graves disease

Graves disease, named after Robert J. Graves, MD,circa 1830s, 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. Graves disease, along with Hashimoto thyroiditis, is classified as an autoimmune thyroid disorder.

In some patients, Graves disease represents a part of more extensive autoimmune processes leading to dysfunction of multiple organs (eg, polyglandular autoimmune syndromes). Graves disease is associated with pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis, myasthenia gravis, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.

Graves ophthalmopathy is shown below.

Graves disease. Varying degrees of manifestations of Graves ophthalmopathy.

Recent studies

Boelaert et al investigated the prevalences of and relative risks for coexisting autoimmune diseases in patients with Graves disease (2791 patients) or Hashimoto thyroiditis (495 patients). The authors found coexisting disorders in 9.7% of patients with Graves disease and in 14.3% of those with Hashimoto thyroiditis, with rheumatoid arthritis being the most common of these (prevalence = 3.15% and 4.24% in Graves disease and Hashimoto thyroiditis, respectively). Relative risks of greater than 10 were found for pernicious anemia, systemic lupus erythematosus, Addison disease, celiac disease, and vitiligo. The authors also reported a tendency for parents of patients with Graves disease or Hashimoto thyroiditis to have a history of hyperthyroidism or hypothyroidism, respectively

Hyperthyroidism, thyroid storm, and Graves disease are conditions of excess thyroid hormone. The elevated level of thyroid hormones can result in clinical manifestations ranging from mild to severely toxic with resultant morbidity and mortality for affected patients.

Pathophysiology

In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter, and the thyrotropin receptor. However, the thyrotropin receptor itself is the primary autoantigen of Graves disease and is responsible for the manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are well defined. Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of hyperthyroidism in healthy subjects by transferring thyrotropin receptor antibodies in serum from patients with Graves disease and the passive transfer of thyrotropin receptor antibodies to the fetus in pregnant women.
The thyroid gland is under continuous stimulation by circulating autoantibodies against the thyrotropin receptor, and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid hormones. The stimulating activity of thyrotropin receptor antibodies is found mostly in the immunoglobulin G1 subclass. These thyroid-stimulating antibodies cause release of thyroid hormone and thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP), and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth.
The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to have little role in the etiology of hyperthyroidism in Graves disease. However, they are markers of autoimmune disease against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic abnormality in persons with autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes may be the cause of CD4 lymphocyte reduction in these individuals.
Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22. Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. The genetic predisposition to thyroid autoimmunity may interact with environmental factors or events to precipitate the onset of Graves disease.
Two new susceptibility loci were found: the RNASET2-FGFR1OP-CCR6 region at 6q27 and an intergenic region at 4p14. Moreover, strong associations of thyroid-stimulating hormone receptor and major histocompatibility complex class II variants with persistently thyroid stimulating hormone receptor autoantibodies (TRAb)-positive Graves disease were found.
Graves disease patients a have higher rate of peripheral blood mononuclear cell conversion into CD34⁺ fibrocytes compared with healthy controls. These cells may contribute to the pathophysiology of ophthalmopathy by accumulating in orbital tissues and producing inflammatory cytokines, including TNF-alpha and IL-6. In a genome-wide association study of more than 1500 Graves disease patients and 1500 controls, 6 susceptibility loci were found to be related to Graves disease (major histocompatibility complex, TSH receptor, CTLA4, FCRL3, RNASET2-FGFR1OP-CCR6 region at 6q27, and an intergenic region at 4p14.
Pathophysiologic mechanisms are shown in the image below.

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.

Epidemiology

Frequency

United States

Graves disease is the most common cause of hyperthyroidism in the United States. A study conducted in Olmstead County, Minnesota estimated the incidence to be approximately 30 cases per 100,000 persons per year. The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves disease being the most common etiology. Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others.

International

Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study in the United Kingdom, the incidence was reported to be 100-200 cases per 100,000 population per year. The incidence in women in the UK has been reported to be 80 cases 100,000 per year.

Mortality/Morbidity

If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie, thyroid storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism of bone and muscle. Cardiac complications and psychocognitive complications can cause significant morbidity. Graves disease is also associated with ophthalmopathy, dermopathy, and acropachy.

• Thyroid storm is an exaggerated state of thyrotoxicosis. It occurs in patients who have unrecognized or inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid surgery, nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute mortality rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the syndrome, the mortality rate is approximately 20%.
• Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be particularly devastating in women, in whom the disease may compound the bone loss secondary to chronic anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The increase in bone loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum calcium and phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than in healthy control subjects, suggesting that FGF-23 is physiologically related to serum phosphate homeostasis in untreated Graves disease.
• Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves disease.
• Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive heart failure can occur.
• Psychiatric manifestations such as mood and anxiety disorders are common. Subjective cognitive dysfunction is often reported by Graves disease patients and may be due to affective and somatic manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis.
• Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial area. The nearly all (>95%) patients with dermopathy had ophthalmopathy. Advanced forms of dermopathy are elephantiasis or thyroid acropachy. Severe acropachy can be disabling and can lead to total loss of hand function.
• Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal lesions or optic nerve compression can be seen in severe Graves ophthalmopathy.
• Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroid-stimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with high TSI titer) are affected. Usually, the TSI titer falls during pregnancy.
• Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

Race

• In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci: AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with autoimmune thyroid diseases in persons of other races.
• Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and in CTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to vary with ethnicity.

