What Causes Graves’ Disease?

Graves’ disease is an autoimmune disorder where your body produces antibodies to attack itself. This can lead to hyperthyroidism, which is an overproduction of thyroid hormones. 

This is the most direct cause of Graves’ disease – autoimmunity. Although the exact trigger is unknown, several environmental and biological factors can activate certain genes related to autoimmunity. Medical experts believe the activation of these genes increases the risk of developing Graves’ disease. 

It is impossible to prevent or change any genetic factors and even some biological factors. However, understanding the changeable environmental factors contributing to Graves’ disease can prompt you to make healthy lifestyle changes. 

So, what causes Graves' disease? 

Direct causes

As outlined above, Graves’ disease is caused by autoimmunity. 

In a normal immune response, antibodies (as defined below) are produced to target a specific foreign substance such as a virus or bacteria so that it can be removed before it causes damage to the body and makes us sick.

Autoimmunity occurs when antibodies cause the immune system to attack the body’s healthy cells. 

The following terms describe some important immune system components in the blood that can be involved in Graves’ disease:

• Antibodies are special proteins that attach to and remove foreign substances such as toxins, bacteria, and viruses. They do this by binding to a specific antigen and destroying it.

• Antigens are foreign particles that become bound to antibodies or T cell receptors so that they can be destroyed and removed. They are responsible for triggering immune responses.

• B cells are specialized cells that produce specific antibodies.

• Cytotoxic T cells directly kill cells infected by a foreign virus or bacteria

• Helper T cells stimulate our B cells to produce antibodies

The autoimmune process 

The autoimmune process leading to the development of Graves’ disease occurs as follows:

1. For some reason (likely genetic), there is a problem with the normal process the body uses to prevent autoimmune reactions.

2. The T cells have an over-sensitive response to an antigen (a substance not recognized by the immune system) in the thyroid gland, allowing them to multiply.

3. The T cells stimulate B cells into producing antibodies (TRAb) against antigens in the thyroid gland cells, which they wrongly see as foreign invaders. 

4. These antibodies bind to the thyroid-stimulating hormone (TSH) receptor on the surface of cells in the thyroid. They activate the receptor to produce a response much like what TSH would have done if the thyroid was functioning normally. 

5. This response can cause: 

• The excessive production and secretion of thyroid hormones (T3 and T4) into the bloodstream

• Enlargement of the thyroid gland (goiter) 

• Progression to an eye disease called ‘Graves’ ophthalmopathy’

Risk factors

Our immune system has evolved to prevent an autoimmune reaction, but genetic and environmental factors can offset this. 

Although the exact reason why antibodies attack our healthy cells is not known, experts believe that a variety of factors may be involved. 

These risk factors do not directly cause Graves’ disease. If you have one or even several risk factors, that does not mean you will get Graves’. However, carrying certain genes increases the risk of developing Graves’ disease, especially if you are also exposed to particular environmental factors. 

Family history and genes 

Approximately one-third¹ of people with Graves’ disease have family members who have either Graves’ disease or another autoimmune thyroid disorder called ‘Hashimoto's disease.’ 

A study in twins showed that about 80% of a person’s¹ risk of Graves’ disease could be genetic. Those who are genetically susceptible may have an immune defect that leads to the production of thyroid antibodies and, subsequently, the excessive production of thyroid hormones and the growth of the thyroid gland.

Environmental factors 

Environmental factors increase the likelihood of developing Graves’ disease, and experts believe they are responsible for about 20% of cases. 

Environmental factors likely trigger immune responses in the genes related to Graves’ disease (listed above). 

Some important environmental factors include:

Psychological trauma or stress 

Studies have suggested a relationship between past trauma² and Graves’ disease. However, the mechanism of how this happens is unknown. 

Stress is also considered a determinant of the severity³ of hyperthyroidism symptoms in people with Graves’ disease. Stress may also reduce the effectiveness of treatment.

However, stress itself isn’t linked to the presence of thyroid autoantibodies. It is more likely that stress triggers Graves’ disease hyperthyroidism in people already at risk due to their genes.

Cigarette smoking

Smoking doubles the risk of developing Graves’ disease,⁴ and it is linked to more severe symptoms. It also triples the risk of developing Graves’ ophthalmopathy.⁴

This relationship is stronger in people who are genetically predisposed to Graves’ disease. Experts believe that smoking can affect the immunity of the thyroid gland. 

