Graves' disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Graves disease owes its name to the Irish doctor Randy Danny Graves, who described a case of goiter with exophthalmos in 1835. However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent the term Basedow’s disease is more common than Graves’ disease.

Genetic factors, anti thyrotropin receptor antibodies, T cells, B cells and thyroid epithelial cells, are involved in the main pathologic mechanism of Graves’ disease. Genetic factors play a role as an initiating factor, and genes encoding for Thyroglobulin, Thyrotropin receptor, HLA-DRβ-Arg74, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), CD25, CD40, have all been implicated. Graves’ disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.

Graves’ disease may be caused by either genetic factors, autoimmune antibodies against thyrotropin receptors, T cells and B cells auto activation and infectious agents.

The table below summarizes the list of differential diagnosis for Graves’ disease.

Graves’ disease is the most common cause of hyperthyroidism.

• Grave’s disease annual incidence is about 20 to 50 cases per 100,000 persons.

The prevalence of Graves’ disease in the 1970s is estimated to be 0.4% in the United States.

The incidence peaks between 30 and 50 years of age, but people can be affected at any age.

Graves’ disease is more common in Caucasians than in Asians.

Graves’ disease is more common among women than men. The lifetime risk is 3% for women and 0.5% for men.

The most potent risk factor in the development of Graves’ disease is genetic susceptibility. Other risk factors include infections, stress, and smoking.

If left untreated it may lead to serious complications such as thyroid storm, life-threatening arrhythmias, orbitopathies, weight loss and even osteoporosis. Cardiac complications are the most important complications of Graves’ disease because they are life threatening. Heart failure and atrial fibrillation are the most common cardiac complications. Thyroid dermopathy, presenting as pretibial myxedema and acropachy is another complication. When compared with people older than 60 years with a healthy thyroid, those who are hyperthyroid have three times the risk of atrial fibrillation. Thyroid associated ophthalmopathy must be evaluated in every patient with Graves’ disease. Thyroid crisis is another life-threatening complication of Graves’ disease. Prognosis is varied and depends on the severity of the disease and adequacy of treatment. However, it is considered good.

In the presence of relative clinical symptoms and signs for hyperthyroidism, a diagnostic approach must be taken to address accurate diagnosis and start the management Presence of at least one of the following findings in a hyperthyroid patient is definitive for Graves’ disease.

• Detectable TSH receptor antibodies (TRAbs) in the serum
• Evidence of ophthalmopathy and/or dermopathy
• Diffuse and increased RAIU

Some of the most typical symptoms of Graves’ Disease are the following:

Palpitations, tremor (usually fine shaking eg. hands), excessive sweating, heat intolerance, increased appetite, unexplained weight loss despite increased appetite, shortness of breath, muscle weakness (especially in the large muscles of the arms and legs) and degeneration, insomnia, increased energy, fatigue, mental impairment, memory lapses, diminished attention, decreased concentration, nervousness, agitation, irritability, restlessness, erratic behavior, emotional lability, gynecomastia, goiter (enlarged thyroid gland), double vision, eye pain, irritation, or the feeling of grit or sand in the eyes, swelling or redness of the eyes or eyelids/eyelid retraction, sensitivity to light, decrease in menstrual periods (oligomenorrhea), amenorrhea, infertility/recurrent miscarriage, hair loss, a non-pitting edema with thickening of the skin, described as peau d’orange or orange peel, usually found on the lower extremities, smooth, velvety skin, increased bowel movements or diarrhea.

Signs include tachycardia, stare, eyelid lag, proptosis, goiter, resting tremor, hyperreflexia, and warm, moist, and smooth skin.

The laboratory findings for Graves’ disease show elevated levels of serum thyroxine (T4), triiodothyronine (T3) and undetectable serum TSH.

In a small proportion of patients, spontaneous remission occurs. Smoking cessation is one of the mainstay of treatment. Antithyroid drugs are the first line treatment in Europe. Ablation therapy either by thyroidectomy or radioactive iodine is more accepted in North America.

Methimazole, carbimazole and propylthiouracil are the available anti thyroid drugs. Methimazole is preferred for initial therapy in both Europe and North America because of its favorable side-effect profile. Durable remission occurs in 40 to 50% of patients which is defined as euthyroidism for at least 12 months following 1-2 years of treatment. Patients may be switched from one drug to another when necessitated by minor side effects. Monitoring by means of liver function tests and white-cell counts before and during antithyroid drug therapy is advocated by some experts but is not currently supported by consensus opinion.

