Graves' Disease: Risk Factors, Etiology and Treatments

Abstract

Graves’ disease in an autoimmune disorder that causes hyperthyroidism in various patient populations.  It is mostly prevalent in Asian and Caucasian women who live in iodine deficient areas but has been found to affect a small number of men and children.  The cause of Graves’ disease is unknown but can be diagnosed by identifying other diseases characteristic of Graves’ disease (thyrotoxicosis, goiters, and ophthalmopathy).  There are various treatment options available, but three main options are utilized in the United States (medication, radioactive iodine, and surgery) that work to put hyperthyroidism in remission and return the body back to homeostasis.  Although research on Graves’ disease has produced any positive outcomes, there are still some areas related to the disorder that are imperative to address such as environmental factors and causation.

Graves’ Disease

Graves’ disease (GD) symptoms were first described by Aristotle and Xenophon in the fifth century after discovering the link between an enlarged thyroid and bulging eye (Gan & Randle, 2019).  Then, in the 19^th century, Robert James Graves identified a combination of three medical issues that collectively effected the thyroid (Gan & Randle, 2019; Lowery & Kerin, 2009).  Today, GD is prevalent in 80% of hyperthyroid patients who account for <1% of the United States population, predominantly effecting Asian and Caucasian females (American Thyroid Association, 2019; Gan & Randle, 2019; Menconi, Marcocci, & Marinò, 2014).  The disease has higher prevalence rates in iodine deficient countries, but genetics and environmental factors also play a major role in the development of GD (Franklyn & Boelaert, 2012; Menconi et al., 2014; Wémeau, Klein, Sadoul, Briet, Vélayoudom-Céphise, 2018).  Various treatment options exist in regard to returning the thyroid to normal functioning, with one option removing the thyroid altogether (Franklyn & Boelaert, 2012; Hussain, Hookman, Allahabadia, & Balasubramanian, 2017; Lowery & Kerin, 2009; Menconi et al., 2014).  The following is an overview of GD, its process, causes, and current treatment options within the United States.

Etiology of Graves’ Disease

Research on GD suggests that the underlying cause of the disease is unknown, but it has been identified as a multifactorial autoimmune disease characterized by three associated disorders—thyrotoxicosis, goiter, and opthalmopathy—and is the most common cause of hyperthyroidism (Franklyn & Boelaert, 2012; Hussain et al., 2017; Lowery & Kerin, 2009; Menconi et al., 2014).  Thyrotoxicosis is a disorder characterized by an excess in the thyroid hormone (Franklyn & Boelaert, 2012).  In this disease process, thyroxine (T4) and triiodothyronine (T3) are synthesized and released by the thyroid, with the latter hormone effecting energy productions and metabolic rates that interrupt cardiac, hepatic, and neuromuscular functions in the body (Franklyn & Boelaert, 2012).  Next, goiter is an enlargement of the thyroid follicular cells (Menconi et al., 2014).  Lastly, opthalmopathy (also known as Graves’ opthalmopathy, GO) is thought to be due to an autoimmune reaction against thyroid antigens and orbital tissues (Menconi et al., 2014). This disease process is demonstrated through enlarged eye tissue that have become inflamed, swelling the skin around the eyes as veins become engorged with fluid (Menconi et al., 2014).  Severe GO symptoms occur in approximately 3-4% of GD patients and such severity causes “compression of optic nerves that result in the loss of vision acuity” (Menconi et al., 2014, p. 399).  Symptoms of GO that are often reported include excessive tearing, eye irritation, pain, and blurred vision (Menconi et al., 2014).

Disease Process of Graves’ Disease

GD is characterized by auto-antibodies that emulate the thyroid stimulating hormone (TSH) by binding to the TSH receptor and becoming activated (Lowery & Kerin, 2009; Menconi et al., 2014).  This activation causes the thyroid hormone to increase the synthesis and release process, which creates the hyperactivity of the thyroid gland (Menconi et al., 2014).  The increase in thyroid hormones begins to effect other organs within the body such as the eyes, skin, and joints (Menconi et al., 2014).

