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Disturbance of the Fetal Thyroid Hormone State Has Long-Term Consequences for Treatment of Thyroidal and Central Congenital Hypothyroidism

Department of Pediatric Endocrinology (M.J.E.K., A.S.P.v.T., D.A.v.T., E.B., B.M.W., J.J.M.d.V., T.V.), Department of Clinical Chemistry, Laboratory of Endocrinology (E.E.), Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: M. J. E. Kempers, M.D., Emma Children’s Hospital Academic Medical Center, Department of Pediatric Endocrinology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: m.j.kempers{at}amc.uva.nl.

Background: During T₄ supplementation of patients with thyroidal (primary) congenital hypothyroidism (CH) TSH concentrations are frequently elevated despite free T₄ (FT₄) concentrations being well within the reference range. To examine the thyroid’s regulatory system, we analyzed thyroid function determinants in children with congenital and acquired thyroid disorders and in controls.

Methods: Retrospectively, plasma FT₄, TSH, and T₃ concentrations were analyzed in T₄-supplemented children aged 0.5–20.0 yr with thyroidal CH, central (secondary or tertiary) CH, or autoimmune thyroid disease and in control children with type 1 diabetes mellitus.

Results: When TSH was within the reference range (0.4–4.0 mU/liter), mean FT₄ in thyroidal CH [1.65 ng/dl; 95% confidence interval (CI), 1.62–1.67] was significantly higher than in autoimmune thyroid disease (1.15 ng/dl; 95% CI, 1.11–1.19) and diabetes (1.08 ng/dl; 95% CI, 1.06–1.10). In central CH, when TSH was less than or equal to 0.02 mU/liter, mean FT₄ was 1.27 ng/dl (95% CI, 1.24–1.29). When FT₄ was within the reference range (0.78–1.79 ng/dl), 43% of the TSH measurements in thyroidal CH were more than 4.0 mU/liter, compared with 18% in autoimmune thyroid disease and 0% in type 1 diabetes mellitus; in central CH, 95% of TSH measurements were less than 0.4 mU/liter.

Conclusions: In T₄-supplemented patients with thyroidal CH, when TSH concentrations are established within the reference range, FT₄ concentrations tend to be elevated, and vice versa. Because this phenomenon could not be observed in acquired thyroidal hypothyroidism, we hypothesize that a pre- and/or perinatal hypothyroid state shifts the setpoint of the thyroid’s regulatory system. In central CH, when FT₄ concentrations are established within the reference range, the pituitary secretes only minute amounts of TSH. For monitoring T₄ supplementation, reference ranges for FT₄ and TSH should be adapted to the etiology of hypothyroidism.

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