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Summary

  1. Top of page
  2. Summary
  3. Subclinical hyperthyroidism
  4. Subclinical hypothyroidism
  5. Conclusions
  6. Reference

Mild thyroid dysfunction is common, and more prevalent than overt hyper- and hypothyroidism. Subclinical (mild) thyroid dysfunction is a biochemical entity characterized by an abnormality of serum TSH associated with normal serum thyroid hormone concentrations. Subclinical hyperthyroidism is thus defined as low or suppressed serum TSH with normal serum-free T4 and T3, while subclinical hypothyroidism is defined as raised serum TSH with normal circulating T4. These biochemical abnormalities are part of the much wider spectrum of thyroid dysfunction which includes overt hyperthyroidism and overt hypothyroidism, but by no means always indicate underlying thyroid disease. There is much debate about the significance of mild abnormalities of thyroid function in terms of symptoms and potential associations with long-term morbidity and mortality and hence much debate about whether to screen for these abnormalities, and, once identified, whether to treat or monitor, and if so, how? Our knowledge base has increased significantly in recent years, principally because studies of large cohorts have begun to define the epidemiology and associations of mild thyroid dysfunction (including short-term and long-term outcomes) and a small but increasing number of randomized-controlled intervention studies have been reported. There is, however, much to learn about these disorders and, given their prevalence, their impact on health.


Subclinical hyperthyroidism

  1. Top of page
  2. Summary
  3. Subclinical hyperthyroidism
  4. Subclinical hypothyroidism
  5. Conclusions
  6. Reference

Epidemiology

Subclinical hyperthyroidism often reflects ingestion of thyroid hormones, typically thyroxine, and in that context is considered ‘exogenous’ in origin. If low serum TSH is found in the absence of thyroid hormone use, then it is labelled ‘endogenous’. For both categories, given the inverse (but nonlinear) relationship between serum free T4 and TSH, complete suppression of serum TSH (to <0·1 mU/l) is generally considered of more pathophysiological significance than the finding of a low but detectable serum TSH (0·1–0·4 mU/l). Exogenous subclinical hyperthyroidism is more common than endogenous and is present in around 20–40% of the subjects prescribed thyroid hormones.[1-3] As expected, low serum TSH is more common in those prescribed thyroxine in higher doses, indicating a degree of over-treatment.[2] Studies of those not taking thyroid hormones also reveal a high prevalence of subclinical hyperthyroidism, with variations in frequency depending on age, gender, race and iodine intake within the population. The National Health and Nutrition Survey (NHANES) in the United States revealed 1·8% of the general population to have low but detectable serum TSH and only 0·7% to have fully suppressed serum TSH (after exclusion of ‘exogenous’ cases),[4] with similar findings from a population prevalence study in Scotland.[5] Both of these studies revealed a higher prevalence in women and a rise in frequency with age. Our own study of almost 6000 community-based subjects aged over 65 years attending general practices in the West Midlands region of England revealed a prevalence of subclinical hyperthyroidism of 2·1% in that age group, again being more common with increasing age. Ninety of 128 subjects with subclinical hyperthyroidism had low but detectable serum TSH, with a relatively small proportion having fully suppressed TSH.[6]

The causes for subclinical hyperthyroidism are shown in Table 1. As well as thyroxine therapy, previous Graves' hyperthyroidism may be associated with suppression of TSH for weeks or even months after successful treatment, although if longstanding indicates persistent thyroid autonomy. Up to 75% of subjects with nodular goitre may also have TSH suppression, again indicating thyroid autonomy. It should be noted, however, that ‘non-thyroidal’ illnesses and therapies with various drugs probably represent the commonest causes for subclinical hyperthyroidism, especially in hospital outpatient or inpatient populations, the most common biochemical finding being low but detectable serum TSH.

