The Syndromes of Resistance to Thyroid Hormone Beta / 罕见病研究

The syndrome of resistance to thyroid hormone(RTH) is a rare syndrome caused by the mutation of thyroid hormone receptor (TR) gene, which reduces the sensitivity of target organs to thyroid hormone (TH) and leads to the dysfunction of TH. Thyroid hormone resistance syndrome β (RTHβ) is caused by the mutations in the THRB gene. The main characteristics of RTHβ are increased thyroxine (T4) in the circulating blood, normal or elevated levels of triiodothyronine(T3), paired with normal or high thyroid-stimulating hormone (TSH) concentration. Clinically, it is easy to misdiagnose RTHβ as hyperthyroidism, and give anti-thyroid drugs, radioactive 131I therapy or surgery, which then leads to the aggravation of TH resistance, so the correct diagnosis of the disease is critical. In this paper, the molecular mechanism, clinical characteristics, diagnosis and treatment of RTHβ are summarized.

Developmental Hypothyroidism Influences the Development of the Entorhinal-Dentate Gyrus Pathway of Rat Offspring

Background@#Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway. @*Methods@#We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole. @*Results@#1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3–cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group. @*Conclusion@#We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

An FT 3/FT 4 ratio greater than 0.4 is helpful in differentiating Graves′ disease from subacute thyroiditis / 中华内分泌代谢杂志

Objective:To search for the clinical indicators in differentiating Graves′ disease from subacute thyroiditis (SAT).Methods:Retrospective analysis was performed on thyroid function measurement of 265 cases of newly diagnosed Graves′ disease, 76 cases of SAT with thyrotoxicosis, 100 cases of non-toxic thyroid nodules, 105 cases of autoimmune thyroid diseases with normal thyroid function, and 151 cases of outpatients with normal thyroid function and without thyroid diseases.Results:Free triiodothyronine(FT 3)/free thyroxine(FT 4) ratio of Graves′ disease patients was significantly higher than that of SAT patients with thyrotoxicosis (0.65±0.29 vs 0.32±0.75, P<0.05). Receiver operating characteristic curve(ROC curve) analysis of FT 3/FT 4 ratio between Graves′ disease group and SAT group showed that FT 3/FT 4 ratio greater than 0.4 with a sensitivity of 98.11% and a specificity of 83.81% for diagnosis of Graves′ disease. Conclusion:FT 3/FT 4 ratio greater than 0.4 is helpful for differentiating Graves′ disease from subacute thyroiditis with thyrotoxicosis.

Understanding thyroid function tests: clinical analysis of thyroid function index abnormalities / 中华内分泌代谢杂志

Thyroid diseases are common diseases in endocrinology. Thyroid function tests have become the most commonly used indicators to diagnose thyroid diseases. This review summarizes several abnormal thyroid function test results that may be encountered in clinical practice and analyzes the causes, which may provide ideas for the clinicians in the diagnosis of thyroid diseases.

Effect of entecavir combined with TACE on the quality of life, liver function and immune function of patients with primary liver cancer / 中国基层医药

Objective:To investigate the effect of entecavir combined with transcatheter arterial chemoembolization (TACE) on the quality of life, liver function and immune function of patients with primary liver cancer.Methods:From January 2017 to December 2018, 120 patients with primary liver cancer admitted to the Second Hospital of Jiaxing were randomly divided into observation group(60 cases) and control group(60 cases). The patients in the control group were treated with TACE, while those in the observation group were treated with entecavir on the basis of the control group.Both two groups were treated for 3 consecutive courses, and 4 weeks as a course of treatment.The short-term effect, KPS score, liver function and immune function of the two groups were compared before and after treatment.Results:The total effective rate of the observation group(71.67%) was higher than that of the control group(50.00%)(χ 2=5.911, P<0.05). The KPS score of the observation group was (84.25±3.67)points, which was higher than that of the control group[(75.58±3.29)points]( t=13.626, P<0.05). After treatment, the levels of ALT [(35.42±6.24)U/L], TBIL [(23.37±2.89)μmol/L] and AST [(37.29±4.23)U/L] in the observation group were lower than those in the control group [(52.29±4.56)U/L, (30.73±3.78)μmol/L and (54.35±3.89)U/L]( t=16.908, 11.982, 22.995, all P<0.05). The CD 3+ [(58.71±2.93)%], CD 4+ /CD 3+ [(39.74±3.45)%] and CD 4+ /CD 8+ (1.65±0.39) in the observation group were higher than those in the control group [(49.63±3.10)%, (31.12±2.13)% and (0.93±0.17)] ( t=16.489, 16.468, 13.109, all P<0.05). Conclusion:Entecavir combined with TACE is effective in the treatment of primary liver cancer, and it can improve the quality of life, liver function and immune function.

