The Thyroid – Too Much and Too Little Across the Ages

The Consequences of Subclinical Thyroid Dysfunction

Jayne A. Franklyn


Clin Endocrinol. 2013;78(1):1-8. 

In This Article

Subclinical Hypothyroidism


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]

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]