Subclinical thyroid dysfunction symptoms in older adults: cross-sectional study in UK primary care

Deborah McCahon; M Sayeed Haque; James Parle; FD Richard Hobbs; Lesley M Roberts

doi:10.3399/bjgp20X708065

Abstract

Background Subclinical thyroid dysfunction — abnormal serum thyrotrophin (thyroid-stimulating hormone; TSH) concentrations with normal free thyroxine (FT4) is common in older people. It remains unclear whether individuals with subclinical serum status experience an increased symptom profile.

Aim To compare the prevalence of those symptoms typically associated with overt thyroid dysfunction in older individuals with a subclinical and euthyroid serum profile.

Design and setting Cross-sectional study, nested within the Birmingham Elderly Thyroid Study (BETS); from 19 UK general practices.

Method Adults living in a community setting (aged ≥65 years), without overt thyroid dysfunction or associated treatment, self-reported the presence or absence of 18 symptoms (while serum result naïve). Serum concentrations of TSH and FT4 were measured to establish thyroid status.

Results A total of 2870 individuals were screened: 2703 (94%) were categorised as euthyroid (normal), 29 (1%) subclinically hyperthyroid, and 138 (5%) subclinically hypothyroid. Symptoms were common in all groups. No significant differences in the prevalence of individual symptoms were observed between the euthyroid and subclinically hypothyroid groups nor in comparison with the subclinically hyperthyroid group. Multivariate logistic regression analysis failed to reveal an association between individual or multiple symptoms and subclinical status.

Conclusion Findings suggest that subclinical thyroid dysfunction does not confer a symptom burden in older individuals and support adherence to guidelines in the non-treatment of subclinical thyroid dysfunction. GPs may use the findings to reassure older people presenting with symptoms that subclinical thyroid dysfunction is an unlikely explanation. The presence of persistently abnormal TSH concentrations may be linked to long-term risks of cardiovascular disease, especially atrial fibrillation, but whether this should prompt treatment and whether such treatment alters vascular outcomes is unknown.

INTRODUCTION

Subclinical thyroid dysfunction is characterised by thyroid-stimulating hormone (TSH) concentrations outside the stated reference range accompanied by free thyroxine (FT4) concentrations within the reference range.¹ Thyroid function tests are commonly requested for older adults in primary care either routinely or in response to presentation of symptoms, and identify large numbers of individuals with subclinical thyroid dysfunction.²^–⁶

The authors have previously demonstrated low levels of progression (<0.5%) of subclinical thyroid dysfunction to overt disease in older individuals over a period of up to 5 years, supporting guidelines that indicate treatment of subclinical dysfunction is not necessary to prevent progression.⁷ However, a better understanding of whether subclinical thyroid dysfunction itself is associated with any symptom excess, which may be amenable to intervention, is still required to guide clinical management of this condition.

A previous community-based population study demonstrated symptoms to be poorly predictive of TSH,⁸ though other research suggests a higher prevalence of symptoms in individuals with subclinical thyroid dysfunction.⁹^–¹¹ However, these studies have significant limitations in their application to primary care or community-based populations being derived from endocrine clinic populations.⁹^–¹¹ Additionally, these data relate to middle-aged populations, and all studies have mean ages in the range 43–47 years, where the overlap of symptoms attributable to older age and thyroid dysfunction are likely to be less widespread and hence more discriminatory.

Therefore, there continue to be calls for further research in subclinical thyroid dysfunction owing to poor understanding of how to best manage this condition.¹²^,¹³ This study aimed to build on previous work and definitively explore whether subclinical thyroid dysfunction in older adults confers additional symptom burden, and also whether specific symptom clusters are associated with subclinical thyroid dysfunction rather than being typical of older-age presentations. Such understanding may enable reductions in the cost of repeat testing in this patient group and also advise further trial outcomes.