Table 1. Causes for subclinical hyperthyroidism
Causes or associations related to thyroid disease and its treatment
Thyroxine therapy
Previous or recent Graves' hyperthyroidism
Graves' ophthalmopathy
Nodular goitre (autonomous nodule(s))
Less common – postpartum, silent and other types of thyroiditis
Causes or associations related to ‘non-thyroidal’ illnesses/conditions and drug therapy
Any significant illness for example, myocardial infarction, liver or renal failure, diabetes mellitus
Therapy with drugs such as glucocorticoids, dopamine, anticonvulsants
Iodine containing compounds for example, amiodarone, radiographic contrast agents
Pregnancy, especially first trimester

The natural history of subclinical hyperthyroidism depends upon its cause and severity (i.e. the degree of reduction in serum TSH below the reference range). Some subjects in whom TSH suppression (usually complete) is associated with Graves' hyperthyroidism or nodular goitre will progress to overt hyperthyroidism, although the incidence is relatively low at around 1–3% per year. In contrast, those in whom low serum TSH values reflect ‘non-thyroidal’ illness or drug therapy typically have low but detectable serum TSH, and the biochemical abnormality often disappears after recovery from illness or cessation of drug therapy. A large study demonstrated that reduced serum TSH (<0·35 mU/l) returned to normal in more than half after a follow-up period of 5 years.[7] This finding is compatible with one of our early screening and follow-up studies in the elderly which showed that of those with low but detectable TSH at initial testing, TSH had returned to normal in 76% at one year, compared with those with undetectable TSH of whom 88% had persistently undetectable TSH.[8] A 10-year follow-up of the same group showed that only 4·3% of those with low serum TSH developed overt hyperthyroidism.[9]

Consequences of subclinical hyperthyroidism

If low serum TSH reflects ‘non-thyroidal’ illness or drug therapy and is consequently transient, it is presumed that it is of little consequence in terms of long-term effects. In these situations, circulating thyroid hormone concentrations (especially T3) are typically low or low normal – the so-called sick euthyroid syndrome. The potential consequences of subclinical hyperthyroidism are probably confined to those in whom suppression of TSH reflects a minor degree of thyroid hormone excess, the major patient groups being those with thyroid autonomy owing to the presence of a nodular goitre or Graves' disease and those receiving thyroxine therapy. These subjects will often have serum T4 values at the upper end of the reference range, and higher than those found in subjects with normal serum TSH. Furthermore, serum T3 concentrations are typically high normal in those with suppressed TSH reflecting thyroid autonomy in contrast to those taking thyroxine in whom T3 is relatively low, a difference which may explain the greater pathophysiological significance of endogenous compared with exogenous subclinical hyperthyroidism.

Symptoms, cognitive function

Relatively small cross-sectional studies have indicated increased palpitation and heat intolerance to be associated with endogenous and exogenous subclinical hyperthyroidism.[10] Our own large and detailed study of cognition, depression and anxiety failed to demonstrate any association with subclinical thyroid dysfunction in those aged over 65 years. [11] There is some evidence that subclinical hyperthyroidism may be associated with increased risk of dementia, but findings are conflicting.[12, 13]

Cardiovascular system

Thyroid hormones are well recognized to exert effects on the cardiovascular system [14] and subclinical hyperthyroidism is associated with similar findings to overt thyroid hormone excess, albeit less marked. Studies of ECG monitoring comparing subjects with low and normal serum TSH have revealed an increase in mean 24 h and nocturnal heart rate, shortening of the systolic time interval and an increase in frequency of atrial premature beats.[10, 15] Echocardiography studies have produced less consistent differences that include increased left ventricular mass and changes in systolic and diastolic function,[16] findings of unclear clinical significance.

Evidence for adverse outcomes associated with subclinical hyperthyroidism has, however, accrued, especially in the context of risk of atrial fibrillation (AF) and its cardiovascular consequences. The seminal study by Sawin et al. of the Framingham cohort of subjects aged over 60 years revealed a 3·1-fold increased relative risk of AF after 10 years associated with suppressed TSH at time zero, with a relative risk of 1·6 in those with low but detectable TSH.[17] Another large retrospective study demonstrated an adjusted relative risk of 2·8 for the finding of AF in subjects with low TSH compared with normal TSH [18] and a further study showed a 2-fold increased incidence of AF in elderly subjects followed for 13 years, which included evidence for an increased incidence in those with low but detectable TSH values.[19] Furthermore, our own cross-sectional study of 5860 subjects aged 65 years and over revealed a higher prevalence of AF confirmed by ECG in participants with subclinical hyperthyroidism than in those with normal serum TSH.[20] We also found that serum free T4 concentration was independently associated with the finding of AF, even in euthyroid subjects with normal serum free T4 and TSH values (Fig. 1), suggesting marked sensitivity in terms of AF risk of even minor degrees of thyroid hormone excess.

image

Figure 1. Prevalence of atrial fibrillation (AF) on resting 12-lead electrocardiogram plotted against serum free thyroxine (T4) concentrations in 5860 subjects aged 65 years and older. The plotted points were obtained by rounding each free T4 measurement to the nearest integer; the superimposed curve is that given by a logistic regression on the actual values of free T4 vs the presence/absence of AF. Reproduced with permission from Gammage et al. Association between serum free T4 concentration and atrial fibrillation. Arch Intern Med 2007 May 14;167(9):928-34.

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There is also evidence linking subclinical hyperthyroidism and mortality, although findings should be interpreted in the context of potential influences of comorbidities or genetic confounding (as recently discussed in the context of overt thyroid dysfunction.) [21, 22] We reported increased deaths from circulatory diseases (both cardiovascular and cerebrovascular) in association with low TSH in a 10-year follow-up study of 1191 subjects aged more than 60 years[9] (Fig. 2). This increased mortality occurred in the absence of increased deaths from other common causes, suggesting that low TSH reflected a degree of thyroid autonomy rather than ‘non-thyroidal’ illness. Although a study of 39 subjects with subclinical hyperthyroidism followed for 20 years did not find adverse outcomes in the very elderly (aged >85 years), increased cardiovascular mortality during 4 years of follow-up was reported in another study of those with low TSH levels.[19, 23] Results of meta-analyses have also been conflicting, although the most recent by Collet et al. [24] has linked subclinical hyperthyroidism with not only with incident AF but also increased risks of all-cause mortality and coronary heart disease mortality, the greatest risks being associated with TSH <0·1 mU/l.

image

Figure 2. Kaplan-Meier survival curves showing the relation between survival from circulatory disease and serum TSH concentration. Reproduced with permission from Parle et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001 Sep 15;358(9285):861-5.

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Musculoskeletal system

Overt hyperthyroidism is associated with increased bone turnover, reflecting a direct effect of thyroid hormone excess on osteoclast function and hence with increased risk of osteoporosis and fracture.[25, 26] Numerous studies have examined potential associations of exogenous and endogenous subclinical hyperthyroidism with changes in bone mineral density (BMD), often with conflicting results probably due to small cohort sizes and heterogeneity with respect to history of previous overt hyperthyroidism, dose and duration of thyroxine therapy and menopausal status. Most studies, and hence meta-analyses, have suggested an adverse effect of subclinical hyperthyroidism in post menopausal women, especially in the context of previous overt hyperthyroidism, with much less evidence for an effect in premenopausal women or in men.[27, 28]

Evidence that such changes in BMD are translated into an increase in risk of osteoporotic fracture, especially fracture of the femur, is relatively limited. A prospective population-based study of fracture of the femur in postmenopausal women identified thyroxine prescription as a possible risk factor for fracture (RR 1·6, 95% CI 1·1–2·3), but this relative risk was no longer significant when a previous history of overt hyperthyroidism was taken into account; previous hyperthyroidism itself being associated with a relative risk of 1·8 (95% CI 1·2–2·6).[29] Our own large study of fracture risk and thyroxine prescription (in which thyroid biochemistry was not available) similarly failed to demonstrate an overall association, although there was an increased risk of femur fracture in the relatively small number of male subjects prescribed thyroxine.[30] Few studies have evaluated possible association between endogenous subclinical hyperthyroidism and fracture risk, although an investigation of 686 women aged >65 years with low serum TSH revealed a 3-fold to 4-fold increased risk of hip or vertebral fracture after adjustment for previous hyperthyroidism and thyroxine prescription when compared with subjects with normal TSH.[31] A recent prospective cohort study has also shown an increase in risk of femur fracture in men aged over 65 years in those with endogenous subclinical hyperthyroidism (HR 4·91, 95% CI, 1·13–21·27) but with no association found in women.[32]