One case of a thyrotropin-secreting microadenoma and resistance to thyroid hormone with P453T mutation in TRβgene / 中华内分泌代谢杂志

[Summary] We investigated a 12-year-old girl with elevated serum FT3 , FT4 , and TSH levels. The sequence of thyroid hormone receptorβ( TRβ) exons revealed a CCT→ACT transition mutation at nucleotide 453 site within exon10,whichresultedinthesubstitutionofcytosinetoadenosinein(P453T). Pituitarymagneticresonanceimage showed a pituitary micoradenoma. The patient underwent transsphenoidal pituitary adenomectomy. Pathological results exhibited positive TSH-β, GH, prolactin, ACTH, and α-HCG staining for the tumor. This is the first case report with thyroid hormone resistance syndrome and thyrotropin-secreting adenoma.

Dietary soy consumption during early pregnancy is not associated with the development of thyroid dysfunction / 中华内分泌代谢杂志

Data were collected through questionnaire from 505 women enrolled during early pregnancy.Based on soy intake frequency,the subjects were divided into three groups:frequent (three or more times per week),conventional ( more than twice per month but less than three times per week),and occasional ( two or fewer times per month).Serum TSH and FT4 were measured by chemiluminescence immunoassay.The urinary concentrations of two primary isoflavones (daidzein and genistein) and creatinine were further assessed in 95 subjects from the three groups.The percentages of frequent,conventional,and occasional consumers were 18.6％,62.6％,and 18.8％,respectively.No difference was found in age,medical records,family history of thyroid diseases,serum FT4,TSH,and prevalence of thyroid dysfunctions among three groups. Both urinary daidzein and genistein levels were significantly higher in the frequent consumers compared with the other two groups.No correlations were found between urinary isoflavone levels and serum FT4 or TSH.These findings suggest that dietary soy consumption during early pregnancy seems not to be associated with the development of thyroid dysfunction.

Relationship betweenserum TSH and dyslipidemia / 中华内分泌代谢杂志

Objective To investigate the relationship between serum thyrotrophin(TSH)and dyslipidemia in subclinical hypothyroid and euthyroid subjects. Methods An epidemiological study on diabetes and thyroid diseases was performed in Dadong community, Shenyang city, in 2007. 110 subjects with subclinical hypothyroidism(SCH)and 1 240 euthyroid subjects were enrolled in the study. Neither history of thyroid diseases nor administration of thyroid-related and lipid-regulating medicines were reported in these subjects. The levels of serum thyroid hormones, lipids, fasting plasma glucose(FPG), and insulin were determined. Results (1)Patients with SCH had significantly lower HDL-C levels than those who were euthyroid.(2)According to the guideline of treatment of adult dyslipidemia in China, the lipid profiles were each categorized. Mean TSH levels were higher in subjects in the dyslipidemia subclass than subjects in the normal subclass. The differences were significant in high LDL-C subclass in overweight individuals. In euthyroid overweight women, mean TSH levels were significantly higher in high LDL-C subclass. In the euthyroid population, TSH was positively associated with total cholesterol in overweight population. The association was not modified by the homestasis model assessment for insulin resistance(HOMA-IR)values.(3)TSH was associated positively with serum triglycerides and negatively with serum HDL-C in women. TSH was positively associated with total cholesterol in overweight population and positively associated with total cholesterol and LDL-C in overweight women after adjustment for age, sex, and body mass index. Conclusion Raised serum TSH seems to be a risk factor of dyslipidemia in subclinical hypothyroid and euthyroid subjects, which is independent of insulin sensitivity.

