Graves disease is an autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies.

Thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone. Its named for Robert Graves, an Irish physician, who described this form of hyperthyroidism circa 1830s Graves disease is associated with pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis, myasthenia gravis, Sjgren syndrome, rheumatoid arthritis, and systemic lupus erythematosus. Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications). Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, low-normal to slightly depressed platelet count.. Investigation of gynecomastia associated with Graves disease may reveal increased sex hormonebinding globulin levels and decreased free testosterone levels. A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels. Thyrotropin-releasing hormone testing has largely been replaced by third-generation thyrotropin assays. A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy
HISTORY

Because Graves disease is an autoimmune disorder that also affects other organ systems, taking a careful patient history is essential to establishing the diagnosis. In some cases, the history might suggest a triggering factor such as trauma to the thyroid, including surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma. Other factors might include interferon (eg, interferon beta-1b) or interleukin (IL-4) therapy. Patients usually present with symptoms typical of thyrotoxicosis. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation. Tachycardia and palpitation are very common symptoms.

Not all patients present with such classic features. In fact, a subset of patients with euthyroid Graves disease is described. In elderly individuals, fewer symptoms are apparent to the patient. Clues may include unexplained weight loss, hyperhidrosis, or rapid heart beat. Young adults of Southeast Asian descent may complain of sudden paralysis thought to be related to thyrotoxic periodic paralysis. There is an association of polymorphisms of the calcium channel alpha1-subunit gene with thyrotoxic periodic paralysis.[20] One third of patients with thyrotoxic hypokalemic periodic paralysis were found to have mutations in the inwardly rectifying potassium channel (Kir2.6).[21] The symptoms of Graves disease, organized by systems, are as follows:

General - Fatigue, general weakness Dermatologic - Warm, moist, fine skin; sweating; fine hair; onycholysis; vitiligo; alopecia; pretibial myxedema Neuromuscular - Tremors, proximal muscle weakness, easy fatigability, periodic paralysis in persons of susceptible ethnic groups Skeletal - Back pain, increased risk for fractures Cardiovascular - Palpitations, dyspnea on exertion, chest pain, edema Respiratory - Dyspnea Gastrointestinal - Increased bowel motility with increased frequency of bowel movements Ophthalmologic - Tearing, gritty sensation in the eye, photophobia, eye pain, protruding eye, diplopia, visual loss Renal - Polyuria, polydipsia Hematologic - Easy bruising Metabolic - Heat intolerance, weight loss despite increase or similar appetite, worsening diabetes control Endocrine/reproductive - Irregular menstrual periods, decreased menstrual volume, gynecomastia, impotence Psychiatric - Restlessness, anxiety, irritability, insomnia

Physical
Most of the physical findings are related to thyrotoxicosis. Physical findings that are unique to Graves disease but not associated with other causes of hyperthyroidism include ophthalmopathy and dermopathy. Myxedematous changes of the skin (usually in the pretibial areas) are described as resembling an orange peel in color and texture. Onycholysis can be seen usually in the fourth and fifth fingernails. The presence of a diffusely enlarged thyroid gland, thyrotoxic signs and symptoms, together with evidence of ophthalmopathy or dermopathy, can establish the diagnosis.

Common physical findings, organized by anatomic regions, are as follows:

General - Increased basal metabolic rate, weight loss despite increase or similar appetite Skin - Warm, most, fine skin; increased sweating; fine hair; vitiligo; alopecia; pretibial myxedema Head, eyes, ears, nose, and throat - Chemosis, conjunctival irritation, widening of the palpebral fissures, lid lag, lid retraction, proptosis, impairment of extraocular motion, visual loss in severe optic nerve involvement, periorbital edema Neck - Upon careful examination, the thyroid gland generally is diffusely enlarged and smooth; a well-delineated pyramidal lobe may be appreciated upon careful palpation; thyroid bruits and, rarely, thrills may be appreciated; thyroid nodules may be palpable. Chest - Gynecomastia, tachypnea, tachycardia, murmur, hyperdynamic precordium, S3, S4 heart sounds, ectopic beats, irregular heart rate and rhythm Abdomen - Hyperactive bowel sound Extremities - Edema, acropachy, onycholysis Neurologic - Hand tremor (fine and usually bilateral), hyperactive deep tendon reflexes Musculoskeletal - Kyphosis, lordosis, loss of height, proximal muscle weakness, hypokalemic periodic paralysis in persons of susceptible ethnic groups Psychiatric - Restlessness, anxiety, irritability, insomnia, depression

Ophthalmopathy is a hallmark of Graves disease. Approximately 25-30% of patients with Graves disease have clinical evidence of Graves ophthalmopathy. Thyrotropin receptor is highly expressed in the fat and connective tissue of patients with Graves ophthalmopathy. Measuring diplopia fields, eyelid fissures, range of extraocular muscles, visual acuity, and proptosis provides quantitative assessment to follow the course of ophthalmopathy. Signs of corneal or conjunctival irritation include conjunctival injection and chemosis. A complete ophthalmologic examination, including retinal examination and slit-lamp examination by an ophthalmologist, is indicated if the patient is symptomatic. Although thyroid nodule(s) may be present, excluding multinodular toxic goiter (especially in older patients) as the cause of thyrotoxicosis is essential. The approach to treatment may be different. Excluding thyroid neoplasia is also important in these patients because reports have indicated that differentiated thyroid cancer is probably more common in patients with Graves disease and may also have a more aggressive course in these patients.

Causes
Graves disease is autoimmune in etiology, and the immune mechanisms involved may be one of the following:

Expression of a viral antigen (self-antigen) or a previously hidden antigen The specificity crossover between different cell antigens with an infectious agent or a superantigen Alteration of the T cell repertoire, idiotypic antibodies becoming pathogenic antibodies New expression of HLA class II antigens on thyroid epithelial cells (eg, HLA-DR antigen)

The autoimmune process in Graves disease is influenced by a combination of environmental and genetic factors. Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22.[4] Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene,[23, 24] and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease.[23] This SNP of the CTLA4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment.[25] There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease.[4, 26] The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases.[27] Alleles of intron 7 of the thyrotropin receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease

Environmental factors associated with susceptibility are largely unproven. Other factors include infection, iodide intake, stress, female sex, steroids, and toxins. Smoking has been implicated in the worsening of Graves ophthalmopathy.

Graves disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens.[28, 29] Stress can be a factor for thyroid autoimmunity. Acute stress-induced immunosuppression may be followed by immune system hyperactivity, which could precipitate autoimmune thyroid disease. This may occur during the postpartum period, in which Graves disease may occur 3-9 months after delivery. Estrogen may influence the immune system, particularly the B-cell repertoire. Both T- and B-cell function are diminished during pregnancy, and the rebound from this immunosuppression is thought to contribute to the development of postpartum thyroid syndrome. Interferon beta-1b and interleukin-4, when used therapeutically, may cause Graves disease. Trauma to the thyroid has also been reported to be associated with Graves disease. This may include surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma.