Graves’ disease


Autoimmune disease caused by an antibody that acts as an agonist on the thryotropin receptor.

The most common cause of hyperthyroidism, with an annual incidence of 20-50 cases per hundred thousand persons, and a lifetime risk of 3% in women and 0.5% in men.

Has an incidence of 1.9 cases for 10,000 population per year.

The disease course changes from an active progressive period characterized by inflammation to a stable and fibrotic, inactive period after 1-3 years.

Thyrotropin receptor autoantibodies stimulate the thyroid to produce thyroid hormone.

The presence of thyrotropin receptor antibodies is pathognomonic for Graves’ disease.

Measuring thyrotropin receptor antibodies is the initial step in differentiating Graves’ disease from other causes of thyrotoxicosis.

This abnormality unregulates thyroid hormone synthesis.

An autoimmune disorder that occurs when the immune system attacks the thyroid gland and causes it to produce too much thyroid hormone.

Also referred to as Basedow’s disease in Europe

The thyroid gland releases the hormones thyroxine (T4) and triiodothyronine (T3).

Although Graves’ disease may affect anyone, it is more common among women and has an onset before the age of 40 years.

Can affect anyone at any age, but it is more common in women.

Family histories and found in approximately half of individuals with GD.

Twin concordance studies suggest up to 80% of risk is due to genetic factors.

Many genes associated with increased risk of GD overlap with those associated with other autoimmune diseases.

Genes associated with increased risk for GV include: HLA-DRB1 *03, HLA-DRB*08, tyrosine phosphatase nonreceptor type 22 (PTPN 22), cytotoxic T- lymphocyte antigen4 (CTLA4), CD25, CD40.

Environmental factors: cigarette smoking, dietary iodine, infection with Yersinia enterocolitiva and stress play a role.

Patients present usually with underlying hyperthyroidism or immune mediated cellular infiltration.

It results in the remodeling of the orbit and upper face resulting in: dry eyes, increased lacrimation, local irritation, and eyelid retraction in mild cases, but can also manifest with pronounced proptosis, diplopia, and optic nerve compression, with potential vision loss in with severe disease.

The most common manifestations are: weight loss, fatigue, palpitations, tremor, and goiter.

10% of patients, particularly older than 60 years have atrial fibrillation.

A palpable goiter is more common in those younger than 60 years.

Can cause a severe, life-threatening crisis known as thyroid storm.

Thyrotropin receptors in orbital tissues such as fibroblasts and adipocytes are the targets of such antobodies and cause the ophthalmopathy.

Critically important Graves disease occurs in 25% of patients, however sub clinical involvement with extreme ocular muscle enlargement is seen radiographically it up to 70% of patients.

Affects approximately 0.5% of population.

The incidence is about 1 in 2,000 people (0.05%).

Annual incidence of 20-50 cases per hundred thousand persons and a lifetime risk of 3% in women and 0.5% in men.

Approximately half the patients with GD have ocular involvement, Graves’ orbitopathy.

Graves’ ophthalmopathy is potentially sight threatening eye disease generally occurring in patients with hyperthyroidism or a history of hyperthyroidism due to Graves’ disease.

A family history of thyroid dysfunction is found in approximately half the patients with Graves’ disease and the pathogenesis is strongly influenced by genetics.

The most common clinical features of Graves’ ophthalomopathy are upper eyelid retraction, edema, erythema of the periorbital tissues and conjunctiva and propptosis.

Eye lid retraction, exophthalmos , extraocular muscle dysfunction, and ocular pain arethe most common manifestations of graves orbitopathy.

Approximately 3-5% of patients have severe disease with pain, inflammation, corneal ulceration or compressive optic neuropathy.

Subclinical involvement of the eye is common with nearly 70% of patients having MRI evidence or CT scan evidence of extraocular muscle enlargement (Enzmann DR).

Occasionally appears as a unilateral process, but will the total imaging usually confirms asymmetric bilateral disease (Wiersinga WM et al).

