History: Graves Disease and Its Story
Since the 1700s, a condition connecting an enlarged thyroid gland and cardiovascular complications had been known to exist. This was briefly affirmed by a physician based on England named Caleb Hillier Perry.
However, it was in the 1830s that Irish Robert James Graves documented a disease not only with thyroid and cardiac manifestations, but with signs affecting the eyes as well. This was characterized with an enlarged thyroid gland, an increased cardiac rate, and a pair of widened, protruding eyes.
Graves then theorized that thyroid pathology brought about the said manifestations, thus the name Graves Disease. [1, 2]
An Image of Robert James Graves, with whom Graves Disease is named after.
Epidemiology: Graves Disease in Numbers
In the United States, there is an estimate of 30 cases per 100,000 persons every year diagnosed to have Graves Disease . It is said to be the most prevalent autoimmune disease in the whole of America, having been diagnosed in 60-80% of patients with hyperthyroidism .
Graves disease is more common in women than it is with men and children. It has an annual incidence of 0.5 per 1000 of women, mostly affecting those in the 40 to 60 years old age bracket. 
Its prevalence rates are similar in Caucasians and Asians, but are lower in Africans . Studies show a 20% concordance rate among monozygotic twins with the disease, lower in comparison to that of the dizygotic ones .
What Causes Graves Disease?
Exact etiology of the disease is unknown. However, risk factors are known to take part in the prevalence of this illness. These factors include genes, gender, infection, stress, and pregnancy.
As previously stated, Graves has a 20% concordance rate among monozygotic twins, as compared to that of the dizygotic ones. Hence, proving its genetic risk. 
Affecting 0.5 per 1000 women, the disease is more prevalent in women than it is in men and children. 
Graves disease has also been associated with infections, particularly to that of Yersinnia enterocolitica and Borrelia burgdorferi. [7, 8]
Stress was also found to be correlated with autoimmunity. Acute stress can induce suppression of the immune system. This is eventually followed by a period of immune hyperactivity, and consequently, autoimmune thyroid disease. 
The most common cause of hyperthyroidism during pregnancy is Graves Disease. Occurring in 1 out of 1500 pregnants, it causes 80 to 85% of hyperthyroidism cases among those infanticipating. 
Graves disease is characterized by an autoimmunity specifically affecting the thyroid glands. People with the disease have their systems create antibodies targeting the receptors of the thyroid stimulating hormone. This eventually leads to hyperthyroidism, increasing the levels of thyroid hormones, which is normally self-regulating with its negative feedback mechanism. [11, 12]
This is an illustration showing Graves disease as an autoimmune disorder. With the system devoid of its negative feedback mechanism, there is an unregulated, increased production of thyroid hormones.
Clinical Manifestations : Signs and Symptoms
Signs and symptoms of Graves Disease are mainly due to the disease’s organ-specific autoimmunity. Aside from the usual manifestations of increased thyroid levels, the disease can be also apparent on the patient’s physical appearance, particularly in the eyes and skin. [3, 11, 13, 14, 15]
- Enlargement of the thyroid gland, or goiter
- Exophthalmos – eye protrusion due to inflammation and swelling of eye muscles
- Excessive tearing and redness of eyes
- Eyelid retraction
- Gritty sensation of the eyes
- Partial Blindness – when pressure on optic nerve due to selling eye muscles is present
- Diplopia – double vision caused by weakened ocular muscles from long periods of inflammation
- Pretibial myxedema – “orange peel”, thickened, erythematous, lumpy and painless skin, usually found along the shins
- Fine and brittled hair
- Thinning of the skin
- Onycholysis – detachment of nails from the nail beds
- Vitiligo – hypopigmentation (lack of pigment) of the skin
- Easy fatiguability
- Heat sensitivity
- Increased sweating
- Inability to sleep
- Irregular menstruation – less frequent and less in amount of blood flow
- Increased heart rate
- Palpitations – fluttering of the chest
- Chest pain
- Difficulty of breathing
- Hand tremors
- Muscle cramps
- Muscle weakness
- Periodic paralysis
- Frequent bowel movements
- Weight loss
- Frequent urination
- Increased thirst
- Easy bruising
These manifestations usually progress, then stabilize within two to three years . The disease is of chronic duration, but is fluctuating. Patients show alternating periods of remission and relapse. Only around 40 % of patients have a single episode in the entire disease course. A few patients may even experience hypothyroidism, which also remit spontaneously .
