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摘要: 甲状腺激素抵抗综合征(RTH)是甲状腺激素受体(TR)基因突变，导致器官对甲状腺激素(TH)的敏感性降低，TH对全身组织器官作用障碍的一种罕见综合征。THRB基因突变导致的RTH称为β型甲状腺激素抵抗综合征(RTHβ)。RTHβ主要特点是循环血中甲状腺素(T4)升高、三碘甲腺原氨酸(T3)水平正常或升高、促甲状腺激素(TSH)水平正常或轻度升高，临床上RTHβ容易被误诊为甲状腺功能亢进症，予以抗甲状腺药物、放射性131I治疗或手术治疗，进而导致TH抵抗加重，因此对该病的正确诊断非常重要。本文对RTHβ的分子机制、临床特征、诊断及治疗予以归纳并总结。
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关键词:
- 甲状腺激素抵抗综合征 /
- THRB基因突变 /
- 甲状腺激素
Abstract: 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.-
Key words:
- thyroid hormone resistance syndrome /
- THRB mutations /
- thyroid hormone
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表 1 高甲状腺素血症鉴别诊断
Table 1. Differential diagnosis of hyperthyroxinemia
疾病名称 临床表现 FT4 FT3 TSH rT3 TT4 TT3 基因缺陷 其他 RTHβ 甲状腺肿、窦性心动过速、轻微神经认知功能障碍 ↑ ↑或N ↑或N ↑ ↑ ↑或N THRB 甲状腺摄碘率升高；L-T3抑制试验：TSH部分抑制 RTHα 神经认知功能障碍、身材矮小、骨发育延迟、心率缓慢、巨颅症、便秘、贫血 ↓ ↑或N N ↓ ↓ ↑或N THRA TSH瘤 甲状腺毒症 ↑ ↑ ↑或N ↑ ↑ ↑ 无 α-GSU↑、α-GSU/TSH↑；MRI影像学存在占位病变、TRH兴奋试验阴性、L-T3抑制试验TSH不被抑制 TBG增多症 无 N N N ↑ ↑ ↑ TBG的基因拷贝数异常 血清TBG↑ FDH 无 ↑或N ↑或N N ↑ ↑ ↑或N ALB 化学发光免疫分析法检测FT3或FT4假性升高、平衡透析或超滤后检测FT3、FT4水平正常 THAAb干扰 无 ↑或N ↑或N N N ↑或N ↑或N 无 THAAb阳性 RTHβ：β型甲状腺激素抵抗综合征；RTHα：α型甲状腺激素抵抗综合征；TBG：甲状腺素结合球蛋白；THAAb：甲状腺激素自身抗体；FDH：家族性白蛋白异常高甲状腺素血症；TSH：促甲状腺激素；FT4：游离T4；FT3：游离T3；rT3：反T3；TT4：总T4；TT3：总T3；α-GSU：血清糖蛋白激素α亚单位；TRH：促甲状腺激素释放激素；N：正常；↑：升高；↓：下降 
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[1] Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities[J]. Endocr Rev, 1993, 14(2): 184-193. [2] Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone[J]. Endocr Rev, 1993, 14(3): 348-399. [3] Fondell JD, Guermah M, Malik S, et al. Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFⅡD[J]. Proc Natl Acad Sci USA, 1999, 96(5): 1959-1964. doi: 10.1073/pnas.96.5.1959 [4] Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions[J]. Mol Cell Endocrinol, 2003, 213(1): 1-11. doi: 10.1016/j.mce.2003.10.033 [5] Yen PM, Ando S, Feng X, et al. Thyroid hormone action at the cellular, genomic and target gene levels[J]. Mol Cell Endocrinol, 2006, 246(1-2): 121-127. doi: 10.1016/j.mce.2005.11.030 [6] Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone[J]. Biochim Biophys Acta, 2013, 1830(7): 3987-4003. doi: 10.1016/j.bbagen.2012.08.005 [7] Weiss RE, Hayashi Y, Nagaya T, et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor[J]. J Clin Endocrinol Metab, 1996, 81(12): 4196-4203. [8] Pappa T, Refetoff S. Human genetics of thyroid hormone receptor beta: resistance to thyroid hormone beta (RTHβ)[J]. Methods Mol Biol, 2018, 1801: 225-240. [9] Takeda K, Sakurai A, DeGroot LJ, et al. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene[J]. J Clin Endocrinol Metab, 1992, 74(1): 49-55. [10] Frank-Raue K, Lorenz A, Haag C, et al. Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene[J]. Eur J Endocrinol, 2004, 150(6): 819-823. doi: 10.1530/eje.0.1500819 [11] Ono S, Schwartz ID, Mueller OT, et al. