Introduction: It is debated whether the presence of subclinical hyperthyroidism (SH) constitutes an increased risk of cardiovascular disease. This review presents a summary of the literature examining the association between SH and atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI) and cardiovascular mortality.
Methods: A systematic literature search of the PubMed database was performed. Studies were included if they were of observational design, about SH in humans, and had AF, HF, MI and/or cardiovascular mortality as outcome, were published in either Danish or English language and included euthyroid controls.
Results: A total of 33 papers were suitable for inclusion. Thus, 13 papers on AF and five papers on HF were included for review and supported an association between SH and AF and HF, respectively. In all, 14 papers on MI and 15 papers on cardiovascular mortality were included for review; but, overall, they did not support an association between SH and MI or cardiovascular mortality.
Conclusions: Based on our review, current literature supports an association between SH and AF and HF, respectively; but not between SH and MI or cardiovascular mortality.
Subclinical hyperthyroidism is associated with atrial fibrillation and congestive heart failure.
Subclinical hyperthyroidism does not seem to be associated with myocardial infarction or cardiovascular mortality.
Intervention studies investigating whether or not treatment of subclinical hyperthyroidism reduces the risk of cardiovascular disease are lacking.
The prevalence of subclinical hyperthyroidism (SH) is around 1% in iodine-replete areas and around 10% in iodine-deficient areas . SH is diagnosed according to biochemical criteria, i.e. a low level of thyroid-stimulating hormone (TSH) and normal levels of circulating peripheral hormones (free thyroxin (T4) and triiodothyronine and/or free triiodothyronine (T3)) .
According to clinical guidelines, antithyroid treatment should be considered if TSH level is < 0.1 mIU/l or if TSH level is between 0.1 mIU/l and the lower limit of the reference range at repetitive measurements and the patient has hyperthyroid symptoms . It is well-known that SH increases the risk of atrial fibrillation (AF)  and osteoporosis,  but it remains unclear if SH also increases the risk of cardiovascular diseases (CVDs) in general.
A number of potential pathophysiological links between endogenous SH and CVD have been described. Overt hyperthyroidism affects the cardiac pacemaker cells resulting in increased chronotropic and inotropic effects. In patients with SH, a higher 24-hour heart rate and an increased number of ventricular and supraventricular extrasystoles have been reported as well as increased ventricular mass and impaired left ventricular performance. Increased carotid intima-media thickness has also been reported in SH patients, and there is an association between increased carotid intima-media thickness and atherosclerotic cardiovascular events, suggesting an increased cardiovascular morbidity and mortality in SH [2, 3]. A small study of SH caused by levothyroxine treatment showed improvement in myocardial structure when tailoring the dose of levothyroxine from TSH level < 0.1 mIU/l to TSH suppression > 0.1 mIU/l, suggesting possible reversibility in cardiac changes in patients with SH – at least in exogenous SH .
Through a systematic literature search, this systematic review explored whether or not there is an association between SH and the risk of developing AF, myocardial infarction (MI), heart failure (HF) and CVD mortality.
A systematic literature search with the search terms ("thyroid dysfunction" OR "subclinical thyroid dysfunction" OR "thyrotoxicosis" OR "subclinical thyrotoxicosis" OR "hyperthyroidism" OR "subclinical hyperthyroidism") AND ("atrial fibrillation" OR "heart failure" OR "myocardial infarction" OR "cardiovascular mortality" OR "cardiovascular disease") was performed in PubMed on 12 March 2020. Included were studies of observational design, about SH in humans, with AF, HF, MI and/or CVD mortality as outcome that were published in either Danish or English language. The search was performed by SBS. When in doubt if a paper should be included, the other authors were consulted for their opinion. The Newcastle Ottawa Quality Assessment Scale (NOS) was used to assess the risk of bias . For cross-sectional studies, a modified version of the NOS was used (https://ugeskriftet.dk/files/a12190701_supplementary.pdf). This systematic review was reported according to the PRISMA guidelines .
The literature search returned 2,145 records (Figure 1, https://ugeskriftet.dk/files/a12190701_supplementary.pdf). Two were duplicates leaving 2,143 records. Among these, 1,839 records were excluded based on title and abstract leaving 304 records. After full text assessment, 271 records were excluded of which 21 were not of observational design, 165 were not about SH/ no information was provided on T3 or T4 in the definition of SH, one was an animal study, 26 did not concern AF, MI, HF or CVD mortality, 19 were guidelines or letters, five did not include euthyroid controls and 34 were inaccessible. This left 33 papers for review: 13 on AF, five on HF, 14 on MI, and 15 on CVD mortality.