The reference range of serum thyrotropin in iodine-sufficient areas: An epidemiological study / 中华内分泌代谢杂志

Objective To verify the criteria proposed by National Academy of Clinical Biochemistry(NACB)guidelines in investigating the factors that affect serum TSH determination, and to determine the reference range of serum TSH in iodine-sufficient areas of China. Methods In 2007, 5 348 inhabitants were enrolled from 3 iodine-sufficient areas of Liaoning Province, and were asked to fulfill the questionnaire. Serum TSH, thyroid peroxidase antibody(TPOAb), and thyroglobulin antibody(TgAb)were determined, and thyroid ultrasonography was carried out. Results The distribution of TSH levels was skewed in healthy people and closely fit the curve of Gaussian distribution after logarithmic transformation. The levels of TSH in subjects of 12-19 years of age were significantly higher than those of other age groups(P＜0.01), and no significant difference was found among the latter groups. TSH level in females [(1.68±1.90)mIU/L] was higher than in males[(1.45±1.92)mIU/L, P＜0.01]. The reference range of TSH was 0.43-4.74 mIU/L in males, and 0.48-5.39 mIU/L in females. Family history of thyroid disease, abnormal thyroid ultrasonography, and positive thyroid antibodies were the factors that influenced TSH level. Conclusion The reference range of serum TSH in iodine-sufficient areas of China is established.

Effects of chronic iodine excess on thyroid function and structure in autoimmune-prone NOD.H-2h4 mice / 中华内分泌代谢杂志

To explore the dose- and time- dependent relationship between the chronic iodine excess and thyroid structure, ultrastructure, and thyroid function in autoimmune-prone NOD. H-2h4 mice. Chronic iodine excess leads to iodine-induced goiter with an ultrastructure of follicle epithelial cells injury in a dose and time dependent way.

The Correlation between Thyrotropin and Dyslipidemia in a Population-based Study

This study investigated the relationship between serum thyrotrophin levels and dyslipidemia in subclinical hypothyroid and euthyroid subjects. A total of 110 subjects with subclinical hypothyroidism and 1,240 euthyroid subjects enrolled in this study. Patients with subclinical hypothyroidism had significantly lower high density lipoprotein cholesterol (HDL-C) levels than those who were euthyroid. The lipid profiles were each categorized and mean thyrotrophin levels were higher in subjects in the dyslipidemia subclasses than subjects in the normal subclasses. Thyrotrophin was positively associated with serum triglyceride and negatively associated with serum HDL-C in women. Thyrotrophin was also positively associated with total cholesterol (TC) in the overweight population along with TC and LDL-C in overweight women. In the euthyroid population, thyrotrophin was positively associated with TC in the overweight population. In conclusion, serum thyrotrophin was correlated with dyslipidemia in subclinical hypothyroid and euthyroid subjects; the correlation was independent of insulin sensitivity.

The prevalence of metabolic syndrome in Liaoning province / 中华内分泌代谢杂志

A total of 3 431 subjects aged 18 years or over from Liaoning province were involved in this study.The prevalence of metabolic syndrome(MS) was 19.50%,being 19.79% in men and 18.44% in women, according to the standard of Chinese Diabetes Society in 2004.Villages had the highest prevalence of MS in women,while cities had the lowest;towns had the highest prevalence of MS in men,while villages had the lowest.The prevalence of MS was increased with both aging and income.The peak of MS is turning to the developing district.

