Background

The relationship between thyroid function and cancer has been a subject of debate for more than 200 years, with studies showing conflicting results [1, 2]. In vitro studies have shown that thyroid hormones not only regulate body metabolism but they also play an important role in cell proliferation and differentiation in normal tissues [3]. Thyroid hormones consist of thyroxine (T4) and triiodothyronine (T3), which is the active form of the thyroid hormone. Both enter cells via transporter proteins whereby T4 becomes converted to T3 by deiodinases. T3 subsequently binds to thyroid hormone receptors, which then forms heterodimers with the retinoid X receptor (RXR) to induce transcription of a number of target genes with thyroid response elements [3].

Subclinical hypothyroidism (SCH) is a form of thyroid dysfunction that is highly prevalent, with a reported prevalence of 5 to 10% of the population worldwide [4]. SCH is defined by elevated thyroid stimulating hormone (TSH) levels with normal T4 levels. Given that the T4 level is within normal range, patients with SCH usually do not experience hypothyroid symptoms. However, given that studies have shown an increased risk of heart failure associated with SCH whereby the TSH levels are > 10 mIU/L [5], it is recommended that patients with SCH and this extent of TSH elevation receive levothyroxine replacement [6]. Currently, there is no consensus as to whether patients with SCH with a TSH level of < 10mIU/L should be treated with levothyroxine as there is uncertainty regarding the clinical benefits of therapy in these cases. According to some studies, less than 50% of patients with SCH receive hormone replacement [7].

Given that thyroid hormone has been shown to play a role in cancer pathogenesis, further studies assessing the association between thyroid dysfunction and its effects on carcinogenesis are needed. This is particularly true for SCH, where the clinical benefits of levothyroxine treatment are unclear. The objective of this study is therefore to determine the influence of thyroid dysfunction, namely SCH, on cancer incidence and cancer mortality via systematic review of the evidence available to date.

Methods

Data source and searches

A systematic search was performed on Ovid MEDLINE from the date of its inception until November 13th, 2017, combining words related to thyroid and cancer (MeSH and non- MeSH terms) to identify studies of thyroid dysfunction and incident cancer and those examining thyroid dysfunction and mortality in cancer patients (Appendix). A second search was performed using Pubmed from the date of its inception until March 12, 2020 (Appendix). No language limitations were used. In addition, we hand-searched the references of included studies to identify additional relevant studies that were not identified in our electronic search.

Study selection

Inclusion criteria comprised of randomized clinical trials assessing treatment of SCH with levothyroxine treatment, cohort and case-control studies reporting SCH, where the thyroid dysfunction chronologically preceded the cancer incidence or mortality by at least a year to reduce the possibility of including studies with reverse causation, meaning that the cancer or its treatment induced the thyroid dysfunction and not the opposite [8]. Articles where the SCH was primary (not secondary to a medical treatment or procedure) were included. Articles reporting iatrogenic hypothyroidism, thyroid dysfunction during pregnancy or were medication induced were not included since the effect of these causes of SCH on cancer might have a different pathophysiology considering that SCH is commonly induced by an autoimmune mechanism [9, 10]. Exclusion criteria were studies using outdated methods to screen or diagnose thyroid dysfunction or cancer, suspected to have a high risk of bias (i.e. recall) according to the study methods, and studies in which the reference and comparison groups have cancer. Studies were screened by two investigators (J.G. and O.Y.) and discrepancies were resolved by a third investigator (K.B.F.).

Data extraction and quality assessment

Data were extracted using a pilot-tested form that included author, year of publication, study design, study period, sample size (overall and by group), type of population, age of the patients, source of the data or database used for the study, follow-up duration, objective of the study, if anti-thyroperoxidase antibodies (TPOAb) had been measured, effect measure, results (adjusted rates, survival times, and mortality rates), and conclusions.

Quality assessment was performed using the Cochrane tool to assess risk of bias in cohort studies [11] and the Newcastle-Ottawa quality assessment scale for case control studies [12]. Data extraction and quality analyses were completed independently by two authors (J.G. and O.Y.). Disagreements were resolved by discussion with a third independent reviewer (K.B.F.).

Meta-analysis was not possible due to the high heterogeneity in study designs, effect measures reported, and outcomes (cancer incidence, mortality, survival time). All the methods followed the PRISMA guidelines for systematic reviews of the literature [13, 14].

Results

Study selection

A total of 37,073 records were identified (Fig. 1); 36,954 were retrieved from Ovid MEDLINE, 117 were retrieved from Pubmed and 2 were retrieved from other sources [15, 16] (cited in other articles obtained via our search). 36,886 articles were found non-relevant after screening the titles and abstracts. One hundred and eighty-four articles were screened via further assessment of the methods described and subsequently 53 articles were thoroughly reviewed for eligibility. Forty-four articles were excluded for the following reasons: 23 studies identified concurrent thyroid dysfunction and cancer (reverse causation cannot be excluded) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38], 1 study used an outdated method to screen for breast cancer (i.e. thermography) [39], 12 studies did not report SCH [40,41,42,43,44,45,46,47,48,49,50,51], 3 studies have potential high risk of recall bias (no specific tool was applied to assess for risk of recall bias at this point; it was identified by the assessor after reading the methods of the article) [52,53,54], 2 studies included iatrogenic hypothyroidism [55, 56], 2 studies had an inappropriate definition of hypothyroidism (both defined hypothyroidism based on use of thyroid hormone replacement without reporting levels of TSH or T4) [57, 58], and 1 study involved cases and controls with a history of cancer at baseline [59]. A total of 9 studies were included in our systematic review.

Fig. 1
figure 1

PRISMA Flow Diagram showing the selection of studies assessing the association between subclinical hypothyroidism and cancer incident risk and cancer mortality. The flow diagram template was adapted from the 2009 PRISMA statement [14]

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Study characteristics

The 9 included studies comprised of 2 case-control studies [7, 60], 3 retrospective cohort studies [16, 61, 62], and 4 prospective cohort studies [8, 15, 63, 64] (Tables 1 and 2). There were no randomized controlled trials identified that studied the effects of treatment of SCH on the risk of cancer or cancer mortality. One included study assessed the effect of SCH on colorectal cancer [7], one study on breast cancer [8], one study on prostate cancer [60], one on thyroid cancer [61] and one on hepatocellular carcinoma [62]. One study analyzed overall cancer incidence [15], and three studies focused on overall cancer mortality [16, 63, 64]. Two of these studies assessed cancer mortality as a secondary outcome [16, 64].

Table 1 Study characteristics of comparative studies evaluating subclinical hypothyroidism and cancer risk and mortality
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Table 2 Effect estimates of cancer risk and mortality in studies comparing patients with untreated to treated subclinical hypothyroidism or euthyroidism
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Quality assessment

Overall, the cohort studies had good quality (Table 3). The study by Fighera et al. [61] had high risk of bias because the exposed and non-exposed groups did not come from the same source population [61]. Also, it was not clear if SCH was identified prior to the cancer outcome [61]. Two studies did not fully adjust for confounder factors present in the exposed and non-exposed groups [16, 62]. Razvi et al. [16] assessed cancer mortality as a secondary outcome and the variables that were adjusted in the analyses were focused for cardiovascular outcomes. Finally, Pinter et al. [62] assessed the association between thyroid dysfunction and overall survival among patients with hepatocellular carcinoma. Unfortunately, the data collected for these patients lacked information on a number of potential confounders related to patient characteristics, including comorbidities.

Table 3 Quality assessment of cohort studies using the Cochrane Tool to assess the risk of bias
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Case control-studies had very good quality overall (Table 4). The identification of cases involved record linkage only to a primary care database in the study by Boursi et al. [7] without independent validation.

