Endocrinology: Thyroid and Parathyroid Flashcards
Thyroid function in the foetus
1) Although T3 and T4 reach the foetal circulation from the mother, the foetus depends on its own thyroid gland for thyroid hormones.
2) Thyroid gland fully differentiated by 11 weeks gestation, but probably not until about 18 weeks that thyroid hormone production commences.
3) By 28 weeks free T4 values reach adult levels. Failure of thyroid gland development or hormone synthesis results in cretinism.
Cretinism
Gross mental retardation due to failure of brain development, and a failure of skeletal development leading to dwarfism.
Maternal TSH receptor stimulating antibodies may cross the placenta; this can lead to transient neonatal hyperthyroidism. Maternal TSH receptor blocking antibodies may likewise result in foetal hypothyroidism
Structure and function of thyroid gland
Spherical follicles of thyroid epithelial cells surrounding colloid (principally thyroglobulin) within a lumen. In addition, parafollicular or C-cells secrete calcitonin.
In each follicle, the epithelial cells are cuboidal when ‘resting’ and ‘columnar’ when under TSH stimulation
Thyroid follicular cells
• secrete thyroglobulin (Tg) and iodine into colloid
• absorb thyroglobulin from colloid
• secrete triiodothyronine (T3) and thyroxine (T4)
directly into the blood stream
Thyroid function: I and Na pump
Thyroid gland incorporates iodide into its cells from plasma by an active transport mechanism in which Iodine follows Na.
This ‘pump’ is influenced positively by TSH and TSH receptor antibodies (in Graves’ disease). Iodine can be blocked for example, digoxin.
Thyroid function: Within the follicular cell I
Iodide is quickly oxidised by thyroid peroxidase (TPO) and hydrogen peroxide and bound to thyroglobulin forming monoiodotyrosine (MIT) and diiodotyrosine (DIT)
Then transferred to the luminal colloid. MIT and DIT combine in a reaction catalysed by TPO, positively regulated by TSH to produce either triiodothyronine (T3) or thyroxine (T4) – all within the colloid.
Thyroid function: Within the follicular cell II
1) Under continued TSH control, colloid droplets are taken up by the thyroid cell via a process of endocytosis, lysosomes fuse with the droplets and proteolysis of thyroglobulin occurs.
2) In the plasma the hormones conjugate with thyroxine-binding globulin (TBG) produced by the liver that binds 70% of T3 and T4, to thyroxine-binding prealbumin, and to albumin.
3) Protein bound, T3 and T4 are inactive and thus are a ‘store’ of bound hormone allowing regulation of the levels of unbound active ‘free’ T3 and T4 available to the tissues.
Thyroid function: T3 and T4
Free T3 is the active hormone. Most T3 production (80%) is extrathyroidal from deiodination of T4. The half life of T3 is one day and of T4 is one week. Thus T4 appears to act as an immediately available source and regulator of T3 rather than as an hormone in its own right.
Control of thyroid function
1) Thyroid-stimulating hormone (TSH), from the anterior pituitary, has a stimulating effect on T3/T4 production.
2) Thyrotrophin-releasing hormone (TRH), which
is stored in the hypothalamus, stimulates TSH production and release.
3) Rising levels of T3/T4 (primarily a rising T3 concentration) have an inhibitory effect on the TRH/TSH axis.
Iodine and thyroid control
1) Thyroid autoantibodies may stimulate or inhibit thyroid function. TSH receptor antibodies may be stimulatory producing hyperthyroidism (Graves’ Disease) or have a blocking action producing hypothyroidism (atrophic thyroiditis).
4) Anti-TPO (thyroid peroxidase) autoantibodies are found in 90% of patients with Graves’ Disease and lymphocytic thyroiditis.
Mechanism of action of thyroid hormones
1) T3 and T4 have major effects on the growth, development and function of most tissues.
2) The main effects are seen on the cell membrane, on the mitochondria and on the cell nucleus.
3) At the cell membrane level there is increased uptake of amino acids when T3 stimulation occurs.
4) The effect on mitochondria is to increase
energy production.
5) T3 combines with T3 receptors within the nucleus, this causes increased or decreased mRNA expression with consequent effects on protein synthesis.
Effects of thyroid hormone
These are widespread and include energy and heat production, an overall catabolic effect – particularly on glucose and fat metabolism, cardiovascular and adrenergic effects, effects on production of other hormones, effects
on bone, foetal development and growth.
Effects of thyroid hormone: heat production
Heat production is brought about by the T3 effect
on mitochondria: there is increased O2 uptake by the mitochondria with production of ATP in most tissues, although not in the brain.
Thyroid hormone is responsible for the increase in basal metabolic rate (BMR) that occurs in hyperthyroidism, and consequently the heat intolerance described by patients.
