Previous studies have suggested that there is an overproduction of
triiodothyronine (T(3)) relative to
thyroxine (T(4)) in patients with
thyrotoxicosis associated with
Graves' disease. To evaluate whether or not an increased ratio of T(3) to T(4) in thyroidal secretion could be contributing to this relative T(3) hyperproduction, T(3), T(4), and
iodine were measured in
thyroglobulin (Tg) from controls and patients with
Graves' disease who had been treated either with
propranolol only or with
antithyroid drugs plus
iodide before surgery. To avoid possible artifacts associated with pulse labeling and chromatography, T(3) and T(4) were determined by radioimmunoassay of
Pronase hydrolysates of purified Tg. Results of analyses of Tg from six control patients and seven with
Graves' disease, not receiving
thiourea drugs or
iodide, showed that the
iodine content of
Graves' disease Tg was not different from normal. Both contained 3.4 residues of T(4)/molecule Tg, but there was 0.39+/-0.08 (mean+/-SD) residue of T(3)/molecule Tg in Graves' Tg as opposed to 0.23+/-0.07 residue T(3) molecule Tg in controls matched for
iodine content (P < 0.01). This difference resulted in a significantly lower T(4)/T(3) molar ratio (9+/-2) in Graves' Tg as opposed to control (15+/-2, P < 0.001). In Tg from patients with treated
Graves' disease,
iodine, T(3), and T(4) were reduced, but the reduction in the latter was more substantial, resulting in a T(4)/T(3) molar ratio of 3.4+/-1. Fractionation of Tg from all groups by RbCl density gradient ultracentrifugation indicated that at physiological levels of Tg iodination, the molar ratio of T(3)/Tg was consistently higher in
Graves' disease. The specific mechanism for this difference is not known, but it is not due to
iodine deficiency. If T(3) and T(4) are secreted in this altered ratio in patients with
Graves' disease, the magnitude of the difference could explain the relative T(3) hyperproduction which is characteristic of this state.