Chapter 17 Thyroid abnormalities
AETIOLOGY
The main function of the thyroid is to produce hormones that regulate the metabolic rate of all cells, energy, cell growth and tissue differentiation.1,2 This is regulated by thyrotropin-releasing hormone (TRH), secreted by the hypothalamus, which activates thyroid-stimulating hormone (TSH), secreted by the pituitary gland, to produce thyroxine (T4) and triiodothyronine (T3) (Figure 17.1).1
The precursors for thyroid hormone production are tyrosine and iodine. The thyroid gland actively accumulates iodine (~ 60 mg/day) in the form of iodide (I–), which leads to a much higher concentration in this gland than elsewhere in the body in order to produce T4 and some T3. These hormones are then released into the circulation where most are bound to transport proteins. Less than 0.1% are unbound (free T3 and T4) and active as hormone. Although the amount of T4 in the blood exceeds that of T3 nearly 50-fold, it is T3 that has much higher biological activity.3,4 Zinc seems to be needed to facilitate the uptake of the hormone by the cells5 and favourably affects T3.6 Some organs and tissues can convert T4 to T3 (mainly liver, kidneys, brain, muscle and brown adipose tissue), with most of the circulating T3 having been produced peripherally7 or in the liver. The conversion of T4 to T3 is accomplished by 5’-deiodinase which is selenium dependent.4,8 In the absence of selenium, reverse T3 (rT3) is produced; this is metabolically inactive.9 Figure 17.2 shows the metabolic pathways of T4 conversion.4
Thyroid function not only depends on sufficient precursors (such as iodine and tyrosine) but also on hormone synthesis regulation and the demand for these hormones. Disturbances in any of these can lead to increased TSH production by the pituitary gland with subsequent (non-toxic) goitre formation. This increased thyroid tissue production is an attempt to produce sufficient thyroid hormones in order to maintain normal blood levels. Figure 17.3 illustrates this. However, if the enlarged thyroid gland overproduces thyroid hormones, leading to hyperthyroidism, it is called a ‘toxic goitre’.10
Thyroid antibodies (to thyroglobulin, peroxidase or thyroid receptor) are only raised in the autoimmune forms of hypothyroidism (Hashimoto’s disease) and hyperthyroidism (Grave’s disease). Gastrointestinal pathogens, through ‘molecular mimicry’, could be responsible for this.1,11 Refer to Chapter 28 on autoimmunity for further details.
In hypothyroidism a disturbance in glucose tolerance has been found to be due to decreased sensitivity to insulin, and raised cortisol and free fatty acids.12 This is not surprising considering that insulin resistance, diabetes type 2, stress (hypercortisolism and hyperadrenalism) and hypothyroidism share a number of common signs and symptoms, taking into account the link between the hormones involved in these conditions. Raised cortisol levels with impaired glucagon response were noted when hypoglycaemia was induced in hypothyroid patients.13 Insulin and glucose control was regained when these patients were given thyroid hormone replacement therapy.14 Further, hypothyroidism, like insulin resistance and diabetes type 2 leads to inhibition of delta 5 and 6 desaturase, impeding the utilisation of dietary omega-3 and omega-6 fatty acids.1 A rise in blood pressure has been noted in the hypothyroid state which normalised on thyroid treatment.15 Conversely, impaired extrathyroidal conversion of T4 to T3 has been found in diseases such as heart and liver disease and diabetes type 2, where there is high plasma free fatty acid concentration with no obvious thyroid pathology.1
Sick euthyroid syndrome, an underfunctioning thyroid with apparently normal test results, can occur as part of a number of health problems. It has been found, for a variety of reasons, to be part of virtually all severe systemic illnesses, fasting and major operations, affecting T3, T4 and rT3.16 Treating obese individuals with hypocaloric diets leads to similar thyroid hormone changes as in anorexia, namely decreases in T3 and T4 and increases in rT3. These hormones will normalise with weight normalisation.17 Certain medications also influence thyroid hormone status by either increasing or decreasing T4.7 It is therefore essential to test for these hormones in these situations in order to determine treatment options.
