DOI: 10.1530/eje.1.02124
European Journal of Endocrinology, Vol 154, Issue 4, 501-510
Copyright © 2006 by Society of the European Journal of Endocrinology
Quality of life in patients with benign thyroid disorders. A review
Torquil Watt1,2,
Mogens Groenvold2,
Åse Krogh Rasmussen1,
Steen Joop Bonnema3,
Laszlo Hegedüs3,
Jakob Bue Bjorner4 and
Ulla Feldt-Rasmussen1
1 Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark, 2 Institute of Public Health, University of Copenhagen, Denmark, 3 Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark and 4 QualityMetric Inc., Lincoln, Rhode Island, USA
(Correspondence should be addressed to T Watt at Department of Endocrinology, Copenhagen University Hospital; Email: T.Watt{at}pubhealth.ku.dk)
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Abstract
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The importance of patient-reported outcomes such as health-related quality of life (HRQL) in clinical research is increasingly acknowledged. In order to yield valid results, the measurement properties of HRQL questionnaires must be thoroughly investigated. One aspect of such a validation process is the demonstration of content validity, i.e. that the questionnaire covers all relevant aspects. We review studies reporting on consequences of thyroid disorders and present the frequency of identified aspects, both overall HRQL issues and classical thyroid symptoms, in order to evaluate which issues are relevant for patients with thyroid diseases. Furthermore, existing questionnaires for thyroid patients are reviewed. A systematic search was performed in the Medline, Cinahl and Psycinfo databases and the reference lists of the relevant articles were hand-searched. Seventy-five relevant studies were identified. According to these studies, patients with untreated thyroid disease suffer from a wide range of symptoms and have major impairment in most areas of HRQL. Furthermore, the studies indicate that impairments in HRQL are also frequent in the long term. Six HRQL questionnaires for thyroid patients were identified. Generally, data supporting the validity of these questionnaires were sparse. According to the available literature, the quality of life of thyroid patients is substantially impaired over a wide range of aspects of HRQL in the untreated phase and continues to be so in many patients also in the long term. Studies systematically exploring the relative importance of these various aspects to thyroid patients are lacking, as is a comprehensive, validated thyroid-specific HRQL questionnaire.
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Background
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The evaluation of health-related quality of life (HRQL) implies evaluations of the impact of a disease and its treatment on all relevant dimensions of the patient’s life. HRQL measurements usually comprise aspects of physical, mental and social well-being and function. Generally, HRQL is best rated by the patients themselves, usually by means of standardized questionnaires. There are two main types of HRQL measures: disease-specific and generic. Disease-specific questionnaires concern issues of particular relevance for patients with a specific medical condition, whereas generic instruments (e.g. SF-36 or EQ-5D) measure aspects common to most patients. Disease-specific measures often demonstrate greater sensitivity than generic measures, while the latter allow for comparison across diseases and treatments and with scores obtained from the general population. A combination of disease-specific and generic measures is generally advocated because each provides complementary information (1, 2). The importance of involving HRQL aspects in the evaluation of thyroid patients is increasingly recognized (3–5). Several features of thyroid diseases motivate this. First of all, benign thyroid disorders are rarely life threatening, and thus their treatment mainly deals with optimizing the quality of life of the patients. Furthermore, the diseases are common and occur at all ages. Moreover, since many thyroid diseases can be treated in several ways (e.g. radioiodine, medical treatment or surgery), exact knowledge of the impact of each treatment modality on the HRQL of the patients is important. To date, no trial has compared validly the HRQL outcome of different treatments and there is still a well-documented lack of consensus regarding choice of treatment (6–15). The detrimental impact of acute thyroid disease on HRQL is obvious and has been documented in several studies (16–18). However, it is the clinical experience of many endocrinologists that some patients have residual complaints despite adequate medical treatment. Application of valid HRQL measurements is crucial for proper clarification of a number of ongoing debates regarding management of thyroid disorders. For example: do patients with subclinical or mild thyroid dysfunction have symptoms and are they fully alleviated by treatment? Is treatment of hypothyroidism with a combination of thyroxine (T4) and triiodothyronine (T3) superior to T4 alone? Does block-replacement therapy as compared with titration therapy of hyperthyroidism result in improved HRQL? Some of the conflicting data regarding these and numerous other questions might be caused by lack of appropriate outcome measures. To ensure valid assessment of a particular patient population, a number of requirements in relation to HRQL instruments have to be documented (19–23) (Table 1
presents the terminology used). First, HRQL deals with the patients’ experience of the disease and its impact on their lives, and is therefore best assessed by the patients themselves. Secondly, the instrument should cover all aspects of HRQL that are relevant to the patients (content validity). Thirdly, empirical tests should evaluate whether the questionnaire measures what is intended (construct validity). For HRQL measures, where no external ‘gold standard’ exists, several approaches to this subject have been implemented: qualitative, cognitive studies exploring patients’ understanding of the items or quantitative studies investigating the underlying measurement model (Table 1). Finally, appropriate measurement properties, including sensitivity and responsiveness, have to be demonstrated; that is, there must be an acceptable ratio between true variance compared with variance due to random error (reliability), the measure must be sensitive to clinically relevant differences and it must be responsive to relevant changes with time. Our review concerns content validity. We present a systematic literature review the purpose of which is to describe complaints and consequences of thyroid disorders found in previous studies.