Table 4 Quality assessment of case-control studies using the Newcastle –Ottawa quality assessment scale
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Cancer incidence

The risk of cancer incidence varied depending on the type of cancer studied. Hellevik et al. [15] found no association between hypothyroidism (i.e. inclusion of SCH and overt hypothyroidism) and overall cancer risk (patients with TSH > 3.5 mIU/L, risk of all cancers adjusted hazards ratio [HR]: 0.96; 95% CI: 0.82–1.12). In this study, individual cancer risks for the more common cancers were also assessed (i.e., lung, colon, prostate, and breast cancer). There were no observed increased risks of lung (adjusted HR: 0.87; 95% CI: 0.43–1.74), colon (adjusted HR: 0.95; 95% CI: 0.60–1.50), prostate (adjusted HR: 0.86; 95% CI: 0.55–1.35), and breast cancer (adjusted HR: 0.85; 95% CI: 0.57–1.25) among patients with a TSH level of > 3.5 mIU/L relative to patients with a TSH level within normal range (TSH: 0.5 to 1.4mIU/L). In contrast, Boursi et al. [7] reported a modest increased risk of colorectal cancer in patients with untreated hypothyroidism and SCH without thyroid hormone replacement compared to euthyroid patients (adjusted odds ratio [OR]: 1.16; 95% CI: 1.08–1.24). This study also assessed the effects of levothyroxine treatment for SCH compared to euthyroid patients and found a protective effect of thyroid hormone replacement against colorectal cancer (adjusted OR: 0.92; 95% CI: 0.86–0.98).

Two studies assessed the association between thyroid dysfunction and breast cancer risk. Kuijpens et al. [8] demonstrated that low levels of free T4 (fT4) are an independent risk factor for the development of breast cancer in peri- and post-menopausal women (risk of cancer in patients with low fT4 levels (≤10th percentile which is equivalent to ≤12.5 pmol/L, OR: 2.3; 95% CI: 1.2–4.6). As mentioned above, Hellevik et al. [15] found no increased risk of breast cancer in patients with hypothyroidism.

Only one study assessed the risk of prostate cancer associated with thyroid function. Mondul et al. [60] reported that hypothyroid men (i.e. inclusion of men with SCH and overt hypothyroidism) had a significantly reduced risk of overall prostate cancer compared to euthyroid men (adjusted OR: 0.71; 95% CI: 0.47–1.06 for TSH ≥ 2.2mIU/L). This result conflicted with that found by Hellevik et al. [15] whereby there was no association between the risk of prostate cancer and SCH or hypothyroidism. Finally, Fighera et al. [61] assessed the risk of thyroid cancer associated with thyroid function and reported an association between serum levels of TSH of > 1.64mIU/L and thyroid malignancy (OR: 2.57; 95% CI: 1.41–4.70).

Cancer mortality

Four articles reported cancer-related mortality outcomes [16, 62,63,64]. Pinter et al. [62], assessed overall survival for 667 patients with hepatocellular carcinoma and found that patients with SCH had a slightly decreased survival time compared to euthyroid patients (median overall survival in patients with SCH: 6.1 months; 95% confidence interval [CI]: 0–13.5 versus 10.8 months; 95% CI: 6.5–15.2). Tseng et al. [63], performed a prospective cohort study of 115,746 patients followed in Taiwan with 10 years of follow-up and reported that SCH was independently associated with increased risk of cancer mortality (adjusted relative risk [RR]: 1.51; 95% CI: 1.06–2.15). Their study showed that the risk of cancer mortality among patients with SCH compared to euthyroid patients was more pronounced in bone, skin, and breast cancer. In a sub-analysis from the same study [63] restricted to patients with SCH defined as having TSH levels between 5 and 9.9 mIU/L, the association between SCH and increased cancer-related mortality remained significant (adjusted RR: 1.61; 95% CI: 1.12–2.31). Razvi et al. [16] conducted a retrospective cohort study using the General Practice Research Database (GPRD; since renamed the Clinical Practice Research Datalink), which is representative of patients followed in primary care in the United Kingdom. They determined that patients with SCH between the ages of 40 and 70 years treated with levothyroxine (n = 1634) had lower cancer-related mortality compared to untreated patients with SCH (n = 1459) (adjusted hazard ratio [HR]: 0.59; 95% CI: 0.21–0.88). Similarly, Waring et al. [64] conducted a prospective study using the Osteoporotic Fractures in Men (MrOS) study cohort which is comprised of 1587 men age ≥ 65 years with baseline thyroid function testing. This study assessed the association between thyroid function, including SCH and the risk of mortality over a mean follow-up of 8.3 years. The results of this study found no association between SCH and the risk of cancer-related mortality compared with euthyroid men (relative hazard: 0.88; 95% CI: 0.44–1.74) (Table 2).

