A significant proportion of patients with nodular thyroid glands develop thyrotoxicosis, and this is directly related to the duration the goiter has been present. Possible explanations for this occurrence were discussed earlier. Typically, the thyrotoxicosis comes about so insidiously that the patient is often unaware of the symptoms.

The symptoms of thyrotoxicosis are those observed with other causes of thyroid hormone excess, and are discussed in Chapter 10. Emotional lability, heightened neuromuscular activity, altered integument, increased metabolic rate, cardiac irritability and tachycardia, and increased motility of the intestine are seen, as in Graves' disease, but infiltrative ophthalmopathy is absent. Toxic adenomatous goiter was first clearly distinguished from Graves' disease by H. S. Plummer and is sometimes known as Plummer's disease72.

Certain features are much more prominent than in Graves' disease, perhaps because the disease usually appears first in the fifth through seventh decades73. Congestive heart failure occurs, and is often resistant to the usual therapeutic measures. Recurrent or permanent atrial fibrillation, or recurrent episodes of atrial tachycardia may dominate the picture. In fact, thyrotoxicosis should be carefully excluded in any goitrous adult with congestive heart failure or tachyarrhythmia. Occasionally muscle weakness is so severe that the patient is unable to climb stairs, or even to walk, when few other symptoms or signs of the disease have become manifest. Emotional lability is often unusually prominent in these patients. Depression, crying episodes, emotional fatigue, and irritability may lead one to conclude that the problem is that of an agitated depression. Frequently the symptoms are confusing because they are coincidental mixed with those of menopause. Although emotional problems may be caused by thyrotoxicosis, the contribution of the thyroid often cannot be defined until the patient has been rendered euthyroid.

Thyrotoxicosis in multinodular goiter can occur for other reasons than nodular autonomy. In the first place, any patient with long-standing diffuse hyperplasia of Graves' disease may develop nodules in the thyroid gland. On the other hand, the normal glandular elements between the nodules may become diffusely hyperplastic, as in any other gland. This condition would be Graves' disease in a multinodular goiter. If the circulating thyroid immunostimulator, typical of Graves' disease, is present in the serum, it would indicate the presence of autoimmune thyroid disease. Several clinical observations support a fundamental distinction between Graves' disease and Plummer's disease. Frequently the hyperactive tissue in the latter is confined to one or a few nodules, as demonstrated by isotopic scan. Exophthalmos is not present in toxic nodular goiter, unless there is concomitant Graves' disease, and these patients have a family background of thyrotoxicosis less frequently. Usually they are older, and thyrotoxicosis is milder and often exists for a long time without much symptoms, but responds much less readily to the administration of antithyroid drugs. Very few patients have recurrent thyrotoxicosis after surgery, and few become hypothyroid. There is a widespread clinical impression that all patients with multinodular goiter will develop thyrotoxicosis if given sufficient time.

Thyrotoxicosis can also develop because a single nodule in the thyroid has become overactive and independent of pituitary control. In as many as 46%, this condition may be T3 thyrotoxicosis74. Nodules causing hyperthyroidism are generally 3 cm or more in diameter. The function of the rest of the gland is suppressed due to the lack of circulating TSH.