Introduction
Subclinical hypothyroidism, also known as compensated hypothyroidism or mild hypothyroidism, is defined biochemically as a raised serum concentration of thyroid stimulating hormone (TSH) with normal serum free thyroxine (FT4).1 It is a common condition, especially in women, and affects about 10% of women of perimenopausal age.2,3 The prevalence increases with advancing age, such that over 20% of women aged 75 years or above have serum TSH levels above the laboratory reference range.3 Autoimmune thyroiditis (Hashimoto’s thyroiditis or autoimmune atrophic thyroiditis) is the commonest cause of subclinical hypothyroidism; other causes include previous treatment with radioiodine, subtotal thyroidectomy, postpartum or subacute thyroiditis, drugs (such as amiodarone, lithium and interferon) and rarely loss-of-function mutations in the TSH receptor gene.
What are the symptoms of subclinical hypothyroidism?
Most patients with subclinical hypothyroidism don’t present with classical symptoms and signs of hypothyroidism. A large questionnaire-based study found a higher prevalence of symptoms in individuals with subclinical hypothyroidism than in euthyroid individuals; however, the association was weak with low sensitivities (3–28%) for individual symptoms in predicting subclinical hypothyroidism.3 Likewise, in a case control study, patients with subclinical hypothyroidism were found to have similar prevalence of symptoms of hypothyroidism as compared to controls, except that the patients with subclinical hypothyroidism had an increased frequency of tiredness.6
How to diagnose subclinical hypothyroidism?
The diagnosis of subclinical hypothyroidism, which is based on laboratory tests, is usually straight forward; a serum TSH level above the normal laboratory reference range, alongside a FT4 within the reference range suggests the diagnosis. The degree of subclinical hypothyroidism is often described as mild (TSH<10 mu/L) or severe (TSH10 mu/L). When interpreting the laboratory results, one must consider various physiological and pathological factors that may affect serum TSH levels. For example, TSH secretion follows a diurnal rhythm with peak levels at night and trough levels during the afternoon;7 therefore, the TSH result may vary depending upon the timing of the blood test. It is also well known that TSH levels progressively increase with age, with some experts suggesting that this phenomenon represents adaption of the hypothalamus-pituitary-thyroid axis to ageing, and we should instigate age specific TSH reference ranges.8,9 Furthermore, ethnicity has also been shown to influence serum TSH levels, with higher TSH levels in Caucasians than in Blacks or Hispanics.9 This is at least partly related to different genetic make-up, as several genetic polymorphisms have been recently shown to be associated with increased serum TSH levels in individuals without thyroid disorders.10 Finally, it has been shown that the variation in the TSH levels in an individual over time is much narrower than the population-based reference range, suggesting that each individual has a TSH set point. Therefore, a deviation from that set point, despite being within the population based reference range, may be abnormal for the individual.11
There are several other conditions associated with a raised serum TSH and normal FT4 apart from subclinical hypothyroidism (Table 1). The presence of heterophile or human anti-animal antibodies can interfere with TSH assay showing spuriously elevated level of serum TSH.12 Furthermore, recent studies have found that about 1.5% patients showing thyroid function tests consistent with subclinical hypothyroidism actually have circulating macro-TSH, which is a biologically inert large molecular complex of TSH and immunoglobulin G.13 Non-thyroidal illness and thyroiditis (subacute, painless or postpartum) can also lead to transient changes in TSH levels. In addition, TSH may be elevated in a patient with untreated Addison’s disease and this returns to normal following treatment with glucocorticoid replacement.
In patients with subclinical hypothyroidism, testing for thyroid peroxidase antibodies (TPO-Ab) is useful because the presence of TPO-Ab confirms autoimmunity as the aetiology of subclinical hypothyroidism. Furthermore, TPO-Ab positivity also has a prognostic value in predicting progression to overt hypothyroidism (see below).
What is the natural history of subclinical hypothyroidism?
If untreated, a small proportion of patients with subclinical hypothyroidism progress to overt hypothyroidism.
Likewise, a longitudinal study of patients over the age of 55 years with subclinical hypothyroidism found an incidence rate of overt hypothyroidism at about 10 cases per 100 patient-years.15 The incidence rate was greater in patients with higher TSH levels, with 1.8 cases per 100 patient-years in patients with TSH 5.0–9.9 mIU/l, as compared to 19.7 cases per 100 patient-years in those with TSH 10.0–14.9 mIU/l.
Interestingly, during the mean follow-up period of 32 months, 37% patients with subclinical hypothyroidism, in the study, normalised their thyroid function without treatment.15
What are the long-term complications of untreated subclinical hypothyroidism?
Cardiovascular disease
A metaanalysis of observational studies found a clear divide in the association between subclinical hypothyroidism and cardiovascular mortality in different age groups, with significant association in individuals younger than 65 years (OR 1.37; 95% CI 1.04–1.79) but not in older individuals.20
In another meta-analysis, which included data from over 55,000 individuals, increasing TSH levels in subclinical hypothyroidism was associated with a higher prevalence of coronary heart disease events and deaths.23 The association was most striking in patients with TSH values 10 mu/L, with hazard ratios for coronary heart disease events and deaths as 1.89 (95% CI 1.28–2.8) and 1.58 (95% CI 1.1–2.27), respectively.