Anti-thyroperoxidase antibodies

Only one study addressed the association between TPOAb and the risk of cancer, specifically breast cancer risk. Kuijpens et al. [8] found that TPOAb were more prevalent in women with a previous or current diagnosis of breast cancer (OR: 3.0; 95% CI: 1.41–6.46). However, the presence of TPOAb was not associated with the development of incident in situ breast cancer during follow-up (OR: 1.1; 95% CI: 0.4–2.7) (Table 2).

Discussion

This systematic review assessed the association between SCH and cancer incidence and cancer mortality. We found that SCH was found to be associated with an increased risk of cancer incidence specifically for colorectal and thyroid cancer and cancer-related mortality. A possible protective effect from untreated hypothyroidism against prostate cancer was also found. However, further studies are required to confirm these associations. Despite that thyroid hormone was found to have a role in breast cell proliferation, there is inconsistent evidence that thyroid function affects the risk of breast cancer. One study found no association between thyroid function and breast cancer risk [15]. Only one study showed that low levels of free T4 were an independent risk factor for breast cancer in peri- and post-menopausal women [8]. Few studies assessed the association between the presence of TPOAb and breast cancer risk with controversial results. Therefore, there is insufficient evidence to suggest whether thyroid function or TPOAb levels are associated with breast cancer risk.

Some studies have elucidated potential mechanisms in which thyroid hormone abnormalities can increase the risk of developing certain cancers [9, 65,66,67]. In breast cancer, it has been hypothesized that an alteration in the iodine metabolism in breast tissues could have a role in its pathogenesis since the sodium-iodine symporter is also present in breast tissue [68]. In addition, T3 can activate thyroid hormone receptors in the breast inducing cell proliferation and lobular growth in a similar fashion as estrogens [69]. In colorectal and prostate cancer, T4 and T3 stimulate the membrane receptor integrin αvβ3, which activates some molecular pathways such as PI3-K and MAPK/ERK1/ 2, triggering cell proliferation and angiogenesis [65]. Recent animal studies have found that the use of tetraiodothyroacetic acid (tetrac), which is a thyroid hormone analogue that inhibits the activation of the membrane receptor integrin αvβ3 on human cancer xenografts lead to tumor regression and decreased tumor growth [70,71,72,73].

Specifically for colorectal cancer, there are two additional nuclear receptors with antagonistic effects involved: TRα1 and TRβ1 [66, 67, 74]. The effect on thyroid hormones on TRα1 results in the stimulation of β-catenin producing cellular proliferation in the colon [74]. Conversely, TRβ1 blocks cellular proliferation when activated by thyroid hormones [67]. As such, the lack of TRβ1 expression is associated with malignant transformation in colon cancer [66]. In regards to thyroid cancer, TSH levels has been shown to be an independent clinical predictor of malignancy in thyroid nodules [75] and it is also implicated in the in vitro expression of growth factors associated with cell proliferation and angiogenesis of thyroid cells. These growth factors include the insulin-like growth factor type 1, epidermal growth factor and the vascular endothelial growth factor [55, 76, 77], which could potentially increase the risk of thyroid cancer.

