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Iodine (as the iodide, I-) is relatively abundant in seawater and seafood is a rich dietary source. Fruit and vegetables also contain significant concentrations of iodine, although the amount depends on the soil and growing region. Areas of iodine deficiency tend to be inland, at high altitude and isolated and daily iodine intake may be as low as 25 μg. The term cretinism, used to define the severe impairment of physical and neurological development resulting from iodine deficiency during fetal and post-natal development, derived from ‘cretein’, a term first used in the Swiss Alps. The word cretin entered the vernacular as a term of abuse indicating severe mental retardation. In 1994, nearly 30% of the world population was at risk of iodine deficiency. The commitment from the World Health Organization in 1990 to eliminate iodine deficiency disorders by the year 2000 (with a policy of iodide supplementation of salt) had reduced the population at risk to less than 15% by 1997.
Increased iodine intake or a deficiency of dietary iodine can both induce goiter formation (Box 3.4). The former results from increased thyroid hormone synthesis and storage as seen in Clinical Case 3.1. Goiter formation in regions of dietary deficiency (the most common cause of goiter), is graphically illustrated in Box 3.3. It is due to reduced thyroid hormone synthesis and the compensatory increased secretion of the pituitary hormone thyrotrophin as a result of the loss of negative feedback (see below).
The functional unit of the thyroid gland is the follicle, a roughly spherical group of cells arranged around a protein-rich storage material called colloid. The follicular cells are orientated with their bases near the capillary blood supply and the apices abutting the colloid.
The process of thyroid hormone synthesis is complex. Once inside the follicular cell, iodide is oxidized to active iodine by hydrogen peroxide. This reaction is catalyzed by the heme-containing enzyme thyroid peroxidase (TPO). Iodine is then actively transported across the apical surface of the follicular cell by the same active process that occurs at the basal surface.
At the apical-colloid interface, iodine is immediately incorporated into the tyrosine residues of the large glycoprotein thyroglobulin molecules. Thyroglobulin is synthesized in the follicular cells and has a molecular weight of around 650 000 with about 140 tyrosine residues, depending on the form of thyroglobulin. Approximately one quarter of these residues can be iodinated. Once iodinated, thyroglobulin is taken up into the colloid of the follicle where, still incorporated in the protein, a coupling reaction between pairs of iodinated tyrosine molecules occurs. The coupling of two tyrosine residues each iodinated at two positions (di-iodotyrosine, DIT) produces tetra-iodothyronine or thyroxine (T4) whilst the combination of DIT with mono-iodotyrosine (MIT) produces tri-iodothyronine (T3). Such coupling can occur within a single molecule of thyroglobulin or between dimerized molecules of the protein. This coupling is catalyzed by TPO.
Thyroid hormones are stored in this state and are only released when the thyroglobulin molecule is taken back up into the follicular cells (Box 3.7). Stimulated by TSH, thyroglobulin droplets are captured by the follicular cells by a process of pinocytosis. Fusion of the droplets with lysosomes results in hydrolysis of the thyroglobulin molecules and release of T4 and T3. About 10% of T4 undergoes mono-deiodination to T3 before it is secreted and the released iodine is recycled.
The effects of thyroid hormones on virtually every cell in the body is manifest in the widespread clinical effects of their lack or excess (Box 3.8). They are very important in growth and development and their role in these processes will be discussed in relation to Clinical Case 3.3 (see page 94).
Many of the actions of thyroid hormones are mediated by their binding to nuclear receptors (Box 3.9) that have a preferential affinity for T3. T3 receptors are, like all the steroid hormone receptors, members of a family of nuclear transcription factors that, in combination with other transcription factors, regulate gene expression in target cells. Unlike some steroid receptors (i.e. those for sex steroids and glucocorticoids), thyroid hormone receptors exist in the nucleus, not the cytoplasm, and may remain bound to DNA in the absence of hormone binding.
There is also evidence that thyroid hormones can have rapid, non-genomic effects on membrane receptors independent of protein synthesis. These include stimulation of sugar transport, Ca2+ATPase activity and increased Na+ transport in muscle. The receptors for these effects have not been identified.
