John M. Scifo II

Loyola University Maryland

1.              Introduction

Autoimmunity is defined by the inability of an immune system to properly differentiate the components of its’ own body from foreign entities. Such a failure to differentiate between the two allows for the immune system to initiate an autoimmune response against the cells and tissues of its’ own body. Thus, any disease that is defined by a defunct immune system as described above is classified as being an autoimmune disease. Graves’ Disease (GD) is such a disease.

Identified as the most prevalent cause of hyperthyroidism, the overactive thyroid that produces and secretes thyroid hormones T3 and T4 at a substantially abnormal and elevated rate suffices to define the overarching scope of Graves’ disease. The hyperactive thyroid of GD is the result of a series of complex and intricate cellular responses initiated by a malfunctioning immune system. Of most pressing concern for the medical community are the drastic increases in metabolic activity throughout the body and onset neuropsychological symptoms that coincides with the increased levels of regulatory thyroid hormones present in a GD patient due to the presence of said hyperactive thyroid.

Both males and females alike over a wide spectrum of age groups are at risk of developing Graves’ disease. However, women between the ages of 30-40 years old are considered to be at the highest level of risk to develop the disease. Furthermore, the disease is considered to have moderate affiliation with being genetically linked. Thus, individuals within a family that has a history of any autoimmune disease are identified as being at an increased risk of developing GD.

Although in isolation it is rarely considered to be life threatening if properly treated, the importance of studying the mechanisms that act to initiate and maintain the symptoms that comprise Graves’ disease is clear, as the disease induces of an array of severe symptoms that can potentially progress into other serious medical conditions. While progress has been made in the identification of the mechanisms that invoke pathogenesis of Graves’ disease, an overarching understanding of the mechanisms at hand has, thus far, eluded researchers. Despite such research limitations, current courses of treatment for the disease, such as (1) surgery, (2) radioiodine treatment, and (3) antithyroid drugs, have effectively resulted in a prognosis that is generally positive.

2. Overview of the Thyroid Gland

In order to understand the underlying mechanisms of Graves Disease, knowledge pertaining to the function of the thyroid gland must first be had. The thyroid gland is located inferior to the thyroid cartilage on the neck of humans (Weetman, 2000). One of the body’s largest endocrine glands, the thyroid gland plays a dominant and critical role in the regulation of body systems. Ultimately, its’ primary functions include: (1) regulation of the body’s metabolic activity, (2) synthesizing proteins, and (3) control other systems’ sensitivity to hormonal signals (Weetman, 2000).

Acting as a primary facilitator of regulatory signals within the body, the thyroid gland synthesizes and secretes hormones derived from tyrosine and iodine, accordingly named as Triiodothyronine (T3) and Thyroxine (T4). The paramount function of these hormones includes: (1) regulation the body’s metabolic rate and (2) regulation of the growth and rate of function within functional systems of the body (Weetman, 2000).

2.1. Thyroid Hormone Regulation.The thyroid gland’s primary product is T4, as it only directly produces and secretes 20% of the body’s T3 supply (Chistiakov, 2003). The remaining 80% of the body’s T3 volume results from the conversion of T4 into T3 by deiondinase enzymes present in the kidney and liver. The synthesis and secretion rate of T4 and T3 hormones is regulated by Thyroid Stimulating Hormone (TSH), which is released into the body’s system via the anterior pituitary gland. Additionally, the volume of Thyrotropin-Releasing Hormone (TRH) present within the body, which is moderated by the hypothalamus, regulates the anterior pituitary’s release of TSH. Ultimately, the regulatory pathway that controls the hormonal output of the thyroid gland is as follows: (1) TRH is released by the hypothalamus. (2) TRH stimulates the anterior pituitary gland to release TSH. (3) TSH binds to the G-protein coupled Thyroid Stimulating Hormone Receptors (TSHR) that are present on the thyroid gland’s cellular membranes. (4) TSHRs’ binding stimulates the thyroid gland, which subsequently induces the production and secretion of T3 and T4 (Weetman, 2000).

The production of hormones by the thyroid gland is further moderated by a negative feedback mechanism present between the thyroid and cells within the anterior pituitary gland that produce TSH called thyrotropes. When T4 levels within the body are elevated to the threshold level, the production of TSH is inhibited, which consequently leads to the inhibition of hormonal production by the thyroid.  Contrarily, when T4 levels are below the designated threshold level, the anterior pituitary is stimulated to produce TSH, which induces elevated rates of production and secretion of T4 and T3 by the thyroid gland (Chistiakov, 2003).

