Introduction

Brief overview of thyroid eye disease 

Thyroid eye disease (TED) makes the muscles, eyelids, tear glands, and the fat around your eyes puff up and feel sore. This can make the eyes and eyelids look red, swollen, and feel bad. Sometimes, the eyeballs may stick out or bulge, making it seem like the person is "staring".¹

Importance of understanding its causes

​​TED is mainly linked with Graves' disease, but it can show up in other thyroid issues too, like Hashimoto's thyroiditis and in people with normal thyroid levels. The immune system responses that affect both the thyroid and the eyes highlight the strong connection between thyroid function and eye health.^2,3

Thyroid eye disease (TED): definition and symptoms

What is TED?

Thyroid eye disease (TED) is an autoimmune disorder where the body's defense system wrongly attacks the muscles and fat near the eyes. This leads to swelling and soreness, turning the eyes and eyelids red and puffy. It can push the eyes out, making them look like they're bulging or staring. When swelling hurts the eye muscles, it can make them sit wrong. This can lead to seeing everything double times(double vision).¹

At times, characteristics of TED like soreness on the front of the eyes (the cornea) or stress put on the nerves of the eye can lead to vision loss. Even though it may show up in people with a normal or underactive thyroid, TED is mainly linked to an overactive thyroid from Graves' disease. Whether before, while, or after finding out they have a thyroid issue, TED impacts around 25% of those with Graves' disease. TED is also called Graves' Orbitopathy (GO) and Graves' Eye Disease (GED).⁴

Common symptoms 

The signs and symptoms of TED include:

• Dry eyes
• Irritated eyes due to a gritty feeling
• Watery eyes
• Red eyes
• Bulging eyes, also called proptosis
• A “stare”
• Double vision, also called diplopia
• Difficulty closing your eyes completely. This can lead to an ulcer on your cornea
• Vision
• Pain behind your eyes and pain with eye movements⁵

Key risk factors for TED

• Gender
• Age
• Smoking
• Graves' Disease
• Radioactive Iodine Treatment
• Family History
• Ethnicity⁶

Connection to Graves’ disease 

Overview of Graves’ disease (autoimmune hyperthyroidism)

Graves' disease is a health issue where your body fights its own cells that can make your thyroid work too much. The thyroid is a tiny, butterfly-like gland at the front of your neck. The hormones from the thyroid help decide how your body uses its energy, and they affect most parts of you, like your heart. With Graves' disease, your body's defense system goes after your thyroid and makes it create more hormones than you need. This causes many parts of your body to work faster than they should.⁷

How Graves’ disease triggers TED

In Graves' disease, the body's defence system hits more than just the thyroid; it goes for the eye area too, leading to TED. But how does it do this? Let’s have a look through the process: 

Autoantibodies and the TSH receptor: In Graves' disease, the body's shield makes antibodies that mistakenly target the thyroid-stimulating hormone (TSH) receptor on the thyroid gland, making it overactive. These antibodies can also bind to similar receptors in other areas on the eye, leading to more irritation and inflammation.⁸

Activation of orbital fibroblasts: ​​When the eye socket cells (orbital fibroblasts) activate, they can change into fat and tissue cells. This makes the fat and tissue near the eyes get big and grow.⁸

Inflammatory response: This begins with swelling that pulls immune cells to the area. This swelling makes the eyes puffy, leading to signs of TED like bulging eyes and double vision.⁸

Mechanical effects: The build-up of swelling in the eye socket, caused by the swelling and growth of fat and connective tissue, places pressure on the eye muscles and optic nerve. This may make it difficult to move the eyes, and, in severe cases, can cause vision problems or even sight loss.⁸

Other thyroid disorders linked to TED

Hashimoto’s thyroiditis and TED

The ways TED works in people with Hashimoto's thyroid disease aren't fully understood. It's more often tied to Graves' disease. However, things like a weak immune system, swelling, and molecular actions in the eye may lead to TED in those with Hashimoto's thyroid problems.²

Euthyroid patients with TED (TED without thyroid dysfunction)

