The metabolic rate of many tissues is controlled by the thyroid hormones, and overactivity and underactivity of the gland pose the commonest of all endocrine problems.
The gland consists of two lateral lobes connected by an isthmus. It is closely attached to the thyroid cartilages and to the upper end of the trachea, and thus moves on swallowing. It is often palpable in normal women. Embryologically it originates from the base of the tongue and descends to the middle of the neck. Remnants of thyroid tissue can sometimes be found at the base of the tongue (lingual thyroid) and along the line of descent. The gland has a rich blood supply from superior and inferior thyroid arteries. The thyroid consists of follicles lined by cuboidal epithelioid cells. Inside is the colloid, which is an iodinated glycoprotein, thyroglobulin, synthesized by the follicular cells. Each follicle is surrounded by basement membrane, between which are parafollicular cells containing calcitonin- secreting C cells.
The thyroid hormones, T. and T, are synthesized within the gland . More T. than T, is produced but T. is converted in some peripheral tissues (liver, kidney and muscle) to the more active T, by 5′-monodeiodination; an alternative 3′- monodeiodination yields the inactive reverse T, (rT,). The latter step occurs particularly in severe non-thyroidal illness (see below).
In plasma, more than 99% of all T. and T3 is bound to hormone-binding proteins (thyroxine-binding globulin, TBG; thyroid-binding prealbumin, TBP A; and albumin). Only free hormone is available for tissue action, where T3 binds to specific nuclear receptors within the cell. Factors affecting TBG.
Oral contraceptive use
Acute viral hepatitis
Chronic liver disease
Drugs causing altered binding
Non-steroidal anti-inflammatory drugs
Globally dietary iodine deficiency is an important cause of thyroid disease as it is an essential requirement for thyroid hormone synthesis. The recommended daily intake of iodine should be at least 140 f.Lgand dietary supplementation of salt and bread has reduced the number of areas where ‘endemic goitre’ still occurs.
Oral contraceptive use
Acute viral hepatitis
Chronic liver disease
Physiology of the hypothalamicpituitary thyroid axis
TRH is released in the hypothalamus and stimulates release of TSH from the pituitary.
2 TSH stimulates the TSH receptor in the thyroid to increase synthesis of both T. and T3 and also to release stored hormone, producing increased plasma levels of T. and T3.
3 T. and T3 feed back on the pituitary and perhaps hypothalamus to reduce TRH and TSH secretion.
Thyroid function tests
RIAs for total T., free T., total T3, free T3 and IRMAs for TSH are widely available. There are only minor significant circadian rhythms, and measurements may be made at any time. Particular uses of the tests are summarized.
TSH MEASUREMENT. IRMAs for TSH now differentiate between normal and low levels and ISH levels now thus discriminate between hyperthyroidism, hypothyroidism and euthyroidism. There are pitfalls, however. These are mainly with hypopituitarism, with the ‘sick euthyroid’ syndrome and with dysthyroid eye disease, all of which may give ‘false’ (i.e. misleading, not incorrect) low results implying hyperthyroidism. As a single test of thyroid function it is the most sensitive in most circumstances but many laboratories prefer to perform at least two tests-serum T3 or free T3 where hyperthyroidism is suspected, serum T4 or free T4 where hypothyroidism is likely.
THYROID HORMONE UPTAKE TESTS (IHUI) are now used much less. There are many forms of this measurement of free protein-binding sites, used to calculate the ‘free thyroxine index’ (FT!). Depending on the method of calculation, high values may imply hypothyroidism or hyperthyroidism; check with your laboratory. IBG is sometimes measured directly.
‘FREE’ T4 TESTS attempt to measure only the unbound active hormone. They thus avoid the need for IHUI and calculation of the FI!. Though not perfect, many of them are adequate for clinical use.
IRH TEST. This has been rendered almost obsolete xcept for investigation of hypothalamic-pituitary dysfunction.
