Investigation of thyroid dysfunction is more likely in patients with high psychological morbidity

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1 Family Practice 2012; 29: doi: /fampra/cmr059 Advance Access published on 2 September 2011 Ó The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com. Investigation of thyroid dysfunction is more likely in patients with high psychological morbidity H Bould a, *,y, V Panicker b,y, D Kessler c, C Durant d, G Lewis a, C Dayan e and J Evans a a Academic Unit of Psychiatry, School of Social and Community Medicine, University of Bristol, Oakfield Grove, Bristol, UK, b Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Western Australia, Australia, c Unit of Primary Care, School of Social and Community Medicine, d Psychopharmacology Unit, University of Bristol, Bristol, UK and e Centre for Endocrine & Diabetes Science, Cardiff University School of Medicine, Cardiff, UK. *Correspondence to H Bould, Academic Unit of Psychiatry, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; helen.bould@bris.ac.uk y Both are first authors for this paper as they contributed equally to this work. Received 20 May 2011; Revised 14 July 2011; Accepted 24 July Background. Mild or subclinical hypothyroidism [raised thyroid-stimulating hormone (TSH) but normal free thyroxine (T4)] affects 5 10% of adults. Symptoms are non-specific and TSH levels are needed for diagnosis. Objectives. We explore the relationship between thyroid function and psychological distress and investigate the usefulness of an expert-designed Thyroid Symptom Questionnaire (TSQ) in identifying hypothyroidism. Methods. DEPTH (DEPression and THyroid) is a cross-sectional study of 325 patients recruited from general practices in Bristol, for whom thyroid function tests were requested by the GP. Subjects completed the TSQ, General Health Questionnaire (GHQ-12) and Patient Health Questionnaire (PHQ) and had blood tests for TSH and free T4. Results. The mean age was 45.7 years; 252 subjects (78%) were female; median TSH was 1.6. Psychological morbidity in this population is high: 54.2% have a GHQ-12 score >3, indicating psychological distress. We found no relationship between TSH and psychological distress [adjusted odds ratio 1.02 (95% confidence interval ), P = 0.78]. The prevalence of hypothyroidism was 6.2% (95% confidence interval %). We found no evidence of an unadjusted association between TSQ score and subclinical hypothyroidism [adjusted odds ratio of 1.09 (95% confidence interval ), P = 0.23]. Conclusions. Those referred for thyroid function tests, although no more likely than others to have hypothyroidism, have high rates of psychological distress. When mild (subclinical) hypothyroidism is detected in patients with psychological distress, it is important that GPs are aware that this is likely to be coincidental rather than causal and offer appropriate treatment. Keywords. Depression, hypothyroid, thyroid, psychological distress. Introduction Mild or subclinical hypothyroidism [raised thyroidstimulating hormone (TSH) but normal free thyroxine (T4)] is common in the general population especially among women, affecting 5 10% of the adult population. 1 Around 10 million tests of thyroid function are performed annually in the UK. 2 Lethargy and low mood are often considered to be symptoms of hypothyroidism. However, a health survey in Colorado (n = ) found that such symptoms were very poorly predictive of hypothyroidism 1 and a large community-based study from Norway (n = ) failed to demonstrate any increase in prevalence of depression in subjects with a raised TSH and normal free T4. 3 The current consensus is that symptoms of hypothyroidism are non-specific, and recent UK guidelines conclude that an underactive thyroid cannot be diagnosed accurately on symptoms alone, 4 although they do not offer advice as to when thyroid function tests should be requested for healthy adult patients. In this study, we looked at the relationship between thyroid function and psychological distress. We also investigated whether an expert-designed questionnaire 163

2 164 Family Practice The International Journal for Research in Primary Care about symptoms of hypothyroidism would help GPs to identify patients with hypothyroidism. We hypothesized that we would confirm the lack of association between psychological distress and thyroid function. We hypothesized that the questionnaire, which has been showntobecorrelatedwithfreet4inpatientsontreatment, would be able to distinguish those with hypothyroidism from those without as it includes multiple symptoms. Methods DEPTH (DEPression and THyroid) is a cross-sectional study of patients recruited from general practices in Bristol. It was established to examine associations between serum thyroid hormone parameters, genetic polymorphisms associated with thyroid function and psychological morbidity. 5,6 Between July 2005 and July 2007, patients aged years from four participating general practices, in whom thyroid function testing had been requested by the managing clinician, were approached to be in the study by the practice phlebotomists. Subjects taking thyroxine, triiodothyronine, carbimazole, propylthiouracil, lithium or amiodarone were excluded to eliminate patients with known thyroid dysfunction or on medication known to alter thyroid function. Participants were asked to complete a four-page questionnaire booklet, which included the 12 questions General Health Questionnaire (GHQ-12). Each item was scored in the normal way (0, 0, 1 and 1), with the total beingthesumofalltheitems.weusedacut-offof>3 to indicate psychological distress. 