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The literature search
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A Medline search on the Medline Subheadings (MeSH) thyroid diseases AND (quality of life OR questionnaires OR psychology OR health status OR psychiatric status rating scales OR brief psychiatric rating scale OR severity of illness index OR patient satisfaction OR psychometrics OR depression OR anxiety OR symptoms [title]) NOT carcinoma, identified 1015 references. The search was repeated in the Cinahl and Psycinfo databases, identifying a total of 2033 references. The abstracts were reviewed and possibly relevant articles reviewed in full length. Further references were identified through the reference lists of these articles. Thus, 2094 references were screened. We also consulted leading thyroid textbooks and included issues listed within these. Seventy-five of the reviewed references were selected, based on the following criteria: the study population (index patients) should be thyroid patients, and the paper should report on patient-experienced consequences of the thyroid disease. Consequences should be documented either as a reported frequency or a higher score on an HRQL scale compared with individuals without thyroid disease. This means that technical or ‘objective’ measures like ‘digit span test’ and ‘ankle reflex relaxation time’ without a subjective equivalent, or reported scale-scores without appropriate control groups were not included. In addition, all measures of symptoms and HRQL impact of thyroid disorders used in these studies were identified.
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Identified HRQL aspects and symptoms relevant to thyroid patients
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The frequencies of the identified issues in untreated patients are presented in Table 2 whereas results from follow-up studies are presented in Table 3.
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Table 2 Quality of life aspects associated with untreated thyroid disease. Prevalences are given in percent, and where no prevalence is available, the presence of the issue is marked with +.
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Table 3 Long-term evaluation of quality of life aspects associated with treated thyroid disease. Prevalences are given in percent, and where no prevalence is available, the presence of the issue is marked with +.
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From Table 2
, it is evident that patients with untreated thyroid disease suffer from a wide range of symptoms and have major impairment in most areas of HRQL. For example, 22–35% of goitre patients, 18–66% of hyperthyroid patients, 7–99% of patients with thyroid associated ophthalmopathy (TAO) and 16–51% of hypothyroid patients experience limitations in usual activities during the untreated phase of their disease. These rather wide ranges are due to different ways of measuring the concepts in the studies, differences in patient populations as well as our categorization of the issues; e.g. the term ‘limitations in usual activities’ covers a wide range of different activities and includes scales from various questionnaires. There is evidence of impaired general health perception in all patient groups; for patients with goitre, hyperthyroidism and TAO this is evidenced by lower scores on scales measuring general health perception compared with scores in normal controls, and thus no percentage is available, whereas for hypothyroid patients dichotomous variables document that 53–100% of patients conceive their health as impaired. Thus, a substantial proportion of thyroid patients experience limitations in their usual activities, perceive their general health as impaired and have social and emotional impairment. Cognitive problems are also prevalent, as is fatigue. Cosmetic concern is also common for all thyroid patients. However, no study has reported on cognitive dysfunction in patients with goitre and only one study has reported on fatigue in patients with TAO. Generally, patients with goitre have been the least studied. All the classical symptoms of hyperthyroidism appear to be consistently prevalent in hyperthyroid patients, whereas the classical symptoms of hypothyroidism are more variably present in hypothyroid patients. The latter may, in part, reflect the wide spectrum of clinical presentation of hypothyroidism, with a high frequency of subclinical dysfunction.
