Toxic Nodular Goiter Treatment & Management

The optimal therapy for treatment of toxic nodular goiter (TNG) remains controversial. Unlike Graves disease, TNG is not an autoimmune disease and rarely, if ever, remits.^[8] Therefore, patients who have autonomously functioning nodules should be treated definitely with radioactive iodine or surgery. The American Thyroid Association and American Association of Clinical Endocrinologists have released guidelines for the management of hyperthyroid and other causes of thyrotoxicosis, including the use of radioactive iodine or surgery to treat toxic multinodular goiter.^[9]

Patients with subclinical hyperthyroidism should be monitored closely for overt disease. Some suggest that elderly patients, women with osteopenia, and patients with risk factors for atrial fibrillation should be treated, even those who have subclinical disease.

• Na¹³¹ I treatment - In the United States and Europe, radioactive iodine is considered the treatment of choice for TNG. Except for pregnancy, there are no absolute contraindications to radioiodine therapy.

  • Much debate exists regarding optimal dosing of radioactive iodine. Patients with TNG tend to have less uptake than do patients with Graves disease; therefore, they are generally considered to need higher doses of Na¹³¹ I. However, studies by Allahabadia and colleagues suggest that fixed doses of radioiodine do not demonstrate any difference in response in these 2 groups of patients (using a fixed dose of 370 megabecquerels).^[10]
  • A single dose of radioiodine therapy has a success rate of 85-100% in patients with TNG. Radioiodine therapy may reduce the size of the goiter by up to 40%.^[11]
  • Failure of initial treatment with radioactive iodine has been associated with increased goiter size and higher T3 and free T4 levels, which suggests that these factors may present a need for higher doses of Na¹³¹ I.
  • A positive correlation exists between radiation dose to the thyroid and decrease in thyroid volume. In patients with uptake of less than 20%, pretreatment with lithium, PTU, or recombinant TSH can increase the effectiveness of iodine uptake and treatment.^{[12, 13]} This treatment may be valuable in elderly patients in whom surgery is considered high risk.
  • Complications
    • Hypothyroidism occurs in 10-20% of patients; this is similar to the incidence rate after surgery and is substantially less than in the treatment of Graves disease.^[14]
    • Tracheal compression due to thyroid swelling after radiation therapy is no longer thought to be a risk.^[15]
    • Mild thyrotoxic symptoms after radioiodine occur in about one-third of patients, and about 4% of patients develop a clinically significant radiation-induced thyroiditis. These patients should be treated symptomatically with beta blockers.
    • Elderly patients may have exacerbation of congestive heart failure and atrial fibrillation. Pretreat elderly patients with antithyroid drugs.
    • Thyroid storm is a rare complication, particularly in patients with rapidly enlarging goiters or high total T3 levels. Patients with these conditions should receive pretreatment with antithyroid drugs.
• Pharmacotherapy - Antithyroid drugs and beta blockers are used for short courses in the treatment of TNG; they are important in rendering patients euthyroid in preparation for radioiodine or surgery and in treating hyperthyroidism while awaiting full clinical response to radioiodine. Patients with subclinical disease at high risk of complications (eg, atrial fibrillation, osteopenia) may be given a trial of low dose methimazole (5-15 mg/d) or beta blockers and should be monitored for a change in symptoms or for disease progression that requires definitive treatment.

  • Thioamides - The role of therapy with thioamides (eg, PTU, methimazole) is to achieve euthyroidism prior to definitive treatment with either surgery or radioiodine therapy. Data suggest that pretreated patients have decreased response to radioiodine. The general recommendation is to stop antithyroid agents at least 4 days prior to radioiodine therapy in order to maximize the radioiodine effect.
    • Antithyroid drugs are often administered for 2-8 weeks before radioiodine therapy in order to avoid the risk of precipitating thyroid storm. Although many physicians no longer consider this treatment necessary, the general consensus is that elderly patients or patients with high risk of cardiac complications should receive this treatment.
    • Antithyroid drugs and beta blockers have side effects, the most common being pruritic rash, fever, gastrointestinal upset, and arthralgias. More serious potential side effects include agranulocytosis, drug-induced lupus and other forms of vasculitis, and liver damage.
  • The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery.
    • The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.
    • The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).
    • PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert)^[16] :
      • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.
      • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
      • For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.
      • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available.
      • Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.
  • Beta-adrenergic receptor antagonists - These drugs remain useful in the treatment of symptoms of thyrotoxicosis; they may be used alone in patients with mild thyrotoxicosis or in conjunction with thioamides for treatment of more severe disease.
    • Propranolol, a nonselective beta blocker, may help to lower the heart rate, control tremor, reduce excessive sweating, and alleviate anxiety. Propranolol is also known to reduce the conversion of T4 to T3.
    • In patients with underlying asthma, beta-1 selective antagonists, such as atenolol or metoprolol, would be safer options.
    • In patients with contraindications to beta blockers (eg, moderate to severe asthma), calcium channel antagonists (eg, diltiazem) may be used to help control the heart rate.

Surgical therapy is usually reserved for young individuals, patients with 1 or more large nodules or with obstructive symptoms, patients with dominant nonfunctioning or suspicious nodules, patients who are pregnant, patients in whom radioiodine therapy has failed, or patients who require a rapid resolution of the thyrotoxic state.

• Subtotal thyroidectomy results in rapid cure of hyperthyroidism in 90% of patients and allows for rapid relief of compressive symptoms.
• Restoring euthyroidism prior to surgery is preferable.
• Complications of surgery include the following:

  • In patients who are treated surgically, the frequency of hypothyroidism is similar to that found in patients treated with radioiodine (15-25%).
  • Complications include permanent vocal cord paralysis (2.3%), permanent hypoparathyroidism (0.5%), temporary hypoparathyroidism (2.5%), and significant postoperative bleeding (1.4%).
  • Other postoperative complications include tracheostomy, wound infection, wound hematoma, myocardial infarction, atrial fibrillation, and stroke.
  • The mortality rate is almost zero.

• Consult an endocrinologist for hyperthyroidism that has not responded to medical therapy or if other comorbid conditions are complicating the patient's condition. Refer patients with amiodarone-associated hyperthyroidism to an endocrinologist. In a multinodular goiter with cold and hot areas on thyroid scan findings, fine-needle aspiration may be required to determine the histologic nature of the cold lesions.
• Consult an endocrine surgeon if medical therapy fails to maintain the euthyroid state, if compromise of the trachea is noted on imaging studies, or if the patient requests surgical removal.
• Consult a thoracic surgeon in the case of a toxic substernal goiter, because the surgeon may be helpful in further diagnostic and therapeutic measures.

• Activity should be restricted to maintain a heart rate of less than 90 beats per minute.