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More TSHR = more places for TSH to bind = increased T3 and T4 production (Holthoff et al., 2020).

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- T and B lymphocyte cells proliferate with not enough regulatory T cells to suppress their overproduction.
-Human leukocyte antigen (HLA-D) has a high affinity for the TSHR gene, which is the receptor for TSH (Holthoff et al., 2020).

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Swelling of muscle, edema, congestion, and eventual ophthalmopathy.

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Cytotoxic T lymphocytes, also known as killer T cells, release cytokines that work with TSI to cause inflammation and growth of extraocular muscles and surrounding connective tissue. This is done by activating preadipocytes and periorbital fibroblasts, which synthesize glycosaminoglycans and fat growth in the retro-orbital area (Elia et al., 2021).

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Symptoms usually include goiter, bulging eyes, red or swollen shins, nausea, vomiting, weight loss, sweating, fatigue and restlessness. Treatments can range from antithyroid drugs to radioactive iodine administration, as well as surgery. (McCance & Heuther, 2019).

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Thyroid stimulating antibodies and cytokines activate:

-periorbital fibroblasts

-preadipocytes

Leads to: synthesis of excess glycosaminoglycans (GAG) which trap water and cause muscle swelling.

This can also lead to: buldging eyes, double vision, congestion, and periorbital edema (Pokhrel & Bhusal, 2022).

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-Auto-antibodies (antibodies against self) are being produced in Graves Disease. These mimic TSH and bind to TSH receptors.
- This continues to increase levels of T3 and T4 even after the negative feedback loop.
- Overactivity of thyroid hormones and thyroid gland growth
(Pokhrel & Bhusal, 2022)

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- Stimulates thyroid gland to produce thyroid hormones (T3 and T4)
- Negative feedback loop will stop the hypothalamus and pituitary gland from releasing more TRH and TSH
(Pokhrel & Bhusal, 2022)

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- Hypothalamus releases thyroid releasing hormone (TRH) -->
- Pituitary gland releases thyroid stimulating hormone (TSH) -->
TSH travels via circulation to the thyroid gland and binds to TSH binding receptors
(Pokhrel & Bhusal, 2022)

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-Stress
-Smoking
-Pregnancy (mostly post-partum)
-Infection
These environmental factors can trigger immune responses on specific genes that lead to Graves Disease (Pruthi, 2022)

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Bahn R. S. (2010). Graves' ophthalmopathy. The New England journal of medicine, 362(8), 726–738. https://doi.org/10.1056/NEJMra0905750

Bartalena, L. (2018, February). Graves’ disease: Complications. Endotext. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK285551/

Desai, R., Marshall, T., Debevec-McKenney, E., Ryan, J., Solar, E., & Norton, B. (2022). Osmosis: Graves disease. Elsevier. Retrieved from https://www.osmosis.org/learn/Graves_disease.

Elia, G., Fallahi, P., Ragusa, F., Paparo, S. R., Mazzi, V., Benvenga, S., Antonelli, A., & Ferrari, S. M. (2021). Precision Medicine in Graves' Disease and Ophthalmopathy. Frontiers in pharmacology, 12, 754386. https://doi.org/10.3389/fphar.2021.754386

Goiter. Baylor College of Medicine. (2022). Retrieved from https://www.bcm.edu/healthcare/specialties/endocrinology/endocrine-surgery/goiter

Holthoff, H. P., Uhland, K., Kovacs, G. L., Reimann, A., Adler, K., Wenhart, C., & Ungerer, M. (2020). Thyroid-stimulating hormone receptor (TSHR) fusion proteins in Graves' disease. The Journal of endocrinology, 246(2), 135–147. https://doi.org/10.1530/JOE-20-0061

McCance, K. L., & Heuther, S. (2019). Pathophysiology (8th ed.). Elsevier.