7,8 They also completed the Patient Health Questionnaire (PHQ) (a nine-question self-assessment validated in determining depressive disorders). This was scored in the standard way, using the sum of the 0 3 scores for each item, and a cut-off of >10 was used to indicate possible cases of depression. 9,10 They were also asked to complete a measure of thyroid symptomatology ( TSQ ). This measure comprises 12 questions, presented in the same format as the GHQ- 12, which relate to the symptoms most commonly reported by patients with hypothyroidism responding to an article in the newsletter of the British Thyroid Foundation (national patient support charity). 11 It is scored in the same way as the GHQ-12, and higher scores indicate more symptoms. It has been used as an outcome measure and shown to be significantly different between patients on thyroxine and controls. 12 A negative linear relationship between TSQ score and free T4 level has been found among patients being treated for hypothyroidism. 13 The GP was unaware of the TSQ score when making the referral for thyroid function testing. Serum TSH and free T4 were measured on a serum sample; measurement was performed by chemiluminescent immunometric assay on the Immulite 2000 (Siemens). The laboratory reference ranges were mu/l for TSH and pmol/l for free T4. We investigated the relationship between psychological distress and thyroid function using logistic regression to compare GHQ and PHQ scores by thyroid status (hypothyroid or euthyroid). Hypothyroidism was defined as TSH >4.00 mu/l; euthyroidism was defined as TSH mu/l. We also investigated whether there was an association with psychological distress across the whole range (including the normal range) of thyroid parameters. We used linear regression to investigate the relationship between GHQ and PHQ scores and log TSH and log free T4 levels. Linear regression was used in order to increase the power to detect any difference that there might be across the range of thyroid function; log transformation was used in order to give a normal distribution of TSH and free T4. We investigated the relationship between symptoms of thyroid disease and thyroid status by using logistic regression to investigate the relationship between Thyroid Symptom Questionnaire score and thyroid status (hypothyroid or euthyroid). We also investigated whether there was an association with symptoms of hypothyroidism across the whole range (including the normal range) of thyroid parameters. We used linear regression to investigate this relationship between the thyroid questionnaire (TSQ) and log TSH and log free T4. This increased the power to detect any difference that might not have been identified in the analyses based on thyroid status. Results Over the study period, 704 subjects were referred for thyroid function tests. Of these, 70 did not consent to take part in the study and 179 were excluded as they did not meet the predefined inclusion criteria. Of the remaining 455 patients, 130 did not complete all the questionnaires, 1 had no documented gender and 1 had no documented TSH. Of the subjects with complete data, 252 (78%) were female and the mean age was 45.7 years (male 47.3 years and female 45.2 years). The mean TSH was 1.89 (SD 1.42) and the median TSH was 1.6. The overall rate of subclinical hypothyroidism (TSH >4.00 mu/l and free T4 within the normal range) was 6.2% (20/325 subjects) [95% confidence interval (CI) %]. The mean TSQ score was 15.7 (SD 6.38), with a range of The prevalence of psychological distress in this population was high: 176 subjects (54.2%) had a GHQ-12 score >3 and 179 (55.1%) scored >10 on the PHQ-9, making them possible cases of depression. We found no evidence of a relationship between TSH as a binary variable ( ; >4.0) and GHQ score [odds ratio 1.02 (95% CI ), P =0.79]or

3 PHQ score [odds ratio 1.02 (95% CI ), P = 0.64]. We found no evidence of a relationship between psychological distress or depression and thyroid parameters when extending the analyses to include values of TSH and free T4 across the normal range. This lack of association between GHQ and log TSH persisted following adjustment for age and sex and clustering by GP practice [beta-coefficient (95% CI to 0.021), P = 0.59], as did the lack of association between GHQ and log free T4 [ (95% CI to 0.004), P =0.41]. We found no evidence in support of our hypothesis that there would be an association between the measure of thyroid symptomatology (TSQ) and TSH as a binary variable, with an odds ratio of 1.06 (95% CI ), P = 0.85 (Table 1). When we adjusted for age, sex, GP practice and GHQ score, there was some suggestion that there might be a relationship between TSH and TSQ score. There was no evidence in support of our hypothesis when extending the analyses to include the relationship across the normal range using continuous log TSH [0.002 (95% CI to 0.022), P = 0.88] or continuous log free T4 (Table 2). We also calculated the prevalence of hypothyroidism using the cut-off of TSH >4.50 mu/l, as used in a large American population study as there is no recent large UK study for comparison. Using this cutoff, 13/325 (4.0%; 95% CI: %) of subjects were hypothyroid. TABLE 1 Discussion Main findings The rate of hypothyroidism in our study of 4.0% using the American definition was very similar to that found an unselected community sample in the USA of 5.1% (95% CI 4.6 to 5.7%) in the white non-hispanic population. 14 The prevalence of psychological distress (GHQ score >3) (54.2%) was more than twice as high as the 19% prevalence found in a study of 2328 consecutive unselected general practice attenders in Bristol. 