However, the lack of randomized prospective scientific assays studies is the primary reason that RAE is not used often before surgery (8).
The pathogenesis of TMNG, which includes a broad spectrum of anatomo-clinical entities ranging from isolated to multiple hyperfunctioning nodules, remains a matter of debate (1�C3). In our patients 91% of hyperfunctioning nodules were multiple, with the majority of patients showing two hyperfunctioning nodules. Along with Graves�� disease, TMNG is the main cause of hyperthyroidism, with the difference that diffuse toxic goitre is most commonly found in iodine sufficient areas. In fact, in iodine insufficient areas 48% of hyperthyroid patients have TMNG, 10% toxic adenoma and 40% diffuse toxic goitre (4). Of our MNG patients, 19.7% had developed TMNG (220 out of 1117 cases).

The functionally autonomous areas synthesize and secrete thyroid hormones independently and aimlessly, thus suppressing TSH secretion; as a result, the remaining thyroid tissue becomes functionally quiescent. Areas of autonomous tissue and areas of inactive tissue thus come to coexist within the same thyroid (5). The functional autonomy acquired by one or more nodules is correlated with goitre ��age��, nodule size and patient age (+60 yr) mainly in female patients. Fifteen years are usually thought to be necessary for TMNG to develop. Our records show the disease to be most prevalent in female patients with an average age of 73 yr. The onset of hyperthyroidism occurred on average 12 yr after diagnosis and ranged from a minimum of 9 to a maximum of 18 yr.

In 1924 David Marine was the first to suspect that iodine deficiency might stimulate the pituitary gland to produce more TSH in order to allow the thyroid to maintain adequate hormone production levels (6). Many studies subsequently demonstrated that a Batimastat diffuse (hyperplastic) toxic goitre undergoing continuous TSH stimulation can evolve towards nodular degeneration with one or two nodules later becoming functionally autonomous and causing thyrotoxicosis. The pathogenesis underlying nodule��s autonomization in MNG patients has also been demonstrated to be the result of multiple causal mechanisms, ranging from chronic TSH stimulation to autocrine and paracrine factors, contributing to the development of active cells that are capable of replication and functional autonomy. In normal thyroid cells proliferation and functional differentiation are controlled by cAMP cascade. Therefore, the fact that hyperthyroidism is associated with TSH-independent toxic nodule growth suggests an anomalous activation of the cAMP regulatory cascade to play a part in their genesis (7, 8).