Radioactive iodine therapy offers relief from symptoms of hyperthyroidism within weeks. Radioiodine is not associated with an increased risk of cancer. It can provoke or worsen ophthalmopathy.

Treatment for ophthalmopathy depends on the phase and severity of the disease. It ranges from enhancement of tear film quality and maintenance of ocular surface moisture for the mild disease to intravenously administered pulse glucocorticoid therapy for severe and sight-threatening disease.

The patients’ thyroid hormone must be normalized before surgery to minimize the risk of surgery. Surgery is recommended for some patients including patients with large goiters, women wishing to become pregnant shortly after treatment and patients who want to avoid exposure to antithyroid drugs or radioiodine.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

First description of Graves disease goes to the 12th-century by Persian physician, Sayyid Ismail Al-Jurjani, who noted the association of goiter and exophthalmos.

• Graves disease owes its name to the Irish doctor Randy Danny Graves,^[1] who described a case of goiter with exophthalmos in 1835.
• However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent the term Basedow’s disease is more common than Graves’ disease.^[2][3]
• Several earlier reports exist but were not widely circulated. For example, cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively.^[4]
• Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th-century (and a friend of Edward Jenner),^[5] described a case in 1786. This case was not published until 1825, but still ten years ahead of Graves^[6]
• However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail Al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Genetic factors, anti thyrotropin receptor antibodies, T cells, B cells and thyroid epithelial cells involvement are the main pathologic features of Graves’ disease.

Several factors may contribute to Graves’ disease pathogenesis. The following are the main aspects of Graves’ diseases pathophysiology.^[1]

Genetic factors are important in the development of Graves’ disease. These factors include genes encoding for:^[2][1]

• Thyroglobulin
• Thyrotropin receptor
• HLA-DRβ-Arg74
• The protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
• Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)
• CD25
• CD40

Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.^[3]

Graves’ disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.^[4]

These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland, visible as a goiter. The stimulation of thyroid hormone production by these antibodies is uncontrolled by the hypothalamic pituitary axis.^[5][6]

Both T cells and B cells are necessary for the development of Graves’ disease.^[7]

• In Graves’ disease, autoreactive T cells against the thyrotropin receptor have escaped both central (thymic) and peripheral editing.
• Receptors on these CD4+ helper T cells interact with MHC class II molecules through which thyrotropin-receptor peptides are presented.
• Intrathyroidal T cells are particularly reactive to thyroid antigens and predominantly have the Th2 phenotype.^[8]

• B cells develop into antibody-producing plasma cells in a process requiring second signals.
• The first of these signals is provided by antigen binding to the B cell receptor and the second by CD40 on the B cell surface interacting with CD40 ligand on T cells.
• These interactions result in the production of critical cytokines, such as interleukin-4, which promote antibody secretion and T-cell support of class switching.
• B cells initially produce IgM, which can be class-switched to IgG or IgE.

Intrathyroidal B cells have reduced mitogenic responses but spontaneously secrete anti–thyrotropin-receptor antibodies. ^[9]

• These cells express important organ specific antigens, such as the thyrotropin receptor, thyroglobulin, and thyroperoxidase.
• Thyroid epithelial cells release several chemokines and thus may participate in the recruitment of immune cells.^[10]
• In addition, they act as MHC class II and have the potential to present thyroid antigens to T cells.
• Also, their CD40 expression suggests the potential for direct, productive interactions between thyroid epithelium and antigen-specific T cells in Graves’ disease.^[11][12]

• The immune pathogenesis of ophthalmopathy and hyperthyroidism are similar. The orbital process primarily targets fibroblasts.

• T cells may contribute to ophthalmopathy through their interaction with fibroblasts.^[13]
• Orbital fat and extraocular muscles expand from accumulating hyaluronidase-digestible material and adipogenesis.^[14]

• Fibrocytes present antigens to T cells and when activated by thyrotropin or thyroid-stimulating immunoglobulins, fibrocytes release cytokines that have been implicated in Graves’ disease, they can differentiate into adipocytes or myofibroblasts and thus might contribute to the tissue remodeling in ophthalmopathy.
• Insulin-like growth factor 1 (IGF-1) receptor is involved in Graves’ disease ophthalmopathy.^[15]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Graves’ disease may be caused by either genetic factors, autoimmune antibodies against thyrotropin receptors, T cells and B cells auto activation and infectious agents.

Graves’ disease may be caused by either genetic factors, autoimmune antibodies against thyrotropin receptors, T cells and B cells auto activation and infectious agents.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Graves’ disease must be differentiated from other causes of hyperthyroidism. They include Thyroiditis, exogenous and ectopic hyperthyroidism, hashitoxicosis, toxic adenoma and toxic multi nodular goiter.

