Are you sure the patient has toxic thyroid nodules?

Signs and symptoms

The signs and symptoms of toxic multinodular goiter (TMNG) or toxic adenoma (TA) depend on the patient’s age. In patients over 50, common findings are nervousness, heat intolerance, palpitations, insomnia, anxiety, increased sweating, weight loss despite increased appetite, goiter or disfigurement of the neck, atrial fibrillation, fine extremity tremor, muscle weakness, and intolerance of a tight collar. In patients over 70, tachyarrhythmias, atrial fibrillation, and anorexia are more common.

Key laboratory findings
  • Thyrotoxicosis: Suppressed serum thyroid stimulating hormone (TSH) and elevated serum total and free triiodothyronine (T3) and total free thyroxine (FT4) levels

  • T3 toxicosis: Suppressed serum TSH and elevated T3 levels

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  • Subclinical thyrotoxicosis (commonly observed in older patients with TMNG): Low or suppressed serum TSH and normal total and free T3 and total and free T4 levels


Neck ultrasound will reveal one or more nodules. Scintigraphy will confirm increased radionuclide uptake in the nodule(s) concomitant with a decreased uptake in the surrounding extranodular thyroid tissue.

What else could the patient have?

The main differential diagnosis is Graves’ disease. This should be differentiated from the TMNG and TA by the presence of ophthalmopathy or serum thyroid receptor blocking antibodies (TRAb) and anti-peroxidase (TPO) antibodies, and rarely, pretibial myxedema. Scintigraphy will show a diffuse thyroid uptake of 123I in Graves’ disease. The association of Graves’s disease with nodules is common in areas with borderline iodine deficiency.

A hot nodule in a Graves’ disease thyroid gland is a rare condition termed the Marine-Lenhart syndrome. Cold thyroid nodules, characterized by decreased scintigraphic uptake, may be associated with TMNG or TA, or less frequently, Graves’ disease, and may be malignant. Differentiated thyroid cancer presenting as a hot nodule is very rare.

Some differential diagnoses are other, less frequent causes of thyrotoxicosis:

Hashimoto’s thyroiditis

Subacute thyroiditis

Painless thyroiditis

Certain medications (amiodarone, interferon-alpha, lithium)

Struma ovarii


During the first trimester of pregnancy, the serum TSH level is often suppressed due to high beta-hCG levels binding to the TSH receptor. Beta-hCG stimulates the thyroid to synthesize and secrete slightly more T4 and T3 necessary to supply the fetus with thyroid hormone during the first trimester.

Key laboratory and imaging tests

  • Low/suppressed serum TSH concentrations with elevated serum total and free T3 and T4 levels. However, dependent on the autonomous cell mass, T3 toxicosis or subclinical thyrotoxicosis may be found.

  • Presence of palpable or sonographic nodule(s).

  • Increased radionuclide uptake in the nodule(s) concomitant with a decreased uptake in the surrounding extranodular thyroid tissue. The most commonly used isotopes are 99mTc and 123I. The nodules are classified as either “cold”, “functioning”, or “hot” depending on whether they show decreased, normal, or increased uptake on scintigraphy, respectively.

Special considerations:

Urinary iodine excretion can be measured in case of suspected iodine excess.

Ultrasound is the imaging method of choice. Computed tomography (CT) and magnetic resonance imaging (MRI) are not routinely performed.

Other tests that may prove helpful diagnostically

Cardiac evaluation: Echocardiogram, electrocardiogram, and Holter monitoring may be necessary, especially for older patients, due to the risk of asymptomatic atrial fibrillation.

Bone densitometry: This is indicated if the patient has a long history of thyrotoxicosis or other risk factors for osteoporosis, such as in peri- and post-menopausal women.

Molecular analysis for germline TSH-R mutations: A germline mutation in the gene encoding the TSH receptor can cause sporadic or familial nonautoimmune hyperthyroidism. These tests can be obtained in patients with relapsing and/or familial nonautoimmune hyperthyroidism. They offer the possibility for family screening, preclinical diagnosis, ablative treatment, and genetic counseling.

