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Assessing the current treatment recommendations for Graves’ disease

February 1, 2018 . 1,883 views . View Full Issue (Volume 7, Issue 3) . Print this page

By: Natalie Rodriguez, PharmD Candidate 2019 Philadelphia College of Pharmacy, University of the Sciences  and Stacey Gorski, Assistant Professor of Biological Sciences

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PRESS SUMMARY

The most common cause of hyperthyroidism, or an over-active thyroid, is an autoimmune disease known as Graves’ disease.  In patients with Graves’ disease, the immune system attacks the thyroid gland and causes it to overproduce thyroid hormones. The increased level of hormones causes patients to experience rapid heart rates, tremors, weight loss, sweating, increased appetites, and oftentimes, Graves’ opthalmopathy – a condition where the eyes appear to bulge from the head. Currently, there are three main treatment options for Graves’, including anti-thyroid drug therapy, radioiodine treatment and a sub-total or total thyroidectomy. Though all are viable treatment options, there is a great deal of uncertainty regarding the safety and effectiveness of each treatment. An analysis of the available literature appears to support total thyroidectomy as the most safe and effective form of treatment, despite most US Graves’ patients undergoing anti-thyroid drug therapy instead.

 

ABSTRACT

Graves’ disease, the most common form of hyperthyroidism, is an autoimmune disease that generally affects more women than men. The primary cause is production of thyroid-stimulating receptor antibodies, which aberrantly overwork the thyroid gland, and cause excessive production of essential hormones, triiodothyronine (T3) and thyroxine (T4). These two hormones are primarily responsible for regulating heart rate, growth and development, body temperature and most importantly, metabolism. The exact mechanism of Graves’ pathogenesis is still not fully understood, but both genetic and environmental factors clearly play a role. Currently, there is no cure for Graves’ disease; however, there are several treatment options, all with varying degrees of effectiveness and skepticism. Here, we investigate and compare the three primary recommended treatment options: anti-thyroid drug therapy, radioiodine therapy and a partial or total thyroidectomy. When administered properly, all treatment options make Graves’ disease a manageable disease with a good prognosis.

INTRODUCTION

Graves’ disease, first discovered by Robert Graves in the 1800’s, is a thyroid autoimmune disorder, in which the thyroid gland aberrantly produces thyroid hormones as a result of autoantibodies attacking thyroid cells.1 It is the most common form of hyperthyroidism, and generally affects women ten times more frequently than men.2 Graves’ disease affects approximately ten million people in the United States, many of whom go undiagnosed for several years.3 Graves’ disease occurs as a result of both genetic and environmental factors. Though not fully understood, it is believed that human leukocyte antigen complexes (HLA) are the main genes involved in this disease. Stress and smoking are two large environmental factors that also play a role in the development of this disease.4 The most common signs and symptoms are weight loss, tremors, irritability, increased heart rate, heat intolerance, frequent bowel movements and difficulty sleeping.2 Additionally, a major sign of Graves’ disease is Graves’ opthalmopathy – swelling around the eyes. Graves’ disease patients can also have goiters, or enlarged thyroid glands.3 People with Graves’ disease are also at risk for developing other autoimmune diseases, such as Addison’s disease, rheumatoid arthritis, type I diabetes, pernicious anemia or lupus.5

 

The Thyroid Gland

The thyroid, a butterfly shaped gland located at the base of the neck, secretes hormones necessary for the proper function, growth, development and metabolism of cells throughout the body. In order for the thyroid gland to function properly, the pituitary gland, found in the base of the brain, must secrete thyroid stimulating hormone (TSH), which binds to a receptor on the thyroid cells and fuels hormone production. In addition to TSH, iodine is another essential element needed for proper thyroid function. Iodine, obtained exclusively from the diet, is primarily absorbed by the thyroid gland and stimulates the production of the two main thyroid hormones, triiodothyronine (T3) and thyroxine (T4).6

The thyroid gland lies right below the Adam’s apple and sits in front of the trachea. When looking at the cellular architecture, the basolateral sides of thyroid cells are found next to capillaries, allowing for iodine entrance into the cell and hormones out into the bloodstream. Inside the cells, there is a large concentration of thyroglobulin, which is required for the production of thyroid hormones.7 Both thyroglobulin and iodine will leave the thyroid cells, travel through the apical membrane and enter the follicular lumen, where hormone synthesis and storage occurs. Once hormone synthesis is complete, T3 and T4 are sent out through the basolateral membrane and into the bloodstream.6

