There appears to be no benefit from treating adults with subclinical hypothyroidism. Treatment has no effect on quality of life or symptoms compared with placebo or no treatment.
Thyroid function tests are commonly performed in general practice for patients who present with a range of symptoms, including fatigue or tiredness. When subclinical hypothyroidism is detected, there is uncertainty whether treatment is worthwhile or how to best monitor success. A recent large study found that hormone levels remain remarkably stable over five years, with few people developing overt hypothyroidism without treatment, suggesting monitoring could be reduced.
This review of 21 trials provides moderate to high-quality evidence that hormone treatment of subclinical hypothyroidism, gives no measurable benefit either. This may help inform practice, spare patients unnecessary treatment, and save NHS resources.
Why was this study needed?
Hypothyroidism is a condition where the thyroid gland doesn’t produce enough hormones, which can have various underlying causes. Hypothyroidism is characterised by low blood levels of free thyroxine (T4) and high levels of thyroid stimulating hormone (TSH), which is released from the pituitary gland to try and stimulate the thyroid.
Subclinical hypothyroidism is diagnosed when there is a raised level of TSH, but normal levels of free T4. It’s thought to affect around 5-6% of adults and is more common in women and older people.
To date, there has been little evidence to guide the management of subclinical hypothyroidism. Two large randomised controlled trials were recently completed. This systematic review added the results from these trials to previous evidence to see whether there is a benefit from treating non-pregnant adults with subclinical hypothyroidism.
What did this study do?
The review combined the results of 21 randomised controlled trials including 2,192 adults with subclinical hypothyroidism. Trials compared thyroid hormone therapy (thyroxine or the synthetic form levothyroxine), given for between three and 18 months, with placebo or no treatment. Participant age ranged from 32 to 74 years, and symptoms were mild to moderate.
Four trials came from the UK, with others from other European countries, Brazil, China, Japan, Iran, and the US. Studies were published from 2001 onwards, with a single study from 1984. Two were industry-funded. Studies assessed varied outcomes, with most looking at body mass index and blood pressure and some looking at quality of life measures. Risk of bias was low overall, and the quality of evidence was rated as moderate to high.
What did it find?
- Treatment was associated with TSH levels returning to a normal range. At study start, TSH levels were in the range 4.4 to 12.8 mIU/L (milli-international units per litre). At follow-up, mean TSH levels had reduced to the normal range in the intervention group (between 0.5 and 3.7 mIU/L) but remained raised in the placebo/no intervention group (4.6 to 14.7mIU/L).
- Thyroid hormone therapy made no difference to participants’ quality of life. Four trials (796 adults) measured general quality of life, using three different questionnaires (General Health Questionnaire, Short Form 36 and EQ-5D). The standardised mean difference (SMD) was -0.11, 95% confidence interval (CI) -0.25 to +0.03. There was moderate variability (heterogeneity) in the results of the four studies.
- Neither was there any effect on thyroid-related quality of life or hypothyroid symptoms (SMD 0.01, 95% CI -0.12 to 0.14; 4 studies, 858 participants). These were measured using a variety of tools but with no heterogeneity.
- The reviewers looked at a number of secondary outcomes measured by the studies including blood pressure and body mass index, depression symptoms, tiredness and cognitive function, but found no treatment effect for any of these outcomes.
- There was a lack of quality evidence for adverse effects, cardiovascular events and mortality.
What does current guidance say on this issue?
The Royal College of Physicians published a statement on the diagnosis and management of primary hypothyroidism in 2011. Recommendations for treatment of subclinical hypothyroidism are drawn from the British Thyroid Association’s 2006 guideline for the use of thyroid function tests in the UK.
The British Thyroid Association recommends levothyroxine if TSH is greater than 10mU/L. If TSH is higher than normal but below 10mU/L, treatment is not routinely recommended except in certain circumstances, such as patients with goitre (swelling of the thyroid gland) or women who are planning pregnancy.
What are the implications?
This review does not support the routine treatment of subclinical hypothyroidism. It coincides with the publication of long-term follow-up of UK adults (aged over 65) with subclinical hypothyroidism, which found a low conversion rate to overt hypothyroidism. These combined findings may reassure practitioners and spare patients unnecessary treatment and the need for repeated blood tests.
There may still be justification for treating people not studied here; for example, those aged over 75 years or with severe symptoms.
The review also did not look at subclinical hypothyroidism with higher levels of TSH. Only two trials (99 participants) included people with TSH higher than 10mIU/L.
Citation and Funding
Feller M, Snel M, Moutzouri E et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA. 2018;320(13):1349-59.
This study was funded by the Swiss National Science Foundation (grant SNSF 320030_172676).
British Thyroid Association, The Association for Clinical Biochemistry, British Thyroid Foundation. UK guidelines for the use of thyroid function tests. London: British Thyroid Association; 2006.
NICE. Hypothyroidism. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2018.
RCP. The diagnosis and management of primary hypothyroidism. London: Royal College of Physicians; 2011.
Roberts L, McCahon D, Johnson O, et al. Stability of thyroid function in older adults: the Birmingham Elderly Thyroid Study. Br J Gen Pract. 2018;68(675):e718-26.
Thyroid UK. Thyroid UK study update January 2012. Clacton on Sea: Thyroid UK; 2012.
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