Graves disease

see also:

• thyroid physiology and hormones
• hyperthyroidism
• Mx of a low TSH
• thyroid storm
• thyroiditis

• Graves-Basedow thyroiditis is an autoimmune disease affecting the thyroid gland which results in “toxic diffuse goitre” and a range of clinical features including hyperthyroidism
• accounts for 50-80% of cases of hyperthyroidism
• the most common cause of diffuse goiter
• named after Robert Graves, who described it in 1835 and the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840 and thus in Europe it is often called Basedow's syndrome.
• Grave's disease results from excessive thyroid gland stimulation due to TSH receptor antibodies (thyrotropin receptor antibodies or TRAbs)
• 5-10x more common in women than men
• onset peaks at 40-60yrs age
• may be precipitated by smoking, stress or post-partum period
• affects some 250 people per million population each year and some 0.5% of males and 3% of women will develop it in their lifetime

• 0.5% of males and 3% of females (7.5x more common in women than in men)
• often starts in ages 40-60yrs but may start at any age

• results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH)
• believed to involve a combination of genetic and environmental factors
  • if one twin has it, there is a 30% chance the other twin will have it
  • there appears to be an association with Yersinia infections but this may not be causal although Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor
• onset may be triggered by:
  • stress
  • childbirth
  • infection eg. EBV / glandular fever / infectious mononucleosis
• smoking increases risk of disease and may worse the eye problems

• general features of hyperthyroidism with low TSH levels and high free T4 and/or free T3
  • 60% have weight loss
• autoimmune features specific to Grave's disease:
  • ophthalmopathy
    • 50% have lid lag, lid retraction or perio-orbital oedema)
  • pretibial myxoedema in 1-2%
  • clubbing in 1%
• 30% remit without Rx
• there is a risk of developing potentially life threatening thyroid storm
• may cause a palpably enlarged non-tender goitre and there may be an audible bruit
• features of hyperthyroidism
  • irritability
  • tremor
  • muscle weakness
    • periodic partial muscle weakness or paralysis in those especially of oriental descent
  • sleeping problems
  • sinus tachycardia
  • atrial fibrillation
  • hypertension
  • poor tolerance of heat
  • diarrhoea
  • unintentional weight loss
  • excessive lacrimation
  • may cause cognitive issues such as anxiety, agitation, mania, psychosis and depression
• 25-80% develop exophthalmos (Graves' ophthalmopathy, a form of idiopathic lymphocytic orbital inflammation) which can be classified as:
  • Class 0 = nil
  • Class 1 = upper lid retraction and stare +/- lid lag
  • Class 2 = oedema of conjunctivae and lids, conjunctival injection
  • Class 3 = proptosis / exophthalmos
  • Class 4 = extraocular muscle involvement (usually with diplopia)
  • Class 5 = corneal involvement (primarily due to lagophthalmos)
  • Class 6 = visual loss due to optic nerve involvement

• exclude thyroid storm
• commence beta blockers and an antithyroid drug
• send bloods for TSH receptor antibodies which is the cause of the thyroid hyperstimulation in Graves but up to 10% will have a negative result
• consider thyroid scan to confirm homogenous goitre
• beta adrenergic blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until such time as antithyroid treatments start to take effect.

• once it has been established that the patient is hyperthyroid and the cause is GD, the patient and physician must choose between three effective and relatively safe initial treatment options:

• Following oral administration, radioactive iodine is transported into thyroid follicular cells resulting in cell necrosis over weeks to months
• The cure rate (euthyroid or hypothyroid) following the administration of a 15 mCi dose of radioactive iodine for Graves disease is 67–81% at 12 months, with hypothyroidism occurring in most and increasing with time
• radiation thyroiditis occurs in approximately 10% of patients with transient worsening of thyrotoxicosis and painful thyroid inflammation in some
• Antithyroid drugs are generally used before the administration of radioactive iodine to promptly achieve euthyroidism and to attenuate exacerbation of thyrotoxicosis should thyroiditis occur.
• not recommended in the presence of moderate to severe active Graves ophthalmopathy as it can exacerbate the eye disease
• avoid close contact with children for several days after dosing
• Following radioactive iodine therapy, women should avoid pregnancy for 6 months to ensure stable euthyroidism; men should allow 4 months for turnover of sperm production

• carbimazole
  • the first line thionamide in almost all patients as it results in a more rapid improvement in thyroid hormone levels, has less hepatotoxicity, and can be given once daily due to its longer half life
  • starting dose of carbimazole is 10–30 mg/day in 2–3 divided doses depending on severity of thyrotoxicosis, although larger doses may be used in severe disease
  • Four weeks following initiation of therapy, clinical review with repeat thyroid function tests should be undertaken to avoid hypothyroidism
  • Antithyroid drug therapy is tapered to a maintenance dose (usually carbimazole 2.5–10 mg) and ceased after 12–18 months of therapy
• Propylthiouracil (PTU)
  • the preferred antithyroid drug in the first trimester of pregnancy, in the treatment of thyroid storm (also inhibits the conversion of T4 to T3), and in patients with minor reactions to carbimazole where radioactive iodine or surgery is not appropriate
  • severe hepatocellular injury occurs with propylthiouracil in 0.1% of patients treated with the drug, and approximately 10% of these patients develop liver failure resulting in either a liver transplant or death
• agranulocytosis (neutrophil count <0.5×109/L) is a rare but life-threatening complication of both antithyroid drugs with an incidence of 0.2–0.5% and due to cross reactivity between the two antithyroid medications, agranulocytosis with one drug is an absolute contraindication to trialling the other
• Male gender, age <40 years, a large goitre, marked elevation of T4 and T3 and possibly a high titre of TSH receptor antibody, are factors associated with a lower rate of remission than average of 50% of patients
• 5–20% of patients in remission eventually develop hypothyroidism due to autoimmune thyroiditis or the presence of TSH receptor blocking antibodies
• Serum TSH concentrations may remain suppressed for several months after normal free thyroid hormone levels are established, so TSH is not a good biomarker to guide drug therapy in the early stages

• usually once the thyroid is euthyroid then thyroidectomy can be considered (it is more dangerous to perform prior to being euthyroid)
  • potential indications for thyroidectomy:
    • large goitre especially if compressing trachea
    • suspected cancer
    • people with ophthalmopathy
    • patient preference - especially likely in younger patients or pregnant patients
  • risks of thyroidectomy
    • recurrent laryngeal nerve injury in 1%
    • hypoparathyroidism
    • post-op haematoma (which can be life-threatening if it compresses the trachea)
    • may require post-op radioiodine
    • the usual risks of surgery - scarring, anaesthetic, infection, etc

• some patients will need specific Rx of their ophthalmopathy such as:
  • lubricant eye drops
  • steroids such as pulse intravenous methylprednisolone
  • orbital decompression
  • eyelid surgery
• many patients will develop hypothyroidism and require thyroxine replacement Rx