Toxic Multinodular Goiter vs. Graves’ Disease

Most of the hyperthyroid patients I see in my practice have Graves’ disease, with toxic multinodular goiter the next most common form of hyperthyroidism.  However, not everyone with hyperthyroidism truly understands their diagnosis, and so I wanted to put together a blog post that differentiates toxic multinodular goiter from Graves’ disease.  In this post I will also discuss the conventional and natural treatment options for toxic multinodular goiter (also known as Plummer’s disease).

What Is Toxic Multinodular Goiter?

Multinodular goiter is the most common of all the disorders of the thyroid gland (1).  As the name implies, this involves a goiter (swelling of the thyroid gland) in the presence of multiple thyroid nodules.  “Toxic” multinodular goiter involves multinodular goiter in the presence of hyperthyroidism, and while many people have a non-toxic multinodular goiter, a large proportion of those with multinodular goiter will eventually develop hyperthyroidism, although this might not occur for a few decades (1).

How Is Toxic Multinodular Goiter Diagnosed?

As for how toxic multinodular goiter is diagnosed, once again, the “toxic” part indicates that the person has hyperthyroidism.  Sometimes the person has a noticeable goiter, while other times the practitioner will need to rely on palpation and/or a thyroid ultrasound.  If the goiter is large enough this can result in symptoms such as dysphagia (difficulty swallowing), cough, and hoarseness.  Similarly, large nodules might be detected through palpation, but a thyroid ultrasound might be indicated.

How Is Graves’ Disease Diagnosed?

I’ve discussed this in great detail in other articles and posts, but essentially Graves’ disease is diagnosed when someone has hyperthyroidism in the presence of either 1) elevated TSH receptor antibodies/thyroid stimulating immunoglobulins, 2) an elevated radioactive iodine uptake test, and/or 3) thyroid eye disease.  A small percentage of people have subclinical Graves’ disease, which is when their thyroid hormone levels are normal, but they have a depressed TSH in the presence of one of the three factors I listed here.

What Causes a Multinodular Goiter?

There are a few different factors that can lead to the development of a multinodular goiter.  Two primary factors are genetics and gender, as there does seem to be a genetic predisposition for this condition, and it’s more common in women.  But there are also some secondary factors, including the following (1):

• Elevated TSH (induced by iodine deficiency, goitrogens, inborn errors of thyroid hormone synthesis). It’s important to understand that having a goiter and/or nodules is common with both hypothyroidism and hyperthyroidism.  An elevated TSH is usually indicative of low or depressed thyroid hormone levels, which can be caused by an iodine deficiency, goitrogenic substances (which can inhibit thyroid function), and/or other factors that can disrupt thyroid hormone production.  Many people with an elevated TSH have Hashimoto’s thyroiditis, which is an autoimmune thyroid condition.  In fact, this is the most common reason why someone has an elevated TSH.
• Smoking, stress, certain drugs. Although one of the studies listed “smoking, stress, and certain drugs” as potential causes, there isn’t a lot of evidence in the research showing that cigarette smoking causes a multinodular goiter, and I couldn’t find a single study showing a correlation between stress and multinodular goiter.
• IGF-1 and other thyroid stimulating factors. In April 2018 I wrote a blog post entitled “Can Insulin Resistance Cause Thyroid Nodules?“, and the answer to this question is “yes!”  Numerous studies show that high amounts of insulin can result in an enlargement of various tissues and organs, including the thyroid gland.  So high insulin levels can be a factor with both a goiter and thyroid nodules.  The insulin-like growth factor (IGF) system plays an important role in regulating normal development and growth of the thyroid and appears to be involved in thyroid cell hyperplasia (2).
• Estrogen dominance/problems with estrogen metabolism. It is well known that estrogen can promote the growth of certain types of cancer cells, but there is evidence that it can also be a potent growth factor for benign and malignant thyroid cells (3) (4).  While having high estrogen levels is an obvious sign of estrogen dominance, normal estrogen levels don’t necessarily rule out estrogen dominance.  First of all, when evaluating blood work, I’ve seen a number of patients have normal, or even low estradiol/estrone levels, but high total estrogens.  Second, if estrogen is normal but progesterone is low, then this is also considered to be a form of estrogen dominance.  Finally, someone can have normal estrogen levels but an unequal distribution of the estrogen metabolites due to problems with phase 2 detoxification (specifically methylation, sulfation, and/or glutathione).

So what happens is that as a result of one of the above reasons someone develops a multinodular goiter, which is initially non-toxic.  But over a period of years there is a greater risk of the person with multinodular goiter developing hyperthyroidism.  Toxic multinodular goiter can be associated with hyperfunctioning thyroid nodules (also known as toxic thyroid adenomas), which means that the nodules autonomously produces thyroid hormone.  In fact, some sources consider ALL cases of toxic multinodular goiter to have nodules that produce thyroid hormone.  Just in case this is confusing, there are a few different scenarios when someone has multinodular goiter in the presence of hyperthyroidism:

Scenario #1: Multinodular goiter with hyperthyroidism caused by nodules that produce thyroid hormone.  Pretty much all sources consider this to be toxic multinodular goiter, while some label the other two scenarios below as multinodular goiter in the presence of hyperthyroidism.

