Toxic Multinodular Goitre

Overview

Toxic Multinodular Goitre (TMNG) is the second most common cause of hyperthyroidism caused by a long-standing goitre and/or iodine deficiency which results in an increased risk of mutation and consequent TSH-independent autonomic function of thyroid nodules to produce excess thyroid hormones. Common clinical manifestations include hyperthyroidism and a painless thyroid goitre with palpable nodules. The disease can be addressed and treated early on, with a good prognosis and clinical outcomes.

Aetiology and Risk Factors

There are two main known causes for TMNG: ¹

• Long-standing goitres that acquire autonomously functioning nodules due to somatic mutations or chronic stimuli 
• Chronic Iodine deficiency: TMNG is more prevalent in iodine-deficient regions as iodine deficiency contributes to formation of thyroid goitres

Pathophysiology

Toxic multinodular goitre typically emerges from nontoxic multinodular goitres over a longer period of time. Below are two main mechanisms for the disease: ^{1, 2}

1. Chronic iodine deficiency:
   1. Results in decreased thyroid hormone production and consequent increased TRH secretion from the hypothalamus
   2. Persistent TSH stimulation of the thyroid gland results in hyperplasia of thyroid tissue -> production of nodules and proliferation of existing ones
   3. Overall leading to NON-TOXIC multinodular goitre  (meaning normal thyroid hormone levels and functions overall in the body)

2. Long-standing multinodular goitres:
   1. Increased risk of multiple somatic mutations of TSH receptors
   2. Leading to a gain of function in the TSH receptors 
   3. Autonomous functioning of thyroid nodules independent of pituitary TSH feedback
   4. Overall results in toxic multinodular goitre due to the increased release of both T3 and T4 hormones and subsequent hyperthyroidism 

Clinical Manifestations

• Most common: Symptoms of hyperthyroidism
  • Heat intolerance, Sweating
  • Palpitations and Tachycardia (including atrial fibrillation)
  • Tremors
  • Weight loss
  • Fatigue
• May have compressive symptoms (dysphagia, hoarseness) if goitre large.
• Clinical examination: ^1,3
  • Painless, long-standing thyroid Goitre with multiple palpable nodules
  • Fine tremors
  • Hyperreflexia
  • Tachycardia

Diagnosis 

The diagnosis of TMG is made through both clinical evaluations and lab investigations

• Thyroid function tests:
  • Suppressed TSH: Due to autonomic functioning of thyroid nodules independent of TSH feedback
  • Elevated T3 and T4: Due to gain of function mutation in TSH receptor 
• Thyroid Ultrasound with doppler:
  • Determines number of thyroid nodules
  • Doppler done to determine vascularity (screening for thyroid cancer)
• Thyroid scintigraphy: Radionuclide thyroid scan done when TSH is low
  • Increased “Patchy” radioiodine uptake by multiple hyperfunctioning nodules (hot areas)
  • Decreased uptake in surrounding thyroid tissue
  • Helpful in differentiating causes of hyperthyroidism

Differential Diagnoses of hyperthyroidism

Treatment

The goals of treatment are to control the hyperthyroidism/thyrotoxicosis and explore possible definitive therapies

1. Symptomatic control for hyperthyroidism:
   1. Beta-blockers: For tremor/palpitations, tachycardia and to prevent cardiac arrhythmias
      1. Propranolol or atenolol 
   2. Antithyroid drugs (Thionamides): To achieve euthyroid state and control before definitive treatment
      1. MOA: Inhibit thyroid peroxidase which in turn decreases thyroid hormone synthesis (T3 and T4)
      2. Drugs: Propylthiouracil or methimazole
2. Definitive therapies:
   1. Radioactive iodine ablation (RIA)
      1. Indications: First line for most patients with TMG
      2. MOA: Effectively shrinks thyroid goitre and address hyperthyroidism
      3. Side note: Complications can include hypothyroidism, development of secondary cancers, thyroid storm
   2. Surgery: Total or near-total thyroidectomy
      1. Indications: Preferred if very large goitres
      2. Provides symptomatic relief in many patients
      3. Removal of thyroid gland will require life-long hormone replacement

Complications and Prognosis

• Some cases of TMG do not require treatment if they are asymptomatic or demonstrate subclinical hyperthyroidism (low TSH but normal T3 and T4)
• If treated, overall, TMG has a good prognosis
• Some complication may include:
  • Progression of hyperthyroidism leading to: Osteoporosis, tachycardia, arrhythmias, thyrotoxicosis
  • Increased risk of thyroid malignancy (low)

References 

1. Khalid N, Can AS. Plummer Disease. [Updated 2023 Mar 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK565856/
2. Holzapfel HP, Führer D, Wonerow P, Weinland G, Scherbaum WA, Paschke R. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab. 1997;82(12):4229-4233. doi:10.1210/jcem.82.12.4441
3. Campbell K, Doogue M. Evaluating and managing patients with thyrotoxicosis. Aust Fam Physician. 2012;41(8):564–72. Available from: https://www.racgp.org.au/afp/2012/august/evaluating-and-managing-patients-with-thyrotoxicos
4. Venkatesh N, Ho JT. Investigating thyroid nodules. Aust Prescr 2021;44:200-4.https://doi.org/10.18773/austprescr.2021.055
5. Croker EE, McGrath SA, Rowe CW. Thyroid disease: Using diagnostic tools effectively. Aust J Gen Pract. 2021;50(1–2):16–21. doi:10.31128/AJGP-10-20-5693. Available from: https://www1.racgp.org.au/ajgp/2021/january-february/thyroid-disease-using-diagnostic-tools-effectively
6. Hughes K, Eastman C. Thyroid disease: Long-term management of hyperthyroidism and hypothyroidism. Aust J Gen Pract. 2021;50(1–2):36–42. doi:10.31128/AJGP-09-20-5653. Available from: https://www1.racgp.org.au/ajgp/2021/january-february/thyroid-disease-long-term-management-of-hyperthyro