Graves Disease

Graves disease is an autoimmune disorder characterised by production of thyroid stimulating immunoglobulins that bind to and activate the thyroid stimulating hormone receptor. This produces sustained, unregulated thyroid hormone overproduction. It is the commonest cause of hyperthyroidism overall.

The same underlying autoimmune process is additionally capable of producing the specific, distinct extrathyroidal manifestations of orbitopathy and, less commonly, pretibial myxoedema (dermopathy). This reflects the broader systemic nature of this autoimmune condition beyond its effects on the thyroid gland alone.

Pathophysiology

• Thyroid stimulating immunoglobulins are autoantibodies directed against and activating the thyroid stimulating hormone receptor. They mimic the normal physiological action of thyroid stimulating hormone itself but without the normal negative feedback regulation that would otherwise limit excess hormone production.
• This drives sustained, unregulated thyroid hormone synthesis and release together with diffuse thyroid gland hyperplasia. It accounts for the characteristic diffusely enlarged, smoothly textured goitre typical of this condition.
• The same underlying autoimmune process underlies the specific extrathyroidal manifestations. It involves T cell mediated inflammation targeting shared antigens expressed both within the thyroid gland and orbital and pretibial tissue.
• Orbital fibroblast activation and resulting glycosaminoglycan accumulation, muscle swelling and inflammation produce the characteristic orbitopathy. Analogous local tissue changes produce the less common pretibial dermopathy.

• The general hyperthyroid symptom constellation, comprising weight loss, heat intolerance, palpitations, tremor and anxiety, occurs as detailed under hyperthyroidism generally.
• Specific, characteristic findings of Graves disease include a diffusely enlarged, smooth, often bruit positive goitre, reflecting the increased vascularity of the hyperactive gland.
• In a substantial proportion of patients there is associated ophthalmopathy, with characteristic proptosis, periorbital swelling and lid retraction. In more significant disease, extraocular muscle involvement produces diplopia (addressed in full detail under Graves ophthalmopathy).
• Pretibial myxoedema is an uncommon but characteristic dermopathy. It presents with non pitting, thickened, often violaceous or brownish skin plaques over the anterior shins. It reflects local glycosaminoglycan accumulation from the same underlying autoimmune process affecting this specific site.
• Thyroid acropachy is a rare additional manifestation comprising digital clubbing with associated soft tissue swelling and periosteal new bone formation of the hands and feet. It occurs in a small proportion of patients, typically in association with more severe ophthalmopathy and dermopathy. It is the least common of the recognised extrathyroidal manifestations of this condition.
• The disease shows a strong female predominance and typically presents in early to middle adulthood. It has a recognised, though incompletely understood, association with other autoimmune conditions.
• It also has a well established relationship with smoking, which significantly worsens the risk and severity of associated ophthalmopathy specifically.

• Suppressed thyroid stimulating hormone together with elevated free thyroxine and free triiodothyronine confirms biochemical hyperthyroidism.
• Thyroid stimulating hormone receptor antibody testing provides specific, sensitive confirmation of the underlying Graves disease aetiology in the great majority of patients.
• Radioactive iodine uptake scanning, where performed, characteristically shows diffusely increased uptake throughout the thyroid gland. This supports the diagnosis and distinguishes Graves disease from the focal or patchy uptake pattern characteristic of toxic nodular disease, or the characteristically low uptake pattern of thyroiditis.
• Formal ophthalmological assessment includes clinical grading of orbitopathy severity where present and, where indicated, orbital imaging. It supports characterisation and staging of any associated ophthalmopathy. The specific approach to this assessment is detailed further under that condition given its particular clinical importance and specific management implications.
• The diagnosis is frequently apparent from the characteristic clinical presentation (diffuse goitre with bruit, together with typical ophthalmopathy where present) combined with the biochemical and antibody findings.
• Radioactive iodine uptake scanning is therefore not required in every case, particularly where the clinical and serological picture is already sufficiently characteristic to confidently establish the diagnosis.

• Antithyroid medication, beta blockade for symptomatic control, and consideration of definitive treatment (radioactive iodine or surgical thyroidectomy) for disease not achieving durable remission, follow the general principles detailed under hyperthyroidism. Specific additional considerations relevant to Graves disease are addressed here.
• A trial of antithyroid medication, typically for twelve to eighteen months, is generally the preferred initial approach in Graves disease specifically. A meaningful proportion (approximately forty to fifty percent) of patients achieve durable remission following this defined treatment course.
• In toxic nodular disease, by contrast, spontaneous remission is not anticipated and definitive treatment is generally favoured from the outset.
• The choice of definitive treatment, where required following relapse after an antithyroid medication trial or as an alternative initial approach, requires careful consideration of the presence and severity of any associated ophthalmopathy. Radioactive iodine treatment carries a recognised risk of triggering new onset or exacerbating pre-existing ophthalmopathy, particularly in smokers.
• Surgical thyroidectomy, or alternatively radioactive iodine treatment combined with prophylactic corticosteroid cover, may therefore be preferred in patients with significant existing or high risk ophthalmopathy.
• Strongly and specifically emphasise smoking cessation in every patient with Graves disease. Continued smoking has a well established, substantial adverse effect on both the severity of associated ophthalmopathy and the response to its specific treatment. Cessation is one of the single most impactful, modifiable interventions available for this aspect of the disease.
• Pregnancy planning requires specific consideration in women of childbearing age with Graves disease. Carbimazole has teratogenic potential, particularly in the first trimester, where propylthiouracil is generally preferred despite its own, generally lower, hepatotoxicity risk.
• Achieve stable, well controlled thyroid function before conception where possible. Pregnancy itself needs specific monitoring, given the physiological changes affecting thyroid function.
• Thyroid stimulating immunoglobulins can pass transplacentally and affect the fetus. Affected women warrant specialist joint endocrine and obstetric management throughout pregnancy.
• Long term follow up includes monitoring for relapse following antithyroid medication discontinuation or incomplete response to definitive treatment. It also includes ongoing monitoring for and management of any associated ophthalmopathy or, less commonly, dermopathy. This underpins longitudinal management of this chronic autoimmune condition with its characteristic multisystem manifestations.