In most tissues (exceptions include brain, spleen and testis), thyroid hormones stimulate the metabolic rate by increasing the number and size of mitochondria, stimulating the synthesis of enzymes in the respiratory chain and increasing membrane Na+-K+ ATPase concentration and membrane Na+ and K+ permeability. Since as much as 15–40% of a cell's resting energy expenditure is used to maintain its electrochemical gradient (pumping Na+ out in exchange for K+), increasing the Na+-K+ ATPase activity, therefore, increases the resting metabolic rate (RMR). RMR may increase by up to 100% in the presence of excess hormones or decrease by as much as 50% in a deficiency.
The clinical signs of intolerance to heat, weight loss and fatigue, as seen in Clinical Case 3.1, are typical symptoms of patients presenting with hyperthyroidism (Box 3.10) and provide evidence of the metabolic action of thyroid hormones on their target tissues. In contrast, the hypothyroid patient is intolerant to cold, is lethargic, gains weight and has a cool, dry skin.
Whilst these metabolic changes associated with hyperthyroidism increase cardiac output, the increase is disproportionate to the increase in metabolic rate. The reason for this is that thyroid hormones have positive inotropic and chronotropic effects on the heart. The chronotropic effects of thyroid hormone (increases in sinoatrial node firing rate, decreases in atrial excitation threshold, decreased refractory period of conduction tissues) may be due to increases in sarcolemmal Na+ transport and Ca2+ influx. The inotropic effects (increase in contractile force) may be mediated by increases in Ca2+-ATPase activity in sarcoplasmic reticulum and increases in the expression of the α-myosin heavy chain.
Like the adrenal cortex and the gonads, the thyroid gland is controlled by hormone secretions from the hypothalamo-pituitary axis. The synthesis and secretion of TSH from the thyrotrophs is stimulated by the tripeptide, thyrotrophin-releasing hormone (TRH). This small peptide, cleaved from a larger pro-hormone, is released from neurosecretory cells in the hypothalamus into the hypothalamo-hypophyseal portal capillaries where it is transported to the pituitary thyrotrophs (Box 3.11). TSH secretion is inhibited by other hormones (including somatostatin and dopamine) and also cytokines, particularly IL-1β, IL-6 and TNF-α.
TSH is a complex glycoprotein hormone, containing approximately 16% carbohydrate. It contains 211 amino acids in two sub-units and has a molecular weight of about 28 000–30 000. The α unit is identical to that of two other glycoprotein hormones secreted by the human anterior pituitary gland, luteinizing hormone (LH) and follicle stimulating hormone (FSH, see Box 6.13). The β unit is unique to TSH and confers biological specificity. The structural homology between TSH, LH and FSH includes ‘knots’ of three disulfide bonds in both α and β sub-units. The glycosylation of TSH is heterogeneous and this affects both its bioactivity and clearance. TSH has a t1/2 in the circulation of about 1 h.
The cell surface receptor for TSH is a typical G-protein linked receptor with 7 helical transmembrane domains, 3 external (E) loops and three internal (I) loops (Box 3.12). The hormone binds to the long extracellular amino terminus whilst the carboxyl terminus is intracellular. There are approximately 1 000 TSH receptors on the basal surface of each follicular cell.
Inactivating mutations in the long extracellular amino-terminal of this receptor have been described and lead to hypothyroidism. In contrast, activating mutations have been described in E1 and E2 and I3 and the 2nd, 3rd, 6th and 7th transmembrane domains, though most are around the 6th and 7th domains. Activating mutations have been reported most frequently in autonomous ‘hot’ nodules (areas of increased growth and activity) of the gland. If present in the germ line and thus heritable (which is extremely rare), such activating mutations cause familial hyperthyroidism. Mutations of Gs (termed gsp) that result in constitutive activation of the G protein have also been described in ‘hot’ nodules.
