing years is usually attributable to Graves' disease. This is an autoimmune condition in which thyroid-stimulating immunoglobulins (TSI) cause hyperthyroidism. As a rule, pregnancy complicates the management of hyperthyroidism, rather than vice versa. However, patients who remain thyrotoxic during pregnancy are at increased risk of maternal and fetal complications, particularly miscarriage and stillbirth. Therefore, bodyweight loss, eye signs and a bruit over the thyroid gland in a pregnant woman warrant thyroid investigation. Investigations should include measurement of serum free thyroid hormone levels [free thyroxine (T4) and free triiodothyronine (T3)] rather than total T4 and T3 levels, because total T4 and T3 levels may be raised in euthyroid pregnancies due to the presence of increased levels of thyroxine binding globulin (TBG). By 20 weeks' gestational age, the fetal thyroid is fully responsive to TSI and to antithyroid drugs. Maternal T4 and T3 and thyrotropin pass across the placenta in small and decreasing amounts as gestation progresses, but thyrotropin releasing hormone, TSI, antithyroid drugs, iodides and beta-blockers are readily transferred to the fetus from the mother. Hyperthyroidism is usually treated throughout pregnancy with an antithyroid drug, preferably propylthiouracil. The smallest dose which controls the disease is given with careful monitoring of free T4 and T3 levels to minimise the risk of fetal hypothyroidism and goitre. Bilateral subtotal thyroidectomy may be an option for a small number of patients with hyperthyroidism in pregnancy.     

慢性充血性心力衰竭患者甲状腺素的变化

目的 研究甲状腺激素(thyroid hormone,TH)水平与慢性充血性心力衰竭(congestive heart failure,CHF)的关系.方法 应用微粒子发光法检测100例老年慢性充血性心力衰竭住院患者及50例健康对照者的血清三碘甲腺原氨酸(FT3)、总三碘甲腺原氨酸(TT3)、游离甲状腺素(FT4)、总甲状腺素(TT4)、反三碘甲腺原氨酸(rT3)及促甲状腺素(TSH)结果老年慢性充血性心力衰竭患者甲状腺素T3水平明显低于健康对照组,低T3综合征的老年CHF患者心力衰竭程度严重.结论 在早期慢性心力衰竭的患者,其T3水平是降低的,且与心力衰竭的严重程度有关.     

UDP-glucuronosyltransferase inducers reduce thyroid hormone levels in rats by an extrathyroidal mechanism.

As many microsomal enzyme inducers have been shown to reduce thyroid hormone levels, this study was conducted to determine if this reduction is produced by directly blocking the synthesis of thyroid hormones, or by indirectly increasing the biotransformation and deactivation of thyroxine (T4) by microsomal enzymes. Surgically thyroidectomized male rats received thyroid hormone replacement therapy by implanted osmotic minipumps, resulting in T4 and T3 serum levels that were similar to those observed in euthyroid controls. Three days after minipump implantation (Day 0), rats were fed diets containing four UDP-glucuronosyltransferase (UDP-GT) inducers: phenobarbital (PB), 3-methylcholanthrene (3MC), pregnenolone-16 alpha-carbonitrile (PCN), or polychlorinated biphenyls (PCB) for 10 days. PB, 3MC, and PCN reduced total (Days 3-10) and free (Days 7-10) T4 serum concentrations 30-50%, whereas PCB produced a 70-75% reduction in total and free serum T4 (Days 3-10). Treatment with PB, PCN, and PCB decreased levels of total T3 (Days 7-10). UDP-GT activity toward T4 was increased by PB, 3MC, PCN, and PCB 270, 400, 570, and 660%, respectively, and was found to correlate with serum T4 levels (total and free). These results demonstrate that reduction of thyroid hormone levels by microsomal enzyme inducers is produced in part by an extrathyroidal mechanism, quite possibly an increase in T4 glucuronidation.     

