Grave's Disease

A 35-year-old woman presents to the clinic with a 3-month history of unintentional weight loss, heat intolerance, and palpitations. On examination, she has a diffuse goiter and exophthalmos. Her pulse is 110 bpm and regular. What is the likely diagnosis?

Pathophysiology

Grave's disease is an autoimmune condition caused by TSH receptor-stimulating antibodies (TSIs). These antibodies mimic the action of TSH, binding to and activating TSH receptors on thyroid follicular cells. This leads to increased thyroid hormone (T3 and T4) production and thyroid gland growth, resulting in hyperthyroidism.

Aetiology

The exact aetiology of Grave's disease is unknown. However, it is believed to be a complex interplay of genetic and environmental factors.

• Genetic Predisposition:
  • Familial clustering and a higher concordance rate in monozygotic twins indicate a genetic component.
  • Specific genes in the HLA region on chromosome 6 have been implicated.
  • Polymorphisms in genes like CTLA-4, CD25, and FCRL3 also contribute to susceptibility.
• Environmental Triggers:
  • Possible triggers include stress, infection, and childbirth.
  • Smoking increases the risk of developing Grave's disease, particularly the development and severity of ophthalmopathy.

Epidemiology & Risk Factors

• Prevalence: 100-200 per 100,000 population in iodine-replete areas. The prevalence is 0.5%, with Grave's disease accounting for ⅔ of hyperthyroidism cases.
• Sex: F:M = 10:1, especially postpartum.
• Age: Typically presents between 20-40 years.
• Family History: Having a history of Grave's disease increases the risk.
• Other Autoimmune Diseases: Individuals with other autoimmune conditions, such as type 1 diabetes mellitus, vitiligo, and Addison's disease, are at increased risk.

Clinical Features

The clinical features of Grave's disease result from the hyperthyroid state and the autoimmune process targeting specific tissues.

• Hyperthyroidism Symptoms:
  • Weight loss despite increased appetite.
  • Heat intolerance and increased sweating.
  • Palpitations and tachycardia.
  • Anxiety, irritability, and emotional lability.
  • Increased bowel frequency and diarrhoea.
  • Fatigue and muscle weakness.
  • Insomnia and difficulty sleeping.
  • Menstrual irregularities, including oligomenorrhoea and amenorrhea.
• Specific Signs of Grave's Disease:
  • Diffuse Goiter: Smooth enlargement of the thyroid gland.
    • Thyroid bruit present.
  • Ophthalmopathy:
    • Periorbital oedema and exophthalmos.
    • Lid lag and retraction, giving a "staring" appearance.
    • Diplopia due to ophthalmoplegia.
  • Dermopathy (Pretibial Myxoedema): Non-pitting oedema, thickening, and redness of the skin, typically over the shins.
  • Thyroid Acropachy: Clubbing of the fingers and toes, soft-tissue swelling and periosteal reaction in the hands and feet.

Investigations

• Thyroid Function Tests (TFTs):
  • Suppressed TSH (often undetectable).
  • Elevated free T4 and free T3.
  • 5% of patients present with T3 thyrotoxicosis, where free T4 is normal and only free T3 is elevated.
• Thyroid Antibodies:
  • TSH receptor antibodies are highly specific for Grave's disease.
  • Anti-thyroglobulin (TG) and anti-myeloperoxidase (MPO) antibodies may also be present, but they are not specific to Grave's disease.
• Other Blood Tests:
  • May show mild normocytic anemia, lymphocytosis, elevated ESR, hypercalcemia, hyperglycemia, and elevated liver enzymes.
• Imaging:
  • Radioactive Iodine Uptake (RAIU) Scan: Shows diffuse uptake of radioactive iodine throughout the thyroid gland, confirming hyperthyroidism and distinguishing Grave's disease from other causes.
  • Ultrasound: Can assess the size and structure of the thyroid gland, helping to identify nodules or other structural abnormalities.
  • CT or MRI: Used in cases of suspected compressive symptoms or for evaluating the extent of ophthalmopathy.
• ECG: may show atrial fibrillation.

Management

The goal of management is to control hyperthyroidism and alleviate symptoms. Treatment options include:

• Antithyroid Drugs (ATDs): preferred in mild disease
  • Carbimazole and propylthiouracil (PTU) are the most commonly used ATDs. Complications include:
    • Foetal goitre and hypothyroidism
    • Carbimazole: agranulocytosis and neutropaenic sepsis, congenital malformations
    • PTU: hepatotoxicity
  • Work by inhibiting thyroid hormone synthesis.
  • Carbimazole is generally preferred in the UK, while PTU is generally used during the first trimester of pregnancy.
  • Treatment duration is typically 12-18 months. Remission rates vary, but around 30% of patients remain euthyroid after drug withdrawal.
  • Dosing is either via titration or block and replace:
    • Titration: start ATD and then reduce until euthyroid.
    • Block and replace: start ATD and add thyroxine once euthyroid.
• Radioactive Iodine (RAI) Therapy:
  • RAI is taken up by the thyroid gland and destroys thyroid tissue, leading to hypothyroidism in most cases.
  • It is a definitive treatment option and often the preferred choice for patients with relapse after ATD therapy, large goitres, or those who are unsuitable for surgery.
  • Contraindications: pregnancy, age <16, breastfeeding or established eye disease (can worsen symptoms).
  • Often require long-term thyroxine after treatment.
• Surgery (Thyroidectomy):
  • Reserved for patients with very large goitres causing compressive symptoms, those who refuse RAI therapy, or those with suspected malignancy.
  • Complications include hypothyroidism, hypoparathyroidism and recurrent laryngeal nerve palsy.
• Beta-blockers (e.g. propranolol):
  • Used to control the sympathetic symptoms of hyperthyroidism, such as palpitations, tremors, and anxiety.
• Symptomatic Management:
  • Lifestyle modifications, such as weight management and stress reduction, can be helpful.
  • Treatment of associated conditions, like ophthalmopathy, is also essential.

Complications & Prognosis

• Thyroid Storm: A rare but life-threatening complication characterized by a sudden, severe exacerbation of hyperthyroidism.
• Ophthalmopathy: Can lead to vision loss if untreated.
• Hypothyroidism: Most patients treated with RAI or surgery will develop hypothyroidism and require lifelong thyroid hormone replacement.
• Osteoporosis: Hyperthyroidism can increase the risk of osteoporosis.
• Proximal Myopathy
• Cardiac Complications: Atrial fibrillation and other heart rhythm disturbances can occur due to the increased metabolic demands. Can lead to heart failure.

Prognosis: With appropriate treatment, most patients with Grave's disease have a good prognosis. However, long-term monitoring is required to manage potential complications, particularly hypothyroidism.