Investigation and treatment

In subjects with subclinical hyperthyroidism taking thyroxine therapy, dose reduction followed by further biochemical testing to ensure that TSH has returned to the reference range is one obvious approach. Whether this is a cost-effective exercise given the frequency of thyroxine prescription in the general population (approximately 1% in the general population and 5% in the over 60 s)[2] and so far inconclusive evidence for adverse long-term clinical consequences (with the possible exception of occurrence of atrial fibrillation) remains unclear. In patients starting thyroxine therapy, it appears appropriate to aim for biochemical as well as clinical euthyroidism, in line with both UK and US guidelines.[33]

Addressing investigation and treatment is more complicated in those in whom suppression of TSH does not reflect thyroid hormone use. Before considering treatment, it is first essential to determine whether TSH suppression reflects autonomous thyroid function, although this is probably only relevant to those with an undetectable TSH value because if TSH is low but detectable this finding is often transient. If undetectable TSH is persistent on repeat testing, then evidence for underlying thyroid disease should be sought. The commonest cause for true endogenous subclinical hyperthyroidism is toxic nodular goitre, especially in the elderly. This may be obvious from history and physical examination but, if not, then thyroid isotope imaging is a reasonable approach to detect a ‘hot’ nodule.

The topic of treatment of endogenous subclinical hyperthyroidism is controversial as no controlled studies showing benefit in clinical outcomes have been performed, although small studies have shown improvement in echocardiographic parameters and bone mineral density.[34, 35] Because of associations with adverse outcomes, especially atrial fibrillation, expert panels have recommended treatment of subclinical hyperthyroidism, proven to reflect true thyroid disease, specifically in those with persistently undetectable TSH, the elderly and those with cardiac risks, heart disease or osteoporosis.[33] Latterly, the suggestion has been made that treatment should be considered for low but detectable TSH in the elderly or with heart disease, driven by a study showing higher atrial fibrillation risk in such groups.[19] If the decision is made to treat, radioiodine is generally the therapy of choice, especially in toxic nodular goitre, long-term carbimazole at low dose being another option.

Because of the absence of evidence for benefit from treatment,[36] population screening for minor abnormalities of thyroid function is not presently recommended.[37]

Subclinical hypothyroidism

  1. Top of page
  2. Summary
  3. Subclinical hyperthyroidism
  4. Subclinical hypothyroidism
  5. Conclusions
  6. Reference

Epidemiology

Subclinical hypothyroidism is a common biochemical finding in the general population, although prevalence figures vary with the characteristics of the populations studied, as well as the upper limit set for TSH measurements. Meticulous studies from the United States and elsewhere have addressed the question of the reference range, taking into account the influence of inclusion or exclusion of subjects with a personal or family history of thyroid disease or those with positive antithyroid antibodies. Evidence from one such study (NHANES III) of a large ‘reference’ population without evidence of thyroid disease indicated that 95% of adults have a serum TSH concentration within the range 0·45–4·12 mU/l,[4] determining that the widely applied upper limit of normal for serum TSH of around 4·5 mU/l remains appropriate. In terms of pathophysiological consequences, experts typically classify subjects with subclinical hypothyroidism into two groups: those with mildly elevated TSH (4·5–10 mU/l) and those with more marked TSH elevation (TSH >10 mU/l).[33]

Overall, the population prevalence of subclinical hypothyroidism is around 5–10%, the diagnosis being more common in women and increasing with increasing age and being higher in white than in black populations.[4] The Whickham survey in the north-east of England reported TSH >6·0 mU/l in 7·5% of women and 2·8% of men.[38] TSH did not vary with age in men but increased markedly in women aged more than 45 years. The NHANES III study in the United States found subclinical hypothyroidism (TSH >4·6 mU/l) in 4·3%,[4] while in a large study of subjects attending health fairs in Colorado, 9·5% had raised TSH, 75% of these cases being in the ‘mild’ (5·0–10·0 mU/l) range and 25% of whom were taking thyroid hormones.[1] Our own study of 1210 subjects aged over 60 years who were recruited from primary care revealed a prevalence of subclinical hypothyroidism of 11·6% in women and 2·9% in men.[8] Significant titres of antithyroid antibodies were found in 46% of those with serum TSH between 5 and 10 mU/l and in 81% of those with a serum TSH greater than 10 mU/l, providing evidence for underlying autoimmune thyroid disease in the majority. However, our more recent community screening study of the elderly in the same geographical area revealed a lower population prevalence of subclinical hypothyroidism of 2·9%, perhaps reflecting more frequent testing of thyroid function and earlier treatment of raised TSH in primary care in the intervening years.[6]