2型糖尿病患者甲状腺功能异常的临床特征分析

目的分析2型糖尿病患者甲状腺功能异常的临床特征。方法检测2010年1月~2011年6月于我院住院的1299例2型糖尿病患者的血清游离T3(FT3)、游离T4(FT4)、促甲状腺激素(TSH)。结果①2型糖尿病合并甲状腺功能异常的发生率为25.2%,其中亚临床甲状腺功能减退占50.1%。②与甲状腺功能正常的糖尿病患者相比,糖尿病合并甲状腺功能异常的患者女性多见,HbA1c较高。结论 2型糖尿病合并甲状腺功能异常较常见,应筛查和随访糖尿病患者的甲状腺功能。     

甲状腺功能正常2型糖尿病患者的机体甲状腺轴微紊乱情况研究

目的 观察甲状腺功能正常的2型糖尿病(T2DM)患者甲状腺轴激素微紊乱及其对胰岛素抵抗的影响.方法 选择2014年7月至2016年7月确诊的初诊T2DM患者80例作为T2DM组;选择同期被OGTT实验证实为糖耐量异常的健康体检者40例作为IGT组;同期体检血糖在正常范围的40例作为健康对照组.观察T2DM组,IGT组和健康对照组3组机体三碘甲状腺原氨酸(FT3),游离甲状腺素(FT4),促甲状腺素(TSH),稳态模型评价胰岛素抵抗(HOMA-IR)和糖化血红蛋白(HbA1c)水平的变化,T2DM患者的T3,FT4,TSH水平与HOMA-IR和HbA1c水平的相关性,及其治疗后水平的变化.结果 T2DM组和IGT组的FT3和FT4水平明显低于健康对照组(P<0.01),T2DM组水平明显低于IGT组(P<0.01),治疗后T2DM机体的FT3和FT4水平较治疗前明显提高(P<0.01);而TSH,HOMA-IR和HbA1c水平明显高于健康对照组(P<0.01),T2DM组水平明显高于IGT组(P<0.01),治疗后T2DM患者机体的TSH,HOMA-IR和HbA1c水平明显较治疗前降低(P<0.01).T2DM患者机体的FT3,FT4和HO-MA-IR水平随着HbA1c水平的升高而出现明显升高(P<0.01),而TSH水平随着HbA1c水平的升高而降低(P<0.01).胰岛素抵抗组的FT3和FT4水平明显低于非胰岛素抵抗组(P<0.01),而TSH和HbA1c水平明显高于非胰岛素抵抗组(P<0.01).结论 甲状腺功能正常的T2DM患者机体存在甲状腺轴功能的微紊乱,其紊乱程度与糖尿病严重程度和胰岛素抵抗指数相关,控制T2DM后机体的甲状腺轴紊乱得到纠正.     

Endocrine changes in patients with acute organophosphate poisoning

In critical illness, several drugs and various stressful conditions modify the functions of neurotransmitters which consequently affect the secretion of pituitary hormones. Although the role of neurotransmitters in the regulation of endocrine system is well known, cholinergic actions have been less investigated. In animals, cholinesterase inhibitors were shown to modify the pituitary-thyroid and pituitary-adrenal axes, and to affect prolactin levels. The aim of the present study was to determine the effect of the organophosphate compounds on endocrine system, particularly pituitary hormones. This prospective study was performed in Medical Intensive Care Unit of Erciyes University Medical School Hospital. Twenty-two consecutive patients (ten males and 12 females aged 28+/-8 years) with organophosphate poisoning were included in the study. ACTH (P<0.002), cortisol (P<0.0005) and PRL (P<0.005) levels were significantly higher during poisoning than after resolution of poisoning. FSH levels were significantly lower during poisoning (P<0. 05). Sick euthyroid syndrome was determined in seven patients (31. 8%). Two of them had low fT3 (with normal fT4 and TSH), two had low fT4 (with normal fT3 and TSH) and three had low TSH (with normal fT3 and fT4) levels. Serum levels of these hormones returned to normal values after resolution of poisoning. The present study demonstrated that organophosphate compounds affected PRL, ACTH and cortisol levels, but did not change LH levels. Organophosphate compounds may result in sick euthyroid syndrome. These conditions may be related to the effects of acetylcholine and direct effect of organophosphate compounds.     

Effects of amiodarone and thyroid dysfunction on myocardial calcium, serum calcium and thyroid hormones in the rat.