Impact of maternal subclinical hypothyroidism during the first trimester on brain development of the offspring: a prospective study / 中华内分泌代谢杂志

Objective To assess the effects of maternal subclinical hypothyroidism (SCH) during the first trimester on neuropsychological development of the offspring by 20-30 months. Methods In this study, 1 761 pregnant women from 10 hospitals with about 8 weeks of gestation were enrolled. Urinary iodine excretion and serum thyrotropin ( TSH ), free thyroxine ( FT4 ), and thyroid peroxidase antibody ( TPOAb ) levels were determined in all subjects. Pregnant women with SCH (TSH≥2.5 mIU/L) were divided into two subgroups using trimester-specific thyroid function reference: group A (2.5 mIU/L≤TSH＜3.93 mIU/L, 18 cases), and group B (TSH ≥3.93 mIU/L, 20 eases). Thirty euthyroid and TPOAb-negative women from the same cohort were selected as controls. Intellectual and motor development score evaluations were performed in the children by 20-30 months of age. Results Children of women with SCH and subgroups A and B had lower mean intelligence scores 6.55,3.39, and 9.40 points compared with those of the control group (P=0. 001, P=0. 125, and P＜0. 001 ); the respective mean motor scores were 6.31,4.35, and 8.07 points being lower than that of the control ( P=0. 003,P=0. 070, and P=0. 001 ). Intelligence scores and motor scores were negatively correlated with TSH levels (r=-0.425, P＜0. 001 and r=-0. 394, P=0. 001 ). Multiple group comparisons revealed that differences of TSH affected intelligence and motor scores (F=9. 277, P＜0. 001 and F=5. 909, P=0. 004). Ordinal logistic regression analysis showed that possibilities for the reduction of filial mental development index ( MDI ) and psychomotor development index ( PDI ) scores in SCH with maternal TSH levels≥3.93 mIU/L were 8.66 and 6.27 times that of controls ( OR = 8.66,95% CI 2.72-27.57, OR =6.27,95% CI 2.03-19.34 ). Conclusion Maternal elevated TSH levels diagnosed by trimester-specific reference during early gestation are independently associated with lowered filial neurodevelopment scores by 20-30 months.

Advances in thyroid hormone transporters / 中华内分泌代谢杂志

Thyroid hormones play important roles in growth, development, and metabolism of various cells and tissues. It has been assumed for a long time that thyroid hormones are lipophilic and enter cells by passive diffusion, but it has become increasingly clear that cellular uptake and efflux of thyroid hormones are mediated by transporters. The discovery of these thyroid hormone transporters will lead to a better understanding of the tissuespecific regulation of thyroid hormones.

Effect of iodine intake on serum thyroglobulin——A five-year prospective epidemiological study / 中华内分泌代谢杂志

Objective To clarify the effect of iodine intake on serum thyroglobulin (Tg). Methods A 5-year prospective study was conducted in the 3 different iodine intake areas in China [Panshan (miht deficiency) ,Zhangwu (more than adequate) and Huanghua (excess)]. A total of 3 099 people with normal serum levels of Tg in 1999 were followed and 2 448 of these participants were feasible to be observed in 2004 and included in the present study. The serum levels of Tg, thyraglobulin antibody(TgAb), thyroid peroxidase antibody(TPOAb) and TSH, thyroid volume, family and personal histories of thyroid diseases were measured and inquried. The general linear model (GLM) was used to explore the determinants of Tg. Results Among the study population at baseline, serum Tg were significantly different in three areas [7.5 (4.4-13. 1) μg/L at Panshan, 6.8 (3.6-11.2)μg/L at Huanghua, 5.9 (3.2-10.7) μg/L at Zhangwu, P<0.01]. They were associated with age, sex and the rate of positive TgAb, abnormal thyroid volume, abnormal TSH and positive personal history of thyroid diseases, in order to control the effects of confounding factors, the data from 1856 subjects with thyroid-related indexes all in normal range and without personal history of thyroid diseases were analyzed to clarify the effect of iodine intake on Tg. The serum Tg among three areas were significantly different in both 1999 and 2004, they were all increased in 5 years with significant augment (△ Tg) among the three areas[3.1 (-0.2-8.0) μg/L at Panshan, 3.5 (0.5-9.0)μg/L at Huanghua vs 2. 5(0.3-6.1) μg/L at Zhangwu,P<0.01]. The GLM analysis revealed that age, Tg and TSH levels at baseline were the determinants of △Tg in addition to iodine intake. Conclusion Iodine intake is a dominant determinant of serum Tg. Age and TSH should also be considered while indicating iodine intake by serum Tg.