The commonest causes for subclinical hypothyroidism (Table 2) are autoimmune thyroiditis (Hashimoto's disease) and previous treatment for hyperthyroidism. Treatment of hyperthyroidism with radioiodine results in hypothyroidism in at least 50% of patients with Graves' disease (depending upon the dose administered), although a lower proportion in those with toxic nodular hyperthyroidism [39] development of subclinical hypothyroidism typically preceding overt thyroid failure. Partial thyroidectomy for hyperthyroidism or nodular goitre is associated with a similar risk of development of hypothyroidism, which is again first identified by a rise in serum TSH. In the early months after both radioiodine treatment and partial thyroidectomy, subclinical hypothyroidism may be a transient phenomenon, not always indicative of progressive or permanent thyroid failure. Graves' disease is itself associated with the eventual development of hypothyroidism in 5–20% (even in the absence of ablative thyroid treatment).[40]

Table 2. Causes for subclinical hypothyroidism
Causes related to thyroid disease and its treatment
Autoimmune thyroid disease (Hashimoto's thyroiditis)
Previous radioiodine treatment for hyperthyroidism
Previous thyroid surgery
Anti thyroid drugs
Previous Graves' hyperthyroidism
Postpartum, silent and other types of thyroiditis
Thyroxine therapy – poor compliance or inadequate dose prescription
Other causes or associations
Radiotherapy to head or neck
Other autoimmune diseases for example type I diabetes, rheumatoid arthritis, Addison's disease, pernicious anaemia
Down's syndrome
Therapy with iodine containing drugs, for example, amiodarone
Other causes for iodine excess (kelp ingestion, radiographic contrast agents)
Lithium therapy
‘Non-thyroidal’ illnesses – especially during the recovery phase

A further major category of patients with a biochemical diagnosis of subclinical hypothyroidism is those already treated with thyroxine for hypothyroidism, a high serum TSH indicating that the dose prescribed is inadequate or compliance poor. We found a raised serum TSH in 25% of subjects in the community prescribed thyroxine, with a close relationship evident between prescribed dose and TSH results, indicating that at least in some patients (especially those prescribed doses of 75 mcg per day or less), the cause for subclinical hypothyroidism was inadequate dose prescription.[2] In those prescribed higher doses, compliance is typically the major issue.

Other groups at particular risk of subclinical hypothyroidism include those with other autoimmune diseases such as type I diabetes mellitus and Addison's disease. Conversely, we have shown that the presence of autoimmune thyroid disease is strongly associated with other autoimmune diseases.[41] Down's and Turner's syndromes are both associated with the development of both subclinical and overt thyroid failure of autoimmune aetiology. The risk of subclinical hypothyroidism during pregnancy is considerable in women identified in the first trimester as having positive antithyroid antibodies. This antibody status also represents a risk factor for the development of post-partum thyroiditis, subclinical or overt hypothyroidism being a feature of postpartum thyroiditis in about 75% of cases.[42] A further cause for subclinical hypothyroidism is radiotherapy to the head and neck (which is itself associated with the development of positive antithyroid antibodies). ‘Non-thyroidal’ illness may be associated with a transient and modest increase in serum TSH, especially in the recovery phase from illness, although in most instances, a raised TSH does reflect underlying thyroid disease. Therapy with drugs such as lithium and amiodarone [43] can induce subclinical hypothyroidism, as can administration of iodine containing compounds such as radiographic contrast agents.

