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1. What is the immunological mechanism involved in Graves disease?

In Graves disease, your immune system creates antibodies that cause the
thyroid to grow and make more thyroid hormone than your body needs.
These antibodies are called thyroid-stimulating immunoglobulins (TSIs). The
TSIs bind to thyroid cell receptors, which are normally docking stations for
thyroid-stimulating hormone (TSHthe hormone responsible for telling the
thyroid to produce hormones). The TSIs then trick the thyroid into growing
and producing too much thyroid hormone, leading to hyperthyroidism.
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.
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
2. How common is Graves disease?
3. What is the relationship between Graves disease and Hashimoto thyroiditis?
GRAVES DISEASE, ONE of the most common autoimmune diseases affecting
humans, is caused by autoantibodies that induce thyrotoxicosis by mimicking
the action of TSH and activating the TSH receptor (TSHR). Although such
thyroid-stimulating autoantibodies are pathognomonic of Graves disease,
autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg) are also
present. The latter two autoantibodies are the classical markers of
Hashimotos thyroiditis, a condition in which thyroid lymphocytic infiltration
and thyrocyte damage may progress to hypothyroidism. Moreover, many
Graves patients have mild lymphocytic thyroiditis. In some instances,
thyroiditis in Graves disease becomes sufficiently extensive as to cure the
hyperthyroidism with resultant hypothyroidism.
4. Is Grave disease hereditary?
Heredity and other characteristics seem to play a role in determining
susceptibility. Studies show, for example, that if one identical twin contracts
Graves' disease, there is a 20% likelihood that the other twin will get it, too.
Also, women are more likely than men to develop the disease. And smokers
who develop Graves' disease are more prone to eye problems than
nonsmokers with the disease. No single gene causes Graves disease. It is
thought to be triggered by both genetics and environmental factors, such as

Graves disease is thought to result from a combination of genetic and

environmental factors. Some of these factors have been identified, but many
remain unknown. Graves disease is classified as an autoimmune disorder,
one of a large group of conditions that occur when the immune system
attacks the body's own tissues and organs. In people with Graves disease,
the immune system creates a protein (antibody) called thyroid-stimulating
immunoglobulin (TSI). TSI signals the thyroid to increase its production of
hormones abnormally. The resulting overactivity of the thyroid causes many
of the signs and symptoms of Graves disease. Studies suggest that immune
system abnormalities also underlie Graves ophthalmopathy and pretibial
People with Graves disease have an increased risk of developing other
autoimmune disorders, including rheumatoid arthritis, pernicious anemia,
systemic lupus erythematosus, Addison disease, celiac disease, type 1
diabetes, and vitiligo.
Variations in many genes have been studied as possible risk factors for
Graves disease. Some of these genes are part of a family called the human
leukocyte antigen (HLA) complex. The HLA complex helps the immune
system distinguish the body's own proteins from proteins made by foreign
invaders (such as viruses and bacteria). Other genes that have been
associated with Graves disease help regulate the immune system or are
involved in normal thyroid function. Most of the genetic variations that have
been discovered are thought to have a small impact on a person's overall risk
of developing this condition.
The inheritance pattern of Graves disease is unclear because many genetic
and environmental factors appear to be involved. However, the condition can
cluster in families, and having a close relative with Graves disease or another
autoimmune disorder likely increases a person's risk of developing the
5. Discuss the risk factors that can influence a persons susceptibility to the
- Family history. Because a family history of Graves' disease is a known
risk factor, there is likely a gene or genes that can make a person more

susceptible to the disorder.

Gender. Women are much more likely to develop Graves' disease than
are men.

Age. Graves' disease usually develops in people younger than 40.

Other autoimmune disorders. People with other disorders of the
immune system, such as type 1 diabetes or rheumatoid arthritis, have an

increased risk.
Emotional or physical stress. Stressful life events or illness may act as
a trigger for the onset of Graves' disease among people who are

genetically susceptible.
Pregnancy. Pregnancy or recent childbirth may increase the risk of the

disorder, particularly among women who are genetically susceptible.

Smoking. Cigarette smoking, which can affect the immune system,
increases the risk of Graves' disease. Smokers who have Graves' disease

are also at increased risk of developing Graves' ophthalmopathy.

6. What are the main immunopathological characteristics or symptoms of the

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

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

7. Is there any specific diet for Graves patients?

Reducing inflammation through a healthy diet is one of the best ways to
enhance immune function, create a healthy gut environment and manage
your autoimmune symptoms. Inflammation can partially be traced to an
unhealthy gut microbiota that is caused by nutrient deficiencies, food
allergies or sensitivities, which all raise autoimmune activity. (4)
Some of the ways that your diet might trigger autoimmune reactions include
eating common allergens like gluten and dairy products, which the immune

system can actually register as a threat when they arent digested properly.
Allergens can contribute to leaky gut syndrome, in which small particles leak
out into the bloodstream through tiny openings in the gut lining, triggering
A well-rounded diet thats filled with anti-inflammatory foods and free from
toxin overload helps resolve bacterial imbalances in the gut that make
symptoms worse. Focus on limiting or avoiding foods capable of aggravating
autoimmune disorders, including:
conventional dairy products
artificial flavorings or dyes
added sugar
GMO ingredients (common in almost all packaged foods which contain
preservatives, high fructose corn syrup and other chemical ingredients)
Foods that can help control Graves disease symptoms include:
fresh vegetables/green juices: these provide vital nutrients and fight
fresh fruit: a great source of antioxidants and electrolytes, but avoid
processed fruit juices
anti-inflammatory herbs: basil, rosemary, parsley and oregano are all antiinflammatory
spices like tumeric, garlic and ginger: known to help boost immune system
bone broth: helps heal the gut and improve detoxification
probiotics: balance bacteria within the digestive tract and fight leaky gut
healthy fats including omega-3s: lower inflammation and helps with
neurotransmitter functions