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Effects of thyroid hormone: Catabolic effects
Thyroid hormones stimulate glycogenolysis in the liver, an increase in insulin breakdown and a rise in glucose absorption from the gut.
Hyperthyroidism is associated with insulin resistance and glucose intolerance, diabetes may be ‘unmasked’ or, its control in a patient with established diabetes may be more difficult.
Effects of thyroid hormone: Cardiovascular and adrenergic effects
The number of alpha adrenergic receptors in cardiac muscle increase
Consequently thyroid hormones have a positive inotropic effect. In patients with thyrotoxicosis, the cardiac output and heart rate increase. Alpha adrenergic receptor activity also increases in other tissues, including skeletal muscle.
The management of the tachycardia and dysrhythmia associated with thyrotoxicosis logically includes a-adrenergic receptor blocker such as propranolol or metoprolol.
In hypothyroidism cardiac output is reduced; pericardial effusions may occur.
Effects of thyroid hormone: Effects on bone
T3 and T4 increase metabolic activity in bone, there
is increased bone resorption and bone formation.
The catabolic effect is predominant in thyrotoxicosis
which results in a net reduction in bone density.
Hypercalcaemia (rarely severe) and hypercalciuria
can occur in thyrotoxicosis, PTH levels will be normal or low.
Effects of thyroid hormone: Gastrointestinal effects
Weight loss and diarrhoea are common symptoms
reported by patients with hyperthyroidism. Constipation, loss of appetite and weight gain are frequent symptoms in hypothyroidism.
Investigation of thyroid function
Low TSH and high fT4 and /or fT3 will ordinarily indicate thyrotoxicosis.
High TSH with low thyroid hormone indicate a hypothyroid state.
In pregnancy there is a rise in TBG with a consequent rise in total T3 and T4 levels: however, the free T3 and T4 levels are little changed.
In very early pregnancy the free T3 and T4 levels may increase due to the effects of hCG. The thyroid gland often increases in size during pregnancy. Post-partum thyroid dysfunction is common (15%).
Thyroid and paediatrics
In children, free T4 levels reach the normal adult range by the end of the first year. Free T3 levels remain high in childhood and early adolescence. In sick patients with non thyroidal illness, a transient rise in TSH and low free T4 and free T3 is often seen. With recovery from the illness, thyroid function tests return to normal.
Thyroid antibodies
Thyroid autoantibody status should also be determined. In patients with Graves’ disease TPO antibodies are positive in approximately 80% of patients. Approximately 90% of patients with Hashimoto’s disease have positive TPO antibodies. It should be remembered that in itself positive antibody status does not constitute a diagnosis of thyroid disorder as at least a third of the normal population will have a positive antibody titre.
Thyroid tumour markers
Thyroglobulin in patients with differentiated (papillary or follicular) thyroid who have undergone complete eradication of thyroid tissue by the combination of surgery and postoperative radioactive iodine therapy.
A rise in thyroglobulin levels indicates persistent or recurrent disease.
Calcitonin is measured in patients with medullary thyroid cancer (MTC) (a tumour that arises from thyroid C cells).
Calcitonin levels are also measured in patients who have undergone surgery for MTC; a raised or increasing level of calcitonin indicates residual or recurrent disease.
Thyroid pathology investigation
1) FNA distinguishes solid from cystic thyroid enlargement.
2) Ultrasound of the thyroid is very sensitive at detecting abnormal thyroid tissue but not specific, and rarely contributes to the diagnosis of thyroid swellings. Useful for targeted FNA and reduces the number of unsatisfactory needle aspirates.
2) Thyroid CT and MRI can delineate the extent of thyroid enlargement in the neck and chest as well as the encroachment/invasion of adjacent structures in benign and malignant disease.
Hypothyroidism
1) Caused by a deficiency of or resistance to thyroid hormone.
2) Primary hypothyroidism is the cause of 95% of adult cases; Hashimoto’s disease (chronic lymphocytic thyroiditis) is responsible for 70% of these.
3) Patients with hypothyroidism sometimes present with a goitre to surgeons. The combination of abnormal thyroid function tests, positive TPO autoantibodies and sometimes aspiration cytology is sufficient to confirm the diagnosis.
Myxoedema
1) Myxoedema, the end result of severe long
standing hypothyroidism, is associated with marked
symptoms and signs, characteristic skin changes and in extreme cases, confusion and coma associated with a very high mortality.
2) The patient has profound hypothermia, and may demonstrate hypoglycaemia, water retention, and hypoventilation.
3) In generalised myxoedema there is accumulation of glycosaminoglycans within soft tissues, and facial and cutaneous oedema (containing mucopolysaccarides, hyaluronic acid and chondroitin sulphate).