Hyperfunctioning Thyroid Nodule

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Hyperfunctioning thyroid nodule 

Definition

A hyperfunctioning thyroid nodule is a solitary or dominant thyroid nodule that produces thyroid hormone independent of TSH (thyroid-stimulating hormone) control. These nodules may cause subclinical or overt thyrotoxicosis and are typically benign in nature.

1. Cause and Etiology

The etiology of hyperfunctioning thyroid nodules is primarily acquired and non-autoimmune. The key contributors include:

  • Somatic activating mutations in:
    • TSH receptor gene (TSHR)
    • GNAS gene (G-protein alpha subunit)

These mutations result in constitutive activation of the TSH receptor, causing continuous stimulation of thyroid follicular cells to produce thyroxine (T4) and triiodothyronine (T3) even in the absence of TSH.

2. Pathophysiology

The pathogenesis involves the following mechanisms:

  • Autonomous nodules escape normal pituitary feedback regulation.
  • Excess hormone production leads to suppression of serum TSH, often suppressing function in the remaining thyroid parenchyma.
  • These nodules are often monoclonal and develop over time.
  • Histologically, they are hypercellular adenomas with reduced colloid and increased follicular activity.

Over time, a single hyperfunctioning nodule can lead to thyrotoxicosis, especially in elderly patients with underlying cardiac comorbidities.

3. Epidemiology

  • Prevalence: Relatively rare cause of hyperthyroidism, accounting for ~5% of cases in iodine-sufficient areas.
  • Age: More common in adults >40 years.
  • Sex: Female predominance (similar to other thyroid disorders).
  • Geographic influence:
    • More prevalent in regions of iodine deficiency (due to TSH-stimulated nodular hyperplasia).
    • Less common in areas with iodine sufficiency or excess.

4. Clinical Presentation

Patients may be:

  • Asymptomatic (subclinical thyrotoxicosis)
  • Have overt hyperthyroid symptoms, including:
    • Weight loss despite normal/increased appetite
    • Heat intolerance
    • Palpitations, tachycardia or atrial fibrillation
    • Tremors, anxiety, insomnia
    • Decreased exercise tolerance
    • Diarrhea or frequent bowel movements
    • Menstrual irregularities

Physical exam may reveal:

  • A palpable thyroid nodule (usually unilateral)
  • Lack of ophthalmopathy (as seen in Graves' disease)
  • No pretibial myxedema

5. Imaging Features

A. Thyroid Scintigraphy (Radionuclide Scan):

  • The most diagnostic imaging modality.
  • Performed with technetium-99m pertechnetate or iodine-123.
  • Shows:
    • "Hot" nodule with increased uptake.
    • Suppression of surrounding thyroid tissue uptake (cold background).
  • Confirms autonomous function.

B. Ultrasound:


  • Hypoechoic to isoechoic solid nodule.
  • May show increased internal vascularity.
  • Margins are typically well defined.
  • No malignant features (microcalcifications, irregular margins, taller-than-wide shape) in most cases.

️ Note: FNA biopsy is often not indicated for "hot" nodules due to their low malignancy risk.

C. Other Imaging:

  • CT/MRI is rarely used except for large goiters or retrosternal extension.

 

6. Treatment

Treatment depends on the size of the nodule, thyroid function, patient age, comorbidities, and preferences.

A. Medical:

  • Beta-blockers for symptom control.
  • Antithyroid drugs (e.g., methimazole) are used temporarily in preparation for definitive treatment.

B. Definitive Therapy:

  1. Radioiodine Ablation (RAI-131):
    • First-line treatment in most patients.
    • Uptake is concentrated in the autonomous nodule.
    • Leads to nodule shrinkage and resolution of hyperthyroidism.
    • May cause hypothyroidism over time.
  2. Surgical Lobectomy:
    • Indications:
      • Large symptomatic nodules
      • Suspicion of malignancy
      • Compressive symptoms (e.g., dysphagia, dyspnea)
      • Pregnancy (in select cases)
    • Offers definitive resolution.
  3. Percutaneous Ethanol Injection Therapy (PEIT):
    • Used in some cases, particularly in Europe.
    • Limited to smaller nodules.

