A B S T R A C T While 3,3',5'-triiodothyronine (reverse TS, rTs) has been detected both in human serum and in thyroglobulin, no quantitative assessment of its metabolic clearance rate (MCR), production rate (PR), or secretion by the thyroid is yet available. This study examines this information in euthyroid subjects and evaluates it in light of similar information about two other iodothyronines in the thyroid: 3,5,3'-triiodothyronine (Ta) and thyroxine (T4). Thus, it was noted that rTs is cleared from human serum at a much faster rate than are Ts and T4; the mean (±-SE) MCR of rT3 was 76.7±5.4 liters/day in 10 subjects, whereas MCR-T3 and MCR-T4 in 8 of them were 26.0±2.2 liters/day and 1.02±0.06 liters/day, respectively. Therefore, even though the mean serum concentration of rT3, 48+2.8 ng/ 100 ml, was much lower than that (128±6.7 ng/100 ml) of T3, the mean PR-rTs (36.5+2.8 ,ug/day) and the mean PR-T3 (33.5±3.7 Ag/day) were similar; in comparison, the mean serum concentration and PR of T4 were 8.6± 0.5 ,ug/100 ml and 87.0±3.9 Mg/day, respectively. These data and those on the relative proportion of rT3, T3, and Ts in 10 thyroid glands were used to assess the significance of the contribution of thyroidal secretion to PRrTs and PR-Ta. It was estimated that whereas thyroidal secretion may account for about 23.8% of serum T3 (or PR-Ta), it may account for only about 2.5% of serum rTa (or PR-rTs). Since peripheral metabolism of T4 is the only known source of rT3 and Ta other than the thyroidal secretion, it could be calculated that as much as 73.0 Ag or 84% of daily PR-T4 may normally be metabolized by monodeiodination either to T3 or to rT3.MCR and PR of various iodothyronines were also examined in five cases with hepatic cirrhosis, where, as documented previously, serum rT3 may be elevated while Received for publication 2 September 1975 and in revised form 20 February 1976. serum Ta is diminished. The mean MCR-rT3 in these cases (41.0 liters/day) was clearly (P < 0.005) less than that (76.7 liters/day) in normal subjects. This was the case at a time when the mean MCR-Ta (26.7 liters/day) and the mean MCR-T4 (1.19 liters/day) did not differ from those (vide supra) in normal subjects. Distinct from changes in MCRs, the mean PR-rT3 (33.0 Ag/day) was similar to, and the mean PR-T3 (10.1 ug/day) and the mean PR-T4 (66.4 Mg/day) were much less than, the corresponding value in normal subjects. Furthermore, while the ratio of PR-rT3 and PR-T4 (rT3/T4) in individual patients was either supranormal or normal, the ratio of PR-Ta and PR-T4 (T3/T&) was clearly subnormal. The various data suggest that: (a) just as in the case of T3, the thyroid gland is a relatively minor source of rT3; peripheral metabolism of T4 is apparently its major source; (b) the bulk of T4 metabolized daily is monodeiodinated to T3 or to rT3; (c) monodeiodination may be an obligatory step in metabolism of T4; (d) monodeiodination of T4 to rTa is maintained normal or is increased in hepatic cirrhosis at a time when monodeiodination of T4 to Ta is decr...

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