Scenario #2: Multinodular goiter with hyperthyroidism that isn’t caused by nodules that produce thyroid hormone.  Once again, some sources don’t consider this to be toxic multinodular goiter, while other sources do.

Scenario #3: Multinodular goiter with hyperthyroidism caused by elevated thyroid stimulating immunoglobulins.  This of course describes someone who has both multinodular goiter and Graves’ disease.

The truth is that it really doesn’t matter what the condition is called, as either way, the goal should be to address the cause of the condition.  So for example, if someone has multinodular goiter with nodules that produce thyroid hormone, the goal should be to address the cause of the goiter and thyroid nodules.  Similarly, if someone has multinodular goiter with nodules that do not produce thyroid hormone, then we still want to address the cause of the problem.  And of course if someone has multinodular goiter and Graves’ disease, then the goal still should be to address the cause of the problem, although it might be more complex since in this scenario there is an autoimmune component to deal with.

What Causes Graves’ Disease?

According to the triad of autoimmunity, in order for Graves’ disease to develop you need 1) a genetic predisposition, 2) exposure to an environmental trigger, and 3) an increase in intestinal permeability (a leaky gut).  Different people can have different triggers, as for some people the trigger can be a food allergen (i.e. gluten), whereas other people can have their condition triggered through an infection (i.e. H. pylori), and even stress can be a trigger.

Signs and Symptoms of Toxic Multinodular Goiter

The signs and symptoms of toxic multinodular goiter are similar to the signs and symptoms of Graves’ disease, which include the following:

• Increased heart rate
• Palpitations
• Tremor
• Weight loss
• Heat intolerance
• Anxiety
• Loose stools
• Hair loss

Because of the goiter, the person might also experience other symptoms such as neck discomfort, difficulty swallowing (dysphagia), and/or difficulty breathing (dyspnea).  Hoarseness is rare, but it does happen at times.  Other possible signs/symptoms include tracheal deviation, external jugular vein engorgement, and rarely a large substernal goiter may result in facial and cervical plethora and edema (5).

Having Toxic Multinodular Goiter AND Graves’ Disease

I have worked with patients who had toxic multinodular goiter, and also had elevated thyroid antibodies.  There are three main types of thyroid antibodies, which include thyroid peroxidase (TPO) antibodies, thyroglobulin antibodies, and thyroid stimulating immunoglobulins.  As I mentioned earlier, one of the ways of diagnosing Graves’ disease is through the presence of thyroid stimulating immunoglobulins.  And I have had some patients with toxic multinodular goiter who had elevated TSI levels.  I’ve also had some patients with toxic multinodular goiter who had negative TSI levels, but had elevated thyroid peroxidase and/or thyroglobulin antibodies.

When someone has toxic multinodular goiter and also has an autoimmune component, you need to do things to improve the person’s immune system health (i.e. find and remove the autoimmune triggers), while also finding and addressing the cause of the multinodular goiter.

Conventional Treatment Options for Toxic Multinodular Goiter

Just as is the case with Graves’ disease, the three main conventional treatment options for toxic multinodular goiter include 1) antithyroid medication, 2) radioactive iodine, and 3) thyroid surgery.  When the goiter is larger most doctors will recommend either radioactive iodine treatment or thyroid surgery.  While removal of the thyroid gland will of course solve the goiter problem, radioactive iodine has been shown to reduce the goiter up to 65% of the original volume (6).  Of course both radioactive iodine and surgery comes with risks, which is why I recommend trying to address the cause of the problem whenever possible.  That being said, there is a time and place for conventional medical treatment.

Although many medical doctors advise their patients with toxic multinodular goiter to receive radioactive iodine or surgery, low dose methimazole treatment might be another option to consider.  A 2019 study looked to compare the effectiveness and safety of long-term methimazole and radioactive iodine in the treatment of toxic multinodular goiter (7).  The results of the study showed that low dose methimazole treatment for 60-100 months is a safe and effective method for the treatment of toxic multinodular goiter, and is not inferior to radioactive iodine treatment.

Three Other Treatment Options Specifically For Thyroid Nodules

Percutaneous ethanol injection

This technique involves injecting ethanol into the toxic nodule under ultrasound guidance.  Studies show that it can be very effective in shrinking benign cystic and mixed thyroid nodules (8) (9).  But what about toxic thyroid nodules?  Well, one study involving twenty autonomously functioning thyroid nodules showed that 17 of 20 patients had significant shrinkage of their thyroid nodules after receiving percutaneous ethanol injection (10).  Another study showed that it can be effective in the treatment of large toxic thyroid nodules (11).  Pain is the most common side effect, but other less common side effects include facial flushing, a drunken sensation, headache, mild dizziness, perithyroidal or perinodal ethanol leakage, intracystic hemorrhage, local hematoma, secondary infection, or vocal cord paralysis, can occur during or after percutaneous ethanol injection for cystic thyroid nodule (12).