7. Prognosis

  • Generally excellent with appropriate management.
  • Radioiodine therapy is curative in most cases.
  • Malignancy risk in hot nodules is <1%.
  • Without treatment, complications include:
    • Persistent thyrotoxicosis
    • Cardiac arrhythmias (e.g., atrial fibrillation)
    • Osteoporosis
    • Cardiac failure, particularly in the elderly

Summary Table

Feature

Description

Cause

Somatic mutations in the TSHR or GNAS gene

Mechanism

Constitutive TSHR activation → excess T3/T4

Prevalence

5% of hyperthyroidism in iodine-sufficient areas

Symptoms

Hyperthyroidism, nodules, and atrial fibrillation in the elderly

Diagnosis

Thyroid scan shows a hot nodule with suppressed gland

Treatment

RAI-131, surgery, beta-blockers, temporary antithyroid meds

Prognosis

Excellent with treatment; low malignancy risk

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 Case study: A 74-Year-Old Woman with a Neck Mass and Intermittent Palpitations – Hyperfunctioning Thyroid Nodule

Hyperfunctioning Thyroid Nodule

History and Imaging Findings

  1. A 74-year-old woman presented with a palpable neck mass accompanied by intermittent episodes of palpitations.

  2. Laboratory evaluation revealed a significantly suppressed thyroid-stimulating hormone (TSH) level of 0.07 µIU/mL. (Reference range: 0.45–5.44 µIU/mL.)

  3. The images below demonstrate findings from a thyroid ultrasound and a thyroid scintigraphy performed 24 hours after administration of a radioactive tracer.

  4. The 24-hour radioactive iodine uptake (RAIU) for the thyroid gland was measured at 19%, which falls within the normal range of 10–35%.



Quiz:

  1. What is the most prominent finding on the thyroid ultrasound?
    (1) A large mixed cystic and solid left thyroid nodule with predominantly cystic components
    (2) A large mixed cystic and solid right thyroid nodule with predominantly cystic components
    (3) A large, predominantly solid left thyroid nodule
    (4) A large, predominantly solid right thyroid nodule

  2. What is the most notable finding on the thyroid scintigraphy?
    (1) Diffuse and homogeneous uptake in both thyroid lobes
    (2) No appreciable radiotracer uptake in the thyroid
    (3) A single hyperfunctioning left thyroid nodule with suppression of the remaining thyroid tissue

  3. What is the most likely diagnosis in this patient?
    (1) Hyperfunctioning thyroid nodule
    (2) Multinodular goiter
    (3) Graves’ disease
    (4) Thyroiditis
    (5) Thyroid neoplasm

  4. Which of the following is a radiotracer that can be used for thyroid scintigraphy?
    (1) Technetium-99m sulfur colloid
    (2) Tc-99m methyl diphosphonate (MDP)
    (3) Iodine-123 (I-123)
    (4) Indium-111 (In-111)

  5. What is the half-life of Iodine-123?
    (1) 6 hours
    (2) 3.2 hours
    (3) 2.8 days
    (4) 8.02 days
    Explanation: Tc-99m = 6 hours, In-111 = 2.8 days, I-131 = 8.02 days

Findings and Diagnosis

Imaging Findings
Thyroid Ultrasound: A mixed cystic and solid left thyroid nodule with predominantly cystic components.
I-123 Thyroid Scintigraphy: A large left thyroid nodule demonstrating focal radiotracer uptake with peripheral uptake and central photopenia, consistent with a hyperfunctioning nodule with cystic components. The remainder of the thyroid gland shows suppressed activity.

Differential Diagnosis

  • Hyperfunctioning thyroid nodule (toxic adenoma)

  • Multinodular goiter

  • Graves’ disease

  • Thyroid malignancy

Final Diagnosis: Hyperfunctioning thyroid nodule (Toxic adenoma)

Discussion

Hyperfunctioning Thyroid Nodule / Toxic Adenoma

Pathophysiology
Endogenous causes of hyperthyroidism include toxic adenoma, multinodular goiter, Graves’ disease, subacute thyroiditis (including Hashitoxicosis), and extrathyroidal sources such as struma ovarii.
Toxic adenomas arise from focal clonal proliferation of follicular thyroid cells that function independently of TSH regulation.
Approximately 20–80% of toxic adenomas harbor activating mutations in the TSH receptor gene, leading to autonomous thyroid hormone production.

Epidemiology

  • The overall prevalence of hyperthyroidism is approximately 1.3%.

  • It is more common in women than in men, with a ratio of approximately 5:1.

  • Toxic adenomas are more frequently observed in younger women, while Graves’ disease tends to be more common in older females.

Clinical Presentation

  • Palpable neck mass/goiter

  • Weight loss

  • Palpitations

  • Heat intolerance

  • Tremor

  • Anxiety

Imaging Findings

  • I-123 Thyroid Scintigraphy: Focal radiotracer uptake in the adenoma with suppression of the remaining thyroid parenchyma

  • Thyroid Ultrasound: Presence of a well-defined thyroid nodule, which may be solid, cystic, or mixed in composition

Management

  • Symptom control with beta-blockers and methimazole

  • Surgical lobectomy in selected cases

  • Radioactive iodine ablation (I-131 therapy) for definitive treatment

Reference

(1)      Reiners C, Schneider P. Radioiodine therapy of thyroid autonomy. Eur J Nucl Med Mol Imaging. 2002;29 Suppl 2:S471-S478.

(2)      Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.


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