Table 2. Characteristics of the included systematic reviews and meta-analyses.
| Study | Design | Study aim | Included studies | Definition of SCH | SCH patients (%) | Summary of findings | AMSTAR-2 Overall confidence |
|---|---|---|---|---|---|---|---|
| Baumgartner et al. (2017) [51] | IPD | To examine the risk of AF in individuals with thyroid function within the normal range and SCH | 11 cohort studies (IPD) | TSH level between 4.5 and 19.9 mIU/L with fT4 levels in the reference range | 1958 (6.5) | The reviewers found no link between SCH and the risk of AF; this was the same for individuals with TSH levels within the normal range. | High |
| Blum et al. (2015) [45] | MA | To assess the association of subclinical thyroid dysfunction with fractures | 13 cohort studies | TSH level of 4.50 to 19.99 mIU/L with normal FT4 levels | 4092 (5.8) | There was no observed association between SCH and fracture risk. | Moderate |
| Chaker et al. (2015) [52] | IPD | To evaluate the association between SCH and stroke | 17 cohort studies | TSH levels of 4.5 to 19.9 mIU/L with normal T4 levels | 3451 (7.3) | There was no overall increase in the risk of stroke events and fatal stroke in patients with SCH than euthyroid patients, except for patients younger than 65 years. | Moderate |
| Collet et al. (2014) [53] | IPD | To compare the risks of CHD mortality and events associated with SCH by thyroid antibody status | 6 cohort studies | TSH 4.5 to 19.9 mIU/L and normal T4 level | 1691 (4.4) | Thyroid antibodies were found to have no effect on CHD events and mortality though SCH patients with higher TSH levels were generally at higher risk of developing these outcomes. | Moderate |
| Dhital et al. (2017) [41] | SR + MA | To look at the association between thyroid function profile and outcomes after acute ischemic stroke | 12 cohort studies | Elevated TSH and normal fT4 (study-specific cut-offs) | Unclear | SCH was associated with better functional outcomes after acute ischemic stroke, but this depended on the initial levels of free T3. | Low |
| Feller et al. (2018) [17] | SR + MA | To examine the association of THT with quality of life and thyroid-related symptoms in adults with SCH | 21 RCTS | Thyrotropin and free thyroxine levels above and within centre-specific reference ranges, respectively | 2192 (100) | There was no association between treatment of SCH and improving thyroid-related symptoms and quality of life (primary outcomes) or cognitive function, depressive symptoms and the other secondary outcomes. | High |
| Gencer et al. (2012) [54] | IPD | To clarify the association between subclinical thyroid dysfunction and HF events | 6 cohort studies | TSH level of 4.5 to 19.9 mIU/L with normal FT4 levels | 2068 (8.1) | Patients with TSH levels higher than 10mIU/L faced a significantly higher risk of HF events. | Moderate |
| Helfand (2004) [36] | SR | To evaluate the benefits of screening for subclinical thyroid dysfunction | 8 RCTs | Elevated TSH and normal T4 | Unclear | Evidence of an association between treatment and reduced symptoms was demonstrated only for SCH patients with TSH >10 mIU/L and those with a history of Graves’ disease. | Low |
| Peng et al. (2021) [42] | SR + MA | To investigate whether THT is associated with decreased mortality in adults with SCH | 2 RCTs and 5 cohort studies | Grade 1 (TSH level 5.0–10 mIU/L); Grade 2 (TSH level >10 mIU/L) with free thyroxine level within the reference range | 21055*3 (100) | Treatment was found to benefit SCH patients younger than 65 years; all-cause mortality decreased by 50%, and cardiovascular mortality decreased by 46%. However, the same did not apply to patients older than 65 years. There was also no overall benefit of treatment on mortality. | High |
| Razvi et al. (2008) [46] | MA | To examine the influence of age and gender on IHD and mortality in SCH | 15 cohort studies | Mild SCH—TSH levels < 10 mIU/L | 2,531 (8.7) | The overall incidence of IHD and mortality was not significantly higher for patients with SCH, but IHD prevalence was found to be significantly elevated for patients younger than 65 years. | High |
| Reyes Domingo et al. (2019) [38] | SR | To synthesize the evidence on the effects of screening and subsequent treatment for thyroid dysfunction | 5 RCTs and 3 cohort studies*2 | Study-specific | Unclear | Evidence was found linking treatment for SCH with reduced all-cause mortality for patients younger than 65 years, but it was determined to be of low quality. | High |
