Thyroid pathophysiology

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Thyroid pathophysiology

Introduction

Thyroxine (T₄) and tri-iodothyronine (T₃) are together known as the ‘thyroid hormones’. They are synthesized in the thyroid gland by iodination and coupling of two tyrosine molecules whilst attached to a complex protein called thyroglobulin. T₄ has four iodine atoms while T₃ has three (Fig 44.1).

Fig 44.1 The chemical structures of T₄, T₃ and rT₃.

The thyroid gland secretes mostly T₄ whose concentration in plasma is around 100 nmol/L. The peripheral tissues, especially the liver and kidney, deiodinate T₄ to produce approximately two-thirds of the circulating T₃, present at a lower concentration of around 2 nmol/L. Most cells are capable of taking up T₄ and deiodinating it to the more biologically active T₃. It is T₃ that binds to receptors and triggers the end-organ effects of the thyroid hormones. Alternatively, T₄ can be metabolized to reverse T₃ (rT₃), which is biologically inactive. By modulating the relative production of T₃ and rT₃, tissues can ‘fine tune’ their local thyroid status. Exactly how this is accomplished is not yet fully understood.

A goitre is an enlarged thyroid gland (Fig 44.2). This may be associated with hypothyroidism, hyperthyroidism or a euthyroid state. Globally, iodine deficiency is the commonest cause of goitre. The WHO estimates that approximately 2 billion people have an inadequate iodine intake making it the commonest preventable cause of neuro-developmental problems. In many developed countries this problem has been overcome by the addition of iodine to a staple food such as iodised salt.

Fig 44.2 A patient with a goitre.

Thyroid hormone action

Thyroid hormones are essential for the normal maturation and metabolism of all the tissues in the body. Their effects on tissue maturation are most dramatically seen in congenital hypothyroidism, a condition which, unless treated within 3 months of birth, results in permanent brain damage. Hypothyroid children have delayed skeletal maturation, short stature and delayed puberty.

Thyroid hormone effects on metabolism are diverse. The rates of protein and carbohydrate synthesis and catabolism are influenced. An example of the effect of thyroid hormones on lipid metabolism is the observation of a high serum cholesterol in some hypothyroid patients. This is a consequence of a reduction in cholesterol metabolism due to down regulation of low-density lipoprotein (LDL) receptors on liver cell membranes, with a subsequent failure of sterol excretion via the gut.

Binding in plasma

In plasma, over 99.95% of T₄ is transported bound to proteins. Thyroxine binding globulin (TBG) carries 70% of T₄, albumin approximately 25% and transthyretin (formerly called prealbumin) around 5%. Over 99.5% of T₃ is transported by the same proteins. It is the unbound, or ‘free’, T₄ and T₃ concentrations that are important for the biological effects of the hormones, including the feedback to the pituitary and hypothalamus. Changes in binding protein concentration complicate the interpretation of thyroid hormone results, e.g. in pregnancy.

Regulation of thyroid hormone secretion

The components of the hypothalamic–pituitary–thyroid axis are TRH, TSH and the thyroid hormones. TRH, a tripeptide, is secreted by the hypothalamus and in turn causes the synthesis of a large glycoprotein hormone, TSH, from the anterior pituitary. This drives the synthesis of thyroid hormones by the thyroid. Production of TSH is regulated by feedback from circulating unbound thyroid hormones. A knowledge of these basics is essential for the correct interpretation of results in the investigation of primary thyroid disease. Remember:

If a patient’s thyroid is producing too much thyroid hormone, then the circulating TSH will be suppressed.

If the thyroid is not secreting enough thyroid hormone, the TSH levels will be very high in an attempt to stimulate the gland to secrete more.

Thyroid function tests

Biochemical measurements in the diagnosis of thyroid disease have traditionally been known as ‘thyroid function tests’. TSH and some estimate of T₄ status (either total T₄ or free T₄) are the first-line tests.

TSH. Measurement of TSH is a good example of how better technology has helped in the diagnosis and monitoring of disease. Early assays for TSH were unable to measure low concentrations of the hormone – the detection limits of the radioimmunoassays overlapped significantly with concentrations of the low end of the reference interval in healthy subjects. Now, very sensitive TSH assays can detect much lower concentrations and it is possible to tell with a greater degree of certainty whether TSH secretion really is lower than normal.

Because of its log-linear relationship with TRH, TSH is very sensitive to derangements in thyroid control, and many laboratories use TSH alone as the first-line thyroid function test. There is, however, one situation in which TSH cannot be used to diagnose primary thyroid disease, or to monitor replacement, namely hypopituitarism. For example, TSH is undetectable post hypophysectomy and an estimate of T₄ status must be used instead to monitor the adequacy of replacement.

Total T₄ or free T₄. Following the introduction of replacement thyroxine or of anti-thyroid treatment, e.g. carbimazole, or indeed following any alteration in dosage, TSH may take many weeks to unsuppress and adjust to its new level. During this time, it is essential to have some estimate of T₄ status. This applies particularly to the monitoring of anti-thyroid treatment; patients can become profoundly hypothyroid quite quickly.

Total T₃ or free T₃. Occasionally it may be useful to have an estimate of T₃ status in addition to T₄. In hyperthyroidism, the rise in T₃ is almost always disproportionate to the rise in T₄; an estimate of T₃ status may permit earlier identification of thyrotoxicosis. In some patients only the T₃ rises – the T₄ remains within the reference interval (T₃ toxicosis).

Antibodies. The titre of autoantibodies to thyroid tissue antigens may be helpful in the diagnosis and monitoring of autoimmune thyroid disease. Anti-thyroid peroxidase (anti-TPO) may be useful in hypothyroidism and stimulating thyroid receptor antibodies in thyrotoxicosis.

Drugs and the thyroid

Various drugs affect thyroid function tests. The effects of some of these are summarized in Table 44.1.

Table 44.1

Drugs affecting thyroid function tests

Drug	Mechanism	Major effects
Amiodarone	Reduced peripheral deiodination Amiodarone can also stimulate or inhibit release of thyroid hormones from thyroid	↑T₄,↓T₃, transient ↑ in TSH Hyperthyroidism Hypothyroidism
Lithium	Reduced thyroid uptake of iodine Reduced release of thyroid hormone	Goitre Hypothyroidism
Anticonvulsants (phenytoin, carbamazepine, phenobarbital)	Displace T₄ and T₃ from binding proteins	↑ free T₄, ↑ free T₃
Heparin	Releases lipoprotein lipase into plasma with resultant increase in free fatty acids. These displace T₄ and T₃ from binding proteins	↑ free T₄, ↑ free T₃
Aspirin	In high concentrations displaces T₄ from transthyretin	↑ free T₄