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Autonomic Nervous System Function in Chronic Exogenous Subclinical Thyrotoxicosis and the Effect of Restoring Euthyroidism

Departments of Endocrinology and Metabolism (C.F.A.E.-R., E.P.M.C., K.A.H., J.W.A.S., J.A.R.), Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; and Centre for Human Drug Research (R.C.S., J.B.), 2333 CL, Leiden, The Netherlands

Address all correspondence and requests for reprints to: E.P.M. Corssmit, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail: e.p.m.corssmit{at}lumc.nl.

Context: Knowledge on the relationship between the autonomic nervous system and subclinical hyperthyroidism is mainly based upon cross-sectional studies in heterogeneous patient populations, and the effect of restoration to euthyroidism in subclinical hyperthyroidism has not been studied.

Objective: We investigated the long-term effects of exogenous subclinical hyperthyroidism on the autonomic nervous system and the potential effects of restoration of euthyroidism.

Design: This was a prospective single-blinded, placebo-controlled, randomized trial.

Setting: The study was performed at a university hospital.

Patients: A total of 25 patients who were on more than 10-yr TSH suppressive therapy after thyroidectomy was examined.

Intervention: Patients were studied at baseline and subsequently randomized to a 6-month thyroid hormone substitution regimen to obtain either euthyroidism or maintenance of the subclinical hyperthyroid state.

Main Outcome Measures: Urinary excretion of catecholamines and heart rate variability were measured. Baseline data of the subclinical hyperthyroidism patients were compared with data obtained in patients with hyperthyroidism and controls.

Results: Urinary excretion of norepinephrine and vanillylmandelic acid was higher in the subclinical hyperthyroidism patients compared with controls and lower compared with patients with overt hyperthyroidism. Heart rate variability was lower in patients with hyperthyroidism, intermediate in subclinical hyperthyroidism patients, and highest in the healthy controls. No differences were observed after restoration of euthyroidism.

Conclusions: Long-term exogenous subclinical hyperthyroidism has effects on the autonomic nervous system measured by heart rate variability and urinary catecholamine excretion. No differences were observed after restoration to euthyroidism. This may indicate the occurrence of irreversible changes or adaptation during long-term exposure to excess thyroid hormone that is not remedied by 6-month euthyroidism.