GD patients endure a gradual progression of symptoms that transpire as the thyroid becomes overactive.  Patients usually report nervousness, difficulty in sleeping, fatigue, weight loss (despite increased appetite), tremors, heart palpitations, difficulty breathing, heat intolerance, sweating, and increased bowel movements (Menconi et al., 2014).  There are also gender and age differences in symptomology. For example, females experience irregular menses while males experience decreased libido, erectile dysfunction, and gynecomastia (Menconi et al., 2014).  Furthermore, elderly patients with GD do not experience the aforementioned symptoms; rather they report apathetic thyrotoxicosis that includes apathy and lethargy with reports of cardiovascular issues such as atrial fibrillation and congestive heart failure (Menconi et al., 2014).  Moreover, elderly GD patients can experience dermopathy, which is non-pitting edema (the touching of a swollen area with no indentation), and acropachy, the clubbing and swelling of soft tissue of the fingers and toes (Menconi et al., 2014).  Both symptoms are rare occurrences and are usually found in GD patients experiencing GO and pretibial myxedema that have persisted over a long period of time (Menconi et al., 2014).

Risk Factors of Graves’ Disease

Genetic Factors

The literature on gene susceptibility suggested high gene effects with low heritability factors.  Gan and Randle (2019) cited twin studies that suggested that 80% of GD cases were due to genetic factors, whereas heritability of GD is considered to be extremely low with several familial thyroid dysfunctions considered to play a role, but the magnitude is uncertain (Menconi et al., 2914).  In regard to specific gene regions, Menconi et al. (2014) identified immune regulating genes (HLA-DR, CTLA-4, CD40, and PTPN22) and thyroid specific genes (Thyroglobulin and TSHR) as the genes impacting hyperactivity in the thyroid.  Franklyn and Boelaert (2012) also identified CTLA4 and PTPN22 as genes that are linked to GD and suggested that these genes are responsible for encoding proteins involved in immune function and are usually the cause of other autoimmune diseases.  Research on genetic factors should continue to identify a more cohesive understanding of the genetic breakdown and associated factors to GD.

Environmental Factors

As with several medical diseases, environmental susceptibility plays a role in the development and activity of GD.  Factors such as smoking, psychological stress, infections (Yersinia enterocolitica), and low iodine intake have been found to maintain and worsen GD (Franklyn & Boelaert, 2012; Menconi et al., 2014).  For individuals that smoke, the susceptibility to GO increases and this disease process worsens—effecting quality of life and mortality rates—yet research efforts have yet to describe specific reasons why (Franklyn & Boelaert, 2012; Menconi et al., 2014).

Diagnostic Process for Graves’ Disease

GD is diagnosed by laboratory findings that identify other diseases that makeup the disorder.  First, thyrotoxicosis is found in elevated T4 and T3 serum levels and undetectable TSH serum (Menconi et al., 2014).  This screening procedure is the first line of the diagnostic process, but it is suggested that measuring free T4 and free T3 can give a more comprehensive evaluation (Menconi et al., 2014).  Antibodies that fight against the TSH receptor, called TRAb, are also found in the serum collected in the laboratory and are present in 98% of undiagnosed GD patients (Menconi et al., 2014).  Next, radioactive iodine uptake (RAIU) is completed by administering a dose of radioiodine into the patients’ systems.  For GD patients, RAIU levels are expected to be low or absent which is indicative of hyperthyroidism and other forms of thyrotoxicosis (Menconi et al., 2014).  Another diagnostic tool is the thyroid ultrasound. Although it is not a required tool for identifying GD, it has been found to improve the likelihood of identifying pertinent symptoms that verify the presence of the disorder (Menconi et al., 2014).  This process is helpful in identifying the size of the thyroid and detecting nodules that are not profound during a physical examination (Hussain et al., 2017; Menconi et al., 2014).  The last screening method is the color flow doppler that is used to estimate blood flow, which increases within the thyroid of GD patients (Menconi et al., 2014).  This is a substitute diagnostic tool if GD patients are pregnant or when radioactive iodine uptake is unavailable (Menconi et al., 2014).  Overall, diagnostic procedures for identifying GD are profound and highly effective which assists in identifying the most effective treatment method/s for individual patients.