Management and treatment of the disease

Who should be treated?

  • All patients with overt thyrotoxicosis.

  • Patients with subclinical thyrotoxicosis and a solitary hot thyroid nodule should be treated, as most hot nodules with subclinical hyperthyroidism will progress to overt hyperthyroidism.

Antithyroid drugs (ATDs)

These are the first-line treatment in all patients with overt thyrotoxicosis. An ATD can be given usually in combination with beta-blocking drugs (preferably nonselective propranolol). The initial dosage is 30 mg/day of methimazole (MMI) once daily or 300 mg/day of propylthiouracil (PTU) as divided doses every 8 hours. Alternatively or additionally, beta-blocking drugs can be used. Higher dosages of ATDs are associated with more frequent adverse effects (3% to 12%).

Long-term antithyroid drug therapy is normally not indicated, with the exception of special circumstances in which the benefits and risks of long-term ATD therapy are weighed against the very low risk of definitive treatment. Elderly patients with concomitant significant comorbidity may be suitable for long-term ATD therapy and, if undertaken, should be monitored every 3 months.

There are two definitive treatment options available for TMNG and TA: thyroid surgery and radioiodine treatment.

Thyroid surgery

The extent of thyroid surgery is determined by preoperative ultrasound and intraoperative morphological inspection. For patients with TA, hemithyroidectomy is usually adequate. For patients with TMNG, near-total or total thyroidectomy is indicated.

The advantages of surgery (removal of all nodular tissue, rapid and permanent resolution of thyrotoxicosis, and confirmed histological diagnosis) should be weighed against the risk of anesthesia, hospitalization, and other risks of thyroid surgery [vocal cord paralysis (~1%), hypoparathyroidism (<1%) for an experienced endocrine surgeon]. The incidence of postoperative hypothyroidism also depends on the extent of thyroid resection. With large goiters (>80 to 100 grams) and particularly if there is a suspicion of malignancy, thyroid surgery is the treatment of choice.

How should I prepare my patient for surgery?

Patients should be treated with an ATD (preferably methimazole) to achieve euthyroidism prior to surgery. Methimazole should be discontinued at the time of surgery. Beta blockers should be slowly discontinued following surgery.

What is the recommended postoperative care?

  • Serum calcium should be measured to monitor for potential hypoparathyroidism, and replacement with oral calcium and calcitriol can be given if needed. This is usually not necessary after a hemithyroidectomy.

  • Evaluate the patient for laryngeal nerve dysfunction.

  • Thyroid hormone replacement should be initiated after near-total or total thyroidectomies. In patients who undergo a hemithyroidectomy, serum TSH and free T4 should be checked 8-12 weeks after surgery and thyroid hormone replacement initiated only if required. In patients who are started on thyroid hormone replacement, serum TSH measurements should be obtained every few months until stable, then once or twice annually thereafter.

Radioiodine therapy

131I therapy is widely used for the treatment of TNMG and TA. It is highly effective to eradicate thyrotoxicosis and to reduce the size of the nodular goiter. The success rate of individually dosed 131I therapy has been reported to range between 85-100% in TA and up to 90% in TMNG. An average thyroid and/or nodule volume reduction of ~40% can be anticipated. Advantages of radioiodine are its simplicity and, in many countries, its outpatient-based applicability.

Disadvantages include the time to achieve euthyroidism (6 weeks to >3 months), during which time antithyroid drug therapy has to be continued and thyroid function monitored at 3-6 week intervals, and the high incidence of hypothyroidism after treatment. Radioiodine treatment is contraindicated in pregnancy, and contraception is advocated for at least 6 months after receiving 131I therapy. Sufficient radiation should be administered in a single dose. Long-term follow-up for the monitoring of hypothyroidism is mandatory.

How do I prepare my patient for 131I ablation?

Use of beta-blockers (to prevent post-treatment tachyarrhythmia) and methimazole should be considered in patients older than 60 years and in those with cardiovascular disease or severe hyperthyroidism. Beta-blockade by itself can be sufficient for young and middle-aged patients.