Quality of studies
Studies were scored according to the NOS with a maximum possible score of nine. Scores are presented in Table 1, Table 2, Table 3 and Table 4. All cohort studies (five on AF, five on HF, 11 on MI and 15 on CVD mortality) had a low risk of bias in selection of cohorts and comparability, and a medium risk of bias in outcome. All case control studies (all on AF, n = 4) had a low risk of bias in comparability of cases and controls and a medium risk of bias in selection of cases and controls and exposure. Cross sectional studies on AF (n = 4) had a medium risk of bias in selection, comparability and outcome. Cross sectional studies on MI (n = 3) had a medium risk of bias in selection and outcome and a high risk of bias in comparability.
The literature search identified 13 observational studies that investigated the association between SH and AF. The studies are presented in Table 1.
Three larger studies investigated the risk of AF in patients with SH. Selmer et al  studied the risk of AF in a large cohort of subjects from primary care in Denmark. Subjects were excluded if they had a history of AF or thyroid illness. The study included 6,276 subjects with SH. The overall incidence rate ratio (IRR) was 1.30 (95% confidence interval (CI): 1.18-1.43) adjusted for sex, age, calendar year, the Charlson Comorbidity Index and socioeconomic status. Vadiveloo et al  examined patients from general practices and categorised them according to the severity of SH (grade one: TSH level 0.1-0.4 mIU/l, grade two: TSH level < 0.1 mIU/l). They found an adjusted hazard ratio (HR) of 1.52 (95% CI: 1.11-2.08) for AF and other arrhythmias and an adjusted HR of 2.07 (95% CI: 1.30-3.29) for patients with grade one and two SH, respectively. Six months after diagnosis of SH, patients with persistent SH still had an increased risk of arrhythmias including AF. Auer et al  performed a cross sectional analysis on inpatients in Austria. The population consisted of 23,638 subjects of whom 613 patients suffered from SH. Patients taking thyroid hormone replacement were excluded. After adjusting for age and known risk factors for AF including hypertension, left ventricular hypertrophy and underlying structural heart disease, they found a relative risk (RR) of 2.8 (95% CI: 1.3-5.8) of AF in patients with SH.
Four studies with fewer participants also showed an association between SH and AF: In an early study from 1990, Tenerz et al  showed an increased number of AF in SH patients selected from an outpatient clinic with an AF prevalence of 28% versus 10% in euthyroid controls (p < 0.05). Cappola et al  investigated patients from the general population in the USA among individuals with a health insurance. After adjusting for age, sex, clinical CVD at study start, AF risk factors and thyroidal medication during the study, SH was associated with AF with a HR of 1.98 (95% CI: 1.29-3.03). Gammage et al  studied elderly patients who received no thyroidal medication and had no history of hyperthyroidism. They reported an odds ratio (OR) of 1.89 (95% CI: 1.01-3.57) when adjusted for AF risk factors. Furthermore, the authors found that the presence of AF was associated with the T4 concentration (OR: 1.08 (95% CI: 1.03-1.14) per 1 pmol/l T4 increase). Wollenweber et al  investigated patients with ischaemic stroke and found a higher prevalence of AF in patients with SH (37%) versus euthyroid patients (23%).
Six studies reported no association between SH and AF. Two of the studies were cross-sectional studies, [14, 15]. One study examined a population with a heavy CVD risk profile or heavy CVD co-morbidity, making it possible that these patients developed AF for other reasons than SH . Two studies examined patients with AF in a case-control design finding no differences in the number of subjects with SH in the groups with or without AF (n = 12 and n = 2, respectively) [17, 18]. One case-control study found a similar prevalence of AF in subjects with SH (n = 1/87) and euthyroid subjects (n = 1/88) .
The literature search produced five observational studies on SH and HF. The studies are presented in Table 2.
Selmer et al  reported data from a large Danish cohort, n = 563,700, of whom 5,979 had SH. All participants were without thyroid disease or CVD at inclusion. Results were adjusted for age, sex and AF at both study start and during the follow-up period, but not for blood pressure or smoking as these factors were unknown. The authors found an increased risk of developing HF in SH patients with an IRR of 1.20 (95% CI: 1.10-1.31), but no evidence of a dose-response relationship with the grade of SH.
Gencer et al  reported on patients from the general population and from an outpatient clinic for HF and found a borderline significantly increased risk of HF (HR: 1.46 (95% CI: 0.94-2.27)) in age- and sex-adjusted analyses among patients with TSH level < 0.45 mIU/l. The association was carried by a significantly increased risk among individuals with TSH level < 0.1 mIU/l (HR: 1.94 (95% CI: 1.01-3.72)). When adjusting for risk factors for HF, a trend towards the same results persisted (HR: 1.92 (95% CI: 0.99-3.71)) in the group of patients with TSH level < 0.1 mIU/l.