From the data presented in Table 3 it appears that persistent HRQL impairment is very frequent among patients with both hyper- and hypothyroidism. About half of the patients have reduced overall quality of life and general health, limitations in usual activities as well as social and emotional problems. Two-thirds are fatigued and about one-third are anxious and have cognitive as well as sexual problems. Furthermore, classical symptoms of hypothyroidism are very frequent among previously hyperthyroid patients and about one-third have persistent hyperthyroid symptoms. However, the association with actual thyroid status has not been addressed in this study. Hypo- or hyperthyroid symptoms have not been examined in long-term follow-up studies of hypothyroid patients and no study has examined the long-term HRQL outcome of goitre treatment. However, there is a general lack of detailed clinical description of the phenotypes of many of the patient populations in these studies and therefore some of the patients classified as hypothyroid may, in fact, be treated goitre patients.
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Available thyroid HRQL questionnaires
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We have identified six thyroid HRQL questionnaires (24–29). In addition, various symptom indices (30–43), most of which were physician administered, and one satisfaction-questionnaire (29) have been published. The present review will focus on the six HRQL questionnaires, but results from studies using the symptom indices are presented in Tables 2 and 3. All the identified HRQL questionnaires target particular thyroid conditions and are not applicable across conditions. No questionnaire measuring the symptoms or impact of non-toxic goitre has been identified.
Hyperthyroidism questionnaires
The Hyperthyroidism Complaint Questionnaire (HCQ) measures residual complaints and psychosocial sequelae in patients treated for hyperthyroidism (24). Thirty-one dichotomous (present/not present) items are summarized in one overall score. Of these, eleven items concern physical symptoms, six are about emotional distress, six evaluate fatigue, and three concern cognitive function whereas existential problems, sleeping problems, anxiety, sexual function and social function are covered by one item each. The development was based on interviews with a small sample of patients with hyperthyroidism, but no documentation of this has been published. Data from a questionnaire study of 303 formerly hyperthyroid patients were analysed for the purpose of item-reduction (i.e. eliminating items with poor measurement properties or yielding little additional information) yet all items were retained based on an argument that they all contributed to the internal consistency of the scale. Cronbach’s 
(cf. Table 1) was 0.93. Correlations between individual items and the overall score were generally low, some as low as 0.21, suggesting problems with uni-dimensionality (i.e. the assumption that all items in a scale measure an underlying construct, and can therefore be summarized into one overall scale). Thus, the appropriateness of collapsing all items, despite the dissimilarity of the covered issues, into one single score is unknown. There was a significant relationship between scores on the HCQ and the degree of self-reported thyroid dysfunction but no further description of the validity of the instrument has been provided. The HCQ has not been used in any subsequent study and apparently is available in Dutch only.
Questionnaires for patients with thyroid-associated ophthalmopathy
The Graves’ Ophthalmopathy Quality of Life Questionnaire (GOQOL) is a disease-specific HRQL instrument for patients with TAO (25, 44, 45). The development was based on a review of existing eye HRQL measures, as well as open-ended questionnaires from 24 patients. It has been pretested in 8 patients. A detailed description of these content validity studies has not been published. The GOQOL consists of 16 items sub-divided into two scales: ‘visual functioning’ and ‘appearance’. Subsequent studies comprising 70–164 well-described patients have shown excellent reliability (25, 44), supported its construct validity (25, 44, 45), and demonstrated good responsiveness (45). According to the developers, the GOQOL is available in six languages (46). However, to our knowledge, the only published validation study regards the Dutch version.
Tehrani and colleagues (26) have also developed a 90-item TAO-specific HRQL instrument in German. Its development was based on contributions from clinicians and was without any patient input. In a study of 104 patients undergoing surgery, the developers found Cronbach’s as low as 0.63 for the 90-item total score. Given the large number of items, this is a low reliability. No construct validation has been performed, but the low internal consistency reliability suggests lack of uni-dimensionality. In validity analyses, the score did not correlate with clinical variables. Thus, these results do not lend strong support for the reliability and validity of this measure.
Hypothyroidism questionnaires
The Chronic Thyroid Questionnaire (CTQ) is a hypothyroidism and patient-specific HRQL questionnaire. It consists of 104 items, each representing a specific complaint, covering four domains: ‘physical complaints’, ‘mood and emotions’, ‘energy and general well-being’, and ‘cognitive complaints’ (27, 47). The development of the CTQ was quite thorough. Based on a literature review, a list of symptoms or problems related to hypothyroidism, potentially responsive to treatment and likely to influence the quality of life of the patients was generated (27). This list was expanded through interviews with endocrinologists and patients. The scoring of the CTQ is unusual: of the 104 complaints, each patient identifies applicable items and rates the degree of discomfort represented by these items. Thus, for a patient with two of the 104 complaints, the instrument consists of two items, whereas a patient with 22 complaints rates 22 items. This approach increases the potential sensitivity of the measure to improvements in the individual patient, but it makes between-patient comparisons and interpretations of what is actually measured difficult and new complaints arising from intervention are ignored in longitudinal studies. We could not identify any studies validating the resulting questionnaire.
