Toxic Multinodular Goiter

Background

• Toxic multinodular goiter is defined as an enlarged thyroid with multiple nodules confirmed by physical exam or ultrasound and with thyroid function tests demonstrating low thyroid-stimulating hormone (TSH) and high free thyroxine (T4) (over hyperthyroidism) or low TSH and normal free T4 (subclinical hyperthyroidism).
• It is more common in older adults, women, and persons in iodine deficient areas.
• The incidence of malignancy among nodules present in a toxic multinodular goiter is similar to that of a nontoxic multinodular goiter.
• Nontoxic multinodular goiter can progress to toxic multinodular goiter over time.

Evaluation

• Suspect the diagnosis in patients with an enlarged thyroid with multiple nodules detected on a physical exam and signs or symptoms of hyperthyroidism.
  • Typical signs and symptoms of hyperthyroidism include fatigue, weight loss, hypertension, nervousness, palpitations, and heat sensitivity.
  • Compressive symptoms from the goiter may occur, such as dysphagia, dyspnea, or neck pressure.
  • In addition to an enlarged thyroid with nodules, physical exam findings may include tachycardia, tremor, and other signs of hyperthyroidism.
• Confirm the diagnosis of toxic multinodular goiter in patients with:
  • enlarged thyroid with multiple nodules confirmed by physical exam or ultrasound
  • thyroid function tests demonstrating low TSH and high free T4 (over hyperthyroidism) or low TSH and normal free T4 (subclinical hyperthyroidism)
  • thyroid scan demonstrating high uptake in multiple discrete areas
• Perform thyroid function tests at the initial evaluation in patients with known or suspected thyroid nodules.
  • Check TSH levels at initial evaluation in all patients with known or suspected thyroid nodules (Strong recommendation).
  • If TSH is low (such as < 0.5 milliunits/L), check free T4 and triiodothyronine (T3) and perform radionuclide scintigraphy (radionuclide scanning) (Strong recommendation).
  • In patients with toxic multinodular goiter, thyroid function tests will show overt or subclinical hyperthyroidism.
    • In overt hyperthyroidism, serum TSH is low (usually < 0.01 milliunits/L) and serum free T4, total or free T3, or both are elevated.
    • In subclinical hyperthyroidism, serum TSH is low and free T4, total or free T3, or both are normal.
• Imaging studies
  • Perform thyroid scintigraphy (using iodine 123 [¹²³I] or ^99mTcO₄^-) if (Strong recommendation):
    • TSH level is low
    • ectopic thyroid tissue or retrosternal goiter is suspected
  • If TSH is low or low-normal (about 0.5-1 milliunits/L) in patients with multinodular goiter, consider radionuclide scintigraphy, and compare to ultrasound images to determine functionality of nodules ≥ 1 cm (Weak recommendation). Evaluate both the nodules that correspond with hyperfunctioning areas on scintigraphy (which do not require fine needle aspiration [FNA]), in addition to nonfunctioning (cold) nodules that meet ultrasound criteria for FNA.

Management

• Management options for hyperthyroidism due to toxic multinodular goiter include radioactive iodine (RAI) therapy, thyroidectomy, or long-term use of low-dose antithyroid medications.
• The optimal treatment approach should take into account clinical and demographic factors, in addition to patient preference.
• RAI therapy
  • RAI therapy is preferred over surgery in patients with:
    • small or medium sized benign goiters
    • history of thyroid surgery or external radiation to the neck
    • advanced age, severe comorbidities, and/or limited life expectancy who are not candidates for surgery
  • Up to 20% of patients may not respond to RAI therapy and require retreatment or surgery.
• Thyroidectomy
  • Thyroidectomy provides the most definitive treatment of toxic multinodular goiter and hyperthyroidism (reported failure rate < 1%).
  • Thyroidectomy is the preferred treatment option for patients with:
    • signs or symptoms of neck compression
    • confirmed or suspected thyroid malignancy
    • large goiter
    • goiter with substernal or retrosternal extension
    • comorbid hyperparathyroidism requiring surgery
  • Manage persistent or recurrent hyperthyroidism following thyroidectomy with RAI therapy (Strong recommendation).
• Antithyroid medications can be used either as pretreatment with RAI therapy or thyroidectomy, or as definitive therapy in select patients.
  • Antithyroid medications as pretreatment prior to definitive therapy
    • Prior to RAI therapy, consider pretreatment with antithyroid medications in (Weak recommendation):
      • older adults (> 60 years old)
      • patients with comorbidities, including cardiovascular disease or severe hyperthyroidism
    • In most cases, young and middle-aged patients usually do not require pretreatment with antithyroid medications prior to RAI therapy. However, some clinicians may choose to pretreat all or most patients, regardless of age or comorbidities.
    • In patients who receive pretreatment with antithyroid medications, consider resuming antithyroid medications 3-7 days after RAI therapy (Weak recommendation).
    • Prior to surgery, render patients euthyroid via pretreatment with antithyroid medications (methimazole), with or without beta-blockers, to reduce risk for precipitating a thyroid storm (Strong recommendation).
  • Consider definitive treatment with long-term use of low-dose antithyroid medications as an alternative to RAI therapy or surgery in select patients with toxic multinodular goiter who are not candidates for more invasive treatment or who prefer this approach.