Graves' Disease

Robert Graves, a distinguished Irish physician and prolific medical author, gives his name to this autoimmune disorder of the thyroid gland. It is usually characterised by hyperthyroidism due to circulating autoantibodies although the whole spectrum of thyroid function may be found in these patients. Thyrotoxicosis and thyroid eye disease frequently occur together (both are required for the strict clinical diagnosis of Graves' disease) but the latter can be mild and difficult to detect.

Go to our dedicated records for more information on:

Thyroid Lumps
Thyroid Function Tests
Hyperthyroidism
Thyroid Disease in Pregnancy
Hyperthyroidism in Pregnancy
Thyrotoxic Storm
Hashimoto's Disease
Thyroid Disease and Surgery
Hypothyroidism

Graves' disease is an autoimmune disorder mediated by B and T lymphocytes, characterised also by the presence of thyroid-stimulating immunoglobulins (TSIs). These are directed at 4 different thyroid antigens:

• Thyroglobulin
• Thyroid peroxidase (or antimicrosomal antibodies)
• Sodium-iodide symporter
• Thyroid stimulating hormone (TSH) receptor

The latter is the primary autoantigen of Graves' disease; the IgG antibodies behave like TSH and bind to the TSH receptor on the thyroid cell causing the thyroid gland to grow and thyroid follicles to produce more thyroid hormone. This gives rise to the features of hyperthyroidism. Although autoantibodies to the three other antigens have less of a role in the pathophysiology of Graves' disease, they are useful as disease markers.

Patients with the anti-thyroid peroxidase (anti-microsomal) antibodies as well as TSI may become hypothyroid in time (about 5%). Some patients produce antibodies which block rather than stimulate the TSH receptors and this produces hypothyroidism. Hence Graves' disease can produce a spectrum from hyperthyroidism to hypothyroidism (some patients are euthyroid).

There is a genetic component that may predispose individuals (susceptibility genes include CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22) and there is a link with a specific HLA haplotype (HLA-B8). Specific gene loci have been identified which are different in different racial groups.

An interaction between genetic predisposition and certain trigger factors are then thought to initiate the disease process.² It has been found that Yersinia enterocolitica, Escherichia coli and other Gram-negative organisms contain TSH binding sites which raises the possibility of infection being one of the environmental factors to consider.³ Other possible triggers include smoking, stress, pollutants, allergy, pregnancy, iatrogenic causes (percutaneous injection of ethanol, interferon therapy such as interferon beta-1b or interleukin-4 therapy), iodine and selenium intake and trauma to the thyroid gland (including surgery).²

• Graves' disease is the most common cause of hyperthyroidism.
• It makes up about 70% of cases of hyperthyroidism.
• In the UK incidence has been reported at between 100 and 200 cases per 100,000 population.
• It is about 8 times more common in women than men.
• It can occur at any age but occurs typically in young women between age 20 and 40 years old.

Patients usually present with symptoms and signs relating to thyrotoxicosis - see dedicated record. These are summarised in the table below.¹ When taking a history, specifically enquire about possible trigger factors (see pathophysiology above). The classical features are:

• A diffusely enlarged thyroid gland (± bruits).
• Ophthalmopathy (clinically evident in 25-30% of patients) - see article on Thyroid Eye Disease for more detail on ophthalmological features.
• Non-pitting, pretibial myxoedema.
• The presence of TSIs (see investigations below).

Not all patients present with classic features of hyperthyroidism. The elderly, for example, experience fewer and more vague symptoms (clues may include unexplained weight loss, hyperhidrosis or a rapid heart beat). Others remain euthyroid or are hypothyroid. Thyrotoxic periodic paralysis has been traditionally described in south east Asian patients. This rare entity is now increasingly being described in patients of other ethnic backgrounds, particularly Arabs.⁴

A long differential list is possible depending on the particular manifestations.

