Thyroid hormone resistance in a large kindred: Physiologic, biochemical, pharmacologic, and neuropsychologic studies

purpose: Thyroid hormone resistance affects the pituitay gland and a variety of other tissues. We studied a large kindred with this disorder and measured a number of clinical markers of tissue metabolism to determine if these markers were useful in elucidating the sites and degree of resistance. patients: A kindred of 89 persons in four generations were identifieda; 44 had throid function tests and 14 (five to 67 years old) were found to have thyroid hormone resistance. results: The inheritance pattern was autosomal dominant, with no common HLA haplotype. Physiologic measurements in five affected members showed marked heterogeneity. Four patients had normal baseline cardiac contractility, but only two experienced a shorteninie of their QK_d interval into the hyperthroid range with triiodothyronine (T₃) therapy. Intrathyroidal ¹²⁷I content was increased in two patients and was normal in two. Bone mineral content was normal in two ment, but two women had marked osteopenia. The propositus, hypothyroid after inappropriate ¹³¹I therapy, had a hypothyroid ventilatory response to hypercapnea. This response became low normal during T₃ (100 μg/day) administration but not durijng long-term thyroxine (T₄0 (300 μg/day) administration. Three other patients had values within normal limits and one had hyperthyroid ventilatory response. Peripheral biochemical markes of thyroid hormone action were measured in 13 affected and 19 unaffected family members. Sex hormone-binding globulin was increased in zero of 13 affected patients (versus 19 of 20 hyperthyroid, χ²; p <0.001); ferritin was elevated in two of 13 patients (versus 11 of 20 hyperthyroid, p <0.02); angiotensin converting enzyme activity was increased in one of 13 patiens (versus 12 of 20 hyperthyroid, p <0.025). The eldest patient had marked cardiac sensitivity despite normal biochemical markes. We attempted to suppress the integrated thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) usingT₃ (72 and 100 percent suppression in two patients), dopamine (40 percent suppression in one), 3,5,3′-triiodothyroacetic acid (TRIAC) (94 percent suppression in one), and verapamil (10 percent and 40 percent suppression in two). Neuropsychologic function was studied in 14 individuals (11 affected, three unaffected). Although mild impairments were detected, they were not specific for throid hormone resistance. conclusion: Affected patients demonstrated great variability in the degree of resistance among tissues and individuals. The decision to treat with thyroid hormone requires careful assessment of numerous physiologic, psychologic, and biochemical parameters.