3,3′-Diiodothyronine Production, a Major Pathway of Peripheral Iodothyronine Metabolism in Man

Abstract

3,3′-Diiodothyronine (3,3′-T₂) has been detected in human serum and in thyroglobulin. However, no quantitative assessment of its clearance rate (CR), production rate (PR), or of the importance of extrathyroidal sources of 3,3′-T₂ relative to direct thyroidal secretion is yet available. This study examines these parameters in seven euthyroid subjects, and in eight athyreotic subjects (H) eumetabolic due to thyroxine therapy (HT₄) (n = 5) or triiodothyronine replacement (HT₃) (n = 3). A highly specific radioimmunoassay for the measurement of 3,3′-T₂ in whole serum was developed. Serum 3,3′-T₂ concentrations were (mean ± SD) 6.0±1.0 ng/100 ml in 13 normal subjects, 9.0±4.6 ng/100 ml in 25 hyperthyroid patients, and 2.7±1.1 ng/100 ml in 17 hypothyroid patients. The values in each of the latter two groups were significantly different from normal. 3,3′-T₂ was detected regularly in normal concentrations in 11 hypothyroid patients eumetabolic by treatment with synthetic T₄, in 10 eumetabolic patients suffering from nonthyroidal systemic illness, and in 2 subjects with elevated serum T₄-binding globulin. The 3,3′-T₂ CR was assessed from data acquired from the ¹²⁵I-3,3′-T₂ constant infusion technique. The 3,3′-T₂ PR was calculated from CR and serum concentration of 3,3′-T₂ determined by radio-immunoassay. In the HT₄ subjects the 3,3′-T₂ CR averaged 840±377 liters/day and 3,3′-T₂ PR 33.9±12.5 μg/day. These results were not significantly different from those in the control group: 3,3′-T₂ CR 628±218 liters/day and 3,3′-T₂ PR 39.8±19.8 μg/day (all corrected to 70 kg body wt). In addition to 3,3′-T₂ PR, T₃, and reverse triiodothyronine (rT₃) PR were determined in three of the HT₄ subjects. In each case studied, the 3,3′-T₂ PR was close to the combined triiodothyronine (T₃ + rT₃) PR. The mean molar ratio of T₂ PR/(T₃ + rT₃) PR was 1.08±0.10. The results obtained in the HT₄ subjects indicate that the production of 3,3′-T₂ is a major route of T₄ metabolism. The combined studies of 3,3′-T₂, T₃ and rT₃ PR in the HT₄ subjects indicate that both T₃ and rT₃ are major precursors of 3,3′-T₂. In the HT₃ subjects, the conversion of T₃ to 3,3′-T₂, determined as the molar ratio of 3,3′-T₂ PR to T₃ PR, ranged from 0.36 to 0.92, providing further evidence that T₃ is a precursor of 3,3′-T₂. From the close agreement between the mean values for 3,3′-T₂ PR in the euthyroid and HT₄ group it is concluded that most, if not all of the 3,3′-T₂ produced in normal humans is derived by extrathyroidal conversion from T₃ and rT₃.