Treatments

Treatment protocols for GD vary by location and depend on patient preference and severity of symptoms.  In the United States GD treatment begins with a medication regimen intended to return the thyroid to its normal functioning (euthyroid).  If patients are unsuccessful with medication, the next step is radioiodine treatment which is expected to restore euthyroidism.   If radioiodine treatments do not resolve the issue, the final option is a partial or total thyroidectomy by an experienced surgeon.  The following outlines each treatment option in further detail and includes the current research findings on the effectiveness of the treatments.

Medication

Anti-thyroid (ATD) medications are the first line of treatment when managing hyperthyroidism and are sometimes used in preparation for a more definitive treatment with radioactive iodine or thyroidectomy (Gan & Randle, 2019; Laurberg Wallin, Tallstedt, Abraham-Nordling, Lundell, and Tørring, 2008; Kotwal & Stan, 2018; Sugino, Nagahama, Kitagawa, Ohkuwa, Uruno, Matsuzu…Ito, 2019).  The goal of ATDs is to control hyperthyroidism and induce remission of GD by inhibiting thyroid peroxidase enzyme and thyroid hormone synthesis (Kotwal & Stan, 2018).  Remission can be seen within the first six weeks of administration and is expected to fully present after three months (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  Remission rates range between 50-60% after 12 months of medication compliance, but no significant improvements in remission have been found after 18 months of administration (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).

When GD patients are prescribed ATDs it is important for physicians to initially assess thyroid function every four to six weeks to ensure a decrease in thyroid activity is present while also watching for a hypothyroid state (Gan & Randle, 2019).  A dose reduction should begin once remission has been identified and at this point, biochemical changes can be monitored every two to three months (Gan & Randle, 2019).  It is imperative to note that treatment failure in GD patients is due to noncompliance of medication regimen and is cause for more invasive treatment options (Gan & Randle, 2019).

There are two ATD medications that are currently prescribed for GD patients and their use is dependent on severity of GD, comorbidity with other diseases, pregnancy, and compliance concerns (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  Physicians are expected to inform GD patients of effectiveness and risks associated with each drug while collaboratively identifying which ATD will be most advantageous (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  The following briefly outlines the two commonly used ATDs, methimazole and propylthiouracil.

Methimazole

Methimazole (MMI) is the recommended medication for treating GD in the United States (Franklyn & Boelaert, 2012; Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  MMI has been identified as the most effective medication in terms of restoring patients to a euthyroid state and has the highest compliance rate due to low dosage and prescribed amount (10-20mg/once per day) (Franklyn & Boelaert, 2012; Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  As with all medications, MMI produces several side effects such as agranulocytosis, rashes, sore throat, fever, and cholestatic hepatitis (Franklyn & Boelaert, 2012).  According to Franklyn and Boelaert (2012), these side effects are more common among patients who are prescribed higher doses, such as 30 mg, at the onset of medication treatment, and physicians are urged to warn GD patients of these potential effects so they can be properly monitored during treatment.  If patients do experience adverse effects to MMI, there is another medication option available to treat GD and hyperthyroidism called Propylthiouracil.

Propylthiouracil

Propylthiouracil (PTU) has the same mechanism of action as MMI, but also inhibits the conversion of T4 cells to active T3 cells (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  Although it has a similar purpose to MMI, PTU requires a higher dosage of 50-100 mg two to three times per day, which impacts patient compliance due to having to take it several times as opposed to once. PTU is prescribed for women who are pregnant or plan to become pregnant within six months of treatment, women who are breastfeeding, GD patients who report side effects to MMI, and those for whom radioactive iodine and/or surgery is not an option (Franklyn & Boelaert, 2012).  Major medical risks are associated with consuming PTU such as agranulocytosis, toxic hepatitis, liver failure, and antibody-positive vasculitis which increases as duration of medication treatment increases (Franklyn & Boelaert, 2012).

