Background: In humans, resistance to thyroid hormone (RTH) caused by mutations in the thyroid hormone receptor alpha (THRA) gene, RTHα, manifests as tissue-specific hypothyroidism and circulating thyroid hormone levels exhibit hypothyroid-like clinical features. Before the identification of patients with RTHα, several Thrα1 knock-in mouse models were generated to clarify the function of TRα1. However, the phenotypes of these mice were not consistent with the clinical presentation of RTHα in humans. For the present study, we generated an RTHα mouse model that carries the Thra1E403X mutation found in human RTHα patients. Here, we report the gross phenotypes of this mouse RTHα model. Methods: Traditional homologous recombination gene targeting techniques were used to introduce a mutation (Thra1E403X) in the mouse Thra gene. The phenotypes of the resulting mice were studied and compared with clinical features observed for RTHα with THRAE403X. Results: Thrα1E403X/E403X homozygous mice exhibited severe neurological phenotypes, such as spasticity and motor ataxia, which were similar to those observed in endemic cretinism. Thrα1E403X/+ heterozygous mice reproduced most clinical manifestations of patient with RTHα, such as a normal survival rate and male fertility, as well as delayed postnatal growth and development, neurological and motor coordination deficits, and anemia. The mice had typical thyroid function with a modest increase in serum triiodothyronine (T3) levels, a low thyroxine (T4)/T3 ratio, and low reverse T3 (rT3) levels. Conclusions: The Thrα1E403X/+ mice faithfully recapitulate the clinical features of human RTHα and thus can provide a useful tool to dissect the role of TRα1 in development and to determine the pathological mechanisms of RTHα.

背景 β型甲状腺激素抵抗综合征(RTHβ)属于罕见内分泌疾病,临床极易误诊、误治.目的 总结RTHβ患者的临床特点,为临床医师了解本病提供帮助.方法 选取2013—2016年于中国医科大学附属第一医院内分泌与代谢病科诊断为RTHβ的患者6例.回顾性分析6例RTHβ患者的临床资料,包括性别、诊断年龄、发病年龄、家族史、主诉、心电图检查结果、甲状腺触诊结果、甲状腺超声检查结果、甲状腺核素静态显像结果、甲状腺功能指标〔游离三碘甲腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)〕、促甲状腺素受体抗体(TRAb)、性激素结合蛋白(SHBG)、血清铁蛋白、脂代谢指标、骨代谢指标、骨密度、基因测序情况等.结果 6例RTHβ患者的诊断年龄均高于发病年龄,患者在确诊RTHβ之前均被误诊为甲状腺功能亢进症,长期服用抗甲状腺药物治疗.患者主诉均存在心悸、多汗,3例伴心房颤动.6例患者甲状腺核素静态显像均显示甲状腺双叶摄取率增高.5例RTHβ患者甲状腺超声显示有甲状腺肿大,4例显示多发结节.6例RTHβ患者血清FT3、FT4水平升高,TSH水平在参考范围,且TRAb均为阴性;血清SHBG和血清铁蛋白均在参考范围;甲状腺激素受体(TR)β基因测序均存在点突变.结论 RTHβ的临床表现存在高度异质性,临床诊断时需注意与甲状腺功能亢进症和甲状腺功能减退症区分,同时注意并非所有的RTHβ患者能检测出TRβ基因突变.对于高度怀疑为RTHβ的患者,可以采用促甲状腺素释放激素(TRH)兴奋试验、左旋-三碘甲腺原氨酸(L-T3)抑制试验或TRH兴奋试验联合L-T3抑制试验进行临床诊断.

背景Graves'Disease(GD)是一种常见的自身免疫性疾病,但其发病机制尚不明确.目的 通过对公共基因芯片数据的分析,找出与GD发病可能相关的基因.方法 在GEO数据库和ArrayExpress数据库中检索"Graves'Disease",得到GSE71956和E-MEXP-2612(截至2019-04-02).利用R语言的"Limma"包对基因芯片的原始数据进行标准化处理并找出差异基因.差异基因共包括对照CD4细胞与GD患者CD4细胞的对比(C-GD CD4)、对照CD8细胞与GD患者CD8细胞的对比(C-GD CD8)、对照者甲状腺组织与短病程GD患者甲状腺组织的对比(C-S)、对照者甲状腺组织与长病程GD患者甲状腺组织的对比(C-L)、短病程GD患者甲状腺组织与长病程GD患者甲状腺组织的对比(S-L).再对差异基因进行多重比较及功能注释分析.结果 维恩图显示,KLF9、RGS1基因同时存在于C-GD CD4、C-GD CD8与C-L差异基因中.氨基酸和类固醇代谢基因可能与GD的发病相关.FMO2、CALHM6和C7基因同时存在于C-S、C-L、S-L差异基因中.长病程和短病程GD患者甲状腺组织CALHM6基因表达水平高于对照者,长病程GD患者CALHM6基因表达水平高于短病程GD患者;长病程和短病程GD患者甲状腺组织FMO2和C7基因表达水平低于对照者,长病程GD患者FMO2和C7基因表达水平低于短病程GD患者(P<0.05).结论 GD的发病可能与KLF9、RGS1的异常表达及氨基酸和类固醇代谢有关,FMO2、CALHM6、C7基因可能与GD的病程相关.