The natural history of subclinical hypothyroidism depends upon the underlying cause and the population studied. One large follow-up study has shown that in those with modest elevation of serum TSH (5·5–10·0 mU/l), the TSH measurement returns spontaneously to the reference range in more than 60% of cases during 5 years of follow-up.[7] Our own study of the over 60 s in the community revealed that the finding of a raised serum TSH identified on screening disappeared in 5·5% after 12 months, while the biochemical abnormality remained stable in 76·7% and relatively few (17·8%) progressed to overt hypothyroidism (defined as raised TSH with serum free T4 below the reference range).[8] Twenty-year follow-up of the Whickham cohort in the north-east of England revealed an annual rate of progression of subclinical to overt hypothyroidism of 2·6% if thyroid antibodies were negative, but 4·3% if antibodies to thyroid peroxidase were present.[44]

Consequences of subclinical hypothyroidism

Symptoms, quality of life and cognitive function

The symptoms of hypothyroidism are neither sensitive nor specific and perhaps unsurprisingly studies addressing the relationship between symptoms suggestive of thyroid hormone deficiency and the biochemical finding of subclinical hypothyroidism have produced conflicting results. The Colorado health fair study revealed a slight increase in the mean number of reported symptoms in those with high TSH compared with euthyroid controls (13·8% vs 12·1%)[1]; however, a cross-sectional study of women aged 18–75 years showed no association of subclinical hypothyroidism with poorer well-being or quality of life.[45] Results are also conflicting with regard to any association with depression or decline in cognitive function, although nearly all large studies have failed to find an association with symptoms of depression or impaired cognitive function. Notably, our own study of 5865 subjects aged over 65 years, of whom, 168 had subclinical hypothyroidism, revealed no association with tests of cognitive function, anxiety or depression.[11]

Cardiovascular system

Overt hypothyroidism results in increases in total and low-density lipoprotein (LDL) cholesterol, as well as changes in other lipoprotein and apolipoprotein concentrations but lipid changes in subclinical hypothyroidism are considerably less marked and the results of studies inconsistent. In the NHANES III cohort, mean total cholesterol (but not LDL) concentrations were higher in subclinical hypothyroid subjects than euthyroid controls, a finding no longer statistically significant once adjusted for factors such as age and use of lipid lowering agents.[46] In general, more marked changes in cholesterol are seen in those with higher baseline cholesterol values and in those with higher serum TSH. Other direct and indirect influences of subclinical hypothyroidism upon the vascular system have been studied in some detail, the most consistent findings being left ventricular diastolic dysfunction together with an increase in systemic vascular resistance and arterial thickness.[47]

These, together with lipid findings, have prompted epidemiological studies of vascular morbidity and mortality, with inconsistent results. In the first reported 20-year follow-up of the Whickham cohort from the north-east of England, there was no association found between a diagnosis of autoimmune thyroid disease and a diagnosis of ischaemic heart disease.[44] In contrast, in the Rotterdam cohort of women over 55 years, there was an association between subclinical hypothyroidism and atherosclerosis (defined as aortic calcification on lateral X-ray) and with a history of myocardial infarction, although no association with incident ischaemic heart disease.[48] In our own study of 1200 subjects aged more than 60 years followed for 10 years, we found no association of subclinical hypothyroidism with circulatory mortality (although 40% had commenced T4 therapy during follow-up).[9] Intriguingly, in the Leiden study of those aged more than 85 years, raised TSH was associated with increased longevity and decreased risk of death from cardiovascular disease.[23] The longitudinal Cardiovascular Health Study in the United States found no association between subclinical hypothyroidism and the incidences of cardiovascular or cerebrovascular diseases, nor with all-cause mortality.[19] Further recent studies, including re-analysis of the Whickham 20-year follow-up data, have found associations of subclinical hypothyroidism with cardiovascular disease morbidity and mortality,[49, 50] although others have not.[51, 52] Crucially, a meta-analysis of individual participant data from 11 prospective cohort studies has shown no overall association of subclinical hypothyroidism with coronary heart disease events, mortality or total mortality, but significant associations when the degree of elevation of serum TSH was stratified, in that coronary heart disease events and mortality risks were significantly increased when analysis was confined to those with serum TSH>10 mU/l.[52] This association with more marked biochemical abnormality is consistent with the results of studies of heart failure, where again incident heart failure risk is evident or is of greater magnitude, when serum TSH is >10 mU/l.[53, 54]

Treatment of subclinical hypothyroidism

Several placebo-controlled randomized studies have investigated the effect of thyroxine replacement therapy on symptoms in subjects with subclinical hypothyroidism, although many of these studies have been small and heterogeneous in terms of underlying disease severity, duration and dose of thyroxine, target TSH values and achievement of euthyroidism. Unsurprisingly, given the weak association of raised TSH with symptoms and well-being, thyroxine treatment has been found to not improve symptoms or mood, unless serum TSH is >10 mU/l.[55] Our own recent randomized-controlled trial of thyroxine in 94 elderly subjects with subclinical hypothyroidism identified through screening in the community showed no beneficial effect as determined by detailed tests of cognitive function.[56]