A representation of how Graves Disease is manifested: with exophthalmos or bulging eyes, and a diffuse, large thyroid gland (goiter).
A patient with Graves Disease exhibiting pretibial myxedema on both lower extremities.
How is Graves Disease Diagnosed?
Assessment of Graves Disease includes a thorough history taking and physical examination. One should elicit the presence of such symptoms stated above, not just on the patient himself, but also among his relatives and family members. Physical evaluation should include palpation of the neck for thyroid enlargement, detection of a thrill from the increased blood flow, auscultation of a bruit, and testing for hyper responsive reflexes.
The anthropometrics and vital signs should be done, noting for tachycardia, weight loss and fever. Skin, extremities, eyes, and nails should not be left unexamined, for these may exhibit signs of Graves disease.  Once with the said clinical manifestations, confirmatory tests for Graves may be performed.
Thyroid function tests can be done, noting for an increase level of thyroid hormone and low level of TSH. Radioactive iodine uptake (RAIU), on the other hand, checks for a high iodine uptake of the thyroid gland. Lastly, a blood sample can determine the presence of antibodies that would specifically imply Grave Disease as the source of illness. 
These are images of the Radioactive Iodine Uptake scans. The one on the left shows that of a normal patient, with normal uptake of iodine; the right is that of a patient with Graves, with increased iodine uptake of the thyroid gland.
Current Treatment Modalities
Instead of focusing on the immune reaction causing Graves, the goal in its management includes regaining the normal states of the thyroid glands, by allowing the body to compensate for the thyroid glands’ hyperactivity. This could be attained thru antithyroid medications, surgery and radioactive iodine.
Medications inhibiting thyroid hormone synthesis, such as Carbimazole, Methimazole and Propylthiouracil, are used for patients with Graves Disease. These may not control the thyroid hormone levels permanently, but 30 to 40% may undergo remission lasting for more than ten years. [6, 14]
Individuals who do not respond well to medications may have their thyroid glands removed thru thyroidectomy. In performing this surgery, most, if not all, thyroid glands are removed. However, thyroid hormone replacement therapy should be needed after the procedure to provide for the hormones the body needs, but can no longer produce. [3, 14]
In the Radioactive Iodine (RAI) treatment modality, the subject must ingest a pill containing the radioactive iodine. This substance induces radiation to the thyroid glands, damaging the cells, and thus, a decrease in the production of thyroid hormones will ensue. It neutralizes hyperthyroidism within 6 to 18 weeks. Like surgery, this requires the subject to have a thyroid hormone replacement therapy to supply the body’s demand for such hormones. [11, 14]
Graves disease does not have a cure. It may subside after doing the said treatment modalities, or may even result in hypothyroidism, or thyroid hormone deficiency. But, these cannot actually remove the causative immunologic disorder. It requires lifelong monitoring of thyroid levels and in some cases, lifelong treatment or supplementation of thyroid hormones. Worst case scenario, untreated conditions may lead to a very lethal condition, known as thyrotoxicosis or thyroid storm. [3, 16]
- Ellis H. Robert Graves: 1796-1852. British Journal of Hospital Medicine. (London). June 2006; 67 (6): 313.
- Jacobson, D. et al. Epidemiology and Estimated Population Burden of Selected Autoimmune Diseases in the United States. Clinical Immunological Immunopathology. 1997; 84: 223-43.
- Vanderpump, H. et al. The Epidemiology of Autoimmune Thyroid Disease: Autoimmune Endocrinopathies. Contemporary Endocrinology. 1999; 15: 141-62.
- Weetman, A. et al. Graves Disease. New England Journal of Medicine. 2000; 343(17): 1236-48.
- Gangi, E. et al. Characterization of Recombinant Yersinia enterocolitica lipoprotein; Implications For Its Role In Autoimmune Response Against Thyrotropin Receptor. Autoimmunity. 2004 Sep – Nov.; 37 (6-7):515-20
- Benvenga, S. et al. Homologies Between Proteins of Borrelia burgdoferi and Thyroid Autoantigens. Thyroid. 2004; 14: 964-6.
- Janeway, C. et al. 2001. Immunobiology: The Immune System in Health and Disease. Nee York: Garland Publishing.
- Shomon, M. Diagnosis of Graves’ Disease and Hyperthyroidism. 2008 June. http://www.thyroid.about.com