3. Graves’ Disease Symptamatology

Patients suffering from GD may exhibit an array of symptoms, including, but not limited to: (1) Anxiety, (2) irregular heart rate, (3) increased perspiration, (4) high sensitivity to heat, (5) brittle hair,  (6) light menstruation periods, and (7) weight loss despite normal food intake. In addition to hyperthyroidism and a swollen thyroid gland, known as a diffuse goiter, the diagnosis of GD typically coincides the presence of ophthalmopathy and/or dermopathy on the upper feet and shins of patients. Furthermore, Graves’ disease is also known to actuate an array of neuropsychological symptoms within patients (Weetman, 2000).

3.1. Graves’ Ophthalmopathy.

Present within a dominating amount of patients with GD, Graves Ophthalmopathy (GO) is a prevalent symptom that often coincides with hyperthyroidism, thus consequently serving as a factor of successful diagnosis. The development of GO can result in immense pain levels, eye inflammation, double vision, or even blindness. Physical features of GO include: (1) extraocular muscle dysfunction, (2) forward protrusion of the eyes known as proptosis, (3) periorbital and eyelid edema, (4) conjunctival chemosis, which results in swelling, and injection, which results in redness, (5) lid lag stare, and/or (6) exposure keratitis (Prabhakar et al. 2003).

3.1.1. Graves’ Ophthalmopathy Pathology. The symptoms induced by GO are mostly understood as being the result of an increased volume of both the orbital fatty connective tissues and the extraocular muscle bodies. It occurs typically when the antigen known as thyroid stimulating hormone receptor (TSHR), which is also the primary antigen involved in hyperthyroidism, present on the connective tissues behind the eyes is subject to an autoimmune response.

Studies have indicated that patients diagnosed with DO have increased orbital adipose tissue volumes and extraocular muscles that are ‘widely’ separated by edematous connective tissues (Prabhakar et al. 2003). The separating edematous connective tissues are laced with abnormally large amounts of glycosaminoglycans (GAGs), which are composed of hyaluronan and chondroitin sulfate. Similarly, an elevated level of GAGs is also present in the fatty connective tissue areas of the posterior area of the orbit. It is hypothesized that the elevated levels of GAGs within such tissues, which are the result of the preceding immune system’s ‘attack’ on the TSHR of local tissues, is the primary culprit behind the increased orbital volume that is characteristic of GO (Prabhakar et al. 2003).

3.2. Physical Abnormalities of the Thyroid in Graves Disease

The thyroid gland of patients suffering from GD typically displays a number of physical abnormalities that act to differentiate it from a healthy thyroid. As a whole, the thyroid gland is diffusely enlarged, so much so that it can sometimes produce a lump in the back of a patient’s neck (Prabhakar et al. 2003). In terms of the gland’s histology, there is often the presence of the following: (1) follicular hyperplasia, (2) intracellular colloid droplets, (3) cellular scalloping, (4) follicular colloid reduction, and (5) multifocal lymphocytic infiltration (Prabhakar et al. 2003). Furthermore, there is often evidence of intrathyroidal lymphocytes present, with the majority of such lymphocytes being T cells and a select amount being B cells (Prabhakar et al. 2003). In some areas of the thyroid, the epithelial cell size may correlate with the intensity of the lymphocyte infiltration. Such a correlation suggests that the secretion of stimulating TSHR-Abs of local B cells may serve as a mechanism for the stimulation of thyroid cells.

4. Mechanisms of Graves’ Disease

While researchers currently hold an underlying understanding of the symptoms that coincide with Graves, the mechanisms of its’ etiology that lead to the production of the autoantibodies, which define the disease, has, thus far, eluded them. Nevertheless, the mechanisms of the autoantibodies’ function, after their preliminary inception, have been successfully identified. 

4.1. Dietary Iodine as a Contributing Factor

In order to maintain the normal production and release of thyroid hormones, a dietary intake of between 100-150 mg/d is needed. However, in the United States, the average intake of dietary iodine is between 300-700 mg/d (Streetman, 2003). This increased amount of iodine intake correlates with the increasing prevalence of hyperthyroidism within the general population, as dietary iodine levels are an important component in the sustainment of adequate hormonal regulation in the thyroid. Being that the hormones of the thyroid are derived from iodine, it is easy to see the implications of a diet that produces too much iodine intake. High levels of dietary iodine intake, as is prevalent within the US, is viewed as a possible contributing factor to the onset and maintenance of GD hyperthyroidism, as it results in the over production of thyroid hormones (Streetman, 2003). Such an availability of hormones serves to facilitate their ability to be perpetually secreted by an overactive thyroid.

Dietary iodine uptake occurs in two fashions within the body: (1) from the gastrointestinal tract (GIT), and (2) from the blood. If uptake occurs in the GIT, the iodine is carried within the body’s circulation as iodine typically is. However, if taken from the blood, the Iodine Pump (IP), located at the base of the thyroid’s follicle, actively transports the iodine to the thyroid gland. The IP’s activity is regulated by the iodine concentration within an individual’s serum. If the serum has a low concentration of iodine, the activity of the pump is increased. Adversely, if the serum’s concentration of iodine is high, the pump’s activity is reduced (Streetman, 2003).