1 Myocardial calcium content was found to be elevated and serum calcium reduced in hypothyroid rats. 2 Treatment of rats with amiodarone at either 30 mg kg-1 or 150 mg kg-1 daily did not result in any significant changes in myocardial or serum calcium. 3 The administration of amiodarone to hypothyroid rats attenuated the changes in serum but not myocardial calcium, suggesting that amiodarone may exert a thyroid hormone-like effect in the hypothyroid state. 4 The administration of amiodarone to thyroid hormone-treated rats resulted in attenuation of the effects on serum calcium and calculated intracellular calcium; this was consistent with an antagonistic interaction between amiodarone and thyroid hormones. 5 Administration of amiodarone resulted in significant changes in circulating thyroid hormone levels in the rat; triiodothyronine was reduced and basal thyrotrophin elevated compared to euthyroid controls. Serum thyroxine was not changed; this is in contrast to the effects in man. 6 Amiodarone does not exert its anti-arrhythmic action via changes in total myocardial calcium content in the euthyroid rat; nonetheless the described interactions between the drug and thyroid hormones may be involved in its mechanism of action.     

肝硬化病人下丘脑-垂体-甲状腺轴的功能变化及临床意义

目的 探讨不同级别肝硬化(LC)病人下丘脑-垂体-甲状腺轴的变化及临床意义.方法 91例LC病人按Child-Turcotte-Pugh(CTP)计分评级分为三组:LC-A组25例,LC-B组35例,LC-C组31例;另选27名健康人作为对照组.血清总三碘甲状腺原氨酸(TT3)、游离T3(FT3)、反T3(rT3)、总甲状腺素(TT4)、游离甲状腺素(FT4) 及促甲状腺激素(TSH) 均采用化学发光法检测,肝功能生化指标用RXL生化分析仪检测,凝血酶原时间(PT)用全自动血凝仪(血凝固法)检测.结果 从LC-A组到LC-C组随着肝硬化级别的增加,血清TT3和FT3水平逐渐降低,rT3渐次增高,TT4/rT3比值顺次下降,血清TT3分别与白蛋白、前白蛋白、载脂蛋白-A1和胆碱酯酶呈显著正相关(df=89,r值分别为0.568,0.260,0.317和0.599,P<0.05),与CTP分值及PT呈显著负相关(df=89,r值分别为-0.447和-0.297,P<0.01),TSH在各组间差异无统计学意义.共26例LC病人出现低T3综合征,LC-A组为0,LC-B组8例(22.9%),LC-C组18例(58.1%).经保肝、支持治疗1~2周后,随着肝功能好转低T3综合征也随之消失.心得安试验仅见FT4有所下降(16.84±3.16)vs (14.00±2.45) pmol·L-1,地塞米松试验未见甲状腺激素及TSH有明显变化.结论 肝硬化失代偿期随着肝功能的下降,发生低T3综合征的比例增多,与甲状腺激素转运蛋白合成功能减退、T4向T3转化减少有关,但随着病情好转低T3综合征便逐渐消失,无须补充甲状腺素.心得安或地塞米松试验对甲状腺功能未产生明显的影响,提示短期适量应用此类药物是安全的.     

Effects of thyroid alterations and carbamazepine on cortical beta-adrenergic receptors in the rat

The effect of alteration in thyroid status on beta adrenergic receptors in the cortex of the rat was assessed. Normal animals were treated with large doses of thyroxine (T4) and triiodothyronine (T3) and thyroidectomized animals were treated with physiological replacement doses of T4 and T3 in order to assess the possible differential effects of these hormones. In addition, a group of rats was treated with a diet of carbamazepine (an anticonvulsant also used in the treatment of manic-depressive illness), which has been shown to reduce peripheral levels of thyroid hormone in humans. The intended manipulations of the thyroid were achieved by the various treatments with thyroid hormone, and carbamazepine-diet-treated animals had significantly lower plasma T4 levels as compared with controls. No significant alteration in the density or affinity of beta-adrenergic receptors in the cortex was noted with major, short-term alterations in thyroid status or with treatment with carbamazepine. It is concluded that even marked, but relatively short-term, changes in thyroid status do not necessarily affect beta-receptors in the cerebral cortex and that carbamazepine may represent an exception to the general proposition that antidepressant agents decrease the number of beta-receptors.     