 

Iodine Uptake

When TSH binds to its appropriate receptor on the basolateral side of a thyroid cell, a sodium-iodide symporter (NIS) is stimulated and brings in one iodide and one sodium molecule. The direct binding of TSH to its receptor regulates the expression of NIS and how much iodine is transported into the cell.8,9 If there is a high concentration of TSH and more receptors are being stimulated, more symporters will be present on the surface, leading to increased iodine uptake. If there is no TSH present, the NIS will incorporate itself intracellularly, thus preventing iodine from entering the cell (Figure 1).8

Once iodine is transported into the cell, it is exported into the follicular lumen through another membrane transporter on the apical side, pendrin. When iodine enters the lumen, it reacts with thyroglobulin, a protein found in the thyroid, and undergoes organification and oxidation reactions with hydrogen peroxide and thyroid peroxidase (TPO), creating two tyrosine residues, monoiodotyrosine (MIT) and diiodityrosine (DIT). These two tyrosine residues will later combine with the help of TPO and hydrogen peroxide to form triiodothyronine (T3) and thyroxine (T4), both bound to thyroglobulin.6,8,10 Once these two hormones are produced, they are then macropinocytosed back into the thyroid cell and the thyroglobulin is deiodinated by iodotyrosine dehalogenase, DELHAL1, and the resulting free T3 and T4 are exported out the basolateral side through the MCT8 transporter into the blood. The thyroglobulin remaining in the cells will then be reused and the cycle will continue (Figure 1). T3 is the primary hormone that is taken up by cells, and T4 is generally found more concentrated in the blood. The final mechanism for thyroid hormone production is the deiodination of T4 to T3, to be used by the cells.6

Figure 1. The transport of iodine and production of thyroxine and triiodothyronine in a thyroid cell. See text for specific details.

 

Graves’ Disease Thyroid Function 

In Graves’ disease, for reasons that are still unclear, thyroid receptor-stimulating antibodies (TRAb), also known as thyroid-stimulating immunoglobulins (TSI), are produced and bind to the same receptor as TSH, essentially tricking the thyroid into overexpressing the NIS transporter.5 This causes a massive influx of iodine into the cells, thus leading to a rapid increase in the production of thyroid hormones. With increased T3 and T4 levels, the cells increase metabolism and the patient will develop Graves’ disease. Diagnostically, Graves’ disease patients will have low TSH and increased T3 and T4 levels.6 The reason for decreased levels of TSH is due to the increased hormone levels, which create a negative feedback, inducing the pituitary gland to inhibit TSH secretion.

 

Treatments

Currently, there is no cure for Graves’ disease, however, there are three viable treatment options to help reduce thyroid function and decrease the signs and symptoms of this disease. The first type of treatment is anti-thyroid drug therapy (ATD), which inhibits the mechanisms for iodine uptake in the cell, thus decreasing hormone production.2 In the second treatment, radioiodine therapy, the thyroid absorbs radioactive iodine (RAI), emitting beta particles, killing thyroid tissue.11 Finally, a thyroidectomy is a treatment in which the patient can have the entire or part of the gland removed, to decrease hormone production.12 All three treatments, though very different in their mechanisms, work to achieve the same goal of decreasing hormone production, with hopes of attaining euthyroidism, the state of a normal thyroid gland.

 

Anti-thyroid drug therapy

Anti-thyroid drug (ATD) therapy is generally the first line of treatment for Graves’ disease patients. Presently, there are two primary medications, methimazole (MMI) and propylthiouracil (PTU), that are used to help reduce the production of thyroid hormones, with the desired outcome of attaining euthyroidism. Anti-thyroid drug therapy is noninvasive and cost effective.13 Additionally, no hospitalization is required, however, life-long follow up with an endocrinologist and several blood tests are essential in order to ensure that the treatment is regulating T3 and T4 production appropriately. Both MMI and PTU have the same primary mechanism—blocking the organification, or incorporation, of iodine into thyroglobulin. This prevents the activity of TPO and hydrogen peroxide, thus inhibiting the formation of MIT and DIT, which are critical to the formation of T3 and T4.8 These two anti-thyroid drugs can also act more downstream and block the coupling of MIT and DIT, by further inhibiting TPO and preventing the direct formation of the hormones (Figure 2).8 The main concerns regarding anti-thyroid drug therapy are the low remission rates, high relapse rates and development of hypothyroidism. Additionally, long-term use of these medications may prove harmful because they suppress the body’s ability to fight infections. Therefore, treatment duration is not recommended for more than eighteen months.14

Figure 2. The effects of anti-thyroid drugs on iodine transport and hormone production. Anti-thyroid drugs work to inhibit the actions of iodine within the thyroid cells to prevent hormones from being produced.