The concentration of thyroid hormones in the circulation is regulated by an homeostatic feedback loop involving the hypothalamo-pituitary axis (Box 3.11). The main effect of thyroid hormones is to reduce the response of the pituitary thyrotrophs to TRH rather than altering the secretion rate of TRH from the hypothalamus. The sensitivity of the thyrotrophs to TRH depends on their intracellular concentration of T3, 80% of which is derived from the intrapituitary conversion of T4 to T3 (see Box 3.29). When circulating concentrations of T4 are low, there is an increase in the number of TRH receptors and in TSH synthesis resulting in an increased TSH response to TRH. The reverse is true in the presence of high circulating concentrations of thyroid hormones. The TSH response to a bolus injection of TRH has been used to diagnose the exact cause of hypo- and hyper-thyroidism, but measurement of thyroid hormones and TSH, using sensitive modern assays, is usually sufficient for diagnosis. Thus, in Clinical Case 3.1 concentrations of thyroid hormones in peripheral blood were high and the negative feedback resulted in unmeasurably low serum concentration of TSH.
This regulatory loop is affected by internal and external factors that alter the rate at which TSH is secreted. It is secreted in a pulsatile fashion with a diurnal variation, peaking around midnight. Environmental temperature may stimulate or inhibit the release of TSH by adjusting TRH secretion. Thus, after 24 h exposure to a cold environment, the plasma concentrations of thyroid hormones increase with a consequent rise in basal metabolic rate and an increase in the endogenous production of body heat. This effect is more marked in rats than humans. Pharmacological doses of glucocorticoids, as prescribed in anti-inflammatory therapy, or seen in Cushing's syndrome inhibit thyroid hormone secretions by reducing the TSH secretory response to TRH. In contrast, estrogens have the opposite effect, increasing TSH secretion and, hence, increasing the activity of the thyroid gland.
A 35-year-old woman came to the outpatient clinic with her 5-month-old child. She had noted increasing tenseness and irritability with her baby, poor sleep, weight loss and palpitations. Her husband was concerned that she had post-natal depression and had taken time off work to look after the family. She had an unremarkable past medical history and had sailed through pregnancy without any problems; she denied depression but felt exhausted all the time. She recalled that her late mother had an operation on her neck in her twenties and that her younger sister had regular vitamin injections for anemia. She ruefully admitted that the recent strain had led her to restart smoking ten cigarettes daily. On examination, she had a moderate diffuse goiter with an audible bruit, a tremor and a resting tachycardia of 100/min. Her eyes were prominent and puffy (see Box 3.16).
Graves' disease is the most common cause of hyperthyroidism and other causes are uncommon or, indeed, rare (Box 3.13). For reasons that remain unknown, it is much commoner in women, particularly those aged 30–50. It affects approximately 3% women and 0.3% men. The family history indicates a genetic predisposition to autoimmune disease. In Clinical Case 3.2, the patient's mother had had Graves' disease and her sister pernicious anemia (also considered to be autoimmune in nature). The exact nature of this genetic predilection remains uncertain but experimental studies have suggested linkage with a number of other genes. These include a linkage with certain histocompatibility complex genes (on chromosome 6) and associations with other diseases that are characterized by markers of autoimmunity, suggesting a primary genetic defect in immune function. The familial associations include pernicious anemia, Sjogren's syndrome, Addison's disease, type 1 diabetes mellitus and primary biliary cirrhosis.
Graves' disease may be distinguished from other causes of hyperthyroidism because it is associated with abnormalities of the eyes and integument. The diagnosis may be confirmed by the detection of autoantibodies to the TSH receptor (Box 3.15). However, the presence of such antibodies is not essential to the diagnosis; indeed, the absence of autoantibodies is usually attributed to the assay.
Treatment of the severe symptoms of eye disease (Box 3.17) are problematic although minor symptoms such as grittiness or sensitivity can be treated with synthetic tears or darkened and wind protective glasses. An interesting point about Clinical Case 3.2 is that she was a smoker. Smoking increases the risk of thyroid eye disease some 7-fold, although the relationship to the number (or duration) of cigarettes smoked is poorly defined and the cause unknown.