Furthermore, a recent meta-analysis of six prospective observational studies, which included individual data from over 25,000 subjects, found a significantly increased risk of heart failure in patients with TSH values 10mu/ L (hazard ratio 1.86; 95% CI 1.27–2.72).24
Cerebrovascular disease
Subclinical hypothyroidism has been shown to be associated with an increased risk of cerebrovascular disease in younger patients. A recent meta-analysis of 17 observational studies (47,573 adult subjects; 3451 with subclinical hypothyroidism) found no overall increased risk of all stroke events (HR 1.05; 95% CI 0.91–1.21) or fatal stroke (HR 1.07; 95% CI 0.8–1.42) in individuals with subclinical hypothyroidism as compared to those with euthyroidism.28 However, there was a significantly increased risk of fatal stroke in younger patients (under the age of 65 years) with subclinical hypothyroidism (HR 2.29; 95% CI 1.41–3.74), and a trend for a higher risk with increasing TSH levels.
Adverse metabolic parameters
Subclinical hypothyroidism has been shown to be associated with several adverse metabolic parameters, which may partly explain the increased cardiovascular and cerebrovascular risk in younger patients with subclinical hypothyroidism.
A recent meta-analysis of 16 observational studies (included 41,931 adults; 4526 with subclinical hypothyroidism) found significantly increased levels of serum total cholesterol, low-density lipoprotein cholesterol and total triglyceride in patients with subclinical hypothyroidism compared to euthyroid individuals; serum high-density lipoprotein cholesterol levels were similar in the two groups.29 Likewise, another meta-analysis showed an association between type 2 diabetes and subclinical hypothyroidism, with a 1.93-fold (95% CI 1.66–2.24) increased prevalence of subclinical hypothyroidism in patients with type 2 diabetes as compared to a healthy population.30 In addition, this study has suggested that subclinical hypothyroidism increases the risk of the development of diabetic complications, including diabetic nephropathy (OR 1.74; 95% CI 1.34–2.28), diabetic retinopathy (OR 1.42; 95% CI 1.21–1.67), peripheral vascular disease (OR 1.85; 95% CI 1.35–2.54) and peripheral neuropathy (OR 1.87; 95% CI 1.06–3.28). Finally, patients with subclinical hypothyroidism have also been shown to have higher plasma homocysteine (a risk factor for atherosclerosis) and insulin resistance (measured by homeostatic index of insulin resistance; HOMA-IR) as compared to healthy individuals.31
Impaired cognitive function
(…) In contrast, another meta-analysis has suggested that younger patients (age <75 years) with subclinical hypothyroidism, particularly those with higher TSH levels, have an increased risk of impaired cognitive function and dementia,34 suggesting more research is required before conclusions can be drawn.
Osteoporotic fractures and frailty
Likewise, there is no evidence to show that subclinical hypothyroidism is associated with an increased risk of frailty in elderly populations.37,38
Mood, mental health and well-being
Subclinical hypothyroidism has been shown to be associated with poor neuropsychological function, mood and quality of life by some studies,39,40 but not by others.41,42 Therefore, the association remains uncertain.
Does treatment with levothyroxine help?
A systematic review and meta-analysis of randomized controlled trials failed to show significant benefit of levothyroxine treatment in improving symptoms, or quality of life, in patients with subclinical hypothyroidism. 43
What are the potential risks of levothyroxine treatment?
As in overt hypothyroidism, levothyroxine treatment in subclinical hypothyroidism is safe provided that thyroid function is monitored regularly and the dose of levothyroxine is adjusted to keep the TSH level within the normal reference ranges. However, both over-treatment and under-treatment are common in patients on levothyroxine,3 and the over-treatment leading to the suppression of TSH can increase the risks of atrial fibrillation and osteoporosis, particularly in elderly patients.50,51 Patients with subclinical hypothyroidism on levothyroxine are likely to be more prone to overtreatment and associated adverse effects than those with overt hypothyroidism. This is supported by a large retrospective cohort study of the UK-based general practice research database, which showed that as levothyroxine treatment is being started at progressively lower TSH values over the study period (2001– 2009), an increasing proportions of the treated patients had suppressed TSH.52
How to manage subclinical hypothyroidism?
As most patients with subclinical hypothyroidism are asymptomatic and there is lack of evidence from randomised controlled trials to show that levothyroxine treatment can prevent associated cardiovascular and cerebrovascular adverse effects, its management remains controversial. However, in view of the associated longterm cardiovascular morbidity and mortality in patients with subclinical hypothyroidism, particularly in young patients and those with high TSH levels, the current guidelines from the American Thyroid Association/the American Association of Clinical Endocrinologists53 and the European Thyroid Association54 recommend treatment of subclinical hypothyroidism with levothyroxine if TSH is 10mu/L. The European guidelines recommend a more cautious approach in treating subclinical hypothyroidism in older patients above the age of 70 years.
Referência :
Post Reprod Health. 2017 Jun;23(2):55-62.