 

MMI, also known as Tapazole, is currently the most commonly used anti-thyroid drug treatment and has a very high potency and long half-life. As a result, it requires lower doses per day. Generally, most adult patients will receive 15-30mg of the drug for mild to moderate Graves’ disease. In patients with severe Graves’ disease, doctors will prescribe up to 60mg of MMI, which is taken in three doses, separated approximately eight hours apart.15 Although today MMI is more commonly used, it is generally not administered to pregnant women, specifically during the first trimester. Though past research states that MMI passes through the placental barrier more readily than PTU, newer findings suggest that the levels are very similar and as a result, there is still uncertainty as to which drug should be administered to this vulnerable patient group.16 Recently, Andersen, SL, and Laurberg, P demonstrated in their  article, “Managing hyperthyroidism in pregnancy: current perspectives” that birth defects are more severe in pregnant women treated with MMI in the first trimester, compared to those treated with PTU.17 Fetal birth defects found with MMI treatment included esophageal and gastrointestinal atresias, abdominal wall defects and ventricular wall defects, while PTU defects were preauricular sinus, fistulas and cysts—further validating the preference of PTU in the first trimester.17 There are several minor side effects associated with MMI treatment in non-pregnant adults as well; these include urticaria, or skin rash, nausea, and drowsiness. Some severe side effects, though rare, include agranulocytosis and leukocytopenia.14

Figure 3. Number of studies supporting an Anti-thyroid Drug Preference.14–19, 41, 42, 45, 49, 50, 72, 76, 77 Articles were identified by the following search terms: “MMI vs. PTU”, “which ATD is most recommended”, “PTU black box warning”, “PTU or MMI”, “propylthiouracil and methimazole”, “PTU MMI”

* Indicates only preferred during pregnancy

 

PTU was the primary drug of choice for Graves’ disease patients in the United States until 2010, when the Food and Drug Administration issued a black box warning due to severe hepatotoxicity.18 PTU, though less commonly used today, has an additional mechanism of action that inhibits the deiodination of T4 to T3, preventing cells from taking up additional thyroid hormones.2 In contrast to MMI, PTU is less potent and has a shorter half-life, necessitating higher doses. Generally, 300-450mg of PTU is prescribed per day to patients with mild to moderate Graves’ disease and it is administered in three separate doses every eight hours. In severe cases, patients can be administered up to 600mg, demanding nine to twelve pills each day.15 Nowadays, PTU is solely administered if patients are allergic to MMI, or if a woman is pregnant or planning to become pregnant and cannot undergo another treatment option.19 Side effects are very similar to MMI, including agranulocytosis and leukocytopenia, however, as previously mentioned, more severe side effects such as hepatotoxicity have also been found in patients treated with PTU.14

 