The effects of Graves' disease on the integument are shown in Box 3.18. Graves' dermopathy is the least frequent of all the associated symptoms and even less is known about its etiology. Like the ophthalmopathy it is associated with an increased production of glycosaminoglycans (predominantly hyaluronic acid and chondroitin sulfate) that causes edema, as in the orbit.
There are three methods of treating hyperthyroidism — drugs, surgery and radioisotopes. None is ideal; each has its own advantages and disadvantages (Box 3.19); none is exclusive and, not infrequently, a combination of therapies is used.
There are three types of drugs used to inhibit thyroid hormone synthesis and release.
High doses of anti-thyroid drugs are initially prescribed to patients with Graves' disease and the dose gradually reduced whilst aiming to keep the patient euthyroid. Alternatively some clinicians use the ‘block and replace’ regimen in which patients are maintained on high doses of anti-thyroid drugs with replacement thyroxine as appropriate.
Anti-thyroid treatment is continued for a somewhat arbitrary length of time (about 18 months) with the hope that the patients will be ‘cured’ (in remission) after a single course. Unfortunately, many patients relapse after stopping the drug.
The fastest acting anti-thyroid agent is iodine itself, reducing thyroid hormone synthesis within three days through a presumed autoregulatory mechanism. It may be given as drops of ‘Lugol's solution of iodine’ or a saturated solution of potassium iodide for 10 days or so. This form of treatment is no longer widely used but is particularly useful in the short term in hyperthyroid ‘storm’ where the degree of thyrotoxicosis becomes life threatening (with, for example, cardiac failure). It has also been used prior to thyroid surgery to reduce the high blood supply to the gland.
Destruction of thyroid tissue is the alternative to drug therapy. This can be done using radioactive isotopes of iodine or surgically.
Radioactive isotopes of iodine have been in use for over 50 years and today 131I, with a radioactive half-life of 8 days is the most commonly used for therapy. Since it has proved almost impossible to calculate a dose of the isotope that would result in euthyroidism in individual patients and 131I treatment is remarkably safe, many clinicians now use a fixed dose of isotope (for example 15mCi or 550MBq) and aim to produce hypothyroidism. Once hypothyroidism is induced, such patients can be treated with oral thyroxine that is cheap, effective and easy to monitor. 131I is also used to treat euthyroid goiters (so as to avoid surgery) and such treatment usually results in a reduction of about 40% in the volume of the thyroid gland.
The ancient Egyptians considered that a goiter added grace and beauty to a female neck. Whilst most women in the 20th century might not agree with this view, they are often reluctant to exchange a goiter for a 7 cm scar on the neck. Thus, unless the goiter is malignant, surgery is usually restricted to large and unsightly goiters that are not treatable medically or with radioiodine. It is important to note that, prior to surgery, the patient must be rendered euthyroid with drugs because of the increased risks of anesthesia and surgery in the hyperthyroid patient.
The most common causes of hypothyroidism are autoimmune in etiology (Box 3.22). Like Graves' disease they may have a number of autoimmune markers, including the presence of autoantibodies. However, unlike Graves' disease, T-cell mediated actions result in thyroid gland destruction rather than stimulation. The symptoms of hypothyroidism are vividly demonstrated in the next case.
A 19-year-old young man presented to the Emergency Room with pain in the left hip and knee. X-rays showed that he had a slipped femoral epiphysis A . At the age of 19.7 years, he was 1.544 m tall and weighed 57 kg. His mother, who had type 1 diabetes mellitus and hypothyroidism, reported him to be a ‘lazy sod … difficult to get out of bed in the morning’. His schoolwork had been poor and he had worn sweaters even during the summer. He looked much younger than his age C and, indeed, his bone age (an index of skeletal development) was markedly delayed at 13.4 years. His pubertal development was also delayed by several years (Tanner stage 3) and his serum testosterone concentration was low at 4 nmol/l (NR 9–25 nmol/l). A moderate size goiter was palpable.
X-ray appearances of the hips at presentation. Comparison of the epiphyses of the right and left femurs shows that the left has ‘slipped’ sideways at the junction with the diaphysis (arrowed).