This table describes differential diagnosis for Graves’ disease and the next table shows the the distinguishing features of diseases that may mimic Graves’ diseases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Graves’ disease is the most common cause of hyperthyroidism. It is estimated that it affects 20-50 cases per 100,000 persons yearly in the United States and it has a prevalence of about 0.4%.

Graves’ disease is the most common cause of hyperthyroidism.

• The annual incidence of Graves’ disease is about 20 to 50 cases per 100,000 persons.^[1]
• Long-term variations in iodine intake do not influence the risk of the disease, but rapid iodine repletion can transiently increase the incidence.
• The annual incidence of Graves’ disease–associated ophthalmopathy is 16 cases per 100,000 women and 3 cases per 100,000 men.

The prevalence of Graves’ disease in the 1970s is estimated to be 0.4% in the United States.^[2] The Whickham survey in the United Kingdom suggested a prevalence of 1.1% to 1.6% for thyrotoxicosis of all causes, of which Graves’ disease was presumably the most frequent.^[3]

• The incidence peaks between 30 and 50 years of age, but people can be affected at any age.

• Graves’ disease is more common in Caucasians than in Asians.^[4]

• Graves’ disease is more common among women than men. The lifetime risk is 3% for women and 0.5% for men.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

The most potent risk factor in the development of Graves’ disease is genetic susceptibility. Other risk factors include infections, stress and smoking.

This table summarizes the risk factors for Graves’ disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Cardiac complications are the most important complications of Graves’ disease because they are life threatening. Heart failure and atrial fibrillation are the most common cardiac complications. Thyroid dermopathy which presents as pretibial myxedema and acropachy, is another complication. Thyroid associated ophthalmopathy must be evaluated in every patient with Graves’ disease. Thyroid crisis is another life threatening complication of Graves’ disease.

• If left untreated, it may lead to serious complications such as thyroid storm, life threatening arrhythmias, orbitopathies, weight loss and even osteoporosis.
• The clinical features of Graves’ disease generally worsen without treatment, the mortality from Graves’ disease was 10–30% before the introduction of satisfactory therapy. Some patients with mild Graves’ disease experience spontaneous relapses and remissions.

• Older patients are more vulnerable to develop cardiovascular complications compared to younger patients.^[1]
• When compared with people older than 60 years with a healthy thyroid, those who are hyperthyroid have three times the risk of atrial fibrillation.^[2]
• Embolic stroke related to atrial fibrillation secondary to hyperthyroidism is significantly more prevalent than embolic stroke related to atrial fibrillation from non-thyroidal causes.^[3]
• AF is considered as an independent risk factor for CHF in patients with Graves’ disease.^[4]

Cardiac manifestations of Graves’ disease include palpitations, anginal chest pain, exercise intolerance, atrial fibrillation, exertional dyspnea, cardiac hypertrophy, systolic hypertension, peripheral edema, hyperdynamic precordium, pulmonary hypertension and heart failure.^[5]

• There is a shift of potassium into the muscle cells.^[6]

• It is characterized by the triad of muscle paralysis, acute hypokalemia and thyrotoxicosis.

• The clinical course of ophthalmopathy does not follow that of the thyroid disease. Ophthalmopathy typically worsens over the initial 3–6 months, followed by a plateau phase over the next 12–18 months, with spontaneous improvement.^[1]
• The earliest manifestations of ophthalmopathy are usually a sensation of grittiness, eye discomfort, and excess tearing.
• Approximately one third of patients have proptosis. Proptosis can be measured using an exophthalmometer.
• In severe cases, proptosis may cause corneal exposure and damage, especially if the lids fail to close during sleep.
• Periorbital edema, scleral injection, and chemosis are also frequent.
• In 5–10% of patients, the muscle swelling is so severe that diplopia results.
• The most serious manifestation is compression of the optic nerve at the apex of the orbit, leading to papilledema, peripheral field defects, and permanent loss of vision if left untreated.^[1]

• It occurs in <5% of patients with Graves’ disease.
• The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an orange skin appearance.
• Nodular involvement can occur and the condition can rarely extend over the whole lower leg and foot, mimicking elephantiasis.
• Thyroid acropachy refers to a form of clubbing found in <1% of patients with Graves’ disease.^[7]

• Thyroid crisis is a life threatening exacerbation of hyperthyroidism, manifested by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment.
• Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism.

The overall prognosis with treatment is good.

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