Radioiodine Therapy

Radioiodine therapy (RAI) is a form of nuclear medicine that entails ingesting a radioactive iodine pill, I131. This treatment is very cost-effective and easy to administer.13 Iodine is absorbed almost exclusively by the thyroid gland, which greatly limits the likelihood of radiation transmission to other parts of the body. Once an I131 pill is ingested, it travels through the gastrointestinal tract and is absorbed into the bloodstream, where it works its way to the thyroid gland.2 When I131 enters thyroid tissue, it works by emitting β particles that slowly cause shrinking and destruction of the thyroid cells (Figure 4).19 Today, many endocrinologists, specifically in the United States, are advocating for RAI therapy to be the primary treatment for Graves’ disease patients, especially pediatric patients.20 However, most primary care physicians continue to use radioiodine as second line treatment instead, if anti-thyroid drug therapy fails.11 When receiving RAI treatment after anti-thyroid drug therapy, MMI or PTU medications must be discontinued at least three days prior to the onset of RAI therapy. Following RAI, patients can return home, but it is advised to avoid prolonged, close contact and to stay approximately six feet away from others, especially infants and pregnant women, to prevent radiation exposure. Most radiation leaves the body within the first two days, predominantly through urine.21 Currently, there is debate as to whether patients should receive a calculated dose of RAI catered to their specific needs, or if fixed doses prove to be more effective. With proper dosing, partial or complete thyroid destruction is possible, leading to euthyroidism; however, hypothyroidism is the far more common outcome.11 In some cases, especially in patients treated with lower levels of RAI, relapse can occur, leading to recurrence of hyperthyroidism. Due to the uncertainty with measured doses, attaining euthyroidism is very difficult, and as a result, continued follow up is necessary to ensure proper thyroid function.  Some side effects of RAI, though transient, include a metallic taste in the mouth, nausea and swollen salivary glands.22 Additionally, RAI can temporarily worsen Graves’ opthalmopathy.23 Radiation treatment is not administered to patients who are pregnant or planning to become pregnant and generally is not given to children under the age of five.19–22

Figure 4. The mechanism of radioactive iodine and uptake within a thyroid cell. Radioactive Iodine- I131 emits beta (β) particles, which slowly attack and destroy thyroid cells within the thyroid gland, eventually inhibiting the thyroid from transporting iodine and creating hormones for the body to use.

 

Thyroidectomy

A subtotal or total thyroidectomy is the least common treatment for Graves’ disease patients. Thyroidectomies are typically only considered for very young patients, women planning to become pregnant, those with large goiters, severe opthalmopathy, relapse from radiation, or patients with malignancies on the thyroid.2,24 For many years, subtotal thyroidectomies were the favored surgical option, because only part of the thyroid tissue is removed, with hopes that the remaining portion can provide an adequate hormone supply for the body.25 In most cases, euthyroidism is not achieved, and the patient can either relapse or be rendered hypothyroid, calling for replacement hormone therapy, and constant follow up by an endocrinologist.13 Most recent studies, however, have shown that doctors are now more commonly performing total thyroidectomies, removing the entire gland, and providing long-term replacement hormone therapy (Figure 6).25 Total thyroidectomies are now preferred to subtotal thyroidectomies because subtotal requires more postoperative regulation due to fluctuations in hormone levels, whereas total thyroidectomies prove more efficient due to easy postoperative treatment. Additionally, it was originally thought that subtotal thyroidectomies carried less risk of complications compared to total thyroidectomies, but recent research disproves this theory.25,26 Some complications of thyroidectomies include hypoparathyroidism, hypocalcemia and laryngeal nerve injury. These complications can lead to low calcium uptake by the body, causing muscle twitches and a decrease in bone growth. Laryngeal nerve injury, one of the more common complications, can make patients incapable of lengthening their vocal cords, preventing them from producing higher pitched sounds. Many of these complications, however, can be prevented with an experienced surgeon.25, 27, 28

Figure 6. Number of studies with a Thyroidectomy Preference.12, 25, 26, 28, 35–38, 53–56, 61, 62, 64, 67, 68, 75, 78–81Articles were obtained using the following search terms: “Subtotal AND Total thyroidectomies AND Graves’ disease”, “Subtotal vs. total thyroidectomies in Graves’ disease patients”, “Bilateral OR total thyroidectomy”, “total vs. subtotal thyroidectomy”  and “Surgery AND Graves’ disease”.

 

RESULTS

Comparing and Assessing the Current Treatment Recommendations

The three main treatment options, anti-thyroid drug therapy, radioiodine therapy, and a total or subtotal thyroidectomy have several different benefits and risks, making the treatment options controversial. Currently, the United States pushes for radioiodine therapy as the first line of treatment, whereas Europe and most of the Pacific Islands advocate for anti-thyroid drug therapy as their primary treatment.29, 30 Because of the varying degrees of effectiveness, as well as side effects, deciding on a treatment option may prove difficult.31, 32 Each treatment option, however, can make Graves’ disease a manageable disease with a good prognosis.