Radioactive Iodine Treatment

The next form of treatment for GD is radioactive iodine (RAI) treatment which was created by Dr. Saul Hertz in 1941 (Kotwal & Stan, 2018).  According to Kotwal and Stan (2018), Dr. Hertz was the first to administer iodine-130 and iodine-131 to GD patients in Massachusetts which damaged thyroid follicular cells and caused a reduction in thyroid hormone levels (Kotwal & Stan, 2018).  This form of treatment has become secondary to ATDs but can be utilized as a first line treatment for patients who choose a more definitive treatment method (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  Patients also choose RAI over the surgical route if they prefer nonsurgical treatment, are high risk due to already having had neck surgery, do not plan to become pregnant within six months of treatment, or there is limited or no access to a surgeon who performs thyroidectomies regularly—at least 25 surgeries per month. (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  70% of patients that receive RAI treatment become euthyroid within four to eight weeks and can expect full remission within six months (Gan & Randle, 2019).  The risks associated with RAI include development or exacerbation of GO, salivary gland dysfunction, thyroid, stomach, or kidney cancer, and radiation thyroiditis (Gan & Randle, 2019; Kotwal & Stan, 2018).

Thyroidectomy

When GD was first identified in the late 1930s, thyroidectomies were the only treatment method used, but with the invention of ATDs and RAI surgery became the final form of treatment for the disease in particular patient populations (Kotwal & Stan, 2018).  Thyroidectomies can be partial or full, and this decision is based on patient preference, severity of symptoms, and lack of effective treatment with ATDs and RAI (Gan & Randle, 2019; Laurberg et al., 2008; Kotwal & Stan, 2018; Sugino et al., 2019).  Partial thyroidectomies have proven to be ineffective due to low remission rates, instability of thyroid function, and costs associated with lifelong follow-up and continuation of other treatment strategies such as ATDs (Sugino et al., 2018).  Subsequently, a full thyroidectomy removes the thyroid gland—the source of hyperactive production of TSH— and produces a higher success rate in GD patients, especially women who plan to become pregnant within six months, patients with comorbid thyroid dysfunctions and/or disorders, large goiters, and active GO patients (Kotwal & Stan, 2018).  The research also suggests that GD patients under 40 years of age are preferred candidates for thyroidectomy, especially children, due to the inconsistencies with taking medications as prescribed and increased rates of recurrence with RAI treatment (Gan & Randle, 2019).

While this surgical procedure produces high rates of success, there are associated risks and contraindications to a thyroidectomy.  For instance, GD patients that are pregnant are only considered for surgery if ATDs are ineffective and the need to control thyroid activity is higher than usual (Kotwal & Stan, 2018; Moleti, Mauro, Sturniolo, Russo, & Vermiglio, 2019).  Other associated risks include vocal cord paralysis caused by laryngeal nerve injury and hypoparathyroidism that Sugino et al. (2018) suggested are caused by inexperienced surgeons (Kotwal & Stan, 2018; Sugino et al., 2018).  As surgeons become experienced in performing such an arduous surgery, technological advances are being considered to improve the surgical process.

Garstka, Kandil, Saparova, Bechara, Green, Haddad, Kang, and Aidan (2018) conducted a study on a futuristic surgical approach of robotic-assisted thyroidectomy.  They conducted studies in the United States and Europe to identify the feasibility and safety of using robotic-assisted surgery to complete thyroidectomies compared to surgery as usual (Garstka, Kandil, Saparova, Bechara, Green, Haddad, Kang, and Aidan, 2018).  According to their findings, GD patients in the United States face similar risks if their thyroidectomy is completed with robotic assistance as compared to surgery as usual, especially when conducted by a high-volume surgeon (Garska et al., 2018).  Although their findings suggest effectiveness of both surgical options, more research needs to be conducted with a higher and more heterogenous sample size to account for various patients affected by GD (Garska et al., 2018).  Overall, patient remission is achievable through various treatment options that are individualized.