4.1.1. Iodine’s Role in T3 and T4 Synthesis. The iodine transported by the IP is taken up by the thyroid’s follicular cells and, subsequently, oxidized within seconds (Streetman, 2003). The enzyme thyroid peroxidase (TPO) produces hydrogen peroxide, which serves to ‘trap’ the iodine (Streetman, 2003). The trapped iodine then binds to free tyrosine, as well as tyrosine residues of the protein thyroglobulin (Tg). This binding leads to the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT) complexes. The MIT and DIT complexes remain intact until the thyroid gland is stimulated. Upon stimulation, the thyroid’s follicular cells absorb Tg and cleave MIT and DIT from the Tg in lysosomes that are present in the thyroid (Streetman, 2003). Thus, the absorption of Tg and the cleavage of iodinated tyrosines MIT and DIT result in the synthesis of T4 and T3 hormones within the thyroid.

4.2. Autoantibodies in Graves’ Disease

The hyperthyroidism that acts to define GD is induced by the actions of autoantibodies to the thyroid stimulating hormone receptor (TSHR-Abs), which are spontaneously secreted from lymphocytes present in thyroid tissues (Chistiakov, 2003). The makeup of these autoantibodies allows for them to explicitly and directly ‘attack’ TSHRs, which, while primarily located on the membrane of the thyroid gland, are also found on adipocytes, fibroblasts, and bone cells, by binding directly to them (Chistiakov, 2003). The TSHR-Ab binding sites on TSHRs, which are located on the extracellular domain of the thyroid cells, are within the same region that normal TSH binds to. This characteristic allows not only for the binding of TSHR-Abs to adequately stimulate the cell via the same mechanistic pathways as TSH, but it allows serves to inhibit future bindings of TSH, this effectively inhibiting the regulatory negative feedback mechanism of TSH (Chistiakov, 2003).

4.2.1. Prolonged Stimulation of the Thyroid.Once the TSHR-Abs binds to the TSHR, they sufficiently activate the receptor. After being activated by the TSHR-Abs, the receptor serves to stimulate the synthesis and subsequent secretion of T3 and T4 hormones (Chistiakov, 2003); the same response that the binding of TSH to the TSHR would provoke in a healthy individual. Additionally, however, the binding of TSHR-Abs also results in thyroid growth, thus making them the cause of the diffused goiters present within GD patients (Chistiakov, 2003).

While ultimately defined by their almost universal stimulatory function, TSHR-Abs can initiate cellular responses that vary in implications upon binding to a TSHR. Present in approximately 50% of GD patients, long acting thyroid stimulators (LATSs) are stimulatory immunoglobulin, which act as antibodies that not only initiate the production of hormones by the thyroid, but also provokes thyroid growth. Important to note is that the response to the binding of LATSs lasts for a significantly longer duration than the response to TSH binding (Prabhakar et al. 2003).

The increased response duration to the LATSs-TSHR binding is present in most TSHR-Abs in variable degrees. The extended duration is due to the autoantibodies’ ability to work absent of the negative feedback mechanism that typically controls the thyroid’s hormonal regulation. The ability to work absent of the negative feedback mechanism is due to the lessened role of TSH in the stimulation pathway. The TSHR-Abs effectively replaces the role of TSH, being that, in GD, such autoantibodies are perpetually present within the body. Thus, in patients with GD, even though TSH secretion may have been terminated due T4 being present at the necessary level for the initiation of the negative feedback mechanism, hormone synthesis and secretion of the thyroid will continue because of TSHR-Abs’ ability to independently stimulate TSHRs (Prabhakar et al. 2003).

4.2.2. Mechanisms of TSHR-Ab Thyroid Stimulation.As previously noted, the paramount function of TSHR-Abs is to stimulate the synthesis and secretion of T3 and T4 through their binding to TSHRs. Their binding does such in two distinct fashions: (1) Stimulation of the sodium-iodine symporter’s synthesis and (2) Stimulation of thyroid adenylate cyclase activity (Prabhakar et al. 2003). The earlier fashion serves to aid in the increased uptake of iodine by they thyroid’s tissues in GD. This allows for the thyroid to have the increased levels of iodine necessary for the prolonged stimulation of hormone production and secretion that is induced by the diseases’ TSHR-Abs. The latter fashion, stimulation of thyroid adenylate cyclase activity, results in the increased synthesis and secretion of thyroid hormones, as well as elevated rates of thyroid cellular survival, which is a contributing cause of the thyroids increased size that is a characteristic of GD. Furthermore stimulating the thyroid’s adenylate cyclese activity may also facilitate the activation of the PKC pathway within the cell, which leads to proliferation of thyroid cells (Prabhakar et al. 2003).

