Toxic Adenoma: Understanding This Single Thyroid Nodule Condition

Thyroid nodules are very common in the adult population, with a prevalence of 5-7% detected through physical examination and up to 76% through ultrasound. Although most thyroid nodules are benign and asymptomatic, some can lead to significant thyroid dysfunction. (55)

One specific type of thyroid nodule, known as a toxic adenoma, is a leading cause of hyperthyroidism. It results from a single overactive nodule that produces excess thyroid hormone. This article aims to explain toxic adenoma, how it develops, and the available treatment options to help manage this condition effectively.

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What Is a Toxic Adenoma?

A toxic adenoma is a thyroid nodule that autonomously produces excessive thyroid hormone, independent of the regulatory mechanisms of the hypothalamic-pituitary-thyroid (HPT) axis, which usually keeps thyroid hormones within a normal range. This condition typically results in hyperthyroidism, or overactive thyroid, characterized by elevated levels of thyroid hormones in the blood.

In some cases, toxic adenoma may cause subclinical hyperthyroidism, where thyroid-stimulating hormone (TSH) levels are suppressed, but free thyroid hormone concentrations remain within the normal range. 

Toxic adenomas are almost always benign (non-cancerous) nodules (32). 

Toxic adenoma is one of the top three causes of hyperthyroidism, along with Graves' disease and toxic multinodular goiter.

Graves' disease is an autoimmune disease in which thyroid antibodies stimulate excessive production of thyroid hormones by the thyroid gland. Unlike Graves' disease, toxic adenoma does not have an autoimmune component. 

A single hyperfunctioning nodule is responsible for making excess thyroid hormone in a toxic adenoma. In a toxic multinodular goiter, on the other hand, several nodules are making extra thyroid hormone. (49) 

How Does Toxic Adenoma Develop?

According to the American Thyroid Association (ATA), the exact cause of most thyroid nodules is unknown. 

However, several factors have been identified that may increase the risk of developing them, including:

• Assigned female at birth
• Increasing age (about 50% of all people have a thyroid nodule by age 60)
• History of thyroid radiation
• Family history of thyroid disease
• Iodine deficiency
• Iron deficiency (21) 
• Smoking
• Alcohol consumption
• Obesity
• Metabolic syndrome
• Increased levels of insulin-like growth factor-1 (IGF-1)
• Uterine fibroids (54) 

Additionally, genetic mutations have been linked to the development of thyroid adenomas. Mutations in the TSH receptor (TSHR) and G protein (GNAS) genes are the most commonly found in toxic thyroid adenomas. These mutations cause aberrant activation of signaling pathways that regulate thyroid hormone production, leading to continuous, unregulated hormone synthesis characteristic of toxic adenomas. (27, 32)

Symptoms of Toxic Adenoma

Toxic adenomas will cause symptoms of hyperthyroidism, including: 

• Heart palpitations
• Heat intolerance
• Increased sweating 
• Anxiety, irritability, and nervousness
• Shakiness and tremors
• Weight loss despite increased appetite
• Diarrhea (loose, frequent bowel movements)
• Fatigue
• Insomnia (difficulty falling or staying asleep)
• Hair loss
• Menstrual irregularities (light or infrequent menstrual periods)
• Infertility

In some cases, thyroid nodules can grow large enough to cause a goiter (an enlargement of the thyroid gland). This may result in a visible lump in the neck and obstructive symptoms such as:

• A sensation of fullness or a lump in the throat
• Neck pain
• Difficulty swallowing or breathing
• Changes in voice

Diagnosing Toxic Adenoma

Thyroid adenoma should be suspected in patients with localized enlargement of the thyroid gland, a single palpable nodule, and/or signs and symptoms of hyperthyroidism.

Step 1: Physical Examination

Patients may present to their doctor with concerns about a visible or enlarged thyroid gland, or a thyroid nodule may be incidentally discovered during a routine physical exam.

When a nodule is suspected, doctors should inquire about (22):

• Hyperthyroid symptoms
• Compressive symptoms 
• Personal history of thyroid disease or radiation exposure
• Family history of thyroid disease

Step 2: Thyroid Function Tests

Perform thyroid function tests at the initial evaluation in patients with known or suspected thyroid nodules:

• TSH
• Free thyroxine (fT4)
• Free triiodothyronine (fT3)

Thyroid function tests will show overt or subclinical hyperthyroidism in patients with toxic adenoma:

• Overt Hyperthyroidism: serum TSH is low or undetectable, and serum fT4 and fT3 are elevated (39) 
• Subclinical Hyperthyroidism: serum TSH is low, and fT4 and fT3 are normal (38) 

Anti-TSH receptor antibody (TRAb) (also called thyroid-stimulating immunoglobulin, or TSI) can help distinguish between Graves' disease (TRAb-positive) and toxic adenoma (TRAb-negative) as causes of hyperthyroidism (28). 