X-ray appearances of the hips after surgical correction.
Facial appearance at presentation (left) and after 7 months treatment of T4 (right).
The cause of the autoimmunity is unknown and since the autoimmune processes in Hashimoto's disease induce destruction of the thyroid gland, it may be surprising to note that it is marked by goiter formation. The goiter is the result of diffuse lymphocytic infiltration (which gives it a number of alternative names such as chronic lymphocytic thyroiditis), together with TSH-stimulated hyperplasia of surviving thyroid tissue due to loss of feedback inhibition from the thyroid hormones. The goiter is usually diffuse with a characteristic — at least to the experienced clinician — ‘rubbery’ feel to palpation. It is rare for it to be painful or problematic by its size and surgery is infrequently required. Other features of this disease are antibodies against TPO and thyroglobulin (usually in much higher titers than in Graves'). Some patients are affected by a period of hyperthyroidism, in which case it is termed ‘Hashitoxicosis’, but the degree of hyperthyroidism is usually milder than in Graves' disease.
Hypothyroidism is also associated with primary thyroid atrophy and termed primary myxedema. The relationship between Hashimoto's disease and myxedema has been much discussed but it seems highly likely that non-goitrous myxedema is simply an end-stage of autoimmune destruction leaving only fibrous remnants. A role for antibodies to the TSH receptor that block the actions of TSH (rather than stimulating the receptor as in Graves' disease) has also been proposed.
The symptoms of hypothyroidism are extremely diverse — as might be predicted (Box 3.23). Clinical Case 3.3 showed a number of classic features including those affecting mental processes, gut motility, metabolic rate and the skeleton. He also presented with pubertal delay, though it is to be noted that hypothyroidism can occasionally present in the teenage years with precocious puberty.
Use of the prohormone thyroxine in the treatment of primary hypothyroidism is cheap and easy to monitor. The conversion of T4 to T3 is physiologically regulated and the dose can be altered according to serum TSH concentrations. No attempt is made to treat the underlying immune disorder. Severe hypothyroidism resulting in ‘myxedema coma’ is not often seen nowadays but may require parenteral T4 or T3 in addition to general supportive measures and hydrocortisone.
It is to be noted that some physiological conditions such as pregnancy may increase T4 requirements whilst gastrointestinal diseases or drugs such as sucralfate may decrease its absorption. Requirements may also be increased by drugs increasing its clearance such as rifampicin whilst some such as amiodarone may decrease T4 to T3 conversion. Diseases such as cirrhosis of the liver or the natural processes of ageing may decrease requirements.
The terms ‘compensated hypothyroidism’ or ‘decreased thyroid reserve’ have been used to indicate the situation in which circulating T4 or T3 concentrations are low-normal but serum TSH concentrations are elevated. There has been discussion over when such patients should be treated with T4. In this controversial area, some have argued that patients with serological evidence of anti-thyroid antibodies are likely to develop clinical hypothyroidism and should be treated.
The term thyroiditis is a term applied to a number of conditions that arise as a result of inflammation of the thyroid gland and, as has been seen, Hashimoto's chronic lymphocytic thyroiditis is the most common. Others are thought to result from infections and give rise to very different clinical features.
Bacterial or fungal infections may precipitate acute thyroiditis whilst subacute thyroiditis, such as De Quervain's, has been attributed to a viral illness. De Quervain's is usually self-limiting, but with a tendency to recur and the diagnosis is made on clinical features (general malaise and a painful thyroid gland). If fine-needle aspiration cytological examination (FNA, see Box 3.33) is performed it may reveal the presence of inflammatory cells. The disease process is associated with evidence of an acute phase reaction (a non-specific reaction leading to the high erythrocyte sedimentation rate) and the release of thyroid hormones from damaged cells. It is not due to hyperfunctioning thyroid tissue and 99mTc scans show reduced or absent iodine uptake (Box 3.6) and thiocarbamides play no part in treatment.