Testing for thyroid function
In hyperthyroidism, T4 and T3 levels are elevated, suppressing TSH. In contrast, in primary hypothyroidism TSH tends to be high with T3 and T4 being low. In secondary hypothyroidism, however, TSH as well as T3 and T4 are low. This latter condition arises from an inability of the pituitary gland to secrete TSH, possibly due to low TRH. By measuring TSH only, this condition can be missed or misinterpreted. Therefore, when there is indication from the symptom picture that thyroid function could be compromised, not only TSH but also T3 and T4 should be measured.18 Table 17.1 gives an overview of the laboratory parameters for each condition, and Table 17.2 shows the reference ranges (which vary somewhat between laboratories) and the ideal ranges of these parameters. In addition, the thyroid should be checked for goitre and nodules by palpation and the latter, if needed, by ultrasound or biopsy.7
Table 17.2 Reference ranges and ideal ranges of thyroid parameters2
| PARAMETER | REFERENCE RANGE | IDEAL RANGE |
|---|---|---|
| TSH | 0.3–5 mU/L | 0.4–2.5 mU/L |
| T3 | 2.6–6.0 pmol/L | 4–5 pmol/L |
| T4 | 9–19 pmol/L | 14–19 pmol/L |
| rT3 | 140–540 pmol/L | < 240 pmol/L |
| Thyroglobulin AB | < 4 IU/mL | < 1 IU/mL |
| Peroxidase AB | < 6 IU/mL | < 1 IU/mL |
| TRAB | < 1 IU/L | < 1 IU/L |
AB = antibodies, TRAB = thyroid receptor antibodies
Laboratory reference values for these parameters encompass 95% of the ‘healthy’ population, and only when individual values are outside this range will further investigations and possibly therapy be instigated by the doctor. However, in a well-functioning thyroid TSH should be between 0.4 and 2.5 mU/L (otherwise the system is labouring—subclinical hypothyroidism (SCH)—see below), with a therapeutic target range of 0.5 to 2 mU/L.19,20 The actual hormones should ideally be in the high-normal range. The ratio of T4 to T3 has been estimated as 4:1 in healthy thyroid function.1 Antibodies should be absent and rT3 should be low.
EPIDEMIOLOGY
Thyroid disorders are much more frequent in women than in men. The overall incidence in Australia is estimated at 5 in 1000 in males and 27 in 1000 in females. No specific figures for hypothyroidism in Australia could be found but in the US populations this is estimated to be 0.3%.21 Approximately 10–12 million people in the USA have hypothyroidism.22 In the UK the annual incidence of primary hypothyroidism is estimated to be 0.6 in 1000 for men and 3.5 in 1000 for women. In total, 3% of the population is taking medication for hypothyroidism.23 In contrast, it is stated that in the US 1–2% of the population is hypothyroid, with a tenfold higher occurrence in women than in men and increasing with age.3 Including SCH, the figures increase to 4.3–9.5%.3 Considering that this condition is generally underdiagnosed, at least in its milder form, the incidence would be much higher.
RISK FACTORS
Subclinical hypothyroidism
SCH has been characterised by elevated TSH with normal T3 and T4.24,25 There is still debate regarding the significance and possible treatment of SCH. Although treatment with T4 and/or T3 has apparently not been shown to provide benefits,26 withholding treatment may be ill advised. Subtle improvements with early hormonal intervention have been observed, thus warranting thyroid hormone replacement in subclinical manifestations.27 Most at risk are the elderly and women over the age of 60 years, with increased risk of developing overt hypothyroidism.25 It is therefore recommended that this population group, people with autoimmune disease and anybody with suggestive symptoms of hypothyroidsism be screened.28 TSH values ranging between 4.5 and 10 mU/L, particularly if antibodies or symptoms are present, may indicate the need for commencement of low-dose T4 treatment.29 However, some researchers consider a TSH range up to 20 μU/L (well above the upper limit of the reference range) as the cut-off before instigating therapy.22
It is interesting to note that the upper limit of normal for TSH has been reduced from 10 μU/L to between 4 and 5 μU/L during the last decade,22 with suggestions that this may be further reduced to 2.5 μU/L in the near future. This is based on the observation that 95% of people with normal thyroid function have values under 2.5 μU/L.20 Suboptimal thyroid function may be due to latent Hashimoto’s disease, which could lead, if not addressed early, to overt hypothyroidism.19,20,22,25 Further, patients with SCH tend to have higher readings of blood pressure, C-reactive protein, homocysteine, cholesterol and LDL, and thus may be presenting with cardiovascular risk factors or disease, including congestive heart failure. Early treatment is therefore recommended;22 this will also improve long-term life quality by preventing the development of overt hypothyroidism and also reducing the risk factors for cardiovascular disease, not to mention the benefits to the health-care system.