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone[J]. J Clin Endocrinol Metab, 1991, 73(5): 990-994. doi: 10.1210/jcem-73-5-990 [12] Ferrara AM, Onigata K, Ercan O, et al. Homozygous thyroid hormone receptor β-gene mutations in resistance to thyroid hormone: three new cases and review of the literature[J]. J Clin Endocrinol Metab, 2012, 97(4): 1328-1336. doi: 10.1210/jc.2011-2642 [13] Pappa T, Refetoff S. Resistance to thyroid hormone beta: a focused review[J]. Front Endocrinol (Lausanne), 2021, 12: 656551. doi: 10.3389/fendo.2021.656551 [14] Pulcrano M, Palmieri EA, Mannavola D, et al. Impact of resistance to thyroid hormone on the cardiovascular system in adults[J]. J Clin Endocrinol Metab, 2009, 94(8): 2812-2816. doi: 10.1210/jc.2009-0096 [15] Owen PJ, Chatterjee VK, John R, et al. Augmentation index in resistance to thyroid hormone (RTH)[J]. Clin Endocrinol (Oxf), 2009, 70(4): 650-654. doi: 10.1111/j.1365-2265.2008.03422.x [16] Stein MA, Weiss RE, Refetoff S. Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder[J]. J Dev Behav Pediatr, 1995, 16(6): 406-411. [17] Brucker-Davis F, Skarulis MC, Grace MB, et al. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study[J]. Ann Intern Med, 1995, 123(8): 572-583. doi: 10.7326/0003-4819-123-8-199510150-00002 [18] Weiss RE, Refetoff S. Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone[J]. Endocrinol Metab Clin North Am, 1996, 25(3): 719-730. doi: 10.1016/S0889-8529(05)70349-2 [19] Furumoto H, Ying H, Chandramouli GV, et al. An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis[J]. Mol Cell Biol, 2005, 25(1): 124-135. doi: 10.1128/MCB.25.1.124-135.2005 [20] Watanabe K, Kameya T, Yamauchi A, et al. Thyrotropin-producing microadenoma associated with pituitary resistance to thyroid hormone[J]. J Clin Endocrinol Metab, 1993, 76(4): 1025-1030. [21] Teng X, Jin T, Brent GA, et al. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T)[J]. J Clin Endocrinol Metab, 2015, 100(7): 2511-2514. doi: 10.1210/jc.2014-3994 [22] Ando S, Sarlis NJ, Oldfield EH, et al. Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor[J]. J Clin Endocrinol Metab, 2001, 86(11): 5572-5576. [23] Ando S, Sarlis NJ, Krishnan J, et al. Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance[J]. Mol Endocrinol, 2001, 15(9): 1529-1538. doi: 10.1210/mend.15.9.0687 [24] Gittoes NJ, McCabe CJ, Verhaeg J, et al. An abnormality of thyroid hormone receptor expression may explain abnormal thyrotropin production in thyrotropin-secreting pituitary tumors[J]. Thyroid, 1998, 8(1): 9-14. doi: 10.1089/thy.1998.8.9 [25] Tagami T, Usui T, Shimatsu A, et al. Aberrant expression of thyroid hormone receptor beta isoform may cause inappropriate secretion of TSH in a TSH-secreting pituitary adenoma[J]. J Clin Endocrinol Metab, 2011, 96(6): E948-E952. doi: 10.1210/jc.2010-2496 [26] Gurnell M, Rajanayagam O, Barbar I, et al. Reversible pituitary enlargement in the syndrome of resistance to thyroid hormone[J]. Thyroid, 1998, 8(8): 679-682. doi: 10.1089/thy.1998.8.679 [27] Després N, Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation[J]. Clin Chem, 1998, 44(3): 440-454. doi: 10.1093/clinchem/44.3.440 [28] Gurnell M, Visser TJ, Paolo Beck-Peccoz, et al. Resistance to thyroid hormone[M]. In: Endocrinology. (DeGroot LJ, Jameson JL. eds.)W.B. Saunders Co.: 2016: 1649-1665. [29] Williams G, Kraenzlin M, Sandler L, et al. Hyperthyroi-dism due to non-tumoural inappropriate TSH secretion. Effect of a long-acting somatostatin analogue (SMS 201-995)[J]. Acta Endocrinol (Copenh), 1986, 113(1): 42-46. [30] Beck-Peccoz P, Mariotti S, Guillausseau PJ, et al. Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201-995[J]. J Clin Endocrinol Metab, 1989, 68(1): 208-214. doi: 10.1210/jcem-68-1-208 [31] Beck-Peccoz P, Piscitelli G, Cattaneo MG, et al. Success-ful treatment of hyperthyroidism due to nonneoplastic pituitary TSH hypersecretion with 3, 5, 3'-triiodothy-roacetic acid (TRIAC)[J]. J Endocrinol Invest, 1983, 6(3): 217-223. doi: 10.1007/BF03350611 [32] Radetti G, Persani L, Molinaro G, et al. Clinical and hormonal outcome after two years of triiodothyroacetic acid treatment in a child with thyroid hormone resistance[J]. Thyroid, 1997, 7(5): 775-778. doi: 10.1089/thy.1997.7.775 [33] Takeda T, Suzuki S, Liu RT, et al. Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone[J]. J Clin Endocrinol Metab, 1995, 80(7): 2033-2040. [34] Crinò A, Borrelli P, Salvatori R, et al. Anti-iodothyronine autoantibodies in a girl with hyperthyroidism due to pituitary resistance to thyroid hormones[J]. J Endocrinol Invest, 1992, 15(2): 113-120. doi: 10.1007/BF03348675 [35] Schueler PA, Schwartz HL, Strait KA, et al. Binding of 3, 5, 3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3[J]. Mol Endocrinol, 1990, 4(2): 227-234. doi: 10.1210/mend-4-2-227 [36] Ueda S, Takamatsu J, Fukata S, et al. Differences in response of thyrotropin to 3, 5, 3'-triiodothyronine and 3, 5, 3'-triiodothyroacetic acid in patients with resistance to thyroid hormone[J]. Thyroid, 1996, 6(6): 563-570. doi: 10.1089/thy.1996.6.563 [37] Hamon P, Bovier-Lapierre M, Robert M, et al. Hyperthyroidism due to selective pituitary resistance to thyroid hormones in a 15-month-old boy: efficacy of D-thyroxine therapy[J]. J Clin Endocrinol Metab, 1988, 67(5): 1089-1093. doi: 10.1210/jcem-67-5-1089 [38] Dorey F, Strauch G, Gayno JP. Thyrotoxicosis due to pituitary resistance to thyroid hormones. Successful control with D thyroxine: a study in three patients[J]. Clin Endocrinol(Oxf), 1990, 32(2): 221-228. doi: 10.1111/j.1365-2265.1990.tb00858.x [39] Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid hormone exposure[J]. JAMA, 2004, 292(6): 691-695. doi: 10.1001/jama.292.6.691 [40] Pappa T, Anselmo J, Mamanasiri S, et al. Prenatal diagnosis of resistance to thyroid hormone and its clinical implications[J]. J Clin Endocrinol Metab, 2017, 102(10): 3775-3782. doi: 10.1210/jc.2017-01251 [41] Paragliola RM, Concolino P, De Rosa A, et al. The first case of association between postpartum thyroiditis and thyroid hormone resistance in an Italian patient showing a novel p. V283A THRB mutation[J]. Thyroid, 2013, 23(4): 506-510. doi: 10.1089/thy.2012.0080 -
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