Some affected patients (approximately 50%) may have some symptoms of hyperthyroidism and, in a later phase of the illness, a temporary period of hypothyroidism may be experienced. During the acute phase, anti-inflammatory oral glucocorticoids (e.g. prednisolone) bring about rapid symptomatic relief.
Riedel's thyroiditis is not associated with features of inflammation but has additional features of fibrotic reaction elsewhere (e.g. retroperitoneal fibrosis in the abdomen). Like Hashimoto's disease, it results in progressive destruction of the thyroid gland that may necessitate T4 replacement therapy.
A 28-year-old man was seen in the outpatient clinic with his wife. He had noted gradually worsening tiredness and fatigability, making his job difficult to maintain. He had gained weight (approximately 3 kg) and his wife had noted that he had worn an extra sweater during the winter months. His feet had been cold in bed and his hair and skin dry. His wife has had to take time off from work to bring her husband to the clinic (because her husband's car was being repaired following damage to both the near- and offside wings) and was naturally keen to see things sorted out quickly. The blood tests showed that the serum T4 was low and the TSH was normal. Thyroid autoantibodies were negative.
This patient had clinical features typical of hypothyroidism. Whilst autoimmunity is the commonest cause of both primary hyper- and hypothyroidism, two noteworthy features indicate that this was not the cause of the hypothyroidism seen in this case. First, the patient was a young male and second, the serum TSH concentration was normal in the face of a low T4 concentration. Thus, in the absence of raised concentrations of TSH with low concentrations of thyroid hormones (as seen in primary hypothyroidism) the cause lay at the level of the hypothalamus or pituitary gland. The fact that the patient had damaged both front wings of his car was another clinical indicator. He has a visual field defect (see Box 7.1) caused by a large benign pituitary tumor that extended above the pituitary fossa and pressed on the optic chiasm. The patient had secondary hypothyroidism due to hypopituitarism.
The most severely affected infants will, however, be left with a permanent decrease in psycho-neurological function, probably reflecting intrauterine events. If there is any doubt about thyroid status (for example, with borderline results), it is better to replace thyroxine up to the age of, say, 2 years when treatment can be stopped under supervision and reassessment performed. The usual dose given is up to ten times the adult mean dose calculated on surface area. In childhood, acquired hypothyroidism (usually autoimmune) characteristically presents, as has been seen, with poor growth, epiphyseal dysplasia or poor school attainment. All features respond very well to T4 replacement.
Goitrous hypothyroidism in childhood may be due to defects in the synthesis of thyroid hormones. The best recognised of these is Pendred's syndrome that is associated with congenital deafness and a defect in the synthesis of a protein (pendrin) thought to be involved in sulfate transport.
The inability of target cells to respond to a hormone is known as hormone resistance and this is a common cause of endocrine disorders. Resistance can result from a reduction or loss of hormone receptors, or an aberrant receptor or signalling molecule.
Measurements of serum thyroid hormone and/or TSH concentrations are often abnormal in patients hospitalized for acute illness (Box 3.26). These are usually reversible disturbances detected by biochemical assays but without associated symptoms of hypo- or hyperthyroidism. Such a condition has been termed ‘sick euthyroid’ syndrome, although a better term is ‘non-thyroid illness’. It is considered to result from the effects of acute illness and/or the drugs treating the illness (Box 3.27) on the synthesis, transport and metabolism of hormones. To understand these it is necessary to discuss the transport and metabolism of thyroid hormones and the concept of ‘total’ and ‘free’ circulating hormone concentrations.
The iodothyronines are virtually insoluble in water and, once released from thyroglobulin, they are very rapidly bound to the plasma proteins, transthyretin (previously called thyroxine-binding prealbumin), thyroxine-binding globulin (TBG) and albumin. These vary in their capacity and affinity for T3 and T4 (Box 3.28); about 70% of circulating thyroid hormones are bound to TBG. Only a tiny fraction (<0.5%) of released thyroid hormones exist in a free form in the circulation and this is in equilibrium with the bound forms of thyroid hormones. The free-hormone hypothesis states that it is only the free thyroid hormones that act on target cells. The bound forms are considered to act as a circulating reservoir. There remains controversy as to whether the ratio of bound to free hormone changes as blood passes through the capillary bed of an organ.