METHOD

Recruitment and participants

This cross-sectional survey was nested within a longitudinal study of thyroid function in an established cohort, the Birmingham Elderly Thyroid Study (BETS) cohort, of 5881 individuals living in a community setting, aged ≥65 years at initial screen, from 19 practices representative of the UK.³^,⁷^,¹⁴^,¹⁵ GPs confirmed eligibility and suitability of follow-up for participants of the original BETS cohort as previously reported.⁷ Individuals were excluded if they were no longer registered with the practice, were deceased, had a diagnosis of overt thyroid dysfunction, had received treatment for thyroid dysfunction, or were judged to be inappropriate for contact, for example, recently bereaved or terminally ill.

Subclinical thyroid dysfunction is a biochemical diagnosis that is common in older age. Though older patients with this diagnosis may report symptoms like those found in overt thyroid dysfunction, it is unknown whether subclinical thyroid dysfunction itself is associated with symptom excess. This large population-based survey demonstrates that subclinical thyroid dysfunction in the older population does not confer additional symptom burden. Findings support current guidance for not treating subclinical thyroid dysfunction in older individuals and provide an evidence base for GPs to use in discussion with patients experiencing symptoms who have mildly abnormal thyroid function test results.

How this fits in

Eligible participants received a postal invitation letter, reply slip, and freepost envelope addressed to the research office. Patients interested in participating were sent a symptoms questionnaire with a request to complete it before attending the research clinic for venepuncture. At the clinic, consent was obtained and a blood sample for thyroid function testing acquired. Samples were collected in plastic vacuette 4 ml serum separator clot activator tubes. Research clinics were conducted over a period of 19 months with symptom details being provided concurrent to individual patient appointments.

Evaluation of symptoms

Participants self-reported the presence or absence of 18 classic symptoms of overt hypo- and hyperthyroidism by questionnaire. The questionnaire was a supplemented version of the Colorado Hypothyroid Symptom survey, a validated questionnaire for assessment of symptoms of thyroid hormone deficiency.¹⁶^,¹⁷ The format of the original survey was preserved; however, six hyperthyroid symptoms identified from the literature were added.¹⁸^,¹⁹ The final questionnaire comprised: six hyperthyroid symptoms (excessive perspiration, tremor, frequent palpitation, sensitivity to heat, fast thinking, weight loss), nine hypothyroid symptoms (hoarse voice, deep tone of voice, dry skin, puffy eyes, muscle cramps, constipation, sensitivity to cold, slow thinking, and weight gain) and three symptoms (poor memory, weak muscles, and lethargy) that can be associated with both hyper- and hypothyroidism.

The questionnaire was piloted by 10 volunteers aged ≥65 years to assess user understanding and experience. Refinements were made based on the feedback obtained.

Thyroid function testing

Thyroid function testing was performed by the Regional Endocrine Laboratory at University Hospital Birmingham, National Health Service Foundation Trust (UHB). Serum TSH and FT4 concentrations were determined for all individuals. If a serum TSH concentration above or below the limits of the reference range was identified, serum free tri-iodothyronine (FT3) was also measured. Serum TSH, FT4, and FT3 concentrations were measured by electrochemiluminescent immunoassays using the Roche E170 (Roche Diagnostics, Burgess Hill, UK). The TSH assay was calibrated against the second international reference preparation 80/558. The associated inter-assay coefficient of variation for TSH was 1.5% (range 0.5–33.0 mIU/L), FT4 2.0–2.5% (9.0–66.0 pmol/L), and FT3 2.0–3.5% (4.0–21.0 pmol/L). The lower limit of reporting for the TSH assay was 0.02 mIU/L and the manufacturer’s quoted mean functional sensitivity was 0.014 mIU/L. Algorithms relating to current local clinical practice and laboratory reference criteria were used to classify thyroid status (Table 1).

View this table:

Table 1.

Classification of thyroid status based on TSH and FT4 concentration

Demographic and lifestyle data

Age and deprivation score were calculated from the participants’ date of birth and postcode, respectively. The Index of Multiple Deprivation 2004 (IMD) was used as a proxy measure of socioeconomic status with higher IMD scores indicating greater deprivation.²⁰ Primary care medical records were reviewed to collect data on medical history and concomitant prescription medication pre-specified as likely to be associated with category of thyroid function, with reported symptoms, or to interfere with tests of thyroid function. Participants self-reported smoking status.

