Last Updated: September 15, 2022

Introduction to Graves Disease

Graves disease is a disorder that was originally described by the Irish physician, Robert James Graves in 1835. His original description referred to the disease as “exophthalmic goiter”. Graves disease is now known to be a syndrome that manifests as hyperthyroidism with a diffuse goiter. Specifically, Graves disease is associated with thyrotoxicosis which is defined as a state of thyroid hormone excess but is not synonymous with hyperthyroidism (result of excessive thyroid function). The major causes of thyrotoxicosis are the hyperthyroidism of Graves disease, toxic adenomas, and toxic multinodular goiter. In addition to hyperthyroidism and goiter, Graves disease is associated with eye disease characterized by inflammation and involvement of intra-orbital structures, dermopathy referred to as pretibial myxedema, and rare involvement of the nails, fingers and long bones known as acropachy.

Graves disease is an autoimmune disease caused by autoantibodies to the thyroid stimulating hormone (TSH) receptor, TSH-R. These antibodies (identified as TSI: TSH-R-stimulating immunoglobulins) bind to the TSH-R on thyroid follicular cells and mimic the receptor activation actions of TSH. The consequences of this hyperactivation of the thyroid are stimulated follicular cell growth, resulting in diffuse thyroid enlargement and increased production of thyroid hormones. With respect to the thyroid hormones, the fraction of triiodothyronine (T3) production relative to thyroxine (T4) is increased.

Graves disease is the most common autoimmune disease in the US affecting 0.5% of the population. Graves disease accounts for 60-80% of all forms of thyrotoxicosis with the prevalence being higher among women than men. Smokers and those individuals with other autoimmune disorders or with a family history of thyroid autoimmunity are more likely to develop the disease than the general population. The disease rarely begins prior to adolescence and typically manifests between 20 and 50 years of age. Across different populations, the rate of the disease can vary dependent upon the intake of iodine with increased prevalence of Graves disease associated with higher iodine intake.

Clinical Features of Graves Disease

Physical Findings

The onset of Graves disease is usually acute, reflecting the sudden production of TSI. Most patients will report the classical symptoms of hyperthyroidism that include weight loss despite increased appetite, heat intolerance, irritability, insomnia, sweatiness, diarrhea, palpitations, muscular weakness and menstrual irregularity. Upon physical examination the classic clinical signs of Graves disease will be diffuse goiter, eye disease, warm smooth skin, hyperreflexia, fine resting tremor, and tachycardia. Each of these symptoms of Graves disease are related to the effects of thyroid overstimulation of metabolism and exacerbation of sympathetic nervous system responses. The sympathomimetic effects include the aforementioned tachycardia as well as hand tremors, anxiety, and gastrointestinal hypermotility. Less common findings include atrial fibrillation and a thyroid bruit reflecting the marked increase in thyroid vascularity. Older presenting patients are more likely to present with depression, weight loss, atrial fibrillation, and congestive heart failure then will be present in younger patients. Although less likely, some Graves disease patients will present with proximal myopathy, cardiomyopathy, malabsorption, hypercalcemia, hepatitis, gynecomastia, and loss of glycemic control in patients with diabetes.

Eye disease affects up to 50% of patients with Graves disease. The pathophysiology of the ocular issues associated with Graves disease are distinct from the sympathomimetic ocular effects of thyroid hormone excess which are identified as thyroid stare, known as the Dalrymple sign (wide open eyes and eyelid spasm). The cardinal features of thyroid eye disease include exophthalmos (abnormal eyeball protrusion), chemosis (conjunctive edema) and when severe, impaired extra-ocular muscle movement. The impaired eye movement is most easily seen during a vertical and lateral gaze test. The consequences of chemosis include infections leading to swollen, congested, watery or gritty eyes. Vision changes also result resulting in loss of visual fields or acuity and diplopia (double vision).

Biochemical Findings

In any patient suspected of hyperthyroidism it is extremely important to perform a comprehensive clinical assessment of disturbances in biochemical processes. To this end, serum TSH is a sensitive index for primary thyroid disease and therefore, the most important initial screening test. Patients who are identified with reduced levels of TSH are likely to have suppression of the hypothalamic-pituitary axis. In these patients it is necessary to subsequently measure for the level of free T3 and T4. In Graves disease associated hyperthyroidism both of these hormones will be elevated in the serum. Care must be taken in interpreting free thyroid hormone levels as artifacts in their measurements are associated with critical illness, disturbances in binding proteins due to drugs or pregnancy, and to the use of heparin as an anticoagulant.

The measurement of serum TSH-receptor antibodies is highly correlated to the confirmation of a diagnosis of Graves disease. In 90% of patients with presumed Graves disease, TSI and  TSH-receptor binding immunoglobulins (TBII) are found and are directly related to the disruption in thyroid function. However, routine measurement of TSI or TBII is unnecessary in patients in whom the diagnosis of Graves disease is confirmed due to thyrotoxicosis with eye changes suggestive of thyroid eye disease. The measurement of TSI and TBII are also useful for assessing the risk of relapse after a course of drug treatment for Graves disease. These drugs include the thionamides, methimazole (MMI), carbimazole, and propylthiouracil (PTU). Measurement of the autoantibodies is also highly useful when assessing the risk of neonatal Graves disease in pregnant women with Graves disease. Other antibodies, including thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies, may be significantly elevated in Graves disease but they are not specific to a diagnosis of the disease. These latter autoantibodies may also be detected in Hashimoto disease (chronic lymphocytic thyroiditis resulting in hypothyroidism). Hashimoto disease is the most common form of hypothyroidism in the US.

Genetics of Graves Disease

The majority of autoimmune diseases, including Graves disease, strongly correlate to polymorphic genes in the major histocompatibility complex (MHC). The human MHC is often referred to as the HLA (human leukocyte antigens) region and HLA encoded molecules are central for the function of the immune system. HLA encoded proteins bind fragments of antigens in the form of peptides and present them to T lymphocytes. HLA molecules are divided into HLA class I (HLA-A, B, C) and class II (HLA-DR, DQ, DP). For a brief, detailed discussion of the HLA molecules visit the Diabetes page.

Use of the “shared epitope hypothesis” in the analysis of autoimmune disorders, it has been determined that there is a primary role of the HLA DRB1 locus in the etiology of Graves disease. In most Graves disease patients increased prevalence of the DRB1*03 DQA1*05 DQB1*02 haplotype is usually observed suggesting that some gene(s) encoded at this locus increase the risk of disease development by 2–3 fold.

Direct analysis of the DNA sequence of exon 2 of the HLA-DRB1 gene in 208 Graves disease patients and 149 controls found an associated polymorphism at amino acid position 74. Variants with arginine at position 74 appear to be overrepresented among Graves disease patients. The possibility that DRB1 position 74 is a primary determinant of Graves disease susceptibility is consistent with the results of another study analyzing DRB1, DQB1 and DQA1 loci in 871 Graves disease patients and 621 controls.