GRAVES' DISEASE

Disease

Brief Summary

Graves’ disease is a disorder that causes hyperthyroidism. What happens is that the immune system attacks the thyroid causing it to produce excessive amounts of thyroid hormones. The thyroid is a butterfly-shaped gland which is wrapped around the trachea. Thyroid hormones control the body’s metabolism, and influence how the body uses energy. Today, this disease is rarely life-threatening. However, it can possibly lead to the development of heart problems and weak, brittle bones. The observable symptoms of the disease include the goiter and ophthalmy - which is the characteristic swelling, redness, and bulging of the eyes. Thus, depending on the severity of the symptoms, Graves’ disease may become dangerous.

Source

Image:

Woman with Graves' Disease

Frequency

Graves' disease occurs in almost any part of the world. Graves' disease is estimated to affect 2%-3% of the general population.

Inheritance

Graves' disease an autoimmune disorder which is inherited in an autosomal recessive manner.

History of Disease

Brief Summary

History of Disease

Caleb Hillier Parry’s findings gave the earliest descriptions of the symptoms of Graves' disease – wherein he related exophthalmos (the bulging of the eyes out of the orbit) and goiter – which was published in 1825 after his death. In 1835, Robert James Graves fully described exophthalmic goiter – now known as Graves’ disease – in his paper.

Pathogenesis

Achondroplasia is caused by a mutation in the FGF3 gene in chromosome 4 at 4p 16.3. This mutation causes a decreased production of fibroblast growth factor receptor 3 which is crucial in the conversion of cartilage into bone which is vital in the proper development of a person. This mutation is inherited in an autosomal dominant manner. More than 80 percent of people with achondroplasia have parents with normal characteristics and are born with achondroplasia due to a recent (de novo) gene modification (mutation).

Pathogenesis

The most recent studies, which were in 1972 and 1977, favored polygenic inheritance for hyperthyroidism and Hashimoto thyroiditis.

A locus for susceptibility to Graves’ disease (GRD1) has been mapped to chromosome 14q31.

Other loci for Graves’ disease include GRD2 (603388) on chromosome 20q13, GRDX1 (300351) on Xp11, and GRDX2 (see 300351) on Xq21.33-q22.

Graves’ disease has also been mapped to several loci that confer susceptibility to autoimmune thyroid diseases, including Hashimoto thyroiditis (HT; 140300): AITD1 (608173) on 6p11; AITD2 (608174) on 5q31-q33; AITD3 (608175) on 8q24; AITD4 (608176) on 10q, and AITD5 (601941) on 18q21.

The image shows how thyroid cells are affected, and are producing the thyroid stimulating hormones (TSH) as a response. Immunoglobulin G (IgG) are produced and bind to the receptors of the thyroid cells.

Image:

Mutated DNA sequence by Graves' disease

Source

Symptoms

fast and irregular heartbeat

ophthalmopathy

heat intolerance

goiter

frequent bowel movements or diarrhea

nervousness or irritability

tiredness or muscle weakness

trembling hands

trouble sleeping

weight loss

The mortality rate and the gravity of the disease is directly related to the severity of the symptoms. Take into account the most common symptoms which are ophthalmopathy and goiter. Since ophthalmopathy is characterized by the swelling and outward bulging of the eyes, severe cases may cause the individual to develop serious eye problems, and even blindness caused by the compression on the optic nerve. The other symptom, which is goiter, is the enlargement of the thyroid gland. Although some goiters are benign, others may be caused by thyroid cancer. Aside from this, large goiters may cause difficulty in breathing or swallowing due to it putting pressure upon the trachea.

Cardiovascular manifestations are frequently found in patients with thyroid diseases. Nitric oxide (NO) – which was measured as plasma nitrate plus nitrite (NOX) concentration – released from endothelial cells, which line the inner surface of blood vessels, plays a role in regulating blood flow, blood pressure, and thrombus formation. The findings of Hermenegildo et al. (2002) indicated that L-arginine, ADMA, and symmetric dimethylarginine (SDMA) plasma levels in the hyperthyroid group significantly increased – wherein most of the individuals had Graves’ disease – while these values of the patients with hypothyroidism were similar to those of the control group. L-arginine and ADMA play a role in NO production. Thus, heart complications, formation of blood clots, and stroke may arise if the disease is left without treatment.

Social Concerns

In 1986, Wit et al. found that neonatal thyrotoxicosis caused by transplacental passage of thyroid-stimulating immunoglobulins (TSI) from the mother with Graves’ disease, and a transient phenomenon, would possibly result to mortality, and intellectual impairment later in life.

In 2003, the findings of Robertson et al. led them to discourage further treatment of Graves’ ophthalmopathy with radiation as the treatment resulted in the development of microvascular abnormalities to unaffected retina, and the progression of existing retinopathy.

Treatment

At present, these are the possible treatment methods for Graves’ disease:

Anti-thyroid drugs (methimazole and propylthiouracil) - medications that stop thyroid from making hormones.
Radioactive iodine (Iodine 131) - destructs the cells of thyroid, preventing it from making high levels of thyroid hormones.
Beta blockers- do not change the amount of hormones in the body, but assists in controlling symptoms.
Surgery: A more permanent treatment, may surgically remove thyroid (thyroidectomy), this can stop it from creating hormones. However, taking thyroid replacement hormones for the remainder of your life is needed.

Patients undergo regular testing every three months to test internal secretion of their TSH levels.

Source

Image:

Treatment for Graves' disease

Clinical Trials

Title:

Safety and Proof of Principle Study of ATX-GD-59 in Male and Female Subjects With Grave’s Disease Not Currently Treated With Anti-thyroid Therapy: An Open Label Study, With an Upward Titration Over Five Dose Levels Administered by Intradermal Injection

Intervention:

Biological - ATX-GD-59

Phase:

Phase 1

Procedure:

Phase 1 study to assess the safety and biological activity of ATX-GD-59 in patients with Graves Disease not currently treated with anti-thyroid therapy. This will be an open label dose titration involving injections on 10 occasions, each two weeks apart. After dosing is complete there will be a 12 week follow up period. Blood samples will be drawn throughout the study to monitor safety and the body's response to the injections. Thyroid function will be measured throughout the trial to monitor Graves disease progression.

Goal:

An adverse event (AE) was defined as any untoward medical occurrence in a subject administered study drug that did not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign, symptom, disease or outcome of death temporally associated with the use of study drug, whether or not considered causally related to the study drug. A drug related AE was defined as an AE with a relationship to study drug of 'possibly related', 'probably related' or 'definitely related' or with a missing or unknown relationship to study drug.

Further details at:

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02973802

Clinical Trials

Expert Directory