Safer J D, O'Connor M G, Colan S D, Srinivasan S, Tollin S R, Wondisford F E
Thyroid Unit, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
J Clin Endocrinol Metab. 1999 Sep;84(9):3099-109. doi: 10.1210/jcem.84.9.5985.
Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T4 and T3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received three escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-beta mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation.
甲状腺激素抵抗(RTH)是由于甲状腺激素受体(TR-β)β异构体发生突变所致。尽管甲状腺激素(T4和T3)水平升高,但RTH患者下丘脑促甲状腺激素释放激素(TRH)和垂体前叶促甲状腺激素(TSH)的中枢分泌仍异常。TR-β突变集中在TR-β C末端的三个热点区域。大多数携带TR-β突变的个体对甲状腺激素具有全身性抵抗,即身体的大多数组织对甲状腺激素反应低下。根据突变的严重程度,受影响个体临床上甲状腺功能正常甚至甲状腺功能减退。TR-β突变是否会导致仅引起中枢性甲状腺激素抵抗的选择性RTH形式仍存在争议。在此,我们描述了一名对逐渐增加剂量的T3具有显著外周敏感性的个体。该受试者参与了一项方案,在13天内接受了三次递增的T3剂量。在基线和每个T3剂量时测量中枢和外周甲状腺激素作用指标。尽管患者静息脉搏对T3仅升高了11%,但其血清铁蛋白、丙氨酸转氨酶、天冬氨酸转氨酶和乳酸脱氢酶分别升高了320%、117%、121%和30%。此外,她的血清胆固醇、肌酸磷酸激酶和深部腱反射松弛时间下降(分别为25%、36%和36%)。在中枢方面,该患者对T3具有足够的抵抗性,以至于口服200μg T3,每日4天,其血清TSH未被抑制。对患者TR的C末端外显子进行测序,发现在一个此前未知有TR-β突变的区域存在R383H突变。我们在此呈现的临床评估是迄今为止对一名已鉴定出TR-β突变个体的中枢性甲状腺激素抵抗表型最全面的记录。