Toxic Multinodular Goiter: A Common Hyperthyroid Disorder

Hyperthyroidism affects approximately 1.2% of the United States population. There are many different causes of hyperthyroidism, with toxic multinodular goiter (TMNG) being among the top three. As people age, thyroid nodules are more likely to develop; in some cases, these nodules become hyperactive, leading to TMNG.

This article will explore TMNG: how it develops, its effects on thyroid health, and how it is managed, providing a deeper understanding of this condition and its role in hyperthyroidism.

[signup]

What Is Toxic Multinodular Goiter?

A healthy functioning thyroid gland makes thyroid hormones, thyroxine (T4) and triiodothyronine (T3), as governed by the hypothalamic-pituitary-thyroid (HPT) axis. This signaling network between the brain and the thyroid maintains circulating thyroid hormone within an optimal range.

TMNG, also called Plummer disease, is the second leading cause of hyperthyroidism when multiple nodules (typically non-cancerous growths) in the thyroid gland make too much thyroid hormone.

A thyroid goiter is an enlargement of the thyroid gland, which can occur in a thyroid producing too little (hypothyroid), too much (hyperthyroid), or normal amounts (euthyroid) of thyroid hormone. The "toxic" aspect of TMNG differentiates it from a simple goiter due to the overproduction of thyroid hormone (17).

How Does Toxic Multinodular Goiter Develop?

According to the American Thyroid Association (ATA), we don't know what causes most thyroid nodules despite occurring in half of all people by age 60. Chronic thyroid gland inflammation, as seen in conditions like Hashimoto's thyroiditis (the most common cause of hypothyroidism caused by an autoimmune attack against the thyroid gland) and iodine deficiency are common causes of thyroid nodules.

The thyroid requires iodine for thyroid hormone synthesis. When iodine deficiency occurs, the thyroid compensates by making more cells (a process called hyperplasia) to prevent hypothyroidism from developing.

Unfortunately, this increased cell division raises the chances of mutations occurring in individual cells. This includes mutations in the thyroid-stimulating hormone (TSH) receptor, which is essential for regulating thyroid function through the HPT axis. (32)

Over time, these mutated cells accumulate and form multiple "toxic" nodules within the thyroid gland that function autonomously (independently from the regulatory signals of TSH) and produce excess amounts of thyroid hormones (32).

Symptoms of Toxic Multinodular Goiter

Most patients with TMNG present with the symptoms typical of hyperthyroidism, including:

Heart palpitations
Excessive sweating
Irritability, anxiety, and nervousness
Insomnia
Unintentional weight loss, despite increased hunger
Diarrhea (frequent, loose bowel movements)
Fatigue
Muscle weakness
Tremor
Thinning skin
Hair loss
Brittle nails
Menstrual irregularities (periods that are infrequent and lighter than usual)
Infertility

A physical exam will often reveal a palpable, enlarged, and nodular thyroid gland due to the presence of multiple nodules.

A significantly enlarged goiter can cause pressure-related symptoms from mechanical obstruction of surrounding neck structures, such as:

Difficulty swallowing
Shortness of breath
Hoarseness of voice

In general, patients with TMNG have fewer signs and symptoms than those with Graves' disease (the most common type of hyperthyroidism caused by autoimmunity against the thyroid gland) (42).

Risk Factors and Causes

TMNG accounts for 15-30% of cases of hyperthyroidism in the United States. While TMNG can occur in anyone, you are more likely to be affected if you are a person assigned female at birth (AFAB) over the age of 40 with a family history of thyroid nodules or goiter (23, 47).

In fact, thyroid nodules are about four times more common in people AFAB than people assigned male at birth (AMAB).

Toxic nodular goiter accounts for about 58% of cases of hyperthyroidism in areas of endemic iodine deficiency. In the United States, people living in the Great Lakes and Mississippi Valley regions are at the highest risk of iodine deficiency due to iodine-depleted soil.

In patients with an underlying nontoxic multinodular goiter, administering iodine as a dietary supplement, iodinated contrast agent, or iodinated medication (such as amiodarone) may induce hyperthyroidism. This is a phenomenon called the Jod-Basedow effect. (34)

Diagnosis of Toxic Multinodular Goiter

The diagnosis of TMNG is made based on the presence of multiple thyroid nodules along with biochemical evidence of hyperthyroidism.

Step 1: Physical Examination and Medical History

TMNG should be suspected in patients with an enlarged thyroid gland, multiple nodules on physical exam, and signs or symptoms of hyperthyroidism (24).

