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Wilmar M. Wiersinga
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands. Subclinical hypothyroidism is defined as an increased serum TSH in the presence of normal serum FT4 and FT3, and subclinical hyperthyroidism as a decreased serum TSH in the presence of normal serum FT4 and FT3. It is assumed that the abnormal TSH concentration is not caused by analytical interference (e.g. heterophilic TSH antibodies), pharmacological interference (e.g. dopamine infusion, high-dose glucocorticoids) or nonthyroidal pathologic interference (e.g. pituitary adenomas, sick euthyroid syndrome). Subclinical thyroid dysfunction thus defined might have exogenous causes (antithyroid drugs, 131I therapy, thyroidectomy, thyroxine treatment) or endogenous causes (auto-immune thyroiditis, Graves' disease, nodular goiter). Cross-sectional and longitudinal studies have provided evidence that subclinical hypothyroidism and hyperthyroidism are the first stage in the transition from the euthyroid to the hypothyroid and hyperthyroid state respectively (Table). Indeed mean FT4 concentrations in subjects with subclinical hypothyroidism are lower and in subclinical hyperthyroidism higher than in euthyroid subjects. The occurrence of an abnormal TSH level prior to abnormal FT4 and FT3 concentrations illustrates the sensitivity of the pituitary thyrotroph for small changes in thyroid hormone production.
The applied definition of subclinical thyroid dysfunction is based on strict biochemical criteria. Nevertheless, the very term 'subclinical' suggests the absence of clinical signs and symptoms. Clinical experience, however, tells otherwise. A trial of thyroxine treatment in subjects with subclinical hypothyroidism results in modest benefits (especially in the relief of non-specific symptoms like tiredness and weight gain) in some but not all patients (1). A few randomized clinical trials have demonstrated improvements in symptom scores and psychometric performance in about one third of the patients with subclinical hypothyroidism (2,3,4). The effect of subclinical hypothyroidism on serum lipids is limited: total plasma cholesterol levels are slightly elevated but thyroid substitution treatment decrease total cholesterol by only 0.4 mmol/l, plasma levels remaining elevated in most patients (5). Likewise, the effect of subclinical hyperthyroidism on bone density is modest. A meta-analysis has indicated that the risk is confined to postmenopausal women, in whom bone mineral density decreases by 5-9% (6); this may increase the lifetime risk of fractures. The other well demonstrated effect of subclinical hyperthyroidism is the development of left ventricular hypertrophy (7) and a trebling of the risk of atrial fibrillation over 10 years (8). It thus cannot be denied that the small changes in thyroid hormone production in patients with subclinical thyroid dysfunction generate clinical signs and symptoms in a minority of them. Consequently, the term "subclinical" seems to be a misnomer, but its use is widespread although classification of thyroid hormone deficiency or excess in grades of biochemical severity would be more appropriate. One of the remaining questions is how to explain that some patients with subclinical thyroid dysfunction experience clinical signs and symptoms whereas other patients are really asymptomatic despite similar serum FT4 concentrations. |