Endocrine hormone abnormalities in Amanita poisoning

Mushroom poisoning from the genus Amanita is being reported with increasing frequency in the United States. Endocrine hormone abnormalities were investigated in four patients who ingested mushrooms of the Amanita genus ("death cap", "destroying angel"). Marked abnormalities were found in the hormones controlling glucose, calcium, and thyroid homeostasis. Insulin and C-peptide concentrations were elevated at admission, indicating that the hypoglycemia associated with Amanita poisoning may not be solely secondary to hepatic failure. Serum calcitonin concentrations were elevated in conjunction with hypocalcemia. Parathyroid hormone concentrations (both the carboxyl- and amino-terminal assays) increased with time, but began returning to baseline as the hypocalcemia disappeared. The thyroxine concentrations were depressed in all four patients, and triiodothyronine (T3) concentrations were undetectable in three patients. Thyroid-stimulating hormone concentrations were never elevated, reflecting an unresponsive pituitary-hypothalamic axis to the development of hypothyroidism or a euthyroid-illness syndrome.     

Effects of vitamin A and/or thyroidectomy on liver microsomal enzymes and their induction in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats

Vitamin A and thyroid hormone status have been shown previously to alter the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. In the present study, we have examined the effects of a vitamin A-excess and a vitamin A-deficient diet on thyroid hormone levels, on selected drug-metabolizing enzymes in liver microsomes, and on their inducibility by TCDD in male Sprague-Dawley rats. Except for a slight increase in serum T3 levels, none of these end points was affected by feeding rats the vitamin A-deficient diet. In contrast, excess dietary vitamin A caused a decrease in serum thyroxine (T4) and triiodothyronine (T3) levels, although the levels of T3 remained in the euthyroid range (60-80 ng/dl). The concentration of liver microsomal cytochromes P-450 and b5 and the basal activity of benzo[a]pyrene hydroxylase and 7-ethoxyresorufin O-de-ethylase were unaffected by excess dietary vitamin A. This result is consistent with our previous observation that the basal activity of these enzymes is dependent more on T3 than on T4 levels. Vitamin A excess markedly suppressed the activity of liver microsomal UDP-glucuronosyl transferase toward 1-naphthol. However, no such enzyme suppression was observed in thyroidectomized rats. This suggests that the suppressive effect of vitamin A on UDP-glucuronosyl transferase activity may be dependent on T3. Neither vitamin A nor thyroid status had any major effect on the inducibility of UDP-glucuronosyl transferase and cytochrome P-450-dependent enzyme activities by TCDD. However, vitamin A and TCDD had a nearly additive effect on suppression of serum T4. It is concluded that liver microsomal enzyme induction is not associated with the modulatory effect of vitamin A and thyroid hormones on the toxicity of TCDD.     

Mental improvement after replacement therapy with thyroxine plus triiodothyronine: relationship to cause of hypothyroidism

We treated 26 hypothyroid women - 11 with autoimmune thyroiditis and 15 who had been treated for thyroid cancer - with their usual dose of thyroxine (T4) or with a regimen in which 50 &mgr;g of T4 had been replaced by 12.5 &mgr;g of triiodothyronine (T3). Patients were first randomly assigned to one regimen for 5 wk and then to a second regimen for an additional 5 wk. The substitution of T3 for a portion of T4 caused expected changes in concentrations of thyroid hormones and thyroid-stimulating hormone (TSH). After combined hormone treatment there were clear improvements in both cognition and mood, the latter changes being greater. The patients who had been treated for thyroid cancer showed more mental improvement than the women with autoimmune thyroiditis, perhaps because they were more dependent on exogenous hormone. Some mood improvements correlated positively with changes in TSH while others correlated negatively with changes in free T4.     

Clinical usefulness of serum total cholesterol as an index of hypothyroidism in patients after cervical radiation

Cervical radiation therapy is often applied to patients with head and neck cancers because radiation has a high sensitivity to these cancers and permits the preservation of functions and physical form. However, it has been shown that various complications can result from radiation therapy. We have encountered some patients who showed hypercholesterolemia resulting from cervical radiation. Therefore, we have paid close attention to the relationship between hypercholesterolemia after cervical radiation and hypothyroidism. Thyroid hormone tests in these patients with hypercholesterolemia after cervical radiation showed high thyroid stimulating hormone (TSH) and low free thyroxine (fT4), indicating the presence of hypothyroidism. After administration of levothyroxine Na, their fT4 levels increased and both TSH levels and serum total cholesterol levels decreased. In conclusion, in patients who have received cervical radiation, we recommend monitoring serum total cholesterol periodically to detect hypothyroidism easily before the appearance of its symptoms.