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Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown., Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis., Design: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue., Results: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios., Conclusion: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.

Antipituitary antibody (APA) has been reported to be detected in patients with autoimmune thyroid disease. Type 2 iodothyronine deiodinase (D2) is expressed in both pituitary gland and thyroid gland. We studied the association of APA and D2 peptide antibody in patients with autoimmune thyroid disease. Rat pituitary gland homogenate and D2 peptide were used as antigens in the present study. APA and D2 peptide antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in sera obtained from 42 patients with Hashimoto's disease, 26 patients with Graves' disease and 70 healthy control subjects. Moreover, D2 activity precipitation assay was performed in some patients with Hashimoto's disease. APA and D2 peptide antibody were elevated in patients with Hashimoto's disease and patients with Graves' disease, compared with control subjects. APA was positive in 32.4% (22/68), D2 peptide antibody was positive in 26.5% (18/68) of patients with autoimmune thyroid disease. APA was positive in 31.0% (13/42) of patients with Hashimoto's disease and 34.6% (9/26) of patients with Graves' disease. D2 peptide antibody was positive in 26.2% (11/42) of patients with Hashimoto's disease and 26.9% (7/26) of patients with Graves' disease. D2 peptide antibody was correlated with APA in patients with autoimmune thyroid disease. Moreover, precipitation of D2 activity was increased in some patients with Hashimoto's disease including a patient who also had idiopathic diabetes insipidus, and was correlated with D2 peptide antibody. These results suggest that D2 antibody may be associated with APA in patients with autoimmune thyroid disease.