Further, a low T3 syndrome has been described with increased proinflammatory cytokines, notably IL6, which inhibits 5’-deiodinase. This is commonly seen in congestive heart failure, and T3 has been shown to be a stronger indicator of all-cause and congestive heart failure mortality than age or dyslipidaemia.22
Stress
Stress seems to play a crucial part in thyroid dysregulation and interference with hormone synthesis by triggering the release of corticotropin-releasing hormone, noradrenaline and cortisol. These hormones have an inhibitory influence on TSH secretion and suppress 5’-deiodinase, thus contributing to the suppression of thyroid function30 (see Chapter 15 on adrenal exhaustion also). The thyroid as well as the adrenal glands requires tyrosine for thyroid hormone and catecholamine synthesis, respectively. Low protein intake and/or impaired protein digestion/use may lead to low tyrosine stores, resulting in low thyroid hormones, especially if this amino acid is required to preferentially produce stress hormones (dopamine, noradrenaline and adrenaline). Urinary cortisol metabolite levels have also been linked to thyroid disorders, both in hypo- and hyperthyroidism, indicative of the influence of stress on thyroid function.31
Iodine
Iodine is a common deficiency worldwide, leading to hypothyroidism.11 It has been found in various parts of Australia (notably Tasmania)32–36 and New Zealand.37,38 Often the first visible sign is the development of a goitre. Congenital hypothyroidism, caused by maternal iodine deficiency, leads to mental and physical retardation in infants known as cretinism.9,39 Iodine reference values, according to the World Health Organization/International Council for the Control of Iodine Deficiency Disorders (WHO/ICCIDD), are given in Table 17.3.
Table 17.3 Iodine reference values1,32,40
| URINARY IODINE (µG/L) | IODINE NUTRITIONAL STATUS |
|---|---|
| < 20 | Severe deficiency |
| 20–49 | Moderate deficiency |
| 50–99 | Mild deficiency |
| 100–199 | Optimal status |
| ≥ 200 | Risk of adverse effects (e.g. hyperthyroidism) |
Selenium
Selenium is needed for the conversion of T4 to T3 (Figure 17.2). If it is low, the result is not only reduced active thyroid hormone (T3), but the resultant accumulation of rT3. Further, rT3 is also known to block the action of thyroid hormone, thus contributing to hypothyroidism. It is therefore important to measure rT3, especially with normal T4 and low T3 results. Hence, when T3 is low selenium deficiency should be considered as rT3 could be elevated.16 Trauma from injury affects thyroid metabolism with lowered selenium levels, and supplementation with selenium has led to faster normalisation of T4 and reductions in rT3.41 In congenital hypothyroidism, selenium (as selenomethionine) was found to lower TSH and thyroglobulin. It was suggested that the mechanism involved feedback to the hypothalamus–pituitary, thus reducing the stimulation of thyroid tissue and increasing intracellular conversion of T4 to T3.42
Similarly, in critically ill patients low selenium and T3 and elevated rT3 have been found, in addition to low TSH and T4. However, not only low selenium but also increased cytokine production during inflammation in these patients are responsible for low 5’-deiodinase; this may explain the elevated rT3. The abnormalities in these parameters have been found to correlate with the severity of the disease.43 Low T4 has been attributed to decreases in thyrotropin as well as T4-binding globulins. Supplementation with T3, not T4, has resulted in improvements. The effect of severe systemic illness on thyroid function has been termed ‘nonthyroidal illness syndrome’ (NTIS).16
Mercury
Workers exposed to mercury vapours had a higher risk of hypothyroidism with decreased T3 and increased rT3 values, especially if they were also low in iodine.44
Molecular mimicry
