Toxic Thyroid Adenoma

Background

• Toxic thyroid adenoma is a single follicular thyroid nodule that produces excess thyroid hormones, resulting in subclinical or overt hyperthyroidism.
  • Nonfunctioning thyroid nodules can become autonomous over time due to mutations of genes that regulate thyroid hormone synthesis, progressing to a hormone-secreting toxic thyroid adenoma.
  • Fewer than 5% of all thyroid nodules are reported to be hyperfunctioning (toxic) adenomas.
• Toxic thyroid adenoma is most common in patients with iodine deficiency, especially older adults and women.
• Activating mutations in the thyroid stimulating hormone receptor (TSHR) and the guanine nucleotide-binding protein G subunit alpha (GNAS) have been found in some toxic thyroid adenomas.

Evaluation

• Suspect the diagnosis in patients with localized thyromegaly, a single palpable thyroid nodule, and signs or symptoms of hyperthyroidism.
• Confirm the diagnosis in patients with both of the following:
  • Thyroid function tests showing overt or subclinical hyperthyroidism.
    • In overt hyperthyroidism, serum thyroid-stimulating hormone (TSH) is low or undetectable (usually < 0.01 milliunits/L) and serum free thyroxine (T4), total or free triiodothyronine (T3), or both are elevated.
    • In subclinical hyperthyroidism, serum TSH is low and free T4, total or free T3, or both are normal.
  • Thyroid scintigraphy showing a single active nodule within the thyroid gland with focal uptake in the adenoma and suppressed uptake in surrounding tissue.
• Perform thyroid function tests at initial evaluation in patients with known or suspected thyroid nodules.
  • Check serum TSH level at initial evaluation in all patients with known or suspected thyroid nodule (Strong recommendation).
  • If TSH is low (< 0.5 milliunits/L), check free T4 and T3, and perform scintigraphy (radionuclide scan) (Strong recommendation).
  • In patients with toxic thyroid adenoma, thyroid function tests will show overt or subclinical hyperthyroidism.
  • Anti-TSH receptor antibody (TRAb) testing may help distinguish between Graves disease (which will be TRAb-positive) and toxic thyroid adenoma (which will be TRAb-negative).
• Imaging studies
  • Perform thyroid scintigraphy (using iodine 123 [¹²³I] or ^99mTcO₄^-) in patients with thyroid nodule and decreased TSH levels (Strong recommendation).
  • Uptake patterns in patients with a toxic thyroid adenoma typically show focal uptake in the adenoma and suppressed uptake in surrounding tissue.
  • Perform thyroid ultrasound with survey of the cervical lymph nodes in all patients with known or suspected thyroid nodules (Strong recommendation).
    • In patients with low TSH who have had thyroid scintigraphy suggesting nodularity, perform an ultrasound with survey of the cervical lymph nodes to evaluate both the nodules that correspond with hyperfunctioning areas on scintigraphy (which do not require fine needle aspiration [FNA]), in addition to any nonfunctioning (cold) nodules that meet ultrasound criteria for FNA.
    • Ultrasound with color flow Doppler can be used when radioactive iodine scans are inadvisable, such as during pregnancy and lactation.
• Toxic adenoma and Graves disease can also be distinguished by physical exam, with the former having a sizeable single thyroid nodule and the latter having diffuse enlargement of the thyroid gland.
• Fine needle aspiration biopsy is generally not recommended for nodules functional on scintigraphy (Weak recommendation). Nodules in children are a possible exception due to higher incidence of nodule malignancy. Surgery for removal of both hot and cold nodules is usually performed in children if overt hyperthyroidism is present.

Management

• Common management options for overt hyperthyroidism due to toxic thyroid adenoma include:
  • Radioactive iodine (RAI) therapy
    • Radioactive iodine therapy (also known as radioiodine therapy or RAI therapy) is an alternative to surgery (thyroidectomy) for patients with hyperthyroidism associated with toxic thyroid adenoma.
    • RAI therapy is preferred over surgery in patients with any of the following:
      • small or medium sized benign nodule
      • 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 15% of patients may not respond to RAI therapy and require retreatment or surgery
    • As RAI therapy can cause a temporary worsening of hyperthyroidism, consider pretreatment with beta-blockers in patients (including asymptomatic patients) at increased risk for complications of hyperthyroidism, such as (Weak recommendation):
      • older adults (> 60 years old)
      • patients with comorbidities, including cardiovascular disease or severe hyperthyroidism
  • Thyroidectomy (thyroid surgery)
    • Surgery for toxic thyroid adenoma includes ipsilateral thyroid lobectomy, or isthmusectomy if the adenoma is in the thyroid isthmus (Strong recommendation), and should ideally be performed by a high-volume surgeon (Weak recommendation)
    • Thyroidectomy provides the most definitive treatment of toxic thyroid adenoma and hyperthyroidism (reported failure rate < 1%).
    • Thyroidectomy is the preferred treatment option for patients with any of the following:
      • signs or symptoms of neck compression
      • confirmed or suspected thyroid malignancy
      • large nodule
      • nodule/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 pretreatment with RAI therapy or thyroidectomy, or as definitive therapy in select patients.
  • 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 patients who receive pretreatment with antithyroid medications prior to RAI therapy, consider resuming antithyroid medications 3-7 days after RAI therapy (Weak recommendation).
    • Some clinicians may choose to pretreat all or most patients, regardless of age or comorbidities.
  • Prior to surgery, render patients euthyroid via pretreatment with antithyroid medications (methimazole), with or without beta-blockers, to reduce risk for precipitating thyroid storm (Strong recommendation).
  • Consider definitive treatment with long-term use of low-dose (5-10 mg/day) antithyroid medications as an alternative to RAI therapy or surgery in select patients with toxic thyroid adenoma who are not candidates for more invasive treatment or who prefer this approach (Weak recommendation).
• Other management options:
  • Radiofrequency or laser ablation may be used in select patients with toxic thyroid adenoma who refuse or have contraindications to treatment with radioiodine therapy, surgery, and long-term antithyroid medications.
  • Reserve ethanol ablation for select patients with toxic thyroid adenoma and compressive symptoms who are not candidates for other treatments (Strong recommendation).