Graves’ ophthalmopathy, also known as thyroid-associated ophthalmopathy or thyroid eye disease may sometimes occur in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis.

Graves’ ophthalmopathy annual adjusted incidence rate of 16 women and three men per 100,000 population (Bartley GB).

Graves’ ophthalmopathy, thyroid dermopathy, and hyperthyroidism arise from a single underlying systemic process with variable expression.

Bilateral ocular symptoms and hyperthyroidism usually occur simultaneously or within 18 months of each other.

Graves’ ophthalmopathy occasionally may precede or follow hyperthyroidism by years (Wiersing WM et al).

Graves’ ophthalmopathy associated with periorbital and retro-orbital inflammation of fat, muscle, and connective tissue.

Almost half of the patients with hyperthyroidism have symptoms of Graves’ ophthalmopathy manifested by dry eyes, photophobia, increased tearing, double vision, the sensation of pressure behind the eyes.

Causes 50-80% of cases of hyperthyroidism.

Causes hyperthyroidism associated with circulating IgG antibodies that bind to and activate G-protein-coupled thryotropin receptor.

The activation of the G-protein-couples thyrotropin receptors stimulates follicular hypertrophy and hyperplasia, thyroid enlargement, increases in thyroid hormone and the fraction of triiodothyronine (T3) relative to thyroxin (T4).

Chracterized by increased oxidative stress, and increased oxygen free radicals.

Majority of patients have psychiatric symptoms manifested by irritability, anger, anxiety or sadness.

45% have anxiety disorder, and 30% have criteria for major depressive disorder.

Thyroid dermopathy is uncommon accounting only for 1-4% of individuals with Graves’ disease.

Thyroid acropachy occurs in only 20% of patients with thyroid dermopathy.

Laboratory findings include a suppressed level of serum thyrotropin and elevated T4 and T3.

Ophthalmopathy is noted in 30-50% of cases but is detected in more than 80% of patients by orbital imaging.

Eye manifestations include proptosis, priority edema, inflammation, exposure keratitis, photophobia, extra ocular muscle infiltration and lid lag.

Eye manifestations vary in severity and have a course that is independent of the thyroid disease.

Female: male ratio is 5:1-10:1.

Peak incidence 40-60 years, but can occur at any age.

Most common cause of hyperthyroidism in children.

Concordance among monozygote twins is 35%.

In individuals with a genetic predisposition stress, infection and recent pregnancy can precipitate the disease.

Aproximately 30% experience spontaneous remissions (Codaccioni JL et al).

Corticosteroids and/or orbital irradiation are effective treatments for Graves’ orbitopathy for moderately severe and active forms of disease.

Mild forms of Graves’ ophthalmopathy may improve spontaneously and usually require local measures such as, artificial tears, ointments and prisms.

In patients with mild disease many have decreased quality of life, 65% have stable disease and about 15% have progression of disease.

Seum selenoprotein P levels are an indicator of oxidative state are lower in Graves’ disease orbitopathy than in control patients.

Selenium 60 mcg b.i.d. in a controlled study and comparing it to pentoxifylline , significantly improved quality of life, ocular involvement, and slowed progression of disease in mild Graves’ eye disease (Marcocci C et al).

Immunomodulatory drugs may reduce inflammation in active disease but have limited effects on long-term sequelae of thyroid eye disease such as disfigurement and disability from proptosis and diplopia.

Patients with severe disease multiple surgical procedures such as overall decompression, strabismus correction, and eyelid repair, as well as cosmetic medical procedures may be employed.

Teprotumumab improves proptosis.

Diagnosis is suspected in a patient with findings of thyrotoxicosis combined with biochemical hyperthyroidism with a low serum TSH, high free T4 or T3.

If a diffuse goiter, with orbitopathy are present no further testing is required to establish a diagnosis.

A false positive diagnosis of hyperthyroidism may occur due to immunoassay interference with biotin, a soluble vitamin commonly used to supplement for hair and nails.

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