Graves' disease
is the most common cause of hyperthyroidism and is due to an autoimmune process. Serum IgG antibodies bind to the thyroid TSH receptor stimulating thyroid hormone production, behaving like TSH. These TSH receptor antibodies can be measured in serum.
There is an association with HLA-B8, DR3 and DR2 and 50% concordance is seen amongst monozygotic twins with a 5% concordance rate in dizygotic twins.
Yersinia enterocolitica as well as Escherichia coli and other Gram-negative organisms contain TSH binding sites. This raises the possibility that the initiating event in the pathogenesis may be an infection with possible 'molecular mimicry' in a genetically susceptible individual, but the precise initiating mechanisms remain unproven in most cases.
Thyroid eye disease accompanies the hyperthyroidism in many cases (see below) but other components of Graves' disease, e.g. Graves' dermopathy, are very rare. Rarely lymphadenopathy and splenomegaly may occur.
Graves' disease is also associated with other autoimmune disorders such as pernicious anaemia, vitiligo and myasthenia gravis.
The natural history is one of fluctuation, many patients showing a pattern of alternating relapse and remission; perhaps only 40% of subjects have a single episode. Many patients eventually become hypothyroid.
Hyperthyroidism
The fetus and maternal Graves' disease
Any mother with a history of Graves' disease may have circulating TSI. Even if she has been treated (e.g. by surgery), the immunoglobulin may still be present to stimulate the fetal thyroid, and the fetus can thus become hyperthyroid, while the mother remains euthyroid.
Any such patient should therefore be monitored during pregnancy. Fetal heart rate provides a direct biological assay of fetal thyroid status, and monitoring should be performed at least monthly. Rates above 160 per minute are strongly suggestive of fetal hyperthyroidism and maternal treatment with carbimazole and/or propranolol may be used.
To prevent the mother becoming hypothyroid, T 4 may be given as this does not easily cross the placenta.
Sympathomimetics, used to prevent premature labour, are contraindicated as they may provoke fatal tachycardia in the fetus.
Hyperthyroidism may also develop in the neonatal period as TSI has a half-life of approximately 3 weeks. Manifestations in the newborn include irritability, failure to thrive and persisting weight loss, diarrhoea and eye signs.
Thyroid function tests are difficult to interpret as neonatal normal ranges vary with age.
Untreated neonatal hyperthyroidism is probably associated with hyperactivity in later childhood.
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