Overview

Graves’ disease is the most common cause of hyperthyroidism, caused by an autoimmune reaction in which TSH receptor autoantibodies stimulate the thyroid gland, leading to an increase in the production of thyroid hormones. It’s named after Dr Robert James Graves, an Irish physician who in 1835 gave one of the first thorough clinical descriptions linking goitre, palpitations and exophthalmos—the classic picture of autoimmune hyperthyroidism. The disease typically affects women more than men and primarily affects those between the ages of 30-50.

Physiology

Physiology of the thyroid gland

The hypothalamic-pituitary-thyroid axis plays a major role in regulating thyroid hormone levels in the body. These hormones play an integral role in metabolism and fetal development, all of which are governed by an intricate feedback mechanism in the HPT axis. Key structures in this axis include the hypothalamus, pituitary gland and thyroid, alongside the key hormones: thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH) and thyroxine (T4) and triiodothyronine (T3).

The hypothalamus produces and secretes TRH, which then stimulates the cells of the anterior pituitary to produce TSH. TSH then stimulates the thyroid gland to produce and release T3 and T4, which are distributed throughout the body to regulate metabolism. The production of T3 and T4 creates a negative feedback loop where they inhibit the release of TRH and TSH once levels get too high. ^{1, 2}

Aetiology and Risk Factors

Being an autoimmune condition, Graves disease is more common in those with a positive family history. Environmental factors such as smoking, stress, infection and pregnancy are known to precipitate it. ³

Pathophysiology

• B lymphocytes produce TSH-receptor antibodies (TRAb).
• T cells sensitised to thyroid follicular cell antigens drive B-cell activation.
• TRAb binds and activates TSH receptors on follicular cells → excess T3/T4 production.
• Results in follicular hyperplasia, goitre (thyromegaly) and clinical hyperthyroidism.

Extrathyroidal manifestations (TSH-receptor expression outside the thyroid; immune-mediated fibroblast activation)

• Graves’ ophthalmopathy: fibroblast/pre-adipocyte activation in retro-orbital tissues → oedema, glycosaminoglycan deposition, fat expansion → exophthalmos, diplopia, periorbital oedema.
• Dermatological: pretibial myxoedema and thyroid acropachy due to fibroblast activation and tissue remodelling.
• Systemic hyperthyroid features: tremor, tachycardia, heat intolerance (↑ catecholamine sensitivity).

Clinical Manifestations

Graves disease most commonly presents with initial signs of hyperthyroidism first, these include:

• Heat intolerance
• Weight loss
• Palpitastions
• Fatigue
• Tremors
• Increased bowel frequency
• In some cases, it can also result in: Menstrual irregularities in women and sexual dysfunction

Clinical examination

• Thyroid goitre
• Tachycardia
• Fine tremors
• Hyperreflexia
• Palmar erythema 

Graves ophthalmopathy features

• Proptosis: Anterior protrusion of the eyeball
• Lid retraction: Eyelids do not fully cover the eyeball, resulting in the upper eyelid being too high or the lower eyelid being too low
• Perioribital oedema
• Chemosis: Swelling of the conjunctiva
• Diplopia 

Graves dermopathy features

• Pretibial myxedema: Bilateral pretibial non-pitting oedema and skin thickening (also referred to as paeu d’orange skin)
• Thyroid Acropachy: Swelling and Clubbing of fingers and nails
• Onycholysis: A condition where the nail plate separates from the nail bed
• Hair loss

Diagnosis 

The diagnosis of Graves’ disease is made through both clinical evaluation and lab investigations. 

• Thyroid function test
  • TSH: Suppressed/decreased due to the negative feedback from excess T3 and T4
  • T3 and T4: Elevated due to stimulation of TSH receptors from antibodies

• TSH receptor antibodies: Elevated (specific to Graves’ disease)
• Imaging
  • Nuclear medicine scan + radioactive iodine uptake: Useful to differentiates Graves’ from toxic multinodular goitre and thyroiditis. Graves’ disease shows a diffuse high uptake of iodine and thyroid enlargement in comparison to patchy and low uptake in TMG and thyroiditis respectfully
  • Thyroid ultrasound with doppler: Investigate thyroid nodules which would have increased vascularity in Graves’.
  • Orbital imaging via CT/MRI

Differential Diagnoses of hyperthyroidism

Treatment 

The treatment of Graves’ disease is dependent on its presentation, but has two key aims: 