TED can also develop in people with normal thyroid function, showing the complexity of the disease. Autoimmune processes, genetics, and environmental triggers may all contribute to TED in people with normal thyroid levels. Early detection and management are crucial to prevent complications.³

This form of the disease, known as Euthyroid Graves’ Orbitopathy (EGO), remains unclear. It is believed that orbital tissues may be targeted by autoimmune processes independently of thyroid function. Some people may first show signs of EGO and then later show signs of thyroid dysfunction, suggesting a link that goes from EGO to the well-known Graves' disease.³

Subclinical hyperthyroidism

Subclinical hyperthyroidism means a small boost in thyroid hormone with no clear signs. Some studies show that even a small off-balance in the thyroid can lead to eye changes linked to TED, but not as bad as observed in Graves’ disease.⁵

Post-treatment thyroid dysfunction (RAI-Induced TED)

Radioactive iodine care (RAI), often used to treat Graves’ disease, may make TED signs worse for a while in some people. This is because RAI makes the immune system react more, leading to more swelling in the eye area. TED risk goes up in smokers and in those with improperly managed thyroid levels after RAI care.⁹

Thyroidectomy 

Taking out the thyroid gland (thyroidectomy) does not often lead to TED getting worse. But, it is key to monitor thyroid hormone levels after the surgery to stop imbalances that may negatively affect eye health.¹⁰ 

Role of thyroid hormone fluctuations

Changes in thyroid levels, which include hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid), can greatly impact the start and growth of TED. It's key to keep these hormone levels normal to manage TED well.

Too much thyroid hormone (as seen in hyperthyroidism) can worsen swelling in TED's. This might lead to puffy, red, and sore eyes. It can also make the disease progress quicker. 

Similarly, low thyroid hormone levels (as seen in hypothyroidism) can also impact TED. Too little thyroid may cause the eyes to swell. In worse cases, this can add to the onset of TED or make TED signs worse.

Additional Risk Factors and Triggers

1. Smoking - Smoking is the number one modifiable risk factor that can promote TED. Those who smoke are seven times more likely to get TED, and smoking makes the illness worse. Stopping smoking is key to keeping TED away⁶
2. Sex - People assigned female at birth (AFAB) are more likely to develop TED, however, people assigned male at birth (AMAB) get hit worse with TED
3. Age- People of all ages can get TED, but it's most often found in adults aged between 30 and 50 years old. Older people with Graves’ disease also have an increased chance of developing TED
4. Radioactive iodine therapy- The treatment with radioactive iodine (RAI), often used for hyperthyroidism, is tied to a higher chance of getting TED, more so in people who smoke. Taking corticosteroids while on RAI treatment could help lower this chance
5. Elevated thyrotropin receptor antibodies (TRAb)- High amounts of TRAb are tied to greater chances of developing TED. These antibodies can make the thyroid gland work too much and lead to eye issues
6. Hypercholesterolemia- High cholesterol levels might add to the risk of TED. Though the full link isn't fully understood, keeping cholesterol levels low may help cut down the risk
7. Family history and genetic factors- If your family has had thyroid issues or immune diseases, your risk of getting TED could be higher. However, scientists are yet to identify which specific genes can increase this risk
8. Other autoimmune conditions- People who have other immune system issues, such as type 1 diabetes or rheumatoid arthritis, could be more prone to get TED. This shows why it's key to keep an eye on eye health in those with immune conditions
9. Stress- Long-term stress may set off immune problems like TED. Practising mindfulness and learning techniques that keep you calm in stressful situations can lower chances of developing TED⁶ 

Summary

TED is a condition often tied to Graves' disease but can also manifest alongside other thyroid conditions or even in people with normal thyroid levels. It leads to redness and swelling near the eyes, causing pain, sight issues, and, in severe cases, loss of sight. The risk factors include smoking, being AFAB, old age, family history, and thyroid treatment like radioactive iodine therapy. Keeping thyroid hormone levels normal, not smoking, and rapid intervention are the primary ways to lessen TED’s effects. Knowing what factors and processes lead to this condition and how TED affects the body can aid in stopping and treating the disease.