Sex

• As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves disease has a female-to-male ratio of 7-8:1.
• The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema have thyroid acropachy.
• Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1.

Age

• Typically, Graves disease is a disease of young women, but it may occur in persons of any age.
• The typical age range is 20-40 years.
• Most affected women are aged 30-60 years

Hyperthyroidism, Thyroid Storm

Hyperthyroidism

Hyperthyroidism presents as a constellation of symptoms due to elevated levels of circulating thyroid hormones. Because of the many actions of thyroid hormone on various organ systems in the body, the spectrum of clinical signs produced by the condition is broad. The presenting symptoms can be subtle and nonspecific, making hyperthyroidism difficult to diagnose in its early stages without the aid of laboratory data.

The term hyperthyroidism refers to inappropriately elevated thyroid function. Though often used interchangeably, the term thyrotoxicosis, which is an excessive amount of circulating thyroid hormone, is not synonymous with hyperthyroidism. Increased levels of hormone can occur despite normal thyroid function, such as in instances of inappropriate exogenous thyroid hormone or excessive release of stored hormone from an inflamed thyroid gland.

Graves disease

Graves disease (diffuse toxic goiter), the most common form of overt hyperthyroidism, is an autoimmune condition in which autoantibodies are directed against the thyroid-stimulating hormone (TSH) receptor. As a result, the thyroid gland is inappropriately stimulated with ensuing gland enlargement and increase of thyroid hormone production. Risk factors for Graves disease include family history of hyperthyroidism or various other autoimmune disorders, high iodine intake, stress, use of sex steroids, and smoking. The disease is classically characterized by the triad of goiter, exophthalmos, and pretibial myxedema.

Thyroid storm

Thyroid storm is a rare and potentially fatal complication of hyperthyroidism. It typically occurs in patients with untreated or partially treated thyrotoxicosis who experience a precipitating event such as surgery, infection, or trauma. Thyroid storm must be recognized and treated on clinical grounds alone, as laboratory confirmation often cannot be obtained in a timely manner. Patients typically appear markedly hypermetabolic with high fevers, tachycardia, nausea and vomiting, tremulousness, agitation, and psychosis. Late in the progression of disease, patients may become stuporous or comatose with hypotension.

Pathophysiology

In healthy patients, the hypothalamus produces thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH); this in turn triggers the thyroid gland to release thyroid hormone.
Thyroid hormone concentration is regulated by negative feedback by circulating free hormone primarily on the anterior pituitary gland and to a lesser extent on the hypothalamus. The secretion of TRH is also partially regulated by higher cortical centers.
The thyroid gland produces the prohormone thyroxine (T4), which is deiodinated primarily by the liver and kidneys to its active form, triiodothyronine (T3). The thyroid gland also produces a small amount of T3 directly. T4 and T3 exist in 2 forms: a free, unbound portion that is biologically active and a portion that is protein bound to thyroid-binding globulin (TBG). Despite consisting of less than 0.5% of total circulating hormone, free or unbound T4 and T3 levels best correlate with the patient's clinical status.

Epidemiology

Frequency

United States

The overall incidence of hyperthyroidism is estimated between 0.05% and 1.3%, with the majority consisting of subclinical disease. A population-based study in the United Kingdom and Ireland found an incidence of 0.9 cases per 100,000 children younger than 15 years, showing that the disease incidence increases with age.^[1] The prevalence of hyperthyroidism is approximately 5-10 times less than hypothyroidism.
Thyroid storm is a rare disorder. Approximately 1-2% of patients with hyperthyroidism progress to thyroid storm.

Mortality/Morbidity

• Thyroid storm, if unrecognized and untreated, is often fatal.
• Adult mortality rate from thyroid storm is approximately 10-20%, but it has been reported to be as high as 75% in hospitalized populations. Underlying precipitating illness may contribute to high mortality.

Race

• White and Hispanic populations in the United States have a slightly higher prevalence of hyperthyroidism in comparison with black populations.

Sex

• A slight predominance of hyperthyroidism exists among females.

Age

• Thyroid storm may occur at any age but is most common in those in their third through sixth decades of life.
• Graves disease predominantly affects those aged 20-40 years.
• The prevalence of toxic multinodular goiter increases with age and becomes the primary cause of hyperthyroidism in elderly persons. 

http://emedicine.medscape.com/article/120619-overview#a0199
http://emedicine.medscape.com/article/767130-overview#showall