Assays for thyroid hormones (see below) may measure the ‘total’ T4 or T3 or the respective ‘free’ fractions. Any reduction of serum TBG concentration (e.g. reduced synthesis in liver disease or increased loss in kidney disease) reduces the concentrations of total T4 and total T3. The feedback loop ‘senses’ changes in free hormone concentration and TSH secretion is modulated to maintain this. Similar compensations occur when TBG concentrations increase, most commonly as a result of pregnancy or estrogen administration.
Removal of an iodine atom from the 5th carbon atom (5′) of the outer tyrosine ring of T4 by Type 1 and Type 2 deiodinases produces T3 whilst deiodination of the inner (5) tyrosine ring by Type 1 and Type 3 deiodinases produces rT3. Further deiodinations at the 3rd and 5th carbon atoms of both outer and inner tyrosine rings produce increasingly inactive diiodo- and monoiodo-thyronines and at the same time conserving iodine. Iodothyronines are excreted in the urine although some T3 and T4 is conjugated with glucuronide and excreted via the bile in the feces.
The decreased circulating concentrations of T3 in the severely ill may be due to a reduction in 5′ deiodinase activity as a result of the low calorie intake and the raised glucocorticoid secretions in response to stress. This reduces the conversion of T4 to T3 and, concomitantly, the conversion of T3 to T2.
The term ‘sick euthyroid syndrome’ presupposes that the results of all the biochemical changes are neutral with regard to thyroid hormone function. There is, in fact, little evidence to support this. However, it can be said that generally thyroid hormone treatment for the severely ill does not bring any clinical benefits.
Assays of circulating thyroid hormone concentrations are usually referred to as ‘thyroid function tests’, often abbreviated to ‘TFTs’. It is clear that they do not measure thyroid ‘function’ since this implies a measure of the effectiveness of thyroid hormone on peripheral tissues, but they are used as surrogate measures. Total (bound plus free) thyroid hormones can be measured by a competitive binding assay after chemically removing the binding proteins. As discussed above, this measurement may not reflect the physiological state since changes in the concentration of binding proteins alter the total hormone concentration. It is possible to measure the concentration of free thyroid hormones in serum samples by an indirect assay method (Box 3.30).
It is to be emphasized that, in the presence of an intact feedback loop, serum TSH concentration reflects the effects of thyroid hormones on the pituitary gland. For this reason serum TSH concentration has been recommended as first-line assay of ‘thyroid function’.
It has been seen that activation of the TSH receptor (whether by the hormone itself or by autoantibodies) is a potent stimulator to thyroid growth; since the receptors are present on every follicular cell, such growth tends to be diffuse.
Experimental studies, however, have shown that numerous cytokines and growth factors can affect thyroid function and these may have clinical implications. For example, they may exert overall inhibitory effects on the hypothalamic-pituitary-thyroid axis and could account for some of the effects seen in non-thyroidal illness. Cytokines may also be involved in the etiology of autoimmune responses and it is noteworthy that the thyroid gland produces more cytokines than any other endocrine gland. Like cytokines, growth factors are present at all levels of the axis and there is evidence that insulin-like growth factor potentiates TSH action on thyrotrophs. This could account for the growth of some nodules.
A 53-year-old woman came to the outpatient clinic. She had no symptoms but gave a history of a lump in her neck being noticed by her primary care physician during a routine ‘well-woman’ check. There was no family history of thyroid disease and she had a blameless past medical history. She was a nonsmoker and was on no medication apart from estrogen replacement therapy for menopausal hot flushes. She had not noticed any change in her voice, or difficulty swallowing or breathing. Examination was entirely normal except for a 3 × 2 cm single nodule in the left lower thyroid pole. Blood tests showed that her total T4 was 196 nmol/l (NR 70–150nmo/l), free T3 7.8 pmol/l (NR 4.0–8.1pmol/l), TSH 2 mU/l (NR 0.5–4.0 mU/l) and thyroid autoantibodies were not present in serum.