Statistical analysis

T-tests and χ² tests were used to compare the participants with subclinical hypo- and hyperthyroidism with euthyroid participants with respect to patient characteristics, for example, demographics, medical history, concomitant disease, and prescription medication. Univariate logistic regression techniques were used to establish unadjusted odds ratios representing the odds of subclinical hypo- or hyperthyroidism in participants reporting presence of individual symptoms, divided by the odds of subclinical hypo- or hyperthyroidism in participants reporting absence of the symptom.

Multivariate logistic regression analysis was then undertaken to further examine the relationship between individual symptoms and thyroid function category, and establish the likelihood of subclinical thyroid dysfunction after controlling for the effects of the covariates: age, sex, deprivation score, smoking status, concomitant disease, and prescription medication. To enable further exploration of the relationship between category of thyroid function and presence of multiple symptoms, uni- and multivariate logistic regression was undertaken to establish the change in odds of a subclinical hypo- or hyperthyroid result as the total number of symptoms reported increased, with and without all other factors being equal.

RESULTS

A total of 4447 individuals were invited to participate in the follow-up screening study (Figure 1). Participants were excluded from the original cohort (n = 5881) if during the 5-year interval period they had died (n = 501), deregistered from participating practice (n = 453), or become unsuitable for contact, as judged by the responsible GP (n = 381). Individuals who had been diagnosed with, or received treatment for, thyroid dysfunction were also excluded (n = 99). Overall, 66% (2936/4447) of those invited attended a research clinic and consented to participate. In total, 2870 (65%) were fully screened and included in the analysis. Reasons for exclusion from the analysis were missing thyroid function test results or missing symptom data (n = 13), and newly identified treatment for thyroid dysfunction (n = 53).

Figure 1.

Study flow diagram.

Description of the subgroups

A total of 2703 participants (94%, N = 2870) were classified as euthyroid, 138 (5%) as subclinically hypothyroid, and 29 (1%) subclinically hyperthyroid. The euthyroid group were slightly younger than the subclinically hyperthyroid group (mean age 76.8 years versus 79.1 years respectively, P = 0.02) and the subclinically hypothyroid group (mean age 76.8 years versus 77.7 years respectively, P = 0.05). The three groups were similar with respect to sex and deprivation score. A significantly higher proportion of the euthyroid group compared with the subclinically hypothyroid group had a previous diagnosis of pulmonary disease (12.9% versus 3.6%, P = 0.03) but there were no statistically significant differences between the euthyroid and subclinical groups with respect to any other concomitant disease or prescription medication (data not shown).

Symptom expression and subclinical hypothyroidism

There were no significant differences between the euthyroid and subclinical hypothyroid groups with respect to presence of individual or multiple hypothyroid symptoms (Table 2). Unadjusted and adjusted odds ratios representing the odds of subclinically hypothyroid status in participants reporting symptom presence, divided by the odds of subclinical status in participants reporting symptom absence, are reported. Visual exploration of the distribution of total number of symptoms reported by the euthyroid and subclinical hypothyroid groups did not demonstrate a clear relationship between multiple symptoms and thyroid function category (Figure 2).

View this table:

Table 2.

Prevalence of hypothyroid symptoms and risk factors for subclinical hypothyroidism

Figure 2.

Total number of hypothyroid symptoms reported by the euthyroid and subclinical hypothyroid groups.

Symptom expression and subclinical hyperthyroidism

For completeness, the prevalence of individual symptoms and total number of symptoms reported in the euthyroid and subclinical hyperthyroid groups are reported in Table 3, though it is acknowledged that a low number of identified subclinically hyperthyroid cases restricts interpretation. No significant differences between the groups were observed with respect to presence of any individual hyperthyroid symptom or total number of symptoms reported. Visual exploration of the distribution of total number of symptoms reported by the groups also failed to demonstrate a clear relationship between total number of symptoms reported and thyroid function category (Figure 3).

View this table:

Table 3.