15 The rate of PHQ depression in our study (55.1%) was also very high in comparison with the 16% found in the primary care attenders in USA. 9 This suggests that those sent for thyroid function testing have higher rates of psychological distress and depression than average GP attenders. We found no evidence of a relationship between psychological distress or depression and thyroid function, as measured by TSH and free T4. We also found no evidence of a relationship between the measure of thyroid symptomatology (TSQ) designed to pick up symptoms of hypothyroidism, and thyroid function, before adjusting for psychological distress. This, along with the low rates of hypothyroidism found by GPs in this study, gives further weight to earlier findings regarding the difficulty of diagnosing hypothyroidism by symptoms alone. 1 The clinical indications for referral for thyroid function testing were not recorded in our study. However, Logistic regression analysis of the relationship between thyroid status as a binary outcome measure (euthyroid: TSH ; hypothyroid: TSH >4.0) and TSQ, GHQ and PHQ Hypothyroid/euthyroid: odds ratio (95% CI, P value) TSQ GHQ PHQ Unadjusted 1.06 ( ), P = (0.90, 1.11), P = ( ), P = 0.84 Adjusted a 1.09 ( ), P = ( ), P = ( ), P = 0.64 Adjusted b 1.21 ( ), P = 0.05 a Adjusted for age and sex; clustered by GP practice. b Adjusted for age, sex and GHQ score; clustered by GP practice. TABLE 2 Psychological morbidity in patients investigated for thyroid dysfunction Linear regression analysis of relationships between log TSH and log free T4 as continuous variables, and TSQ, GHQ and PHQ 165 TSQ GHQ PHQ log TSH: odds ratio (95% CI, P value) Unadjusted ( to 0.022), P = ( to 0.015), P = ( to 0.003), P = 0.17 Adjusted a ( to 0.027), P = ( to 0.021), P = ( to 0.004), P = 0.28 Adjusted b ( to 0.043), P = 0.28 log free T4: odds ratio (95% CI, P value) Unadjusted ( to 0.006), P = ( to 0.007), P= ( to 0.003), P = 0.51 Adjusted a ( to 0.004), P = ( to 0.004), P= ( to 0.002), P = 0.36 Adjusted b ( to 0.008), P = 0.42 a Adjusted for age and sex; clustered by GP practice. b Adjusted for age, sex and GHQ; clustered by GP practice.

4 166 Family Practice The International Journal for Research in Primary Care the findings suggest that those referred for thyroid function tests have high rates of psychological distress. We speculate that there are several possible explanations for this association. For example, GPs may wish to exclude any easily treated cause of fatigue or may be fearful of being accused of negligence should they miss a diagnosis of hypothyroidism. Alternatively, GPs may be using the test as a means of engaging the patient who presents with psychological distress and demonstrating that they are not dismissing somatic symptoms. Normal test results may then provide the opportunity to begin a discussion about psychological problems. Another possibility is that the GP may believe that low mood or related symptoms can be a symptom of hypothyroidism. Despite being a widely held and taught belief, 16 there is in fact strong evidence that this is not so. 1,3 This could lead to causal misattribution for those patients in whom a borderline or mildly elevated TSH is identified. GPs might treat the hypothyroidism, in the belief that this is the cause of the low mood, and might not return to explore the possibility of other causes of psychological distress. This in turn might reinforce patterns of somatic attribution in patients with psychological disorders. It might also be associated with under-recognition of psychological disorders in this group and the high proportion of dissatisfied patients on thyroxine. 17,18 Limitations These findings must be interpreted cautiously as there are a number of important limitations. Firstly, the relatively small sample size means that our results may be consistent with a modestly increased likelihood of identifying hypothyroidism in those sent by their GP for testing compared to in a randomly selected sample. Furthermore, we have no data on the nature of the consultation that prompted the test. By excluding those with known thyroid disease and those taking medication known to affect thyroid function, we assume that the reason for testing was to exclude thyroid disease as a cause of presenting symptoms, either to reassure the patient or because the GP thought that this may be a possible cause of the symptoms. We also have no data on subsequent treatment of the patients studied, so our thoughts about the possible outcomes are speculative. Implications for practice and future research Further research is needed to clarify reasons for requesting thyroid function tests among GPs and the results and benefits of performing them. It would also be useful to establish whether undertaking a test of thyroid function is beneficial in the reattribution of physical symptoms to psychological causes. Clearer guidance needs to be given on whom, and when, to test for thyroid function, given that few symptoms have any predictive value, and patients are likely to be started on thyroxine when they are still asymptomatic. 19 It is also important to disseminate the knowledge that a large body of research has found no evidence that undiagnosed hypothyroidism is a risk factor for depression, and remind GPs to keep psychological morbidity in mind even if hypothyroidism is diagnosed. Acknowledgements All biochemical testing was performed at the Bristol Royal Infirmary, Bristol, UK. Declaration Funding: The Depth study was conducted with funding from the Avon and Wiltshire Mental Health Partnership NHS Trust. Grant number AWP 428. Ethical approval: Bath Research Ethics Committee REC reference number 05/Q2001/84. 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