Nanchen et al  explored elderly patients with either a history of CVD or CVD risk factors; among these, 71 participants had SH. They found that SH patients had an increased risk of developing HF, particularly patients with TSH level < 0.1 mIU/l (age and sex adjusted HR: 4.61 (95% CI: 1.71-12.47)).
In contrast to these studies, Rodondi et al  found no increased risk of developing HF in SH (n, SH = 44). Asvold et al  investigated a cohort of the Norwegian general population including 524 patients with SH and found no association between HF and SH in analyses adjusted for age, smoking, BMI and sex (HR: 1.52 (95% CI: 0.86-2.69)).
The literature search produced 14 observational studies about SH and MI. The studies are presented in Table 3.
Golledge et al  explored the association between TSH and T4, respectively, and the incidence of new-onset CVD in elderly men with no history of thyroid dysfunction. They found no increased risk of MI when using the traditional definition of SH (low-level TSH and normal levels of T4 and T3). However, a significant association between T4 in the upper reference range and an increased risk of developing MI appeared with an adjusted HR of 1.29 (95% CI: 1.06-1.59).
Afsar et al  investigated patients with chronic kidney disease and SH and their risk of developing coronary heart disease. There was an increased risk of cardiovascular events (acute MI, angina pectoris, and need for by-pass surgery) with a HR of 4.83 (95% CI: 1.13-20.66) when adjusted for age, sex, hypertension, diabetes and smoking. When adjusting for haemoglobin, estimated glomerular filtration rate, fibroblast growth factor-23, high-sensitive C-reactive protein, and high-density lipoprotein-cholesterol, the results became insignificant.
The literature search revealed another 12 studies that failed to find an association between MI and SH [11, 15, 16, 20, 23, 26-32]. Selmer et al , Asvold et al  and Martin et al  investigated large cohorts of the general population in Denmark, Norway, and USA, respectively, and found no association between MI and SH (adjusted IRR: 1.02 (95% CI: 0.89-1.18), adjusted HR: 1.37 (95% CI: 0.91-2.05) and adjusted HR: 1.14 (95% CI: 0.83-1.58), respectively).
The literature search produced 15 observational studies investigating SH and CVD mortality. The studies are presented in Table 4.
After 7.5 years of follow-up, Sgarbi et al  found an increased risk of CVD mortality with an unadjusted HR of 4.5 (95% CI: 2.1-10.1) in patients with SH compared with euthyroid participants. The increased risk persisted after adjustment for age, sex, smoking and other factors. However, the study is limited by the small number of deaths (n = 14) of which only eight were due to CVD.
Parle et al  found an increased risk of CVD mortality in SH from year one to five during follow-up (adjusted HR = 2.2 (95% CI: 1.1-4.4)). At the end of the study (an average of eight years of follow-up), a borderline significantly increased risk persisted. Drechsler et al  investigated the risk of sudden cardiac death in diabetic haemodialysis patients with SH and found similar results with a borderline statistically significantly increased risk at the end of follow-up (adjusted HR: 1.51 (0.96-2.38)).
The remaining studies found no association between SH and CVD mortality [11, 16, 23, 24, 29, 31, 34-39]. Asvold et al  presented the largest cohort of 524 patients with SH and found a HR of death from coronary heart disease of 1.60 (95% CI: 0.96-2.68) adjusted for age, sex, BMI, and smoking, but the results only reached borderline significance. Zijlstra et al  studied the effect of persistent SH (defined as SH in two blood analyses taken at a six-month interval) on a combined endpoint of death from coronary heart disease, MI and stroke and found a HR of 0.51 (95% CI: 0.24-1.07) in a multivariate adjusted analysis indicating a decreased risk. However, the result was only borderline significant.
In summary, the systematic literature search presented above supports an association between SH and AF, which is in line with prior reviews and meta-analyses [40, 41]. Five studies add to the evidence on this association. In particular, the larger studies support an association [7-9]. However, Vadiveloo et al investigated arrhythmias in general and not AF specifically . Studies that reported no association between SH and AF were generally of a weaker design (e.g., cross-sectional), reported on smaller cohorts, or had very few events of AF, suggesting lack of power to detect an actual difference. A Mendelian randomisation study investigating the association between thyroid dysfunction and CVD found evidence of a causal association of SH and AF, supporting this association . Gammage et al  found that the risk of AF increased with a higher level of T4 within the reference range. This is in contrast to the findings of a Mendelian randomisation study investigating the effect of different thyroid parameters on AF not supporting an association of AF with increased T4 within the reference range . Sawin et al  analysed data from the Framingham Heart Study (background population, USA) and found a RR of AF in patients > 60 years of age with TSH level < 0.4 mIU/l of 3.0 (95% CI: 1.7-5.5) after ten years of follow-up. The result was adjusted for T4 and other factors, indicating that the risk of AF is increased due to TSH concentration independently of T4. It should be mentioned that Sawin et al included both SH and hyperthyroid subjects in their analysis.