Effect of thyrocytes from transgenic mice expressing thyroid specific MHC class Ⅱ on autologous T lymphocyte in vitro / 中华内分泌代谢杂志

Thyrocytes expressing MHC class Ⅱ molecules were separated from transgenic mice and were co-cultured with autologous spleen T lymphocytes. T cells did not proliferate and were not activated, but CD4+ T cells were promoted into apoptosis.

Prospective study on the effect of different iodine intakes on goiter and thyroid nodules / 中华内分泌代谢杂志

Objective To investigate the epidemiological characteristics of non-toxic goiter and non-toxic thyroid nodules in the regions with different iodine intakes and the factors influencing the occurrence, development and outcome of goiter and thyroid nodules. Methods 3 385 subjects, who had taken part in the previous survey in 1999 with the ultrasonic examination of thyroid, were composed of individuals in Panshan with chronic mild iodine deficiency,in Zhangwu with more than adequate iodine "after iodine supplementation and in Huanghua with excessive iodine. These 3 groups of subjects were followed up in 2004. Results (1) The cumulative incidences of diffuse goiter in Panshan ,Zhangwu and Huanghua were 7.1% ,4.4% and 6.9% ,respectively ,being the lowest in Zhangwu (P<0.01) and those of nodular goiter were 5.0% ,2. 4% and 0.8%, respectively, being the highest in Panshan (P<0.01). (2) The incidences of single nodule were 4.0% ,5.7% and 5.6%, respectively, and those of multiple nodules 0.4%, 1.2% and 1.0%, respectively. (3)The result of logistic analysis showed that iodine deficiency,iodine excess and positive thyroid autoantibodies (TAA) were the independent risk factors for the occurrence of goiter. (4)In Zhangwu ,the incidence of non-toxic goiter in the group with positive TAA was higher than that in the group with negative TAA(P<0.01) ,while there were no such differences in Panshan and Huanghua. (5)In these three regions, the rates of positive TAA in the individuals with diffuse non-toxic goiter were higher than those in the healthy subjects (P<0.05). And in Huanghua,the rate of positive TAA in subjects with non-toxic nodular goiter was also higher than that in the healthy individuals (P<0.05). Conclusion Iodine deficiency and iodine excess may both induce the raising incidence of goiter. Nodular goiter is prevalent in iodine deficient district and diffuse goiter is the predominant form in places with iodine excess. Thyroid autoimmunity is associated with occurrence and maintenance of goiter, and this phenomenon is more obvious in the community with previous iodine deficiency followed then by treatment with more than adequate iodine.

The changes of thyrotropin level in euthyroid population:a 5-year follow-up study in communities with different iodine intakes / 中华内科杂志