• Anxiety
• Depression
• Hashimoto thyroiditis
• Phaeochromocytoma
• Pituitary tumours
• Papillary carcinoma of thyroid
• Drugs (cocaine, amfetamines and other stimulant drugs)
• Heart disease
• Carcinoma of the colon (causing change in bowel habit)
• Other causes of hyperthyroidism (drugs, toxic multinodular goitre, thyroiditis, iodide)
• Amiodarone⁵
• Exogenous thyroxine
• Toxic thyroid adenoma

• Blood tests:
  • Thyroid function tests:
    • Ultrasensitive thyrotropin assays are now best way of screening for thyroid disorders
    • TSH is suppressed in most patients with thyrotoxicosis
    • Free T3, free T4, free T3 index and free T4 index all usually increased but may be normal with suppressed TSH
    • TSIs are usually raised in adults - more variable in children⁷
    • Other antibodies may also be raised
  • Full blood count:
    • Normocytic, normochromic anaemia may be found
    • Low WCC and platelets occasionally (relative lymphocytosis and monocytosis)
  • Biochemistry:
    • Decreased total cholesterol and triglyceride
    • Reduced free testosterone
    • Increased sex hormone-binding globulin
    • Reduced parathyroid hormone (PTH) levels
    • Hypocortisolaemia may exist in severe disease⁸
  • HbA1_c may be raised, reflecting worsening diabetic control
  • Liver function tests should be monitored for liver toxicity caused by thioamides (antithyroid medications)
• Imaging:
  • Radioactive iodine scanning (useful in differentiating cause of hyperthyroidism) shows diffusely increased uptake.
  • Ultrasound confirms smooth thyroid swelling and findings of scans with colour-Doppler evaluation are predictive of radioiodine treatment outcome.¹
  • CT scanning used to evaluate proptosis and ascertain effects of treatment.

• Pernicious anaemia
• Vitiligo
• Type 1 diabetes mellitus
• Autoimmune adrenal insufficiency
• Systemic lupus erythematosus
• Other autoimmune diseases

Go to records on hyper and hypothyroidism (links in introduction) for management of these conditions. You may also find our record on Antithyroid Drugs helpful. Management can be summarised as follows:

• A patient with severe symptoms and signs of hyperthyroidism needs admitting.
• A patient with overt but not severe signs needs referring for specialist management.
• Thionamides should only be started under specialist supervision.
• It is worth noting that the extrathyroidal manifestations are not improved by treatment directed at the thyroid gland but may respond to immunosuppressive drugs.¹⁰
• Beta-blockers may be helpful for the management of marked adrenergic symptoms.
• Urgently refer patients with severe ophthalmopathy (deterioration of vision, change in quality of colour, disc swelling, globe subluxation, corneal opacity, inability to fully close lids).
• Routinely refer all other patients with suspected ophthalmopathy.

• Complications can arise from treatment, particularly agranulocytosis from antithyroid drugs.
• Progressive ophthalmopathy (see Thyroid Eye Disease article).
• Maternal Graves' disease can lead to neonatal hyperthyroidism.¹
• Thyroid cancer (is slightly more common).
• Thyrotoxic heart disease (atrial fibrillation, heart failure).¹¹
• Osteoporosis which can compound post menopausal osteoporosis in women and therefore be severe.¹²
• Sarcopenia and myopathy due to muscle protein breakdown.
• Psychocognitive complications (e.g. mood and anxiety disorders).¹

If left untreated, Graves' disease can progress to severe thyrotoxicosis leading to a thyroid storm (see article) which can be fatal.¹

Ultimately patients will eventually become hypothyroid and require thyroid replacement.¹ There may be a recurrence of hyperthyroidism after treatment from remaining thyroid tissue. There is a slightly higher risk of thyroid cancer in patients with Graves' disease. Ophthalmic problems follow an unpredictable course but generally in the long term, they become quiescent. Surgery has little - if any - effect on the course of the ophthalmopathy.

Robert James Graves (1796-1853) was an Irish physician and teacher. He was a prolific medical author. His paper 'Newly observed affection of the thyroid gland in females' was published in the London Medical and Surgical Journal in 1853.