Prevalence of hyperthyroid symptoms and risk factors for subclinical hyperthyroidism

Figure 3.

Total number of hyperthyroid symptoms reported by the euthyroid and subclinical hyperthyroid groups.

DISCUSSION

Summary

This population survey suggests that symptoms commonly associated with overt thyroid dysfunction are relatively prevalent in older individuals living in a community; however, This study did not demonstrate a greater prevalence of any established symptoms in those with subclinical thyroid dysfunction compared with euthyroid controls. Furthermore, presence of multiple symptoms were not associated with subclinical thyroid dysfunction.

Strengths and limitations

The strengths of this study are the large number of unselected older individuals investigated and the simultaneous and detailed evaluation of thyroid function, self-reported symptoms, concomitant disease, and prescription medication. Evidence-based development of the symptom questionnaire was employed to ensure that the most relevant and sensitive symptoms, reflecting a variety of metabolic processes and involving a range of organ systems, were selected and captured. Furthermore, all participants completed the questionnaire before thyroid function testing so that their responses were not influenced by knowledge of their thyroid status.

This study did not evaluate other clinical effects, such as altered cardiac morphology, which may be attributed to subclinical thyroid dysfunction. Further evidence in such impacts is needed in relation to unselected populations to fully determine any consequence of living with marginally altered TSH or FT4.

Comparison with existing literature

This study failed to identify symptoms that alone, or in combination, are associated with subclinical thyroid dysfunction in older individuals. This contrasts with previous studies,⁹^–¹¹ which identified an increased symptom burden, but whose findings are likely to be influenced by the recruitment from secondary care endocrine settings and smaller cohorts.

It is also noted that direct comparison with these studies is not supported by the much younger populations recruited, with the study presented here being the first significant screening study to explore symptom profiles in an older cohort, that is, the general population who are most likely to receive thyroid function testing and be identified with subclinical thyroid states.

These findings support those of a smaller retrospective case-note study conducted in a primary care geriatric service that found no significant difference in the frequencies of any signs or symptoms associated with hypothyroidism between subclinical and euthyroid individuals.²¹

Implications for research and practice

Overall findings suggest that subclinical thyroid dysfunction does not confer a symptom burden in older individuals living in a community. This lack of association further supports adherence to guidelines in the non-treatment of subclinical thyroid dysfunction and provides an evidence base for GPs to use in discussion of symptoms and associated likelihood of subclinical dysfunction explaining these in their older patients.

In older individuals the diagnosis of subclinical thyroid dysfunction should be based on laboratory results indicating persistently (over a period of 3–6 months to effectively exclude acute non-thyroidal and drug-related causes) abnormal TSH levels alongside FT4 levels within reference range.²²

In terms of management of subclinical thyroid dysfunction, the findings of a recent meta-analysis and systematic review incorporating data from 21 trials does not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism. Results of this review consistently demonstrated no association of therapy with improved outcomes.²³

The evidence to guide management of subclinical hyperthyroidism remains inconclusive with few interventional studies showing benefit in clinically important outcomes. Since epidemiological data demonstrate an increased rate of atrial fibrillation, heart failure, and coronary heart disease with subclinical hyperthyroidism, current European Thyroid Association guidelines recommend that treatment of subclinical hyperthyroidism be considered in older patients with cardiovascular disease, diabetes, and renal failure to avoid longer-term risks.¹⁵^,²⁴^,²⁵ National Institute for Health and Care Excellence guidelines on the assessment and management of thyroid disease were published in November 2019.²⁶ Considering this evidence, in the presence of persistently low levels of TSH (especially levels <0.1 mIU/L) alongside pre-existing cardiovascular disease and increased cardiovascular risk factors, GPs may want to discuss, with their patients, the possible long-term risks of subclinical hyperthyroidism in order to determine whether to intervene or abstain from treatment; however, such discussions will be limited by uncertainty on whether this association is clinically significant and the lack of any evidence on the effectiveness of treatment for reducing any risks associated with subclinical hyperthyroidism. Treatment of all grades of hyperthyroidism should most appropriately be instituted by endocrine specialists.²⁷

Further large-scale, longitudinal research is required to establish the clinical significance of the aetiology of subclinical hyperthyroidism and the impact of treatment on cardiovascular endpoints to guide management strategies.

