Description
Graves’ disease is an autoimmune disorder and the most common cause of hyperthyroidism. It accounts for approximately 60-80% of all hyperthyroidism cases globally. Characterised by an overactive thyroid gland (thyrotoxicosis), the condition leads to excess production of thyroid hormones (T3 and T4).
T3 (triiodothyronine) and T4 (thyroxine) are thyroid hormones which regulate the body’s metabolism, including heart rate, digestive function, muscle control, brain development and bone maintenance. T3 is more active than T4, which is converted into T3 in the body’s tissues.
Pathogenesis
Graves’ disease results from antibody-directed stimulation of the thyroid-stimulating hormone (TSH) receptor, with the production and release of T3 and T4, causing hyperthyroidism. These abnormal antibodies, known as thyroid-stimulating immunoglobulins (TSI), mimic the action of TSH, leading to overproduction of thyroid hormones and growth of the thyroid gland.
Epidemiology, Risk Factors & Associations
- More prevalent in women (ratio of 5:1).
- Most common between the ages of 30 and 60, with an incidence of 20 cases per 100,000 people.
- Paediatric Graves’ disease accounts for 5% of all cases (incidence 5 per 100,000 children), and it is more common in older adolescents with a lower female predilection (F:M of 3.5:1).
- Genetic predisposition accounts for 80% of the risk, while environmental factors such as smoking, iodine excess, selenium deficiency, and vitamin D deficiency account for the rest.
- Also associated with a 10x increased relative risk of other autoimmune diseases including rheumatoid arthritis, pernicious anemia, systemic lupus erythematosus, Addison disease, coeliac disease, and vitiligo.
Clinical Features
Patients with Graves’ disease present with symptoms of thyrotoxicosis, including tremor, heat sensitivity, unexplained weight loss, and anxiety. A goiter is often present.
Extrathyroidal manifestations can occur, affecting 20-25% of cases, and include:
- Graves’ ophthalmopathy (orbitopathy): lid retraction, proptosis, optic nerve compression, diplopia
- Thyroid dermopathy (formerly called pretibial myxedema)
- Thyroid acropachy
- Encephalopathy associated with autoimmune thyroid disease (EAATD).
Complications
Untreated Graves’ disease can lead to severe complications, including increased risk of thyroid cancer (most common is papillary thyroid carcinoma), Graves’ ophthalmopathy, thyroid storm, cardiovascular problems (such as atrial fibrillation and heart failure), and osteoporosis.
Pathological Features
Histopathology
- Macroscopic: The affected gland shows diffuse, symmetrical enlargement, with a fleshy red cut surface.
- Microscopic: Plump follicular cells with increased amounts of eosinophilic cytoplasm and hyperplastic follicles with papillary epithelial infoldings are seen. There is evidence of colloid reabsorption, including ‘scalloping’ at the apical membrane and variable follicle collapse and exhaustion.
Radiological Features
General Features
- Thyroid-associated orbitopathy characterised by bilateral and symmetrical enlargement of the extraocular muscles. An increase in retrobulbar fat volume (mostly affects levator palpebrae superioris muscle) is also seen, which may compress the superior ophthalmic vein leading to venous congestion.
US
- Enlarged, often hyperechoic, thyroid gland
- Heterogeneous thyroid echotexture
- Absence of nodularity in uncomplicated cases
- Increased vascularity (‘thyroid inferno’) on Doppler
NM
- Radioactive iodine-123 imaging demonstrates homogeneously increased activity in an enlarged gland
- Technetium-99m pertechnetate shows homogeneously increased activity in an enlarged thyroid gland
CT
- Higher risk of iodinated contrast media-induced thyrotoxicosis
Diagnosis
Diagnosis is confirmed by the presence of suppressed TSH, elevated T4 and T3, and positive TSH receptor antibodies (TSI, TGI, TBII). This is supported by clinical presentation and radioactive iodine uptake, which is typically increased.
Differential Diagnosis
For hyperthyroidism, consider Marine-Lenhart syndrome, toxic thyroid adenoma, toxic multinodular goiter, subacute thyroiditis, postpartum thyroiditis, silent thyroiditis, pituitary adenoma, struma ovarii, metastatic thyroid carcinoma, and factitious hyperthyroidism.
Management
First-line treatment includes antithyroid medications like methimazole or carbimazole. For medication-resistant Graves’ disease, patients can opt for radioactive iodine or thyroidectomy. Regular monitoring is essential to track disease status and adjust treatment as needed.