Thyroid: III Thyroid Pathophysiology
Mrs JA, a 41-year-old part-time nurse presented to her GP with a 6-month history of weight loss of 10 kg. On questioning she was eating well but complained of diarrhoea. She had also noticed that she felt exhausted and had developed insomnia. On further questioning she admitted to feeling increasingly hot and shaky and to having muscle weakness of the legs, particularly climbing stairs. She was normally well and had not seen the doctor since her last pregnancy 8 years before. A blood test showed the following results: free T4 49.7 pmol/L; total T4 225 nmol/L; TSH <0.01 mU/L.
She was referred to an endocrinologist at the local hospital where initial investigations confirmed a diagnosis of Graves’ disease. She was treated with carbimazole and propranolol for the first month of treatment followed by carbimazole alone. Subsequently, after discussing the therapeutic options, she opted to have 131I therapy which was given as an outpatient when she had become euthyroid. She was followed up at regular outpatient visits and 6 months later complained of lethargy, weight gain and feeling cold all the time. Clinically she had features of hypothyroidism and blood tests were as follows: free T4
crinologist commenced thyroid hormone replacement therapy and 3 months later she was well and her blood tests were normal.
There are a number of causes of hyperthyroidism but over 90% of cases are accounted for by autoimmune thyrotoxicosis (Graves’ disease, approximately 75%), toxic multinodular goitre (approximately 15%) and solitary toxic adenoma (approximately 5%). Transient thyrotoxicosis may be associ- ated with thyroiditis and certain drugs may be responsible, particularly amiodarone. Very rarely patients present with thy- rotoxicosis secondary to TSH-secreting tumours of the pitui- tary, pituitary thyroid hormone resistance syndrome, extrathy- roidal hormone excess or secondary to thyroid carcinoma.
Clinically, the features of thyrotoxicosis may be divided into those caused by thyroid hormone excess and seen in all cases of hyperthyroidism and those associated with autoim- munity and seen in patients with Graves’ disease only (Fig. 15a and b; Table 15.1). Treatment is either with antithyroid drugs (alone or in combination with thyroxine replacement therapy), radioactive iodine ablation using 131I or surgery. Choice of treatment depends on the underlying cause and may be influenced by the patient’s age, other coexisting disease, particularly in the elderly, or the presence of thyroid-associated ophthalmopathy.
Thyroid Function Tests
Thyroid hormone measurement
Only about 1% of thyroid hormones are in the metabolically active ‘free’ state as both T4 and T3 are tightly bound to trans- port proteins in the plasma (Chapter 13). Assays of ‘total’ T4 or T3 measure mainly the protein-bound hormone. This may be affected in a number of ways by conditions affecting protein concentration. Thus spuriously high total T4 measurements will occur in pregnancy and in women taking the oral contraceptive pill as estrogen increases thyroxine binding globulin (TBG) synthesis. Inappropriately low measurements may be found in individuals with congenital TBG deficiency or severe liver disease.
Assays of ‘free’ thyroid hormones are now widely available and are not generally affected by changes in plasma binding protein concentrations.
Thyroid stimulating hormone measurement Measurement of TSH is the most widely used thyroid function test. It is less subject to assay interference and reliably predicts thyroid function in accordance with the principles of negative feedback. Thus in hyperthyroidism the TSH concentration is undetectable. In primary hypothyroidism, TSH concentrations are elevated and in secondary hypothyroidism the low free T4 level is accompanied by low TSH concentrations.
Other biochemical tests of thyroid function, such as TRH tests, have been used only rarely since the advent of highly sensitive TSH assays.
Biochemical tests of thyroid function may be supplemented by imaging techniques to investigate thyroid structure and function:
1. Thyroid ultrasonography will reveal the presence of single or multiple nodules and cysts. Needle aspiration for cytology or cyst drainage and thyroid biopsy may be conducted under ultrasound control.
2. Thyroid scintigraphy or radionuclide imaging is helpful in the diagnosis of thyroiditis, when isotope uptake is greatly diminished in contrast to the uniform increase seen in thyrotoxicosis. A clinically solitary nodule may be revealed as a ‘cold’ nodule on scanning, requiring further investigation for possible malignant disease.
Thyroid cancer usually presents as a swelling in the thyroid gland. It is a relatively rare malignancy and the majority of thyroid nodules will prove to be benign. Investigations include fineneedle aspiration cytology, with or without thyroid scintigraphy. Most malignancies are papillary carcinomas; other tumours include the more aggressive follicular carcinomas and rapidly progressive anaplastic lesions. Medullary thyroid carcinomas arising in thyroid C cells may be found in isolation or as part of the MEN 2 syndrome (see Chapter 50).