Acknowledgments

The authors would like to thank the participants and GPs, the general practice staff that facilitated collection of data, Peter Lewis, Penelope Clark, and the staff at the Regional Endocrine Laboratory who conducted the thyroid function testing. The co-investigators for BETS I and/or BETS II were Sue Wilson, Jayne Franklyn, Michael Gammage, Roger Holder, Andrea Roalfe, and Helen Pattison.

Notes

Funding

This study was funded by the National Institute for Health Research (NIHR) via the National School for Primary Care Research. Deborah McCahon was also supported via funding from the Primary Care Research Trust (PCRT) and the Midland Research Practices Consortium (MidReC). FD Richard Hobbs acknowledges his part-funding from the NIHR School for Primary Care Research, the NIHR Collaboration for Leadership in Health Research and Care (CLARHC) Oxford, the NIHR Oxford Biomedical Research Centre (BRC UHT), and the NIHR Oxford Medtech and In-Vitro Diagnostics Co-operative (MIC). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Ethical approval

Ethical approval for the study was obtained from the North Staffordshire Local Research Ethics Committee (reference number: 07/H1204/136; approval date: 19 December 2007) before commencement of the research.

Provenance

Freely submitted; externally peer reviewed.

Competing interests

The authors have declared no competing interests.

Contributors

Deborah McCahon and Lesley Roberts contributed equally to the authorship of this paper.

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Received April 9, 2019.
Revision requested May 22, 2019.
Accepted June 21, 2019.

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[1] 1.↵
Beckett G,
Toft AD
(2003) First line thyroid function tests — TSH alone is not enough. Clin Endocrinol 58(1):20–21.
OpenUrl CrossRef PubMed

[2] Beckett G,

[3] Toft AD

[4] 2.↵
Evans TC
(2003) Thyroid disease. Prim Care 30(4):625–640.
OpenUrl PubMed

[5] Evans TC

[6] 3.↵
Wilson S,
Parle JV,
Roberts LM,
et al.
(2006) Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey. J Clin Endocrinol Metab 91(12):4809–4816.
OpenUrl CrossRef PubMed

[7] Wilson S,

[8] Parle JV,

[9] Roberts LM,

[10] et al.

[11] 4.
Evered DC,
Ormston BJ,
Smith PA,
et al.
(1973) Grades of hypothyroidism. Br Med J 1(5854):657–662.
OpenUrl Abstract/FREE Full Text

[12] Evered DC,

[13] Ormston BJ,

[14] Smith PA,

[15] et al.

[16] 5.
Fatourechi V
(2009) Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 84(1):65–67.
OpenUrl CrossRef PubMed

[17] Fatourechi V

[18] 6.↵
Allport J,
McCahon D,
Hobbs FDR,
Roberts LM
(2013) Why are GPs treating subclinical hypothyroidism? Case note review and GP survey. Prim Health Care Res Dev 14(2):175–184.
OpenUrl

[19] Allport J,

[20] McCahon D,

[21] Hobbs FDR,

[22] Roberts LM

[23] 7.↵
Roberts L,
McCahon D,
Johnson O,
et al.
(2018) Stability of thyroid function in older adults: the Birmingham Elderly Thyroid Study. Br J Gen Pract, DOI: https://doi.org/10.3399/bjgp18X698861.

[24] Roberts L,

[25] McCahon D,

[26] Johnson O,

[27] et al.

[28] 8.↵
Parle JV,
Franklyn JA,
Cross KW,
et al.
(1991) Assessment of a screening process to detect patients aged 60 years and over at high risk of hypothyroidism. Br J Gen Pract 41(351):414–416.
OpenUrl Abstract/FREE Full Text

[29] Parle JV,

[30] Franklyn JA,

[31] Cross KW,

[32] et al.