Objective To determine the factors that influence the development of abnormal thyrotropin (TSH) level in an euthyroid population.Methods We conducted a follow-up study in 3 communities with different iodine status.Of the 3403 euthyroid subjects at baseline screened in 1999,80.1% ( n = 2727 ) was visited and sampled in 2004 for measuring TSH,thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb).Results Iodine status in the 3 communities were stable.Decreased TSH level( <0.3 mU/L) developed in 2.5% (n =68) of sampled subjects,while raised TSH level( > 4.8 mU/L) in 2.4% (n = 64).A logistic analysis showed that risk factors for developing decreased TSH level included positive conversion of TPOAb (OR = 5.5 ),positive TPOAb both in 1999 and in 2004 ( OR = 4.0),positive TgAb in 2004 ( OR = 3.7) and TSH < 1.0 mU/L in 1999 ( OR = 2.6).Risk factors involved in developing raised TSH level included iodine status of Zhangwu community ( OR = 4.1 ),iodine status of Huanghua community ( OR = 3.9),positive TgAb in 2004 ( OR = 3.7 ),positive TPOAb both in 1999 and 2004 (OR =3.6),positive conversion of TPOAb (OR =2.7) and TSH > 1.9 mU/L in 1999 (OR = 2.6 ).Conclusions Exposure to long-term iodine excess imposes danger of developing hypothyroidism.The risk will be even higher when exposing to iodine adequacy after correction of iodine deficiency.An interval between 1.0 and 1.9 mU/L of TSH level was optimul with the least probability of developing abnormal TSH level.

A study on the mechanism of iodine-induced thyroid epithelial cell injury in the induction of autoimmune thyroiditis / 中华内科杂志

Objective To investigate the effect of iodine excess on thyroid follicle epithelial ultrstructure and the relationship between thyroid iniury and autoimmune thyroiditis. Methods NOD.H-2h4 mice and Kunming mice were randomly divided into four groups receiving plain water,5 fold,10 fold,and 100 fold excessive iodine water.4,8 and 24 weeks after receiving iodine water,the mice were killed.After fixation with osmic acid and dual staining with uranyl chloride and citrate lead,thyroid gland ultrstructure was examined with electron microscopy.Resuits Iodine treated NOD.H-2h4 mice exhibited marked accumulation of peroxisome and secondary lysosomes,apoptosis and necrosis of thyroid epithelial cell.damage of thyroid follicles and lymphocvtic infiltration.The observed changes induced by iodine were in a dose dependent way.Conclusion The oxidative iniury on the thyroid epithelial cells induced by iodine excess might be the prerequisite for the creation of autoimmune thyroiditis.

Chronic effects of excessive iodine intake on apoptosis of thyrocytes in Wistar rats / 中华内分泌代谢杂志

Objective To explore the chronic effects of mild and moderate iodine excess and iodine restriction on apoptosis of thyrocytes. Methods Wistar rats were exposed to 4 different doses of iodine: 4 μg/d (control), 6 μg/d (1.5 fold iodine excess), 12 μg/d (3 fold iodine excess), and 24 μg/d (6 fold iodine excess) for 1, 2, 4 and 8 months. Some rats treated for 8 months were fed with 4 μg/d iodine for another 3 months. Urinary iodine concentration was monitored by arscnic/cerium catalyzing spectrophotography. Apoptosis was determined by flow cytometry after Annexin V-FTTC staining and uhrastructure assessment under electronic microscope. Cell cycle kinetics was analyzed by flow eytometry after propidium iodine staining. Fluorescent measurement by DCFH-DA probe was used to determine the intracellular reactive oxygen species (ROS) level. Expressions of apoptic proteins were analyzed by flow cytometry and immunohistochemistry. Results Apoptotosis rate and ROS production in thyrocytes were significantly increased in 3 and 6 fold iodine excess groups after 4 months and 8 months (all P < 0.05), which was reversed with iodine restriction. 6 fold iodine exposure was proved to cause a reduction of cells in GOG1-phase (64% and 67% vs 80%, both P < 0. 05) and a concomitant accumulation in S-phase (5% and 6% vs 3%, both P <0.05) after 4 months and 8 months. Expressions of Fas, FasL and TRAIL proteins in 3 and 6 fold iodine excess groups after 8 months were increased by 2 to 4 times compared with control group and did not return to normal after iodine restriction. Bcl-2 and Bax remained constant. Positive correlations were observed among iodine amount, apoptosis rate and ROS level in 6 fold iodine excess group after 8 months (r = 0. 637-0.790, P < 0.01). Conclusion Chronic iodine excess results in thyrocyte apoptosis due probably to generation of ROS.