Several placebo-controlled randomized trials have assessed the effect of thyroxine replacement on the lipid profile. Meta-analyses of intervention studies with T4 have generally shown only minor effects on the lipid profile, one important meta-analysis revealing reductions of 0·2–0·3 mm in total and LDL cholesterol values after T4 treatment, with no associated change in triglycerides.[57] This analysis revealed that changes in lipid concentrations were not significant in subjects with baseline serum cholesterol concentrations >6·2 mm or in subjects with untreated subclinical hypothyroidism compared with those with inadequately treated thyroid dysfunction.

Whether thyroxine treatment has a positive impact on cardiovascular events has not been directly investigated, although improvements in systolic and diastolic function as well as endothelial function and carotid intima-media thickness have all been described.[58, 59] Indirect evidence of a beneficial influence on clinically relevant outcomes comes from the finding that thyroxine treatment of subclinical hypothyroidism was associated with lower heart failure risk and lower all-cause mortality in two studies when compared with untreated subjects.[50, 54]

One situation where opinion is consistent with regard to treatment of even mild subclinical hypothyroidism with thyroxine is in the context of pregnancy or desire for conception. There is evidence that miscarriage rates and rates or premature delivery are lower if subclinical hypothyroidism is treated with thyroxine,[60] and indeed some evidence that thyroxine treatment of biochemically euthyroid women with thyroid autoimmunity improves pregnancy outcome,[61] which coupled with evidence that even mild thyroid hormone deficiency is associated with an adverse effect on childhood neurodevelopment,[62] has led specialist associations and expert groups to support the role of thyroxine treatment.[33] It is notable, however, that a recent seminal study by Lazarus et al.[63] has demonstrated that antenatal screening of pregnant women (at a median gestational age of 12 weeks three days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at age 3. The wider topic of subclinical thyroid dysfunction and pregnancy and foetal development has been reviewed extensively elsewhere and is addressed in recent guidelines.[63-65]

Outside the context of pregnancy, there is considerable debate as to the role of thyroxine therapy in subclinical hypothyroidism, especially in mild cases. The association between serum TSH values >10 mU/l and adverse findings such as faster progression to overt hypothyroidism, hyperlipidaemia, and latterly vascular end points, has led to a consensus view in support of treatment with thyroxine in this group. It is much less clear that those with modestly elevated serum TSH (<10 mU/l) should be treated.[33] A US consensus panel of experts concluded there was insufficient evidence to warrant treatment of those with mildly elevated TSH (who should have repeat testing at 6–12 monthly intervals to detect disease progression)[33] but clinical factors such the presence of possibly relevant symptoms, positive thyroid antibodies or the presence of other cardiovascular risk factors are often taken into consideration when making treatment decisions. Clarity regarding this group of subjects requires the results of large-scale randomized trials with clinically relevant end points. Such trials would also inform decisions regarding population screening, while at present most experts, including UK and US specialist groups, argue this is unjustified.[36]

Conclusions

  1. Top of page
  2. Summary
  3. Subclinical hyperthyroidism
  4. Subclinical hypothyroidism
  5. Conclusions
  6. Reference

Mild thyroid dysfunction is common, especially in the elderly. The investigation of large data sets is beginning to identify associations of subclinical thyroid disease with adverse clinical outcomes, although these are largely limited to more ‘extreme’ cases of subclinical thyroid dysfunction, that is, fully suppressed serum TSH or serum TSH greater than 10 mU/l. While evidence is scanty that treatment in these situations is helpful, the strength of associations is nonetheless increasingly driving intervention. The hope is that, given the frequency of these biochemical abnormalities, the evidence base will improve – through completion of randomized-controlled trials – thus better informing our decisions about population or targeted screening, investigations, treatment and follow-up.

Reference

  1. Top of page
  2. Summary
  3. Subclinical hyperthyroidism
  4. Subclinical hypothyroidism
  5. Conclusions
  6. Reference
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