The Cooperative Thyrotoxicosis Therapy Follow-Up Study has followed patients treated for hyperthyroidism in 26 medical centers in the United States and England. At 6 years of follow-up, the incidence of thyroid cancer mortality and leukemia was not increased in the patients treated with ¹³¹I compared to the patients treated with other modalities [40, 41]. At a mean follow-up of 21 years, there was no difference in overall cancer mortality in the ¹³¹I-treated patients compared to the general population. However, there was a small but significant increase in thyroid cancer deaths (SMR 3.94. CI: 2.52–5.86) in the ¹³¹I-treated patients [42]. Patients who died from thyroid cancer were more likely to have had toxic nodular goiter, suggesting that the increased risk in thyroid cancer might be related to nodular goiter itself and not to RAI.

Population-based studies have found an increased risk in CVD and all-cause mortality in patients with hyperthyroidism treated with ¹³¹I when compared to mortality estimates in the general population [43, 44]. A major limitation in these studies is the inability to differentiate the contribution of the RAI treatment itself to the increased mortality which could be solely explained by hyperthyroidism.

Appearance of Graves-like disease after RAI for TMNG or AFTN has been repeatedly reported. Its occurrence is rare between 1 and 4 % [45, 46]. It usually manifests 3–6 months after RAI with elevation of thyroid hormone levels, appearance of thyrotropin receptor antibodies (TRAB), and a thyroid scan showing diffuse radioiodine uptake.

Thyroglobulin, a protein synthesized solely by follicular cells in the thyroid gland, is released to the systemic circulation after RAI. Therefore, it is thought that an increase in thyroid antigens following RAI may stimulate an immune response toward the TSH receptor.

In a study evaluating the risk to develop Graves’ disease after RAI, the phenotype occurred more commonly for TMNG than for toxic adenoma with rates of 2 % and 0.3 %, respectively, but none of those with toxic nodular goiter that didn’t receive ¹³¹I developed the disease [46]. This finding suggests that RAI therapy induces the thyroid autoimmune response. If a patient with TMNG or toxic adenoma develops recurrence of hyperthyroidism months after RAI therapy, it is much more likely to be from recurrence of autonomy than Graves’ disease. However, we recommend getting a thyroid ¹²¹I uptake and scan, and if there is diffuse uptake throughout the gland, Graves’ disease is more likely, and treatment with ATDs or retreatment with RAI should be considered.

The thionamide compounds available in the United States are methimazole (MMI) and propylthiouracil (PTU). Carbimazole (CBZ) is another thionamide available and commonly used in some European and Asian countries. These compounds alleviate hyperthyroidism by inhibiting thyroid hormone synthesis. They inhibit the oxidation from iodide to iodine and iodine organification catalyzed by thyroperoxidase, a necessary step for the incorporation of iodine into thyroglobulin. Thionamides also inhibit coupling of iodotyrosines and alter the structure of thyroglobulin [47]. Carbimazole is metabolized to methimazole in serum. Propylthiouracil, but not methimazole or carbimazole, inhibits the conversion from T4 to T3 in extrathyroidal tissues.

ATDs control hyperthyroidism but don’t cause remission in toxic nodular goiter. After 12 months of therapy with ATDs, 95 % of patients with TMNG have recurrence of hyperthyroidism when ATDs are discontinued [48]. If ATDs are chosen as the main treatment, lifelong therapy will be required. Accordingly, surgery, radioactive iodine, or other ablative therapies are usually preferred over ATDs in the treatment of TMNG and AFTN (see Table 8.1). A study evaluating the effects of long-term therapy with methimazole in diffuse toxic goiter compared to RAI showed that methimazole therapy for 10 years is overall safe. Euthyroidism was achieved in 93 % of patients on MMI [49]. There were more thyroid test abnormalities at follow-up in the group that received RAI. However, there was a high number loss to follow up over all.

Nevertheless, long-term therapy with ATDs can be considered in elderly individuals with cardiac disease or other significant comorbidities when the risk for radioactive iodine or surgery is high. This is of particular importance for TMNG, because other therapeutic modalities to be discussed later, such as radiofrequency or thermal ablation, are effective in toxic adenomas but less so in TMNG.

Allergic reactions such as pruritus, rash, urticaria, and arthralgias occur in 5 % of people taking these medications and are the most common side effects. Agranulocytosis, polyarthritis, vasculitis, and hepatitis are rare but serious side effects. Agranulocytosis, which is an idiosyncratic reaction, occurs in 0.2–0.5 % with MMI, CBZ, or PTU [50]. Polyarthritis, vasculitis, and fulminant hepatitis are more commonly reported with PTU than MMI (frequency <1 %) [50]. Fulminant hepatitis occurs in 1:10,000 adults on PTU and is more common in children [26]. Liver dysfunction can also occur with MMI and is usually a cholestatic pattern [51]. Given the concern of significant hepatitis with PTU associated with deaths and liver transplantation, in most circumstances, MMI and CBZ are the first-line drug therapies for hyperthyroidism.

Radiofrequency ablation or radiofrequency thermal ablation (RFA) is the most utilized of the ablative therapies. Its use is based on the principle that ultrasound-based energy delivery into the thyroid tissue will raise the local temperature to about 101–105°C which will lead to local thrombosis followed by ischemia and fibrosis and subsequent shrinkage of the treated tissue volume (see Fig. 8.1). The needles employed are 14–18 G, some allowing further deployment of one to four expandable hooks that are then making contact with multiple portions of the targeted nodule. The procedure in all cases is performed under continuous ultrasound guidance. There are at least two techniques in practice: fixed-needle technique and “moving-shot” technique which are distinguished by the degree of manipulating the needle during the procedure. The energy delivered per nodule is a variable between reports, and it has been delivered for most patients in multiple sessions (mean is about two sessions/nodule from combining multiple studies data). The sessions were repeated based on thyroid function and/or nodule size response and performed 1–2 months apart. Local anesthesia with 2 % lidocaine has been employed for the superficial cervical tissue and the thyroid capsule. In most cases the cystic content, if present, is aspirated before the energy is delivered. No significant side effects or hospitalization was noted in these patients. A sensation of heat in the neck was reported by patients. That did not affect the course of the procedure. If pain developed the power was decreased or ablation stopped completely for few seconds. Some reports described repeat biopsies prior to procedure to ensure the benign character of the treated lesions.