All three treatments have the same common goal: attaining euthyroidism. However, it is very unlikely that any treatment will achieve this goal long-term. Anti-thyroid drug therapy can transiently achieve euthyroidism, however, once taken off medication, the patient will usually relapse or be rendered hypothyroid.33 Radiation therapy has had much controversy due to the limited amount of research and though a common treatment option recommended by endocrinologists, this treatment frequently results in hypothyroidism due to excessive destruction of the thyroid.34 This is primarily due to the uncertainty of how to accurately calculate a dose specific to each patient, making it extremely difficult to administer the perfect regimen of RAI that will achieve euthyroidism. As a result, most primary care physicians will use fixed doses, which in some cases will not be enough to treat the patient, keeping them at a hyperthyroid state. Consequently, RAI therapy can result in both hypothyroid or hyperthyroid states, calling for additional follow up and treatment. In a study comparing different fixed doses of RAI it was found that higher doses proved more effective than lower ones—71.4% of patients treated with 370 megabecquerel (MBq) were rendered hypothyroid after one treatment, while over 30% of patients treated with 185 MBq required additional doses.34 Subtotal thyroidectomies can also be extremely difficult to regulate. Individual surgeons use different techniques to determine how much of the thyroid to remove, and as a result, several outcomes can occur. In subtotal thyroidectomies, patients can transiently achieve euthyroidism, but eventually develop hyperthyroidism or hypothyroidism several months later. Over 60% of subtotal thyroidectomy patients are rendered hypothyroid and about 15% remain in a hyperthyroid state, requiring additional treatments.27 Although anti-thyroid drug therapy, RAI and subtotal thyroidectomies can prove successful in treating Graves’ disease, each treatment will result in maintaining some functionality of the thyroid gland, calling for regular thyroid function tests. Total thyroidectomies, regardless of the patient’s situation, will always result in a definitive state of the thyroid—hypothyroidism, thus calling for thyroid-replacement hormone therapy for the remainder of the patient’s life.12

 

Although no treatment option can ultimately achieve permanent euthyroidism, other factors should be considered when deciding on a treatment plan. While anti-thyroid drug therapy and RAI treatment are considered cost-effective, the varying results require life-long follow-up, and if hypothyroidism results, thyroid-hormone replacement therapy. Furthermore, if the patient relapses and becomes hyperthyroid, another treatment is required. ATD patients also require many blood tests in order to regulate the patient’s liver function and blood cell counts, as a means to prevent serious side effects. Thyroidectomies are expensive to conduct and difficult to find an experienced surgeon. When comparing total and subtotal thyroidectomies, In, H et al, found that total thyroidectomies offer the more cost effective treatment.13 Although subtotal thyroidectomies, in theory, seem to be the best treatment option, more often than not, they result in hypothyroidism or hyperthyroidism, requiring life-long follow up, constant thyroid regulation and depending on the patient’s situation, either thyroid-replacement hormones or additional treatment.35 The uncertainty in outcomes and the inevitability of hypothyroidism makes subtotal thyroidectomies less appealing.13, 36 We analyzed recent literature and found that the majority of studies conducted between 1990-2017 tend to prefer total thyroidectomies to subtotal thyroidectomies (Figure 6).  While total thyroidectomies are expensive to conduct, they also offer a definitive outcome, with minimal follow-up. Since there is no chance of relapse, total thyroidectomy patients are administered life-long thyroid hormone replacement medications, such  levothyroxine for the remainder of their lives.25 When looking at all treatment options, more likely than not, a patient will eventually be rendered hypothyroid. Thyroid levels after ATD, RAI and subtotal thyroidectomies are more difficult to regulate due to thyroid function fluctuations and as a result, more monitoring of the patient is required until stabilization occurs, thus calling for more doctor’s visits and lab tests. Total thyroidectomies, however, offer a definitive outcome, making it easier to stabilize a patient more quickly, calling for less follow up.13

 

Finally, when considering Graves’ disease treatment options, side effects and complications should be taken into consideration. While anti-thyroid drug therapy may not have many severe side effects, altering white blood cell counts and liver damage can be incredibly detrimental to the patient. There is also a great deal of uncertainty in RAI therapy regarding the chances of developing cancer later in life and as a result of this ambiguity, many patients are skeptical with this treatment option. Thyroidectomies have complications as well, however, with an experienced surgeon the rates of complications are often transient. In an experiment conducted in Italy, 14,934 thyroidectomies were conducted in 42 different endocrine surgery units. Of those 14,934 surgeries, 9,599 of them were total thyroidectomies—1.3% of the patients developed permanent laryngeal nerve injury, and 2.2% developed permanent hypocalcemia.37 Based on these results, with an experienced surgeon, severe complications are rare, making total thyroidectomies an extremely effective treatment option.26, 38