[33] 9.↵
Reuters VS,
Buescu A,
Reis FA,
et al.
(2006) Clinical and muscular evaluation in patients with subclinical hypothyroidism. [In Portuguese]. Arq Bras Endocrinol Metabol 50(3):523–531.
OpenUrl CrossRef PubMed

[34] Reuters VS,

[35] Buescu A,

[36] Reis FA,

[37] et al.

[38] 10.
Vigário P,
Teixeira P,
Reuters V,
et al.
(2009) Perceived health status of women with overt and subclinical hypothyroidism. Med Princ Pract 18(4):317–322.
OpenUrl PubMed

[39] Vigário P,

[40] Teixeira P,

[41] Reuters V,

[42] et al.

[43] 11.↵
Biondi B,
Palmieri EA,
Fazio S,
et al.
(2000) Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 85(12):4701–4705.
OpenUrl CrossRef PubMed

[44] Biondi B,

[45] Palmieri EA,

[46] Fazio S,

[47] et al.

[48] 12.↵
Cooper DS,
Biondi B
(2012) Subclinical thyroid disease. Lancet 379(9821):1142–1154.
OpenUrl CrossRef PubMed

[49] Cooper DS,

[50] Biondi B

[51] 13.↵
Ruggeri RM,
Trimarchi F,
Biondi B
(2017) Management of endocrine disease: l-thyroxine replacement therapy in the frail elderly: a challenge in clinical practice. Eur J Endocrinol 177(4):R199–R217.
OpenUrl Abstract/FREE Full Text

[52] Ruggeri RM,

[53] Trimarchi F,

[54] Biondi B

[55] 14.↵
Roberts LM,
Pattison H,
Roalfe A,
et al.
(2006) Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 145(8):573–581.
OpenUrl CrossRef PubMed

[56] Roberts LM,

[57] Pattison H,

[58] Roalfe A,

[59] et al.

[60] 15.↵
Gammage MD,
Parle JV,
Holder RL,
et al.
(2007) Association between serum free thyroxine concentration and atrial fibrillation. Arch Intern Med 167(9):928–934.
OpenUrl CrossRef PubMed

[61] Gammage MD,

[62] Parle JV,

[63] Holder RL,

[64] et al.

[65] 16.↵
Canaris GJ,
Steiner JF,
Ridgway EC
(1997) Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med 12(9):544–550.
OpenUrl CrossRef PubMed

[66] Canaris GJ,

[67] Steiner JF,

[68] Ridgway EC

[69] 17.↵
Canaris GJ,
Manowitz NR,
Mayor G,
Ridgway EC
(2000) The Colorado thyroid disease prevalence study. Arch Intern Med 160(4):526–534.
OpenUrl CrossRef PubMed

[70] Canaris GJ,

[71] Manowitz NR,

[72] Mayor G,

[73] Ridgway EC

[74] 18.↵
Crooks J,
Murray IP,
Wayne E
(1959) Statistical methods applied to the clinical diagnosis of thyrotoxicosis. Q J Med 28(110):211–234.
OpenUrl PubMed

[75] Crooks J,

[76] Murray IP,

[77] Wayne E

[78] 19.↵
Klein I,
Trzepacz PT,
Roberts M,
Levey GS
(1988) Symptom rating scale for assessing hyperthyroidism. Arch Intern Med 148(2):387–390.
OpenUrl CrossRef PubMed

[79] Klein I,

[80] Trzepacz PT,

[81] Roberts M,

[82] Levey GS

[83] 20.↵
Noble M,
Wright G,
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Subclinical thyroid dysfunction symptoms in older adults: cross-sectional study in UK primary care

Abstract

INTRODUCTION

METHOD

Recruitment and participants

Evaluation of symptoms

Thyroid function testing

Demographic and lifestyle data

Statistical analysis

RESULTS

Description of the subgroups

Symptom expression and subclinical hypothyroidism

Symptom expression and subclinical hyperthyroidism

DISCUSSION

Summary

Strengths and limitations

Comparison with existing literature

Implications for research and practice

Acknowledgments

Notes

Funding

Ethical approval

Provenance

Competing interests

Contributors

Discuss this article

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