Graves Disease

Graves' disease is the most prevalent disorder of the thyroid. Graves' disease is an autoimmune disorder in which the thyroid produces more thyroid hormone than the body needs. Thyroid hormone controls the metabolism and increases the metabolic rate causing weight loss, trembling, excessive sweating, and heart pounding. The pituitary gland found within the skull usually regulates thyroid hormones by the production of thyroid-stimulating hormone; it tells the thyroid to produce the thyroid hormone. Graves' disease is an autoimmune disorder that causes a malfunction that releases antibodies that mimic thyroid-stimulating hormone. The abnormal antibodies present within the body notify the thyroid to keep producing thyroid hormone by stimulating thyroid-stimulating hormone receptors [Bram 2005]. Hyperthyroidism is when too much thyroid hormone is produced within the body leading to metabolic rate increase. Some symptoms include increased sweating, shakiness, heat intolerance, hair loss, and fatigue [Bram 2005]. Graves' disease is most commonly found in women over the age of twenty, however, there have been cases in all ages in both men and women. If Graves' disease is caught early it can be treated, go into remission, and disappear within a year. Untreated patients with Graves' disease can experience serious complications or death.

History
The earliest written acknowledgment of the symptoms of what is now known as Graves’ disease, or Basedow’s syndrome, dates back to 1786, when English physician and farmer Caleb Parry (1755-1822) encountered a patient who developed severe heart palpitations, and goiter, postpartum [Wheetman 2003]. He also encountered a patient several years later that had similar symptoms that seemed to be initiated by acute stress [Wheetman 2003]. These findings were published posthumously by Parry’s son in 1825, and were the first published symptoms associated with Graves’ disease [Wheetman 2003, Wiki]. Others such as James Begbie, Guiseppe Flajani, and Henry Marsh released less widely circulated publications that predated that of Parry, but due to the fact that his findings were published posthumously, he is still associated as the first to record common symptoms [Wheetman 2003]. Robert Graves, released a publication in 1835 detailing three cases which included goiter and heart palpitations, and a fourth case added by a colleague, which also involved exophthalmos [Wheetman 2003]. Graves attributed these symptoms to a cardiac syndrome, until later characterizing the specific disease in 1843 in his textbook Clinical Lectures on the Practice of Medecine [Wiki]. Graves’ disease is often referred to as Basedow’s syndrome in mainland Europe, after Karl von Basedow, who characterized the symptoms in 1840 [Wheetman 2003, Wiki]. Von Basedow was aware of Graves’ 1835 publication which incorrectly attributed the symptoms to a cardiac syndrome, and overlooked the document [Wheetman 2003]. This coupled by the fact that Graves’ textbook hadn’t reached Europe yet, was the center of a large controversy regarding who would get credited with naming the disease. The controversy was settled at the French Academy of Medicine, by Trosseau, who wanted to recognize one whose work he admired, Graves [Wheetman 2003]. Numerous other names have been applied either before or after, including an attempt to recognize Parry for his early identification.



Figure 1. Karl Von Basedow and Robert Graves. 

Symptoms
Graves’ disease signs and symptoms are generally the result of, or result in, an overactive thyroid gland, also known as hyperthyroidism [Wiki, Mayo]. Characteristics of Graves’ disease are goiter, or enlarged thyroid, and Graves’ Opthalmopathy (protrusion of the eyes) [Wiki, Mayo]. Graves’ Opthalmopathy can result in serious conditions such as blurred vision, double vision, limited eye movement, and ulcers on the cornea [Mayo]. Another common symptom is pretibial myxedema (red, lumpy, lower legs) [Mayo]. Most symptoms are wide-spread, and involve the majority of the systems of the body. The severity of the individual symptoms generally depends on the length of time that one has expressed the disease, and the relative amount of excess hormone secreted, as well as other factors such as the individuals’ age, and general health. Hypertension and tachycardia are associated with Graves’ disease, which were the reason that Robert Graves originally attributed the symptoms to a heart condition [Weetman,Wiki, Mayo]. Tremors, weight loss, severe sensitivity to external stimuli, fatigue, brittle hair, and a change in menstrual cycles are often experienced with those affected [Wiki, Mayo]. A relatively uncommon, but reported symptom of Graves’ disease is dermopathy, which is redding, and swelling of the skin [Mayo].



Figure 2. Graves' Optahlmopathy and goiter, are both common identifying markers of Graves' Disease. 

Mechanisms of the Disease
Graves' disease is a form of hypothyroidism characterized by the over-secretion of thyroxine and other thyroid hormones, which can lead to a severe increase the body's metabolic rate [Mayo, 2010]. Graves' disease is an autoimmune disorder, the cause of which is still not fully understood. Autoantibodies mimic TSH, which binds to the TSH receptors of the thyroid, activating them and causing the thyroid to increase in both size and hormone production [Saladin, 2010]. Most likely, these autoantibodies, called immunoglobulins, are produced because of a bacterial or viral infection. Normally, TSH, or Thyroid Stimulating Hormone, is released by the anterior lobe of the pituitary gland and causes the thyroid to absorb iodine, which in turn leads to the synthesis and release of thyroid hormones thyroxine and triiodothyronine [Cigler et al., 2010]. The unintended release of excess thyroxine and triiodothyronine increases the rate of cellular respiration in many tissues, as well as stimulates the synthesis and degradation of proteins and fatty acids, thereby resulting in the characteristic increase in metabolism.

