Incomplete thyroid hormone synthesis in multinodular goitre   A characteristic finding in multinodular goitre is accumulation in the gland of abundant thyroglobulin with a relatively low iodine and thyroid hormone content. This is illustrated in fig 3 showing results on thyroglobulin obtained by fine needle aspiration from euthyroid patients with multinodular goitre. Regular cold areas were avoided during aspiration. For comparison thyroglobulin is shown obtained from patients with untreated Graves' disease, untreated autoimmune hypothyroidism, and control subjects. They all lived in the same area with a relatively low iodine intake. Compared to control, aspirates from multinodu-lar goitre contained more thyroglobulin. The thyroglobulin had a low iodine content, and the fraction of total iodine present as part of T4 and T3 was lower than normal. As a result the hormone content of thyroglobulin was low (fig 3). There was a shift in the balance between T3 and T4 with relatively more T3 being formed. Such a shift is well known in iodine deficient thyroglobulin from experimental animals. It is a consequence of an increase in monoiodotyrosine compared to diiodotyrosine for coupling. Thyroglobulin from patients with Graves' disease and patients with autoimmune hypothyroidism had a normal T4 content, whereas the T3 content was above normal with a high T3 /T4 ratio. This is a reponse to chronic stimulation also found in animal experiments. Even the hyperstimulated thyroid glands from patients with Graves' disease and with hypothyroidism (as judged from T4 content) maintained a normal iodine content of thyroglobulin. Thyroglobulin with a low iodine and low thyroid hormone content was found only in multinodular goitre. It may indicate that defective iodination and coupling of thyroglobulin to generate thyroid hormones is a central process in the development of multinodular goitre. The patients with multinodular goitre were euthyroid with serum TSH in the normal range. There was a small but significant shift in the balance between T3 and T4 in serum with relatively more T3, corresponding to the higher T3 content of thyroglobulin. Much more pronounced shifts towards T3 in serum were observed in patients with Graves' disease and patients with primary hypothyroidism. The follicular cells are rich in enzymes deiodinating T4 , released from thyroglobulin or taken up from the blood, to T3 . This activity is enhanced by stimulation of the follicular cells. It is the most important mechanism behind the relatively high serum T3 in Graves' disease and probably also in untreated hypothyroidism. Apparently T4 to T3 deiodination in the thyroid is minimally affected in euthyroid multinodular goitre. The mechanisms leading to accumulation of thyroglobulin with a low iodine and hormone content in multinodular goitre are unknown. Thyroidal iodine content is an important down regulator of many processes in the thyroid, presumably including cell proliferation. Experimental results indicate that this regulation is mediated via an organic iodine containing compound, suggested by some investigators to be an iodolipid. It may be speculated that impaired iodination of organic compounds, as illustrated here by low thyroglobulin iodination, plays a key role in autonomous progression of multifocal cell proliferation in multinodular goitre. Even more speculative is that enhanced mutagenesis (and cell death?) due to excessive generation of e.g. H2O2 , to compensate for the low organic iodine content, would contribute to the heterogeneity. TSH stimulation of follicular cells may well be involved in goitrogenesis in endemic areas with severe iodine deficiency. On the other hand, there is no increase in serum TSH during goitrogenesis in multinodular goitre in areas with mild iodine deficiency. In such areas the iodostate of the thyroid seems to be the main driving force.
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