The Thyroid Symptom Questionnaire (TSQ) consists of twelve items: six items on cognitive complaints, five items on physical symptoms and one item on fatigue, summarized in one overall score (28). The items were selected on the basis of patient responses to a notice in the British Thyroid Foundation newsletter, inviting patients to tell about persisting complaints despite replacement therapy with L-thyroxine. Moderate correlations with the generic HRQL questionnaire General Health Questionnaire (GHQ-12) were found, but no other evidence of validity has been presented.
Recently, a new hypothyroidism-specific HRQL questionnaire has been developed: the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) (29). ThyDQoL is an 18-item questionnaire measuring the impact of hypothyroidism on various domains of HRQL: overall quality of life (two items), limitations in usual activities (six items), social function (four items), fatigue (two items), emotional well-being (two items), sexual function, cosmetic complaints, weight problems, and bodily discomfort (one item each). Items are scored individually in a two-step procedure: both impact and importance of the items are rated, and the item score is derived by the multiplication of these two ratings. No multi-item scales are constructed. Problems with this approach are the reduced inter-individual comparability of the measure and the sensitivity to a confounding effect of coping. Content validity was ensured by interviews with 38 hypothyroid patients. However, a quarter of the patients had hypothyroidism secondary to treatment of other thyroid disorders. No information regarding the time since diagnosis or the present thyroid status of the interviewees is provided; all patients, except one, were undergoing treatment with L-thyroxine. Measurement properties (dimensionality, reliability, construct validity, sensitivity, and responsiveness) have not yet been evaluated.
Comparison of the questionnaires
The relationship between the identified issues and the thyroid questionnaires is presented in Table 4. The CTQ includes items relating to a wide range of the identified issues. However, since these assessments are based on one single item, the reliability is probably low for each issue. The well-documented GOQOL questionnaire, which is concerned very specifically with the limitations and social/cosmetic consequences of TAO, covers only three of the identified issues, but since each issue is assessed by multiple items, reliability is probably high. Questionnaires like the HCQ and TSQ produce an overall score, but if the set of issues covered are multidimensional, one overall score might not be the best way of summarizing results. For example, the HCQ combines existential problems and hand tremor into the overall scale score. Regarding HCQ, the lack of items tapping hypothyroid symptoms renders it less suitable for follow-up studies, considering the high frequency of these symptoms among patients treated for hyperthyroidism, as presented in Table 3. None of the hypothyroidism questionnaires consider hyperthyroid symptoms, which might also (albeit not yet studied) be present as a result of the treatment of these patients. This is probably especially important if the measure were to be used for evaluation of the presently intensely discussed issue of T3-supplementation in hypothyroid patients, in view of the expected higher degree of fluctuations in the serum-concentration of T3. The ThyDQoL is concerned with more generic aspects of HRQL but, like the CTQ, it is prone to random error due to the use of only single items.
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Table 4 Relationship between HRQL aspects and the available thyroid HRQL questionnaires. If the questionnaire has items relating to the issue it is marked by •.
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Conclusion
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According to the available literature, HRQL impairment in patients with benign thyroid disorders is prevalent, both in the untreated phase and in the long term. A wide range of problems has been reported, covering both generic and specific aspects of HRQL. However, many of the studies are small and use unvalidated measures. Most of them lack a thorough clinical description of the patients and include patients covering a wide range of phenotypes and aetiological dissimilarities. No available questionnaire has the potential to cover all aspects relevant to patients in longitudinal studies, where individual patients may shift from one thyroid state to another as a result of natural history or treatment. The available questionnaires lack documented coverage of relevant HRQL issues and, apart from the GOQOL, they all lack a thorough validation. With this review, we have identified the possibly relevant issues reported in the literature. These data are valuable as a basis for the development of HRQL questionnaires possessing content validity. The next step towards valid measures of disease-specific HRQL in thyroid patients would be to test the relevance of the issues presented here among samples of experts as well as properly characterized thyroid patients.
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Acknowledgements
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We wish to express our gratitude to chief physician, Professor Peder Charles PhD for inspiration and to Marianne Klose MD for valuable discussions. This study has been supported by grants from the Danish Medical Research Council, the Agnes and Knut Mørk’s Foundation, the Aase and Ejnar Danielsen’s Foundation and the Else and Mogens Wedell-Wedellsborg’s Foundation.
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Received 19 December 2005
Accepted 13 January 2006
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