Graves Disease, Thyroid Eye Disease, and COVID-19

COVID-19 has caused disease in close to 500 million people worldwide, according to the World Health Organization. While the airways are its primary target, SARS-CoV-2 may enter many organs via the protein angiotensin-converting enzyme 2 (ACE-2).  ACE-2 is highly expressed in thyroid cells, and COVID-19 has been reported to cause thyroid dysfunction both during and after infection with SARS-CoV-2. COVID-19–related autoimmune thyroid manifestations include Graves’ disease and thyroid eye disease (TED), although COVID-19 can lead to multiple other thyroid dysfunctions.

Presentation of patients with new TED to a prominent chain of Indian eye hospitals had increased 25% during the first 2 years of the COVID-19 pandemic.

This observation poses enticing questions

Is there a link between COVID-19, thyroid autoimmunity, and its complications (including TED)? 

Could COVID-19 vaccination and thyroid autoimmunity be connected? 

Might these observations be influenced by COVID-19 public health measures and delays in seeking healthcare? 

Or are these findings purely coincidental and unrelated to the COVID-19 pandemic?

Understanding Graves Disease and TED

To address these questions, we must review our understanding of how Graves disease and TED occur. Graves disease is an autoimmune disorder of the thyroid caused by stimulatory thyroid-stimulating hormone receptor antibodies, leading to hyperthyroidism.

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the US population.

TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye signs and symptoms that can negatively affect patients’ quality of life, be disfiguring, and in rare cases threaten vision.

The exact events that trigger thyroid autoimmunity are not known; however, we believe a complex interplay between genetic and environmental factors occur, including:

Genetics: Genes with polymorphisms predisposing to Graves disease include human leukocyte antigens (HLA), particularly class II genes for HLA-DR; TSHR; CLTA-4; CD40; and PTPN22.

Age: Graves disease has a low incidence in childhood, rising thereafter until the age of approximately 50 years, after which the incidence plateaus or decreases slightly.

Sex: Women have an approximately five times higher risk for Graves disease than men.

Race: Black persons and possibly Asian persons/Pacific Islanders have higher rates of Graves disease, at least in the United States.

Cigarette smoking: Cigarette smoking is a clear environmental risk factor for the development of Graves disease and TED.

Two other possible triggers for Graves disease are stress and infection.

Stress and Graves Disease. Stress has been implicated as a trigger of Graves. Other autoimmune diseases have also been suggested to have increased risk after stressful events. 

One theory of how stress could cause Graves disease in susceptible people is by releasing hormones, including catecholamines and cortisol, that shift the immune response toward antibody production that is pathognomonic of Graves disease. 

Psychological stress imposed by a global pandemic is therefore a potential (although unproven) trigger for Graves disease and TED.

Infection and Graves diseaseInfection with such bacteria as Yersinia enterocolitica and Helicobacter pyloriand by viruses including parvovirus, Epstein-Barr virus, and hepatitis C virushave also been proposed to cause Graves disease.

One hypothesis for this link is that the hyperinflammatory disease state associated with COVID-19 triggers a series of immune responses in genetically susceptible individuals, leading to activation (or reactivation) of Graves disease and TED. 

Most cases have occurred in middle-aged women, the prime demographic for developing Graves disease. 

The smoking status of these individuals has not been reported.

Reactions Induced by Adjuvants?

Thyroid autoimmune phenomena have been reported after both inactivated and messenger RNA COVID-19.

Graves disease and/or TED have been reported to occur days to weeks after receipt of either a first or second dose of vaccine. Investigators have questioned whether these reactions may represent an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). 

Adjuvants in vaccines are used to enhance the immune response using a reduced amount of antigen, thus creating an extended and lasting immune response. 

Potential mechanisms by which adjuvants disrupt the ‘immunologic balance’ of the host include molecular mimicry (similarities between foreign and self-antigens), excessive cytokine production (promoting inflammation), and defective immune regulation (by regulatory T cells). Association does not necessarily imply causation. Given the sheer number of people being diagnosed with COVID-19 worldwide every day, it is inevitable that some patients seeking medical attention for respiratory symptoms (or other COVID-19 complications) may have preexisting Graves disease and/or TED.

Reassuringly, cases of postvaccination ASIA leading to thyroid autoimmunity appear to be exceedingly rare, although there is potential for underreporting of cases or a lack of awareness among clinicians.

COVID-19 restrictions, lockdowns, and stay-at-home orders have also led to delayed healthcare-seeking behavior. 

“This has been observed across a spectrum of disease, including medical emergencies (eg, acute coronary syndrome), and surgical emergencies (eg, acute appendicitis), and in cancer care. “

Abnormal thyroid function is associated with more severe TED. 

Any delays in diagnosis of Graves disease and timely commencement of antithyroid therapy will undoubtedly contribute to more severe disease at presentation.

COVID-19 has presented the world with many challenges, not least in deciphering causation from association. 

However, the pandemic also presents opportunities for us to ask questions and then learn more about disease processes in many organs. 

The anecdotal data from India regarding recent TED presentations is one such example. 

With additional high-quality data, we will be able to definitively address the roles of stress, infection, possibly vaccination, and behavioral adaptations to the public health responses in the development.

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