Bone Gla protein and sex hormone-binding globulin in nontoxic goiter: parameters for metabolic status at the tissue level

Several patients with nontoxic goiter have reduced serum TSH levels, as measured with new sensitive assays. Whether this is a sign of subclinical hyperthyroidism, thus having the potential of adverse effects on different organs with time, is not known. We have measured serum levels of 2 markers of thyrometabolic status at the tissue level, bone gamma-carboxyglutamic acid-containing protein (BGP), reflecting the function of osteoblasts, and sex hormone-binding globulin (SHBG), reflecting the function of hepatocytes, in 44 patients (41 women and 3 men) with nontoxic goiter (11 diffuse and 33 nodular goiters; serum T4, T3, free T4, and free T3 levels had been normal and stable for at least 0.5 yr). Serum TSH levels ranged from normal to unmeasurably low values (less than 0.05 mU/L). Serum TSH levels correlated negatively to serum BGP levels (r = -0.60; P less than 0.001). Due to the postmenopausal surge in serum BGP levels, premenopausal women (n = 21) were tested separately without changing the significance (r = -0.53; P less than 0.02). Expressing serum BGP values as a percentage of the mean value in control subjects of the same age and sex did not change the correlation (r = -0.63; P less than 0.001). Six patients had serum BGP levels above the normal range, and patients with reduced serum TSH levels (less than 0.45 mU/L; n = 12) had significantly enhanced serum BGP levels median, 1.53 nmol/L (range, 1.02-4.24) vs. 1.23 nmol/L (0.62-3.71); P less than 0.05]. Serum TSH also correlated negatively to serum SHBG levels (r = -0.56; P less than 0.001; women alone: r = -0.58; P less than 0.001). Eight patients had serum SHBG levels above the normal range, and patients with reduced serum TSH levels had significantly enhanced serum SHBG levels, expressed as a percentage of the mean control value for the relevant sex 203% (range, 75-288) vs. 120% (42-317); P less than 0.01]. It is concluded that the lower serum TSH levels in patients with nontoxic goiter, the higher are serum BGP and SHBG levels. This suggests a progressively generalized (not only pituitary) tissue overexposure to thyroid hormones, the lower the serum TSH levels. Therefore, the finding of a reduced serum TSH level in patients with nontoxic goiter might reflect supraphysiological levels of T4 and/or T3, which could possibly be harmful.