What is the necessary follow-up after 131I ablation?

Serum free T4, T3, and TSH levels should be checked 1-2 months after radioiodine therapy. These should be repeated every 2 months until stable, then annually thereafter.

Other treatments

For some patients with toxic thyroid nodules that are not suitable for surgery or radioiodine therapy, there are new promising approaches, specialy minimally invasive procedures:

Percutaneous ethanol injection – This is a relatively uncommon technique in which sterile 95% ethanol is injected into the toxic nodule under ultrasound guidance. A significant reduction has been seen in nodules <30mL before treatment. Advantages include its low cost, safety during pregnancy, and the rare occurrence of hypothyroidism. The major disadvantages are the potential necessity of multiple injections and potential side effects, including hematoma, pain, transient fever, and transitory dysphony.

Percutaneous laser ablation – This is a new treatment modality done under ultrasound guidance in which toxic nodules are thermally ablated. Possible lymphocytic infiltration can occur after ablation and regrowth can occur. It is a minimally invasive procedure, and more studies are needed before it is accepted as an alternative treatment.

Percutaneous radiofrequency thermal ablation – This is also a treatment modality done under ultrasound guidance in which toxic nodules are thermally ablated with an exposure time variable between 5 and 7 min, reaching a maximum temperature variable between 101 and 105°C. However, the difference between radiofrequency thermal ablation and laser ablation is that the last may require more than one session and/or the insertion of multiple optic fibers for treating large nodules. The effectiveness of radiofrequency thermal ablation seems to be slightly superior to laser ablation, and the adverse effects somewhat fewer.

How should I decide between the possible definitive treatment options?

  • Preferred in the elderly; patients with significant comorbidities; patients with prior surgery or scarring in the anterior neck; patients with a small goiter; and those with lack of access to a high-volume thyroid surgeon

  • Contraindicated in pregnancy; lactation; coexisting thyroid cancer; patients unable to comply with radiation safety guidelines; and women planning a pregnancy within 4-6 months of treatment

Thyroid surgery
  • Preferred in patients with signs and symptoms of anterior neck compression; patients with coexisting thyroid nodules in which there is a risk of malignancy; patients with hyperparathyroidism; patients with a large goiter (>80 grams) or those with retrosternal or substernal extension; and patients who require rapid correction of the hyperthyroid state.

  • Contraindicated in patients in which there are significant surgical risks

When should I switch my treatment choice?

In patients with severe or refractory hyperthyroidism, thyroid surgery should be considered. In patients with mild hyperthyroidism following 131I administration, the use of methimazole may be considered until the full effect of the radioiodine is achieved.

The need for additional radioiodine therapy is approximately 20% in patients with toxic multinodular goiter. However, the risk of hypothyroidism is 3% after 1 year and 64% after 24 years, depending on the treatment modality and degree of TSH suppression at the time of radioiodine administration, particularly for patients less than 50 years old.

What’s the Evidence?/References

Bahn, RS, Burch, HB, Cooper, DS, Garber, JR, Greenlee, MC. “Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists”. Endocr Pract. vol. 17. 2011. pp. 456-520. (Guidelines by the American Thyroid Association and American Association of Clinical Endocrinologists on the diagnosis and management of thyrotoxicosis.)

Sandrock, D, Olbricht, T, Emrich, D, Benker, G, Reinwein, D. “Long-term follow-up in patients with autonomous thyroid adenoma”. Acta Endocrinol (Copenh). vol. 128. 1993. pp. 51-5. (Although data on progression from subclinical to overt thyrotoxicosis in patients with multinodular goiter are scarce, this study demonstrates an incidence of 9% to 10% of overt thyrotoxicosis during a follow-up period of 7 to 12 years.)

Holm, LE, Hall, P, Wiklund, K, Lundell, G, Berg, G. “Cancer risk after iodine-131 therapy for hyperthyroidism”. J Natl Cancer Inst. vol. 83. 1991. pp. 1072-7.