Studies of populations (such as Whickham in Northern England or Framingham in the US) have indicated that multinodular thyroids occur in around 5% of the population with a marked female preponderance (10:1). Autopsy studies have indicated a much higher incidence of nodular thyroid disease, indeed up to 50%, with multinodular disease outnumbering single nodules by about 4 to 1. The incidence increases markedly in people over 50 years of age. It is much higher in areas of iodine deficiency indicating the importance of iodine in the etiology of nodularity.
The clinical index of a nodule, which makes no assumption of the underlying pathology, is the ability to detect one by palpation. Generally, (fat necks notwithstanding) this needs a lump 1 cm in diameter before it can be felt. However, if ultrasound scanning is used, it is more often than not that nodules some 2–3 mm in diameter are detected. The clinical relevance of such micronodularity detected on an ultrasound scan is very doubtful. However, the detection of a thyroid nodule(s) by palpation raises the important clinical question; is the lump malignant?
Tumors of the thyroid gland may be primary (arising from cells within the thyroid gland) or secondary due to malignant cells which have spread from other tissues (Box 3.31). Those arising from parafollicular cells which secrete calcitonin (giving rise to medullary cell carcinomas) are discussed. Lymphomas may arise from infiltrating lymphocytes and, though they are much more common in Hashimoto's disease, they are still very rare. Other tumors such as sarcomas from smooth muscle cells within the gland are also exceedingly rare.
The majority of primary tumors arise from epithelial cells of the thyroid gland and are, therefore, termed adenomas if benign and carcinomas if malignant. The epithelial cell tumors are sub-classified as either papillary or follicular according to their histological appearance. These tumors are found more often in women (2 to 4 fold more often than men), aged 45–50 years. In areas with adequate iodine intake, the commonest tumor is papillary, accounting for some 80% of all tumors. Where iodine intake is low there is a relative increase in follicular and anaplastic carcinomata, though no overall increase in frequency. A number of factors, both genetic and environmental has been implicated in the etiology of epithelial tumors (Box 3.32).
There are three conundra. The first is that, whilst nodular thyroid disease is common in the general population, only about 30 people in a million are diagnosed clinically with thyroid cancer annually and 6 people in a million die each year of the disease. This is a minute fraction of all cancer deaths and the risk of thyroid cancer causing death is extremely low.
The second conundrum arises because it is difficult to differentiate benign from malignant primary epithelial tumors by their histological appearances. The commonly used criteria of histological malignancy are invasion of blood vessels or lymphatics and breach of the capsule containing the nodule cells. When thyroid glands are examined at autopsy the histological features of papillary cancer are seen in 5 to 25% of thyroid glands examined. Thus, thyroid nodules and histological appearances of thyroid cancer are extremely common yet clinical disease is rare.
Clinical suspicion of malignancy may be raised by the speed of growth of a nodule or the involvement of the esophagus, trachea or recurrent laryngeal nerve (giving a hoarse voice and difficulty in breathing or swallowing). However, the only certain clinical benchmark is the behavior of the tumor; if it spreads (or metastasizes) it is malignant.
This 99Tc scan of Clinical Case Study Q3.1 taken at a time when the patient denied taking any medications for several months. (Compare the image with a normal scan (shown in Box 3.6).
Question 1: Using your knowledge of the hypothalamo-pituitary-thyroid axis feedback loop, how may the serum assays be interpreted and what are the possible diagnoses?
Question 2: How would you distinguish between these possibilities?
The small diffusely enlarged thyroid gland.
The 99mTc scan of the patient performed during her admission.
Question 1: Given the clinical features and the serum assay results, what is the most likely diagnosis?
Question 2: In light of your answer to question 1, how should the 99mTc scan of the thyroid be interpreted?
Question 3: How should she be treated?
Photograph of the child in Clinical case study Q3.3 taken by his mother a few weeks after birth
Question 1: What is the diagnosis and how is it related to the mothers previous medical history?
Question 2: How can it be confirmed and treated?
Question 3: Could it have been predicted and what is the likely prognosis?