To our knowledge, this is the first systematic review of the literature that analyzes the effect of SCH specifically on the risk of incident cancer and cancer-related mortality. Previous systematic reviews of the literature and meta-analysis focused exclusively on breast cancer [1, 2, 78], and two of these systematic reviews were focused on studying the effect of overt hypothyroidism on breast cancer [1, 78]. Taking into consideration that overt hypothyroidism is almost always treated, these systematic reviews cannot analyze the isolated effect of the hypothyroidism itself on cancer, which constitutes a source of bias from those studies. In addition, it is difficult to determine whether their hypothyroidism persisted throughout follow-up. Furthermore, all of them included only cross-sectional studies [1, 2, 78], which are temporally ambiguous and may be affected by reverse causality whereby the thyroid dysfunction is caused by the development of cancer. As acknowledged by Kuijpens et al. [8], the presence of TPOAb can be concurrent with breast cancer but their presence does not necessarily imply a risk of developing cancer in the future. This observation supports the hypothesis that the presence of concurrent TPOAb and breast cancer in cross-sectional study designs could be more related to reverse causation.

Two large cohort studies found an association between SCH and overall cancer-related mortality. Tseng et al. [63] performed a cohort study involving 115,746 participants and found a 2.06% cancer death rate among individuals with SCH versus 1.31% among euthyroid individuals (p = 0.0051). Consistent with this finding, Razvi et al. [16] performed a cohort study using the GPRD, involving 4735 individuals and found a 41% decreased risk of cancer related mortality among younger individuals aged 40 to 70 years who received treatment for SCH compared to untreated individuals with SCH. There was no statistical significant difference in the risk of cancer related mortality among older individuals aged over 70 years with treated versus untreated SCH. This finding is consistent with the study conducted by Waring et al. [64] which utilized data from the MrOS cohort which consists of men ≥65 years. In this study, 1248 euthyroid men were compared with 89 men with subclinical hypothyroidism and there was no association between subclinical hypothyroidism and cancer mortality. These findings suggest that treatment of SCH or being in a euthyroid state may decrease cancer-related mortality among younger individuals. However, these studies are limited by the lack of adjustment for confounding by indication as patients with known cancer may be less likely to receive treatment for SCH if they have a poorer prognosis compared to a cancer patient who is less ill. Furthermore, the findings by Razvi et al. [16] and Waring et al. [64] were from a sub-analysis and the studies did not adjust for all potential confounders in the association between SCH and cancer-related mortality.

Our study has several strengths. We included cohort studies [8, 15, 16, 61,62,63,64] and case-control studies [7, 60], excluding cross-sectional studies to address the issue of reverse causality. This systematic review included studies that assessed the risk of various cancers, including the most common cancers such as colorectal, lung, prostate, and breast, and overall cancer risk. In addition, some of the included studies were large, with sample sizes larger than 20,000 patients [7, 15, 63]. All studies had at least 5 years of follow-up, an important consideration for studies of cancer, and potential reverse causality was addressed by excluding studies whereby the cancer diagnosis was made within 12 months of exposure assessment. The quality analysis demonstrated that the included studies had a low risk of bias. Thus, the results of the included studies provided reliable evidence for the association between thyroid dysfunction and cancer incidence and related mortality.

This systematic review had some limitations. There was a high heterogeneity of the studies, especially in terms of different risk measures and outcomes reported. Consequently, we were unable to perform a meta-analysis. Moreover, some of the studies combined individuals with SCH and overt hypothyroidism [7, 8, 15, 60,61,62], decreasing the strength to the conclusions on the role of SCH in cancer pathogenesis. Furthermore, the study by Pinter et al. [62] diagnosed SCH on the basis of T4 levels, which is different from the definition of SCH used in the other studies. As such, there was heterogeneity in the definition of SCH between studies. Finally, there may be publication bias whereby studies with null findings are not published.

Conclusions

In summary, SCH may be associated with an increased risk of colorectal and thyroid cancer. Treatment of SCH may be associated with a decreased risk of cancer-related mortality among younger individuals. Overall, there is a paucity of studies addressing the association between SCH and incident cancer risk and cancer mortality. Given the difference of cancer pathophysiology in various cancers, further studies are needed to assess the association between untreated SCH and the risk of different individual cancers.