4.3. The Immune System’s Role In Graves’ Disease

In GD, the thyroid cells, or thyrocytes, that serve to communicate with the immune system typically express abnormal proteins, such as: HLA Class II molecules, CD40, adhesion molecules, cytokines, TNF-a, IFN-g, and IL-1(Prabhakar et al. 2003). These differing thyrocyte characteristics are hypothesized to provoke an abnormal autoimmune response that exacerbates the symptoms of hyperthyroidism. Furthermore, germinal centers are known to form within the thyroid tissues of patients suffering from GD (Prabhakar et al. 2003). Such centers act to intensify the autoimmune responses, which subsequently serves to further the inflammation of the thyroid gland. While these factors are important in understanding the course of GD, the T cell response in GD is considered to be of paramount importance in the pathogenesis and maintenance of the disease.

4.3.1. T Cell Response in Patients with Graves’ Disease. Patients suffering from GD demonstrate an atypical Th2 T cell response; where as healthy individuals normally display a dominating CD8 or Th1 T cell response (Prabhakar et al. 2003). The reversal of dominating responses is caused by a rare circumstance, in which B cell activation is T cell dependant. Such a B cell activation mechanism induces the secretion of IL-10 cytokines, which explicitly facilitate only the Th2 response that is prominent in GD patients.

The importance of a Th2 response in GD can be seen upon the understanding of the role that CD8 cells play in context of the immune system’s thyroid management. CD8 cells are known to work against Th2 cellular responses, actively striving to suppress them (Prabhakar et al. 2003). This is evidenced in studies that demonstrate the presence of significantly increased CD8 levels during the acute periods of GD. CD8 cells are also recognized as having the ability to guard against the infiltration of thyroid tissues by B cells. The failure of CD8 cells to achieve a dominant immune response over the Th2 cells produces a cellular environment that is lacking in the proper biological mechanisms that guard against lymphocyte tissue infiltration, which consequently gives rise to the infiltration of thyroid tissues by lymphocytes (Prabhakar et al. 2003).

Effectively, the aftermath of a dominating Th2 T cell response produces an environment in which the thyroid is subject to infiltration of lymphocytes, which serves to evoke an autoimmune response of antibodies that helps facilitate the onset of GD symptoms. The combination of such a response and the following TSHR-Ab/TSHR interactions facilitate the onset of GD’s symptoms.

5. Neuropsychological Manifestations of Graves Hyperthyroidism.

There has been a persistent documentation pertaining to the manifestation of neuropsychological symptoms within patients suffering from Graves’ hyperthyroidism. Most notably, individuals suffering from the disease have reported symptoms of cognitive impairment, predominantly in their memory and concentration, as well as psychiatric symptoms of depression and increased anxiety. The nature of such symptoms in GD patients is very controversial, as there is sufficient published research literature that supports both, hyperthyroidism being the facilitating factor of symptom onset and it not playing a role in the onset of neuropsychological symptoms.  However, in 2005 Bunevicius et al. conducted psychiatric research pertaining to the prevalence of mood and anxiety disorders in women with treated hyperthyroidism caused by Graves’ disease.

5.1. Mood and Anxiety Disorders in Women with Treated Hyperthyroidism Caused by GD

Bunevicius et al. (2005) set out to compare the prevalence of mood and anxiety disorders in women, the primary risk group of GD, whom have been treated for Graves’ hyperthyroidism versus the prevalence of the same disorders in women lacking a history of and thyroid disease. The experimental sample of the study consisted of 30 inpatient women that were being treated for Graves’ hyperthyroidism, while the control sample was comprised of inpatient women that were being treated for non-thyroidal issues. They evaluated the diagnosis of anxiety and mood disorders using a standard Mini-International Neuropsychiatric Interview and for mood and anxiety ratings using the Profile of Mood States (POMS). At the time of testing, 14 of the 30 patients in the experimental sample group were still suffering from a hyperthyroid, while the other 16 were euthyroid, having a thyroid that had been restored to its normal functional levels.

In comparison to the control group, there was a statistically significant greater prevalence of social anxiety disorder, generalized anxiety disorder, major depression, and total mood and anxiety disorders within the experimental group. Furthermore, the experimental group held increased symptom scores according to the POMS than the control group. The experimental sample group also held a significantly higher medical history in their prevalence of mania or hypomania, as well as lifetime bipolar disorder. These findings were consistent within the experimental subgroups of patients with hyperthyroid and euthyroid patients alike.

Ultimately, the study yielded findings that allowed for the researchers to conclude that hyperthyroid has a significant role in the onset of psychiatric symptoms within graves disease. This conclusion was reached based on their findings that demonstrated an elevated prevalence of mood and anxiety disorders within women being treated for hyperthyroidism.

6.             Discussion