1. Rapid symptom control
   1. Beta blockers: Should be started as soon as hyperthyroidism is diagnosed (even before confirming that the cause is graves disease)¹¹
      1. This is done to address tachycardia and prevent the development of cardiac arrhythmias, especially in patients with prior cardiovascular disease and the elderly
      2. Atenolol is the drug of choice, with a dose of 25-50mg orally taken once daily
      3. Target pulse: 60-90bpm

2. Reduction of thyroid hormone secretion: 3 options
   1. Antithyroid drugs (thionamides)¹¹
      1. Goal of thionamide therapy is to reach a euthyroid state within the treatment period of 3-8 weeks
      2. Indications: Mild disease, small  goitre
      3. General MOA: Thionamides inhibit thyroid peroxidase which in turn decreases thyroid hormone synthesis (T3 and T4)
      4. Drugs: Methimazole or Propylthiouracil

2. Radioiodine
   1. Less expensive and lower complication rate in comparison to surgery
   2. Indication: Preferred definitive therapy of hyperthyroidism in non-pregnant patients WITHOUT moderate-severe Graves ophthalmopathy (can worsen it) 
   3. Radioiodine (iodine-131) is administered as an oral capsule, through which it induces extensive tissue damage of the thyroid gland, resulting in its ablation through the release of beta rays

3. Surgery: Thyroidectomy 
   1.  Indications: Severe hyperthyroidism and a very large or obstructive goitre and moderate to severe Graves’ ophthalmopathy 

Complications and Prognosis

Complications include:

• Graves ophthalmopathy: Can later result in optic neuropathy and corneal breakdown 
• Graves’ dermopathy
• Atrial fibrillation
• Bone mineral loss: From hyperthyroidism
• Thyroid storm

Graves’ disease generally has a good prognosis if treated promptly. However, risk of relapse is common after antithyroid drug therapy. The disease has remission rates of approximately 45%, with most relapses occurring within 4 years of treatment. Risk factors of relapse include ophthalmopathy, young age, large goitre size and smoking.

References

1. Emanuele MA, Emanuele NV. The endocrine system: Alcohol alters critical hormonal balance. Available from: https://www.researchgate.net/publication/8025856_The_endocrine_system_Alcohol_alters_critical_hormonal_balance
2. Hasudungan A. Graves’ Disease | Thyroid | Endocrinology. YouTube. 2021. Available from: https://www.youtube.com/watch?app=desktop&v=KzM8BiSnKQM&t=53s&ab_channel=ArmandoHasudungan
3. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. [Updated 2017 Nov 7]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448195/
4. Smith TJ, Hegedüs L. Graves’ Disease. N Engl J Med. 2016;375(16):1552–1565. doi:10.1056/NEJMra1510030
5. Bartley GB, Fatourechi V, Kadrmas EF, et al. Clinical features of Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol. 1996;121(3):284–290. doi:10.1016/s0002-9394(14)70276-4
6. Davies TF, Andersen S, Latif R, et al. Graves’ disease. Nat Rev Dis Primers. 2020;6(1):52. Published 2020 Jul 2. doi:10.1038/s41572-020-0184-y
7. Perros P, Neoh C, Dickinson J. Thyroid eye disease. BMJ. 2009;338:b560. Published 2009 Mar 6. doi:10.1136/bmj.b560
8. Bahn RS. Graves’ Ophthalmopathy. N Engl J Med. 2010;362(8):726–738. doi:10.1056/NEJMra0905750. 
9. Chaker L, Cooper DS, Walsh JP, Peeters RP. Hyperthyroidism. Lancet. 2024;403(10428):768-780. doi:10.1016/S0140-6736(23)02016-0
10. Col NF, Surks MI, Daniels GH. Subclinical thyroid disease: clinical applications. JAMA. 2004;291(2):239-243. doi:10.1001/jama.291.2.239
11. Törring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine–a prospective, randomized study. Thyroid Study Group. J Clin Endocrinol Metab. 1996;81(8):2986-2993. doi:10.1210/jcem.81.8.8768863
12. Sjölin G, Holmberg M, Törring O, et al. The Long-Term Outcome of Treatment for Graves’ Hyperthyroidism. Thyroid. 2019;29(11):1545-1557. doi:10.1089/thy.2019.0085