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.

OBJECTIVE:Thyroid peroxidase (TPO) is essential for thyroid hormone biosynthesis. TPO mutations might lead to congenital hypothyroidism. In the present study, we analysed the function of a compound heterozygous TPO mutation in a Chinese family.DESIGN:We studied a 23-year-old Chinese girl with a history of growth retardation and severe constipation from the age of 3 months, who was diagnosed as having congenital hypothyroidism.METHODS:Genomic DNA was extracted from peripheral blood samples obtained from the patient's family members. The genomic DNA was sequenced to detect mutations in a panel of genes associated with congenital hypothyroidism. Bioinformatic analysis and structural modelling predicted the potential disease-causing potential mutant genes and the microstructure of the mutant protein, respectively. Western blotting and ELISA were used to measure protein expression, and guaiacol oxidation assay measured the TPO activity of the mutant protein.RESULTS:We identified a compound heterozygous mutation (c.C1993T, c.T2473C) in the TPO gene. Bioinformatic analysis predicted that the TPO mutations were potentially disease causing. Structural modelling predicted damage to the microstructure of the mutant TPO protein. Western blotting and ELISA showed reduced protein levels of the mutant TPO protein compared with that of the wild-type protein. The mutant TPO protein showed weaker activity compared with that of the wild-type protein.CONCLUSIONS:A novel compound heterozygous mutation of TPO gene was identified in a Chinese family. This mutation might alter the extracellular microstructure of TPO, and decrease its expression and the activity, resulting in congenital hypothyroidism.

The diagnosis and treatment of 1 patient with hypokalemia and rhabdomyolysis caused by Glycyrrhiza uralensis is reviewed. The related literature and its pathogenesis are reviewed, so as to improve clinicians' understanding of hypokalemia and rhabdomyolysis caused by Glycyrrhiza uralensis..

Objective To investigate the stability and reliability of serum thyroid hormone levels measured by the Roche automatic electrochemiluminescence immunoassay system and to compare the differences in these levels in different strains of rats and mice.Methods From November 2016 to March 2017,we selected 60 Kunming mice and 30 SD rats aged 7–8 weeks;30 Kunming mice aged 7–8 weeks (randomly assigned to the experimental thyroid hormone elevation group, experimental thyroid hormone reduction group and normal thyroid hormone group,10 in each group) and 30 SD rats aged 7–8 weeks (randomly assigned to the experimental thyroid hormone elevation group,experimental thyroid hormone reduction group and normal thyroid hormone group,10 in each group);outbred strains of SD rats,inbred BN rats,outbred Kunming mice, inbred C57BL/B6N mice age 10 weeks,20 in each strain.The automatic electrochemiluminescence immunoassay system was used to detect TT3,TT4,FT3and FT4.Results The within-assay coefficients of variation (CVs) of serum thyroid function indicators in Kunming mice and SD rats were 0.697%–1.853% and 0.946%–1.253%,respectively,while the inter-assay CVs were 1.389%–2.670% and 1.150%–2.834%,respectively.The levels of TT3,TT4,FT3,and FT4in the experimental thyroid hormone elevation group of Kunming mice and SD rats were higher than those in the normal thyroid hormone group,while those in the experimental thyroid hormone reduction group were lower than those in the normal thyroid hormone group (P<0.05). The CVs of serum thyroid function indicators were > 5.000% in all strains of rats and mice,while there was a tendency for inbred strains' serum thyroid function indicators to outperform those of the outbred strains.Conclusion The Roche automatic electrochemiluminescence immunoassay system shows stability in the detection of thyroid hormone levels in rats and mice.It distinguished the differences in thyroid functions in the experimental thyroid hormone elevation group,experimental thyroid hormone reduction group and normal thyroid hormone group.