Franklyn, JA, Maisonneuve, P, Sheppard, M, Betteridge, J, Boyle, P. “Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study”. Lancet. vol. 353. 1999. pp. 2111-5. (These population-based studies, comprising more than 35,000 patients, treated with 131I have not shown any increased risks of thyroid cancer, leukemia, or other malignancies, reproductive abnormalities, or congenital defects in the offspring.)

Hall, P, Boice, JD, Berg, G, Bjelkengren, G, Ericsson, UB. “Leukaemia incidence after iodine-131 exposure”. Lancet. vol. 340. 1992. pp. 1-4. (This review summarizes the incidence of leukemia following I-131 exposure.)

Kang, AS, Grant, CS, Thompson, GB, van Heerden, JA. “Current treatment of nodular goiter with hyperthyroidism (Plummer's disease): surgery versus radioiodine”. Surgery. vol. 132. 2002. pp. 916-23. (This study shows that surgery versus radioiodine in patients with Plummer's disease are both safe and effective procedures, but surgery is able to reduce neck goiter symptoms more rapidly and definitively.)

Parle, JV, Maisonneuve, P, Sheppard, MC, Boyle, P, Franklyn, JA. “Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study”. Lancet. vol. 358. 2001. pp. 861-5. (The authors describe an increased cardiovascular mortality rate in patients with low serum TSH levels in this 10-year cohort study in the United Kingdom.)

Faggiano, A, Ramundo, V, Assanti, AP, Fonderico, F, Macchia, PE. “Thyroid Nodules Treated with Percutaneous Radiofrequency Thermal Ablation: A Comparative Study”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 4439-4445. (One of the new approaches options to treat toxic nodules. The authors describe not only a significant decrease of the nodule volume, but also as improvement of the thyroid hormone levels.)

Additional references

Baek, JH, Lee, JH, Valcavi, R, Pacella, CM, Rhim, H. “Thermal ablation for benign thyroid nodules: radiofrequency and laser”. Korean J Radiol. vol. 12. 2011. pp. 525-540.

Berghout, A, Wiersinga, WM, Smits, NJ, Touber, JL. “Interrelationships between age, thyroid volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter”. Am J Med. vol. 89. 1990. pp. 602-8.

Bogazzi, F, Miccoli, P, Berti, P, Cosci, C, Brogioni, S. “Preparation with iopanoic acid rapidly controls thyrotoxicosis in patients with amiodarone-induced thyrotoxicosis before thyroidectomy”. Surgery. vol. 132. 2002. pp. 1114-7.

Brix, TH, Hansen, PS, Kyvik, KO, Hegedus, L. “Cigarette smoking and risk of clinically overt thyroid disease: a population-based twin case-control study”. Arch Intern Med. vol. 160. 2000. pp. 661-6.

Cakir, B, Gul, K, Ugras, S, Ersoy, R, Topaloglu, O. “Percutaneous laser ablation of an autonomous thyroid nodule: effects on nodule size and histopathology of the nodule 2 years after the procedure”. Thyroid. vol. 18. 2008. pp. 803-805.

Ferrari, C, Reschini, E, Paracchi, A. “Treatment of the autonomous thyroid nodule: a review”. Eur J Endocrinol. vol. 135. 1996. pp. 383-390.

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Holm, LE, Lundell, G, Israelsson, A, Dahlqvist, I. “Incidence of hypothyroidism occurring long after iodine-131 therapy for hyperthyroidism”. J Nucl Med. vol. 23. 1982. pp. 103-7.

Kang, AS, Grant, CS, Thompson, GB, van Heerden, JA. “Current treatment of nodular goiter with hyperthyroidism (Plummer's disease): surgery versus radioiodine”. Surgery. vol. 132. 2002. pp. 916-23.

Knudsen, N, Bulow, I, Laurberg, P, Ovesen, L, Perrild, H. “Parity is associated with increased thyroid volume solely among smokers in an area with moderate to mild iodine deficiency”. Eur J Endocrinol. vol. 146. 2002. pp. 39-43.

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