Infections

Infections such as H. pylori (a bacterial infection of the mucus membrane lining the stomach) can contribute to Graves’ disease. It is thought that the H. pylori antigens may be involved in developing autoimmune thyroid disease.

An infection of Yersinia enterocolitica is also associated with the development of Graves’ disease.

Exposure to iodine

Iodine is an important mineral that helps the thyroid gland produce thyroid hormones. However, excessive exposure to iodine can lead to hyperthyroidism and is a risk factor for Graves’ disease.

Studies show that excessive iodine may increase thyroid autoimmunity.⁴

Plus, excessive iodine exposure in Graves’ disease patients may reduce the effectiveness of antithyroid drugs used to treat the disease. 

Pregnancy and the postpartum period 

Women who currently have or have had Graves’ disease have a 1% to 5% chance⁵ of transferring the disease to their baby across the placenta, causing fetal hyperthyroidism. 

The risk of postpartum Graves’ disease, which occurs three to nine months after delivery, is elevated for women who stopped treatment for hyperthyroidism during their pregnancy. 

Medication 

Highly active antiretroviral therapy (HAART) 

HAART is an HIV treatment. It has been shown that Graves’ disease can develop 8 to 12 months after starting this medication.

Cytokine IL-1 alpha 

This treatment plays a key role in reducing inflammation and joint destruction in Graves’ disease.

Cytokine IL-2 and IFN alfa

Interleukin-2 (IL-2) and interferon alfa (IFN-alpha) are used for chemotherapy. They can worsen autoimmune thyroid disorders⁴ or even induce them through direct thyroid action.

Campath 

Campath is a special type of antibody used to treat multiple sclerosis (MS).

In a study of people with MS, one-third of the participants developed Graves’ disease within six months during recovery from T-cell depletion. 

Radiation to the neck area

Radiation to the neck area, such as for the treatment of Hodgkin's disease, increases the chances of developing Graves’ disease and Graves’ ophthalmopathy.⁴ 

Other biological factors

Gender

Women are more likely to develop various autoimmune conditions, including Graves’ disease. Experts believe this correlation is related to the female sex hormone estrogen. 

An existing malfunctioning immune system, e.g., diabetes, arthritis 

Other types of autoimmune disorders can increase an individual’s risk of developing Graves’ disease. These include rheumatoid arthritis and type 1 diabetes.

What causes a relapse of Graves’ disease?

Although Graves’ disease can be treated, there is always a risk of relapse. Even with successful treatment with antithyroid medications, 50% of people⁶ experience a relapse.

The causes of a relapse of Graves’ disease are similar to the causes of the initial disease. However, a few factors may further elevate the risk of relapse.

A review of studies showed some factors that could predict relapse before treatment for Graves’ disease has even begun, although each individual factor has only a small effect. These include:

• Smoking cigarettes

• Being a young male

• Having a large goiter size or thyroid volume 

• Having severe hyperthyroidism at initial diagnosis

• High and persistent levels of thyroid autoantibodies at the end of treatment

• Occurrence of orbitopathy (swelling behind the eyes, resulting in bulging of the eye)

Graves’ dermopathy and Graves’ ophthalmopathy 

Graves’ dermopathy and Graves’ ophthalmopathy are closely related to Graves’ disease.

Graves’ ophthalmopathy occurs in about 30% of people with Graves’ disease. Graves’ dermopathy, however, is much less common.

Like Graves’ disease, the underlying cause of these two conditions is an autoimmune response.

Graves ophthalmopathy

TSH receptors are not only found in the thyroid but in other places such as the connective tissue and muscles surrounding the eyes. When a particular antibody (thyroid-stimulating immunoglobulin) binds to a TSH receptor on the surface of cells behind the eye, it leads to inflammation, swelling, scarring, and an outward bulging of the eye. 

Graves dermopathy

Like Graves' ophthalmopathy, medical professionals believe that TSHR receptors in the connective tissue underneath the skin act as an antigen and are responsible for an immune response. This leads to red, swollen, and thickened skin, particularly on the shins and the tops of the feet. 

The lowdown

Although Graves’ disease is directly caused by an autoimmune response, several genetic and environmental risk factors can indirectly trigger or increase the risk of developing Graves’ disease. 

Although we cannot prevent Graves’ disease, especially since genetics play a large part, knowing the risk factors allows you to make beneficial lifestyle changes preemptively.