Primary hypothyroid patients show a high basal ISH level with an excessive rise; hyperthyroid subjects show suppression with a minimal increment of ISH. Flat responses are also seen in pituitary disease, with solitary autonomous nodules, Graves’ eye disease and excessive thyroxine replacement, and in patients on steroids or with Cushing’s syndrome.
Problems in interpretation of thyroid function tests There are three major areas of difficulty.
SERIOUS ACUTE OR CHRONIC ILLNESS. Thyroid function is affected in several ways, with reduced concentration and affinity of binding proteins, decreased peripheral conversion of T4 to T3, with more rT3 and reduced hypothalamic-pituitary ISH production. Systemically ill patients can therefore have an apparently low total and free T4 and T3 with a normal or low basal ISH (the ‘sick euthyroid’ syndrome). Levels are usually only mildly below normal and the tests should be repeated after resolution of the underlying illness.
PREGNANCY AND ORAL CONTRACEPTIVES. These lead to greatly increased IBG and thus to high or high-normal total T4 and high IHUI levels. The normal physiological changes during pregnancy are not fully understood but . rarely cause clinical problems.
DRUGs. Many drugs affect thyroid function tests by interfering with protein binding. The commonest are listed in Table 16.22. Basal TSH should be measured.
Serum antibodies to the thyroid are common and may be either destructive or stimulating; both occasionally coexist in the same patient.
1 Destructive antibodies may be directed against the microsomes or against thyroglobulin; the antigen for thyroid microsomal antibodies is the peroxidase enzyme. They may be detected by haemagglutination techniques and are found in up to 20% of the normal population, especially older women, but only 10-20% of these develop overt hypothyroidism.
2 ISH receptor antibodies (TRAb). These IgG antibodies can be measured in two ways:
(a) By the inhibition of binding of ISH to its receptors (ISH-binding inhibitory immunoglobulin, TBII).
(b) By demonstrating that they stimulate the release of cyclic AMP (thyroid-stimulating immunoglobulin/antibody TSI, TSAb). These antibodies are seen in Graves’ disease. Long-acting thyroid stimulator (LATS) assay and LATSprotector (LATS-P) assay also demonstrate TSH antibodies but bear little correlation to clinical thyroid disease. These latter tests have been superseded by the above.
Underactivity of the thyroid may be primary, from disease of the thyroid, or secondary to hypothalamicpituitary disease (reduced TSH drive).
Causes of primary hypothyroidism
ATROPHIC (AUTOIMMUNE) HYPOTHYROIDISM. This is the commonest cause of hypothyroidism and is associated with microsomal autoantibodies leading to lymphoid infiltration of the gland and eventual atrophy and fibrosis. It is six times more common in females and the incidence increases with age. The condition is associated with other autoimmune disease such as pernicious anaemia. In some instances the condition shows intermittent hypothyroidism with recovery.
HASHIMOTO’S THYROIDITIS. This form of autoimmune thyroiditis, again commoner in women and commonest in late middle age, produces atrophic changes with regeneration, leading to goitre formation. This is usually firm and rubbery but may range from soft to hard. Thyroid microsomal antibodies are again present, often in very high titres. Patients may be hypothyroid or euthyroid, though may go through an initial toxic phase, ‘Hashitoxicity’. Thyroxine therapy may shrink the goitre even when the patient is not hypothyroid, though this may take a long time.
IODINE DEFICIENCY. In mountainous areas (the Alps, Himalayas, South America, Central Africa) dietary iodine deficiency still exists, in some areas as ‘endemic goitre’ where goitre, occasionally massive, is common. The patients may be euthyroid or hypothyroid depending on the severity of iodine deficiency. The mechanism is thought to be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing iodine deficiency.
DYSHORMONOGENESIS. This rare condition is due to genetic defects in the synthesis of thyroid hormones; patients develop hypothyroidism with a goitre. One particular familial form is associated with sensorineural deafness (Pendred’s syndrome).
Ectopic thyroid remnants
Defects of hormone synthesis
Other drugs, e.g. lithium, amiodarone
Post subacute thyroiditis
External neck irradiation
Peripheral resistance to thyroid hormone
Isolated TSH deficiency