THYROID GLAND FUNCTION IN GRAVES’ DISEASE

While the ultimate cause(s) remain uncertain, the patho-physiologic mechanisms are more clear. The thyroid gland is functioning at an accelerated rate. Cell membrane adenyl cyclase activity in tissue from Graves' patients is higher than in normal thyroids, and the increment coincides with TSAb in the serum ¹¹³, which acts on TSH receptors to cause the response. Clearance of plasma iodide by the gland is increased from the normal rate of 10-20 ml/min to 40 to several hundred ml per minute. We have estimated iodide clearance in one patient to exceed 2 liters/min. For this reason, the percentage of a tracer dose of 131I found in the gland at 24 hours is characteristically elevated. Thyroid peroxidase activity is increased. Because of rapid secretion, the period of retention of iodine within the thyroid is reduced, causing the characteristic drop in RAIU between 12 and 24 hours after administration of a tracer. The total quantity of iodine in the gland is variable. In previous years it tended to be reduced, but now it is often elevated because of increasing amounts of iodine in our diet. The volume of the gland is characteristically but not invariably increased. Thyroid hormones, TG, small amounts of an iodinated albumin-like protein ¹⁰⁷, and iodotyrosines ¹¹⁵ are released into the blood at increased rates. The latter two components are normally either not secreted or are released in minute amounts.

Many studies with radioiodine have confirmed the accelerated physiologic activity of the thyroid in Graves' disease. Thus, labeled hormones appear as plasma PB131I more rapidly and reach higher levels than in normal persons after administration of 131I. The rate of turnover of plasma hormones is also increased. Accelerated degradation is almost certainly secondary to hypermetabolism and not a primary event ¹¹⁶, although it has been reported that accelerated T4 turnover persists after therapy for thyrotoxicosis ¹¹⁷.

With the general hyperactivity of the thyroid, excess TG is released and serum TG levels are elevated in active Graves' disease. After therapy the levels tend to fall, and normalization during antithyroid therapy is an excellent predictor of remission ¹¹⁸. This excessive release of TG leads to formation of circulating immune complexes with anti-TG antibodies, and can lower the titer of these antibodies in the serum.

An important abnormality in thyroid function during Graves' disease is that the uptake of 131I by the thyroid is not suppressed by administration of exogenous T4 or T3 (119,120). This fact holds true even if large amounts of hormone are given. Indeed, administration of T3 may cause, on average, a slight increase in the 24-hour radioiodine uptake. This abnormal response to the administration of thyroid hormone occurs in spite of responsiveness of the thyroid to administered exogenous TSH, as measured by augmented release of thyroid hormone. It may persist after thyrotoxicosis has been ameliorated by surgery, but typically suppressibility returns in time after treatment. Nonsuppressibility is observed so regularly that it was used for many years as a criterion for diagnosis in doubtful cases. Nonsuppressibility is caused by stimulation of the thyroid by TSAb, and independence of feedback control via TSH. There is a general, but not complete, correlation between T3 nonsuppressibility and positive assays for TSAb ¹²¹. Even long after apparent remission of Graves' disease, some patients show some resistance to T3 suppression or TSH stimulation ¹²². Also, some euthyroid relatives of Graves' disease patients show these abnormalities in the absence of overt thyroid disease.

The pituitary does not respond to TRH in the thyrotoxic state, either in hyperthyroid Graves' disease or when thyroid hormone is administered. Some patients with "euthyroid Graves' disease" respond to TRH and others do not; the responses do not correlate with the results of T3 suppression tests ^123,124. For the diagnosis of Graves' disease, suppression of serum TSH is currently the most useful criterion, as it is more convenient than the TRH test and preferable to the T3 suppression test in patients with heart disease. Test results are not uniformly abnormal in patients with euthyroid Graves' disease.