 

Although there is still a great deal of uncertainty in which treatment option offers the best outcome, many factors can contribute to a patient deciding on a particular treatment. Through a meta-analysis of the recent literature, we found several studies and were able to compare each study’s recommendation for Graves’ disease patients (Figure 7). Although treatment plans vary in countries around the world, there is evidence to support that total thyroidectomies offer the safest and most cost-effective treatment for Graves’ disease patients, with easy post-operative procedures and minimal follow up.

Figure 7. Literature based comparison of Treatment Options for Graves’ Disease Patients 13, 20, 23, 30, 31*, 33, 38, 46, 48, 51, 52, 54, 59*, 63, 65, 69, 70*, 71, 73, 74 Articles were identified using the following search terms: ““RAI vs. ATD”, “ATD or thyroidectomy”, “RAI or thyroidectomy”, “Graves’ disease treatment options”, “cost-effective AND Graves’ disease treatment” (radioactive iodine OR RAI) AND (anti thyroid drug OR ATD)”, “(anti thyroid drug OR ATD) AND Thyroidectomy”, “(radioactive iodine OR RAI) AND Thyroidectomy”, “Graves’ disease treatment AND best outcome”, and “Treatment recommendations for Graves’ disease patients.” ATD = Anti-thyroid Drug Therapy, RAI = Radioiodine Therapy, T = Thyroidectomy.

*reference used twice in comparison

 

CONCLUSION

When diagnosed appropriately, Graves’ disease can be an extremely manageable disease with a good prognosis. Through more research, scientists may soon be able to determine the causes of this disease and further understand the production of autoantibodies that trigger the increased production of T3 and T4.

 

Recently, Apitope, a drug discovery and development company, launched a phase I clinical trial for the treatment of Graves’ disease.39 Their approach involves suppressing pathogenic T helper cells with antigen-processing independent epitopes. These synthetic peptides do not require antigen-presenting processing, but allow for IL-10 activation, which induces regulatory T cells and elicits an anti-inflammatory response. By suppressing the immune response, this treatment is working to induce T cell tolerance to the TSH receptor and decrease TRAb production.40 This treatment option, though still not fully explored and tested, may be a promising and viable long-term treatment option in the near future.

 

As potential new promising therapies loom in our future, Graves’ disease patients still have several treatment options available to help to control their symptoms. Though presently, no single treatment offers a definitive chance at euthyroidism, there are viable options in helping to manage the disease. Currently, anti-thyroid drug therapy and RAI treatment are more commonly administered to patients, especially here in the US; however, total thyroidectomies may prove to be a more worthwhile option. Although thyroidectomies are expensive, the minimal follow-up, definitive outcomes and low risk of complications prove effective.

 

Literature Meta Analysis

Research articles included for analysis were found searching the PubMed database and were limited to those published between 1990 and 2017. Articles were found using several unique keywords and search terms. For anti-thyroid drug preference, “MMI vs. PTU”, “which ATD is most recommended”, “PTU black box warning”, “PTU or MMI”, “propylthiouracil and methimazole”, and “PTU MMI” were used. For thyroidectomy preference, the following terms were used: “Subtotal AND Total thyroidectomies AND Graves’ disease”, “Subtotal vs. total thyroidectomies in Graves’ disease patients”, “bilateral or total thyroidectomy”, “total vs. subtotal thyroidectomy” and“Surgery AND Graves’ disease” were used. When comparing all three treatment options, the above search terms in addition to “RAI vs. ATD”, “ATD or thyroidectomy”, “RAI or thyroidectomy”, “Graves’ disease treatment options”, “cost-effective AND Graves’ disease treatment” (radioactive iodine OR RAI) AND (anti thyroid drug OR ATD)”, “(anti thyroid drug OR ATD) AND Thyroidectomy”, “(radioactive iodine OR RAI) AND Thyroidectomy”, “Graves’ disease treatment AND best outcome”, and “Treatment recommendations for Graves’ disease patients.” were used. A total of 67 references were identified and 53 were used in the analysis.

 

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