| Rodondi et al. (2006) [47] | MA | To determine whether SCH is associated with an increased risk for CHD | 5 cohort, 6 cross-sectional and 3 case-control studies | Elevated TSH and a normal T4 (no pre-specified cut-offs) | 1409 (10.8) | Compared to euthyroid patients, CHD was 1.6 times more likely in patients with SCH; this association was constant throughout the included studies but less pronounced in the prospective cohorts. | High |
| Rodondi et al. (2010) [55] | IPD | To assess the risks of CHD and total mortality for adults with SCH | 11 cohort studies | Serum TSH level of 4.5 mIU/L or greater to less than 20 mIU/L, with a normal T4 concentration | 3450 (6.2) | SCH patients with TSH levels higher than 10mIU/L had a significantly higher risk of CHD events and mortality than euthyroid patients. | High |
| Rugge et al. (2015) [39] | SR | To assess the benefits and harms of screening and treatment of subclinical and undiagnosed overt hypothyroidism and hyperthyroidism in adults* | 13 RCTs and 1 cohort study | 4.5–10.0 mIU/L (mildly elevated) or ≥10 mIU/L (markedly elevated) TSH levels with normal thyroxine | Unclear | Reviewers found a potential association between SCH and cardiovascular disease but inconclusive evidence that treatment would be beneficial; SCH treatment was also not associated with improved cognitive function or quality of life. | Moderate |
| Singh et al. (2008) [48] | MA | To compare the relative risk for incident CHD events, cardiovascular-related and total mortality associated with subclinical thyroid abnormalities | 6 cohort studies | Serum TSH above 4.0–5.0 mIU/L with normal free T4 (range 0.7–1.8 ng/dL) | 1365 (10.2) | SCH was linked to a significant risk of CHD at baseline and both CHD and cardiovascular mortality during follow-up. On the other hand, all-cause mortality was not found to be increased with SCH. | Low |
| Sun et al. (2017) [43] | SR + MA | To explore the relationship between subclinical thyroid dysfunction and the risk of cardiovascular outcomes | 16 cohort studies | TSH levels >3.6 to 6 mIU/L (study-specific) | 5178 (7.2) | There was a significantly higher risk of CHD and cardiovascular mortality for SCH patients younger than 65 years, but the same effect was not observed for patients older than 80 years. A slightly higher risk of AF and HF was also associated with SCH. | Moderate |
| Villar et al. (2007) [40] | SR | To assess the effects of thyroid hormone replacement for SCH | 12 RCTs | TSH level above the upper limit of the reference range with normal values of total T4 or free T4 (FT4), with or without T3 or free T3 (FT3) measurements | 350 (100) | It was not possible to assess the benefits of SCH treatment on reducing cardiovascular mortality. However, there was also no significant impact of levothyroxine on health-related quality of life and symptoms. | High |
| Wirth et al. (2014) [44] | SR + MA | To assess the risk for hip and non-spine fractures associated with subclinical thyroid dysfunction | 7 cohort studies | TSH level greater than 4.5 to 20.0 mIU/L and an FT4 level in the reference range | Unclear | No association between SCH and fracture risk was found, but the reviewers could not assess the effects of treatment vs no treatment due to insufficient data. | Moderate |
| Yan et al. (2016) [49] | MA | To identify the relationship between subclinical thyroid dysfunction and the risk of fracture | 5 cohort studies | TSH level greater than 4.0 to 5.5 mIU/L (study-specific) | 2580 (0.9) | A link between SCH and higher fracture risk was not found, but the reviewers acknowledge that they had limited data. | Low |
| Yang et al. (2019) [50] | MA | To assess the association between subclinical thyroid dysfunction and the clinical outcomes of HF patients | 14 cohort studies | Elevated TSH values in the presence of normal FT4 values | 2308 (10.9) | Both adjusted and unadjusted analyses showed a significantly higher risk of all-cause mortality and cardiovascular death associated with SCH for patients with heart failure. | Low |
THT—Thyroid Hormone Therapy; SR–Systematic Review; SR + MA–Systematic Review and Meta-Analysis; MA–Meta-analysis; IPD–Individual Participant Data analysis; SCH–Subclinical Hypothyroidism; CHD–Coronary Heart Disease; AF–Atrial Fibrillation; RCT–Randomised Controlled Trial; HF–Heart Failure; IHD–Ischaemic Heart Disease; Thyroxine–T4, fT4, thyroid hormone; Thyrotropin–Thyroid Stimulating Hormone (TSH)
*this was an update to Helfand et al. [36], but because the searches did not overlap, this was considered a separate review.
*2only for the relevant research question on clinical outcomes for SCH.
*3the authors report potential overlap between the studies; hence the estimate may be incorrect.