Our review mainly supports an association between SH and an increased risk of HF. Selmer et al  performed a large register-based cohort study in Denmark providing results supporting an association between SH and HF. However, it was not possible to adjust for smoking in this study, which affects both the risk of thyroid disease and CVD. Asvold et al  and Gencer et al  performed studies similar to each other but came to different conclusions. Gencer et al found an increased risk of HF in patients with TSH level < 0.1 mIU/l. Asvold et al only studied patients with SH as a whole and found an increased risk of HF, but this risk was not statistically significant. This may suggest that AF development depends on the grade of SH. In addition, Gencer et al included patients from an outpatient clinic for HF, suggesting that patients with HF may be more sensitive to SH. Another possible explanation for this observation is that patients with various co-morbidities are followed in outpatient clinics, and blood sampling (including thyroid screening) may therefore be performed more frequently than in healthier subjects not followed in a clinic, indicating surveillance bias. It is also of note that AF and HF are closely associated diseases. Therefore, it is possible that the increased risk of HF is caused by an increased risk of AF or vice versa. However, whether such a relationship exists cannot be elucidated from any of these studies.
Only two studies reported an increased risk of MI in SH patients [24, 25]. However, they both had significant limitations since MI was only a secondary endpoint in one study  and MI was not analysed as an independent endpoint in the other . The literature search revealed 12 studies that found no association between SH and MI. Consequently, the current literature does not support an association between SH and MI. A meta-analysis found an association between coronary heart disease and SH, but MI was not investigated separately . This also applies to many of the studies included in our review; several studies analysed MI as a combined endpoint with chronic ischaemic heart disease, stroke or cardiac death, making it difficult to assess the risk of MI independently.
Our review contains only scarce evidence of a potential association between SH and CVD mortality. The literature search produced a somewhat large number of studies on the risk of SH and CVD mortality not supporting an association between the two. However, most studies comprised populations with fewer than 100 subjects with SH, suggesting that the studies may be underpowered. In addition, the study populations were heterogeneous (e.g., patients with diabetes receiving haemodialysis and patients with cardiovascular morbidity) and thus their findings may not be applicable to the general population. They were also different regarding the endpoints, e.g., cardiac death defined solely as death from coronary heart disease or solely from ventricular arrhythmia/congestive HF or not further specified. One study even combined the endpoint death from coronary heart disease with non-fatal MI and stroke. The various definitions on CVD mortality complicate any definite conclusions, but overall, our findings do not support an association between SH and CVD mortality. A number of reviews/meta-analyses already exist exploring the risk of CVD mortality in patients with SH, but results are conflicting. Most reported either no increased risk of CVD mortality in patients with SH [46, 47] or data were insufficient to draw any definite conclusions [40, 48]. One meta-analysis  found an increased risk but the risk was significant only in subgroup analyses of studies with convenience sampling on cardiac patients, chronically ill geriatric patients and patients with acute cardiac disease. However, surveillance bias may also be a possible explanation for this observation.
As all the present studies are of observational design, it is unknown whether treatment of SH will reduce the risk of AF and HF. Antithyroid treatment is associated with different side effects including minor and transient ones but also potentially life-threatening adverse effects even though these are rare. Since the overall risk of adverse effects of medical treatment seems negligible , treatment of endogenous SH (radioactive iodine for multi nodular toxic goiter/antithyroid drugs for Graves’ disease) may seem reasonable in light of the observed association with AF and HF, especially in elderly patients. This is also in accordance with the present European guidelines . SH is associated with severe disease and therefore should be regarded a biochemically milder form of thyrotoxicosis but with the same physiological consequences, supporting that medical treatment should be considered.
The current literature does not provide convincing evidence of an association between SH and MI or cardiovascular death. In contrast, evidence seems to support an association between SH and AF and HF, respectively. Future randomised intervention trials are needed in order to support a possible causal relationship between SH and AF and HF, respectively, and to determine whether treatment of SH reduces the risk of AF and HF.
Correspondence: Stine Bech Smedegaard. E-mail: Stinsmed@rm.dk
Accepted: 20 August 2020
Conflicts of interest: Disclosure forms provided by the authors are available with the full text of this article at Ugeskriftet.dk/dmj
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