Graves' Disease

Robert Graves, a distinguished Irish physician and prolific medical author, gives his name to this autoimmune disorder of the thyroid gland. Graves' disease is associated with symptoms and signs of thyrotoxicosis with ophthalmopathy, acropachy (clubbing of the fingers) and pretibial myxoedema.

Thyrotoxicosis and eye disease frequently occur together (both required for the strict clinical diagnosis of Graves' disease), but the latter can be mild and difficult to detect. It can exist without thyrotoxicosis.

Pathophysiology

Graves' disease is an autoimmune disorder (mediated by B and T lymphocytes), characterised also by the presence of thyroid-stimulating immunoglobulins (TSIs). These antibodies - (IgG antibodies) are directed against the TSH receptor on the thyroid cell causing the thyroid gland to grow and thyroid follicles to produce more thyroid hormone and often also against the soft tissues of the orbit causing periorbital oedema,proptosis, and ophthalmoplegia.¹ The autoimmune process can manifest itself elsewhere in the body as pre-tibial myxoedema (discrete non tender darker areas of raised skin) or finger clubbing.
The 4 best known antigens are:

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

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). A genetic predisposition has been identified and there is a link with a specific HLA haplotype. Specific gene loci have been identified which are different in different racial groups. Possible triggers include stress, iatrogenic causes, trauma, infections and genetic predisposition.

Epidemiology

• Grave's 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 commoner in women than men.
• It can occur at any age, but occurs typically in young women between age 20 and 40 years old.

Presentation

History

• Take a careful history (consider triggers such as treatment with interferon and interleukin-4)
• Typical hyperthyroid symptoms are usual
• Common symptoms are:
  • Palpitations
  • Tremor
  • Anxiety
• Less obvious to the patient (particularly the elderly) are:
  • Weight loss
  • Sweaty palms
  • Frequent bowel habit
• Less commonly there is:
  • Proximal weakness
  • Tiredness (fatiguability)
  • Poor sleep
  • Poor concentration
• Eye symptoms occur:
  • Eye pain
  • Gritty eyes
  • Diplopia
  • Photophobia
  • Refractive changes (even visual loss)

Examination

Important physical findings of Graves' disease include: Features of hyperthyroidism (see above and below) Diffusely enlarged thyroid gland (with occasionally thyroid bruits and thrills) Onycholysis (4th and 5th fingernails) Pretibial myxedematous changes (skin like orange peel) Acropachy Ophthalmopathy: Found in about a quarter of Grave's disease sufferers Widened palpebral fissures Proptosis Lid lag Lid retraction Ophthalmology assessment recommended

• General:
  • Sweaty
  • Anxious
  • Depression
  • Irritable
• Skin:
  • Warm, moist skin (palms with hand shake)
  • Fine hair
  • Vitiligo
  • Alopecia
  • Pretibial myxoedema
  • Onycholysis
• Cardiovascular:
  • Tachycardia
  • Atrial fibrillation
  • Left ventricular hypertrophy
• Respiratory:
  • Dyspnoea
• Gastrointestinal:
  • Diarrhoea
  • More frequent bowel habit
• Renal:
  • Polyuria and polydypsia but no other evident cause
• Neuromuscular:
  • Tremor
  • Proximal muscle weakness
  • Hyperactive tendon reflexes
• Skeletal:
  • Acropachy
  • Osteoporosis²
  • Raised calcium and alkaline phosphatase
• Menstrual/endocrine:
  • Irregular periods
  • Gynaecomastia

Differential diagnosis

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

• Anxiety
• Depression
• Hashimoto thyroiditis
• Phaeochromocytoma
• Pituitary tumours
• Papillary carcinoma of thyroid
• Drugs (cocaine, amphetamines and other stimulant drugs)
• Heart disease
• Carcinoma colon (causing change in bowel habit)
• Other causes hyperthyroidism (drugs, toxic multinodular goitre, thyroiditis, iodide)
• Amiodarone³
• Exogenous thyroxine
• Toxic thyroid adenoma

Investigations⁴

• Blood tests:
  • Thyroid function tests:
    • Ultrasensitive thyrotropin assays now best way of screening for thyroid disorders
    • TSH is suppressed in most patients with thyrotoxicosis
    • Thyroid hormones:
    • Free T3, free T4, free T3 index and free T4 index all usually increased
    • May be normal with suppressed TSH
    • TSIs usually raised
    • 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:
    • Raised alkaline phosphatase and calcium levels
    • Decreased total cholesterol and triglyceride
    • Reduced free testosterone
    • Increased sex hormone-binding globulin
    • Reduced parathyroid hormone (PTH) levels
• Imaging:
  • Radioactive iodine scanning shows diffusely increased uptake
  • Ultrasound not particularly useful- confirms smooth thyroid swelling
  • CT scanning used to evaluate proptosis

Associated diseases

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

Management^5,4,6,7

See thyrotoxicosis article and hypothyroidism article.
The extrathyroidal manifestations are not improved by treatment directed at the thyroid gland, but may respond to immunosuppressive drugs.⁸

Complications

• Complications can arise from treatment, particularly agranulocytosis from antithyroid drugs.
• Thyroid cancer (is slightly more common).
• Thyrotoxic heart disease (atrial fibrillation, heart failure)⁹
• Osteoporosis²

Prognosis

Ultimately patients will become hypothyroid and require thyroid replacement. 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 Grave's Disease.

Historical

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.

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Document references

1. McKenna TJ; Graves' disease.; Lancet. 2001 Jun 2;357(9270):1793-6.
2. Boelaert K, Franklyn JA; Thyroid hormone in health and disease.; J Endocrinol. 2005 Oct;187(1):1-15. [abstract]
3. Rajeswaran C, Shelton RJ, Gilbey SG; Management of amiodarone-induced thyrotoxicosis.; Swiss Med Wkly. 2003 Nov 22;133(43-44):579-85. [abstract]
4. Reid JR, Wheeler SF; Hyperthyroidism: diagnosis and treatment.; Am Fam Physician. 2005 Aug 15;72(4):623-30. [abstract]
5. Hyperthyroidism, Clinical Knowledge Summaries (March 2008)
6. Abraham P, Avenell A, Park CM, et al; A systematic review of drug therapy for Graves' hyperthyroidism.;Eur J Endocrinol. 2005 Oct;153(4):489-98. [abstract]
7. Birrell G, Cheetham T; Juvenile thyrotoxicosis; can we do better?; Arch Dis Child. 2004 Aug;89(8):745-50. [abstract]
8. Gittoes NJ, Franklyn JA; Hyperthyroidism. Current treatment guidelines.; Drugs. 1998 Apr;55(4):543-53. [abstract]
9. Osman F, Gammage MD, Franklyn JA; Hyperthyroidism and cardiovascular morbidity and mortality.;Thyroid. 2002 Jun;12(6):483-7. [abstract]