Pruthi, S. (Ed.). (2022, June 14). Graves' disease. Mayo Clinic. Retrieved from https://www.mayoclinic.org/diseases-conditions/graves-disease/diagnosis-treatment/drc-20356245

Pokhrel, B., Bhusal, K. (2022, June 22). Graves Disease. StatPearls. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK448195/

Thyroid eye disease. British Thyroid Foundation. (2021). Retrieved from https://www.btf-thyroid.org/thyroid-eye-disease-leaflet#:~:text=What%20is%20Thyroid%20Eye%20Disease,or%20'bulging'%20eyes).

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It's an autoimmune disease from type II hypersensitivity that is exacerbated by stress, smoking, and exposure to iodine. Family history of the condition can predispose individuals to developing it.

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Thyroid follicles increase production of mostly triiodothyronine (T3) and some thyroxine (T4) - thyroid hormones

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- enlarged thyroid gland (goiter) ("Goiter", 2022; McCance, 2019)

symptoms of hypermetabolism:
- menstrual cycle alterations
- GI: weight loss, increased peristalsis, nausea, vomiting, anorexia, abdominal pain
- increased sweating, flushing, warm skin, heat intolerance
- increased cardiac output and decreased peripheral resistance, tachycardia at rest, loud heart sounds, supraventricular dysrhythmias, left ventricular dilation and hypertrophy
- restlessness, compulsive movement, short attention span, fatigue, tremor, insomnia, increased appetite, emotional lability
- dyspnea, reduced vital capacity
(McCance, 2019)

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Hyperplasia = goiter (enlarged thyroid)

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Antigens in the thyroid gland stimulate T lymphocytes. They in turn stimulate
B lymphocytes to synthesize thyroid stimulating immunoglobulin (TSI) in thyroid cells, bone marrow, or lymph nodes. TSI binds to and continuously activates thyrotropic receptors, which can lead to overproduction of TSH.

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A form of thyrotoxicity, hyperthyroidism involves excess thyroid stimulating hormone (TSH) secretion from the thyroid gland. It controls the amount of thyroid hormone released. Graves disease is a cause of 50-80% of hyperthyroidism cases, mostly in women (McCance & Heuther, 2019).

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- rare skin condition
- red, swollen shins (McCance, 2019)
- nodular or diffuse thickening of pretibial skin (Bahn, 2010)
(Image: Bartalena, 2018)

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It's an endocrine gland that produces thyroid hormones triiodothyronine (T3) and thyroxine (T4), which maintain homeostasis in the body, and ensure proper organ function and body metabolism (McCance & Heuther, 2019).

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- bulging eyes
- red, dry eyes
- protracted eyelid
- pressure or pain
- double vision
- results from inflammation around eye (McCance, 2019)
- half of patients with Graves disease have symptoms of ophthalmopathy
(Bahn, 2010)

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-Family History
-Sex: It is more common for women to have Graves' disease than men.
-Other autoimmune disorders: Examples are Type 1 diabetes and Rheumatoid Arthritis
(Pruthi, 2022)

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- Surgical orbital decompression and glucocorticoids (McCance, 2019)
- radioactive iodine treatment may not help or may make symptoms worse ("Thyroid eye disease", 2021)

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- complete or partial removal of the thyroid (thyroidectomy)
- lifelong hormone replacement therapy (levothyroxine)
(Pruthi, 2022)

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- absorbed only by thyroid tissue
- causes cell death -> hypothyroidism (McCance, 2019)
- lifelong hormone replacement therapy (levothyroxine) (Pruhti, 2022)

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Antithyroid drugs: interfere with the thyroid's ability to use iodine to produce hormones (Pruthi, 2022)
- methimazole
- propylthiouracil (McCance, 2019)

Other drugs:
- beta blockers to treat cardiac symptoms (Pruthi, 2022)

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Does this condition conform to the traditional definition?

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Does this condition conform to the traditional definition?

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- non-cytotoxic
- tissue specific reaction
- infiltration of lymphocytes
- stimulation of antibodies (IgG, IgM) directed against TSH receptor on thyroid cells (McCance, 2019)