GD effects >1% of the American population and is most prevalent in Asian and Caucasian women in iodine deficient areas.  While research efforts are being made to identify a cause of GD, there are currently other diseases associated with the disorder that improve the chances of GD being diagnosed.  There are several treatment options available, with ATDs, RAI, and thyroidectomies being the top three in the United States that work to reduce hyperactivity of thyroid through various mechanisms of action.  Future research efforts should focus on identifying causes of GD and possible preventative methods that could decrease chances of developing the disease, while also considering explanations to environmental factors that attribute to the cause and maintenance of the disorder.

References

• American Thyroid Association. (2019). General information/press room. Retrieved from: https://www.thyroid.org/media-main/press-room/
• Franklyn, J. A., & Boelaert, K. (2012). Thyrotoxicosis. The Lancet, 379(9821), 1155–1166.               https://doi.org/10.1016/S0140-6736(11)60782-4
• Gan T, Randle RW. The Role of Surgery in Autoimmune Conditions of the Thyroid. Surgical Clinics of North America. 2019;99(4):633-648. https://doi:10.1016/j.suc.2019.04.005.
• Garstka, M., Kandil, E., Saparova, L., Bechara, M., Green, R., Haddad, A. B., … Aidan, P. (2018). Surgery for Graves’ disease in the era of robotic-assisted surgery: a study of safety and feasibility in the Western population. Langenbeck’s Archives of Surgery, 403(7), 891–896. https://doi.org/10.1007/s00423-018-1713-y
• Hussain, Y. S., Hookham, J. C., Allahabadia, A., & Balasubramanian, S. P. (2017). Epidemiology, management and outcomes of Graves’ disease-real life data. Endocrine, 56(3), 568-578. https://doi:10.1007/s12020-017-1306-5.
• Kotwal, A., & Stan M. (2018). Current and future treatments for Graves’ disease and Graves’ ophthalmopathy. Thieme 50, 871-886. https://doi.org/10.1055/a-0739-8134
• Laurberg, P., Wallin, G., Tallstedt, L., Abraham-Nordling, M., Lundell, G., & Torring, O. (2008). TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs,               surgery, or radioiodine: a 5-year prospective randomized study. European Journal of Endocrinology, 158(1), 69–75. https://doi.org/10.1530/EJE-07-0450

References

• Lowery, A. J., & Kerin, M. J. (2009). Graves’ ophthalmopathy: The case for thyroid surgery. The Surgeon, 7(5), 290–296. https://doi.org/10.1016/S1479-666X(09)80007-3.
• Menconi, F., Marcocci, C., & Marinò, M. (2014). Diagnosis and classification of Graves’ disease. Autoimmunity Reviews, 13(4–5), 398–402. https://doi.org/10.1016/j.autrev.2014.01.013
• Moleti, M., Di Mauro, M., Sturniolo, G., Russo, M., & Vermiglio, F. (2019). Hyperthyroidism in               the pregnant woman: Maternal and fetal aspects. Journal of Clinical & Translational  Endocrinology, 16, 100190. https://doi.org/10.1016/j.jcte.2019.100190
• Sugino, K., Nagahama, M., Kitagawa, W., Ohkuwa, K., Uruno, T., Matsuzu, K., … Ito, K. (2018). Change of surgical strategy for Graves’ disease from subtotal thyroidectomy to               total thyroidectomy: A single institutional experience. Endocrine Journal, 66(2), 181-              186. Retrieved from: file:///C:/Users/simon/Documents/PCOM%20Fall%202019/Physiology/Articles%20for%20Paper/change%20of%20surgical%20strategy%20for%20graves%20disease%20from%20subtotal%20thyroidectomy%20to%20total%20thyroidectomy.pdf
• Wémeau, J., Klein, M., Sadoul, J.-L., Briet, C., & Vélayoudom-Céphise, F.-L. (2018). Graves’ disease: Introduction, epidemiology, endogenous and environmental pathogenic factors. Annales d’Endocrinologie, 79(6), 599–607. https://doi.org/10.1016/j.ando.2018.09.002