The syndromes of resistance to thyroid hormone

The syndromes of resistance to thyroid hormone are characterized by reduced clinical and biochemical manifestations of thyroid hormone action relative to the circulating hormone levels. In practice, most patients are identified by the persistent elevation of serum levels of T₄ and T₃ with “inappropriately” nonsuppressed TSH, in the absence of intercurrent acute illness, drugs, or alterations of thyroid hormone binding to serum proteins. More importantly, administration of supraphysiological doses of thyroid hormone fail to produce the expected suppressive effect on the secretion of pituitary TSH and/or to induce the expected metabolic responses in the peripheral tissues. Since the publication of the index cases in 1967 (1), 347 subjects have been reported who exhibit the characteristics of the syndrome (Refs. 1–129 and our personal communications and observations). In this review, we summarize all cases known to us, present their common features as well as unusual manifestations, and attempt to analyze and relate both clinical and laboratory findings. Special emphasis is given to recent advances in diagnostic procedures and in genetic studies which, in addition to identifying the etiology of the resistance, have contributed to the understanding of the molecular mechanisms of thyroid hormone action. The ultimate goal is to provide more accurate means of establishing the diagnosis, earlier recognition of the disorder, and more effective approaches to therapy.