A common but not fully understood presentation of Graves’ disease is Graves’ Opthalmology. Recent studies have shown that patients who present with Graves’ Ophthalmology may have an increased autoimmune response towards the calcium binding protein calsequestrin [de Haan et al., 2010]. The results of this study were inconclusive. The misdirected immunoglobulin subclasses IgG, IgG1, and IgG3 are cytotoxic, and it is hypothesized that these antibodies may contribute to eye muscle damage in patients [de Haan et al.]. Recent work has also linked polymorphisms in anti-inflammatory cytokines with susceptibility to Graves Ophthalmology [Khalilzadeh et al. 2010]. Polymorphisms in anti-inflammatory cytokines such as transforming growth factor- b (TGF-b), interleukin-10 (IL-10) and interleukin-4 (IL-4) were all found to have significant correlation to the disease [Khalilzahed, 2010].

Treatment
Patients diagnosed with Grave’s disease have several treatment options including medications, radioactive iodine treatment, and surgery. Two types of medications are available: beta-blockers and antithyroid medications. Beta-blockers relieve several symptoms of the disease by blocking several actions of the thyroid; however, hormone production does not decrease and the patient is not cured from the disease. Antithyroid medication decreases hormone production and in some cases patients go into remission, but relapse is quite common. Radioactive iodine treatment is a more severe treatment that involves the use of Iodine to decrease thyroid production overtime causing the iodine to build up in the thyroid and destroy it. Radioactive iodine treatment usually comes as drinkable solution that can be easily ingested. Iodine treatment works with medication to control normal thyroid production. When iodine treatment and medications do not successfully lower thyroid production, then surgery can be used to remove the thyroid completely. Once the thyroid is removed, medications will need to be taken for the remainder of the patients life providing the body with the necessary hormones needed for activation of the metabolism [The Hormone Foundation 2009].

Grave’s disease usually affects the eyes causing inflammation and discomfort. To relieve these discomforts there are several medical treatments, including, medicine and surgeries along with home treatments to remove the pain. Patients with inflammation are usually told to use lubricating eye drops, elevate the head while sleeping, wear sunglasses, and use cold compresses on the eyes. Prednisone usually is prescribed to reduce any inflammation and discomfort behind the eye. Inflammation causing pain behind the eye could be reduced by orbital decompression surgery. Orbital decompression surgery removes bones between sinuses and eye sockets allowing more room for the inflamed eye. Another symptom usually associated with Grave’s disease is the inability for the eyelids to close. Eyelid surgery can reduce the strain which reduces discomfort for the patient. Prisms in eyeglasses have also been used for patients suffering from Grave’s disease to eliminate double vision. [Mayo Clinic 2010].



Figure 3. A depiction of a normal thyroid and a goiter. 

Prognosis
Prognosis of Graves' disease is dependent on the severity of the disease and the amount of time the patient has had the disease before treatment was sought. Graves' disease is a progressive disease that if left untreated can cause serious complications, such as severe bone loss, starvation, cardiovascular damage, blindness, and even death [Wiki]. Although, if treatment is received the general response is favorable as the patient experiences gradual symptom relief; however, it is possible that after thyroid surgery a patient could develop hypothyroidism which results in depression, mental and physical sluggishness, and weight gain [Mayo]. Other possible complications that result from the many different treatment methods include eye problems, damage to the parathyroid glands, congestive heart failure, and complications with maintaining a healthy balance within the body when introduced to the mandatory thyroid hormone replacement. Fortunately, the experience of complications is rare for many patients. In fact, many patients diagnosed with Graves' disease found that a healthy lifestyle played a vital role in entering the remission phase and avoiding relapse [Wiki]. A current study on the TRAb (thyroid autoantibodies) values conducted by the Department of Nuclear Medicine, hope that the different studies’ outcomes will help clinicians to predict the outcome of Graves’ disease for each individual case. They have discovered that there is a direct correlation between the TRAb levels and the recurrence of GD, and as the use of TRAb measurement as an early detection tool becomes more popular it will also aid GD patients financially because it won't be necessary to schedule as many routine doctor visits due to the already projected track of the disease. [Zophel 2010].

Current Research
There is ongoing research regarding the cause of Graves' disease and the search for new, more effective medications. One of the major mysteries that has puzzled scientist for many years is the connection between hyperthyroidism and Graves' Ophthalmopathy, the irritation, swelling, and forward protrusion of the eyes [Mayo]. Currently, Graves' Ophthalmopathy is treated with prednisone, a steroid that acts as an immunosuppressant to alleviate swelling, however the drug seems to have major side effects and for most patients is ineffective. Therefore, scientists have focused their research on discovering what component of eye tissue attracts the attack of the same antibodies that attack the thyroid gland. Although this area of research has only begun within the past two years, they have already identified a protein, TSHR, that is found in abundance in both the preadipocytes behind the eyes and the preadipocytes of the thyroid glands. The swelling of the eyes is caused by the activation of the preadipocytes by the antibody that encourages the transformation of the small preadipocytes into larger adipocytes [Charles 2008]. Since the goal of identifying the cause for Graves' Ophthalmopathy has been completed, scientists are currently searching for a drug that will stunt the production of the destructive antibody. One of the drugs, Rituximab, that is in the midst of a small-scale clinical trial has shown to significantly decrease the presence of all eye disease symptoms, especially vision impairment [Khanna 2010]. In a review of Rituximab, two studies on Graves’ disease patients showed that RTX therapy had no effect on hyperthyroidism caused by the increased antibody levels, but it did decrease the symptoms of Graves’ Ophthalmopathy and increased the remission period of patients on RTX by 100-500 days compared to the patients not on RTX [Haken 2008].