In hyperthyroidism thyroid hormones are high, suppressing TSH. The increased T3 and T4 is evidently due to an antithyroid autoantibody thyroid-stimulating immunoglobulin, which acts like TSH but is not controlled by the same negative feedback mechanism.10 Certain gram-negative bacteria, such as Yersinia enterocolitica and Escherichia coli, have been shown to contain TSH binding sites. It could therefore be possible that infection with these organisms could initiate hyperthyroidism through ‘molecular mimicry’.11
CONVENTIONAL TREATMENT
Hyperthyroidism
Depending on the severity of the disease, hyperthyroidism is treated with drugs that suppress the production of thyroid hormones, radioactive iodine to destroy part or all of the thyroid gland, or surgery to remove some or all of the thyroid. The latter two are likely to require thyroid hormone replacement for life.11
In order to make treatment effective but not detrimental to health, in total thyroidectomy a replacement dose of T4 is usually given at 1.6 μg/kg body weight, with an absorption rate of approximately 65%, resulting in a daily dose of 100–200 μg. It is best taken 1 hour prior to or 2–3 hours after meals. It takes 4–6 weeks for hormone levels to adjust to treatment.22
Hypothyroidism
The aim of treatment is to normalise thyroid function, and the treatment of choice for hypothyroidism is levothyroxine sodium (l-T4). In primary hypothyroidism, optimisation is achieved when TSH levels are 0.5–2 mU/L,22,45 and in secondary hypothyroidism (where TSH is low) with T4 and T3 levels in the upper normal range. When two doses of l-T4 were compared, one to bring T4 into the middle and the other into the upper range of normal, the higher dose resulted in lower BMI, cholesterol and LDL. When the high dose of l-T4 was combined with liothyronine (l-T3) at a ratio of 9:1, further benefits were obtained.22
This indicates that in certain situations l-T4 alone is insufficient to return thyroid function to normal. It is estimated that in 10–20% of hypothyroid patients symptoms will persist. This could be due to impaired conversion of T4 to T3 (see above under ‘Selenium’), a polymorphism in the enzyme 5’-deiodinase,22 plus several others.46 Treatment with liothyronine (l-T3) should therefore be considered when T4 alone does not improve symptoms or laboratory parameters.16,22 This is particularly the case in secondary hypothyroidism due to other ill health where there is impaired conversion from T4 to T3. In vivo, however, T3 has a short half-life, leading to supraphysiological peaks without normalisation of TSH. Slow-release formulations are therefore needed.22
To overcome the problem regarding when to give T4 and when T3, combination preparations are available. However, apart from using the l-T3 with its half-life problems, the studies done on this have not included measures that indicated the need for T3.47 To overcome the instability of T3, desiccated extract of beef or pork thyroid have been used.22,45 (Desiccated bovine or porcine thyroid extract is contained in some natural formulations currently on the market and which are available to naturopaths.) This was the standard treatment before l-T4 was available commercially, but reproducible results were difficult, if not impossible, to obtain due to the variability of thyroid hormone content in these preparations.22
In younger people diagnosed with hypothyroidism, treatment with T4 should be instigated at the highest calculated dose, whereas in older people the dose should be conservative and slowly titrated up to avoid complications, particularly in those people with coronary artery disease. However, long-term treatment above the optimal dose can lead to osteoporosis and atrial fibrillation and should therefore be avoided.22,45 In autoimmune hypothyroid women planning pregnancy, TSH levels should be kept below 2.5 μU/L, with a 30% increase in l-T4 dosage once pregnancy has been confirmed.22
Table 17.4 lists the treatments currently employed to treat hypo- and hyperthyroidism.
Table 17.4 Conventional treatment for hyper- and hypothyroidism
| CONDITION | DRUG | ACTION |
|---|---|---|
| Hyperthyroidism | Propylthiouracil Carbamidazole (active metabolite: methimazole) | Antithyroid drugs: inhibit formation of thyroid hormone; immunosuppressive |
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