Step 3: Imaging

Various imaging modalities are recommended to assess thyroid anatomy and function in diagnosing thyroid nodules:

• Thyroid Ultrasound is a non-invasive procedure that uses high-frequency sound waves to create detailed images of the thyroid gland. It helps detect the presence, size, location, and characteristics of thyroid nodules, differentiate between solid and cystic nodules, and identify suspicious features suggestive of malignancy. (23) 
• Radionuclide Iodine Uptake Test (Scintigraphy) is a functional imaging test that uses a small amount of radioactive iodine (preferred) or technetium to assess thyroid activity. In the case of toxic adenoma, the scan will show a single "hot" area with increased uptake, indicating a hyperfunctioning nodule. (23) 

Step 4: Fine-Needle Aspiration (FNA) Biopsy

FNA biopsy is a minimally invasive procedure in which a thin, hollow needle is used to extract a small sample of cells from a thyroid nodule for microscopic examination to evaluate for malignancy. 

FNA is generally not indicated for toxic thyroid adenomas due to their low risk for malignancy but may be performed if the nodule has suspicious features, such as: 

• Irregular borders
• Microcalcifications
• Hypoechogenicity (appears darker on ultrasound than the surrounding tissue)
• Larger than 1 cm in diameter

Treatment Options for Toxic Adenoma

The rapid and lasting reversal of hyperthyroidism is the goal of treatment for toxic adenoma. This is typically achieved with radioactive iodine (RAI) therapy, surgery, and antithyroid medications. (36) 

Radioactive Iodine Therapy

RAI therapy treats hyperthyroidism by targeting the thyroid gland's ability to absorb iodine, which is required for thyroid hormone synthesis. In RAI therapy, a small dose of radioactive iodine-131 is administered orally. Once inside the thyroid cells, the iodine-131 emits beta radiation to destroy overactive thyroid tissue and restore normal thyroid function. (33) 

RAI therapy is the preferred treatment modality in patients with (22, 36): 

• Advanced age
• Severe comorbidities
• History of neck surgery or scarring in the neck
• Small or medium-sized benign nodule
• Sufficient RAI uptake for successful therapy

Toxic adenoma cure rates with RAI therapy have been reported as high as 95%.

Surgical Removal (Thyroidectomy)

Thyroidectomy is the surgical removal of part or all of the thyroid gland. It is the most definitive treatment option for toxic adenoma and hyperthyroidism, producing nearly 100% cure rates (failure rate is less than 1% for toxic adenoma). (36)  

Surgery is the preferred treatment option for patients with (36):

• Signs or symptoms of neck compression
• Large nodule
• Comorbid hyperparathyroidism requiring surgery
• Suspected thyroid cancer

The rate of hypothyroidism (underactive thyroid) following lobectomy (removal of one lobe of the thyroid gland) varies from 2-3%. Other risks associated with surgery include (36):  

• Bleeding
• Hypocalcemia (low serum calcium levels)
• Injury to the vocal cords

Antithyroid Medications

Antithyroid medications, including methimazole and propylthiouracil, inhibit the production of thyroid hormones. They are typically used as a pretreatment for RAI therapy or thyroidectomy to normalize thyroid hormones and alleviate hyperthyroid symptoms (36). 

Long-term, low-dose treatment with antithyroid medications might be considered in the following scenarios (36): 

• Older patients with decreased life expectancy
• Pregnancy
• Patients who are poor candidates for other treatment options
• Patients who prefer this option over RAI therapy or surgery 

Prognosis and Long-Term Management

In most cases, thyroid adenomas have an excellent prognosis when treated appropriately. 

Complications associated with untreated toxic adenomas are related to excess thyroid hormone and include: 

• Heart problems: atrial fibrillation, stroke, and heart failure
• Brittle bones (osteoporosis) and increased fracture risk
• Thyroid storm is a life-threatening complication characterized by a sudden and severe worsening of symptoms, including high fever, rapid heart rate, agitation, and potentially multi-organ failure.

Patients with a history of toxic adenoma need to stay up-to-date on routine follow-ups with their doctors for continued screening of possible recurrence and the management of any side effects of treatment. 

Additionally, while the risk of malignancy in toxic adenomas is generally low, there is a small but notable increased risk of developing thyroid cancer. Therefore, continued surveillance through blood testing and imaging for suspicious nodules is recommended.

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Key Takeaways

• Toxic adenoma is a single overactive thyroid nodule and a leading cause of hyperthyroidism. 
• Patients should see their doctor if they experience symptoms of hyperthyroidism, notice a lump in their neck, or have a personal or family history of thyroid disease. 
• Toxic adenoma is a highly manageable condition with a good prognosis for return to normal thyroid function when diagnosed early and managed with individualized treatment.