In taking a comprehensive patient history, doctors should ask about (24):

Patient age
Family history of thyroid disease
Personal history of nontoxic multinodular goiter or other thyroid disease
Smoking history
History of living in iodine-deficient areas
Use of iodine-containing medications and supplements
Symptoms of hyperthyroidism
Obstructive symptoms of goiter

Step 2: Blood Tests

Thyroid function tests should be ordered during the initial evaluation in patients with known or suspected thyroid nodules:

For patients with TMNG, thyroid function tests will show overt or subclinical hyperthyroidism:

In overt hyperthyroidism, TSH is low, and free T4 and/and free T3 are elevated
In subclinical hyperthyroidism, TSH is low, and free T4 and free T3 are normal

Step 3: Imaging Studies

A diagnostic thyroid/neck ultrasound should be performed in all patients with a suspected thyroid nodule or goiter. Ultrasound can provide valuable information, including:

Thyroid gland size
Size and location of nodule(s)
Nodule composition (e.g., solid or cystic)
Presence or absence of cervical lymphadenopathy (enlarged lymph nodes in the neck (18)

In patients with low TSH, a radionuclide thyroid uptake scan (thyroid scintigraphy) should also be performed to determine whether the nodule is hyperfunctioning ("hot"), indistinguishable from normal thyroid tissue ("warm"), or nonfunctioning ("cold") (18).

This nuclear medicine imaging procedure evaluates the thyroid gland's function and structure using a small amount of radioactive iodine (preferred) or technetium.

In patients with TMNG, scan results reveal patchy uptake with multiple "hot" areas of increased tracer uptake (32).

Treatment Options for Toxic Multinodular Goiter

The ATA recommends patients with TMNG be treated definitively with radioactive iodine (RAI) therapy, thyroidectomy, or in select cases, with long-term, low-dose antithyroid medications (18).

Antithyroid Medications

Antithyroid medications, such as methimazole, block the formation of thyroid hormone by the thyroid gland to treat hyperthyroidism and bring thyroid hormones back into normal range.

Antithyroid medications are not recommended as long-term treatment for most patients with TMNG and overt hyperthyroidism, but they can be used short-term as patients are preparing for other curative interventions (32).

Antithyroid medications can be considered as definitive treatment for TMNG in the following scenarios:

Subclinical hyperthyroidism
Patients prefer to avoid exposure to radioactivity and are not opposed to lifelong antithyroid medication therapy
Advanced age
Increased likelihood of surgical complications
Contraindications to ablative therapy (37)

Radioactive Iodine Therapy

RAI therapy involves the administration of radioactive iodine, which selectively targets hyperfunctioning thyroid tissue (such as in nodules) to destroy and reduce its activity permanently. Treatment goals are to ablate autonomously functioning nodules, restore thyroid function tests to within an optimal range, and reduce goiter size.

RAI therapy is indicated for patients with:

Small or medium-sized benign goiters
History of thyroid surgery or external radiation to the neck
Advanced age or comorbidities that make them poor candidates for surgery (2)

Studies indicate that the success rate of RAI therapy for TMNG ranges from 81-94%. The median time to reach euthyroid status after RAI therapy is typically around 5 weeks, although some patients may take longer (up to 24 months) to stabilize.

RAI therapy not only addresses hyperthyroidism but also significantly reduces thyroid volume by up to 65% of its original volume, making it an effective option to relieve the obstructive symptoms of goiter.

Surgery (Thyroidectomy)

Thyroidectomy is the surgical removal of a part (partial) or all (total) of the thyroid gland.

The benefits of thyroidectomy in treating hyperthyroidism include:

Nearly 100% cure rate
Ability to identify incidental cancers
Ability to quickly achieve euthyroid states (14)

The disadvantages of thyroidectomy include the risks of:

Operative complications
Hypocalcemia (low serum calcium levels)
Vocal cord paralysis
Need for lifelong thyroid hormone replacement (14)

The ATA recommends thyroidectomy for the following patients with TMNG:

Large goiter
Compressive symptoms
Confirmed or suspected thyroid cancer
Comorbid hyperparathyroidism requiring surgery (18)

Managing and Monitoring TMNG

Regardless of the course of treatment decided upon, patients will require close and routine follow-up to monitor TMNG.

For patients managed nonoperatively, regular follow-up exams will include:

Measuring thyroid function tests
Physical exam
Thyroid ultrasound or other imaging techniques to monitor the growth of the thyroid nodules (37)

For patients treated surgically, the ATA recommends the following for monitoring:

Serum calcium (with or without intact parathyroid hormone levels)
Provide oral calcium and vitamin D supplementation as needed
Start thyroid hormone replacement as indicated by thyroid hormone function labs
Measure TSH every 1-2 months until stable, and then annually (37)

Prognosis and Long-Term Outlook

Most patients treated for TMNG have a good prognosis. Early intervention typically leads to effective management of symptoms and prevents complications associated with uncontrolled hyperthyroidism. (32)

Complications of untreated TMNG include:

Cardiovascular Issues: arrhythmias, hypertension, stroke, and heart failure (20)
Muscle and Bone Health: osteoporosis, increased risk of bone fractures, and muscle weakness (19)
Thyroid Storm: A life-threatening condition characterized by an extreme exacerbation of hyperthyroid symptoms, leading to fever, tachycardia, and potential organ failure (45)
Psychological Effects: anxiety, psychosis, and sleep disturbances (28)
Goiter Complications: difficulty swallowing, hoarseness of voice, and airway obstruction (3)

Overall mortality rates are higher in patients with untreated hyperthyroidism due to complications arising from cardiovascular issues and other systemic effects.