Percutaneous laser ablation

This treatment is also done under ultrasound guidance.  The advantage of this is that it is minimally invasive.  A few studies show that laser ablation is safe and effective in reducing nodule volume and neck symptoms (13) (14).  The downside is that it also doesn’t do anything to address the cause of the thyroid nodule, and as a result, regrowth of the thyroid nodule can occur.  But if someone is looking to shrink the thyroid nodule sooner than later they can always choose to do this and still address the underlying cause.  A few studies show that this can help to reduce the size of autonomously functioning thyroid nodules that are associated with toxic multinodular goiter (15) (16).  This treatment might also be an option for malignant thyroid nodules (17).

As for the side effects, one journal article showed complications occurring in 0.5% of cases (8 patients), and all consisted of voice changes due to vocal cord palsy, with complete recovery after 3 months (17). Minor complications were reported in 0.5% of cases (9 patients), including subcapsular or perithyroidal hematoma and skin burn (17).

Percutaneous radiofrequency thermal ablation

This is yet another treatment that is performed under ultrasound guidance, and it involves thermally ablating the thyroid nodules.  Although laser ablation might sound more appealing to some people, the advantage of radiofrequency thermal ablation is that from what I understand a single treatment is usually required, whereas with laser ablation multiple treatments might be necessary, although not always.  And this treatment can be used for autonomously functioning thyroid nodules (18).  That being said, for someone who is facing thyroid surgery or radioactive iodine, I think that either percutaneous laser ablation or radiofrequency thermal ablation are options to consider. Some of the potential side effects include a transient voice change, hyperthyroidism, hematoma, skin burn, edema, coughing, and nausea/vomiting (19).

When Should You Consider These Procedures?

You might be wondering when these three other treatment options should be considered.  Ultimately this is your decision, and I definitely would consider these over a thyroidectomy or radioactive iodine whenever possible.  You just need to keep in mind that none of these procedures do anything to address the underlying cause of the condition.  So for example, if you have problems with estrogen metabolism or insulin resistance, you ideally would want to address these problems first and see if the thyroid nodules decrease.

Even if you choose to get one of these alternative treatment options for your thyroid nodules, it might be challenging to find a clinic that will perform these procedures.  I did have a patient who got percutaneous radiofrequency thermal ablation through the University of Virginia in 2019.  But I’m sure there are other clinics and practitioners that perform these procedures.

Also, remember that these three alternative methods focus on thyroid nodules, but not the goiter.  Some of the factors I described in this blog post can cause the development of both a goiter and thyroid nodules, but there can be other causes of a goiter.  When I was dealing with Graves’ disease I had a small goiter that resolved after treatment, and many people with overt hypothyroidism develop a goiter.  Very large goiters usually won’t get back to their normal size when following a natural treatment approach, and surgery or radioactive iodine might be considered in some of these cases.

Natural Treatment Options for Toxic Multinodular Goiter

As I mentioned earlier, genetics and gender are both factors with the development of multinodular goiter, and so of course these can’t be modified.  However, other factors can be addressed, such as doing things to decrease insulin resistance, supporting estrogen metabolism and detoxification, and correcting an iodine deficiency.  I’ve discussed these in separate articles and blog posts on my website, and recently I created a video on estrogen metabolism you might want to check out.

The three main factors I would focus on are 1) balancing blood sugar/correcting insulin resistance, 2) supporting estrogen metabolism, and 3) supporting the phase 2 detoxification pathways.  There is overlap between #2 and #3, as healthy estrogen metabolism is dependent on healthy methylation, healthy sulfation, and healthy glutathione.  I discuss the six different pathways of phase two detoxification in a blog post I wrote entitled “How To Optimize Detoxification Part 2”.

Is the approach the same if someone has toxic multinodular goiter?  I bring this up because a lot of the research focuses on non-toxic multinodular goiter.  With my toxic multinodular goiter patients I still address the factors I discussed in this blog post (estrogen metabolism, insulin resistance, etc.), although if someone tests positive for an iodine deficiency you do want to make sure to be cautious with iodine supplementation.  While an iodine deficiency can be a factor in the development of a multinodular goiter, in some cases of toxic multinodular goiter with hyperfunctioning nodules, supplementing with iodine can exacerbate the hyperthyroidism.

What’s Your Experience With Toxic Multinodular Goiter?

If you have toxic multinodular goiter I’d love to hear what treatments you have gone through, and so please share your experience in the comments section below.  Have you done anything to address the cause of your condition, such as address estrogen metabolism or insulin resistance?  And if so, did this help?  I’d especially be interested in hearing from anyone who has thoroughly researched or actually received percutaneous ethanol injection, laser ablation, or radiofrequency thermal ablation.