Lesley Roberts

Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction

Context The relationship between subclinical thyroid dysfunction and disorders of cognition and mood is unclear. Contribution The authors studied 5868 general practice patients 65 years of age or older with a detailed medical history, thyroid tests, and standardized tests of cognition and mood. They found no association between subclinical thyroid dysfunction and anxiety, depression, or cognitive impairment in prediction models that adjusted for age, sex, social deprivation, medications, and comorbid diseases. Implications This study provides good evidence that subclinical thyroid dysfunction is not related to disorders of cognition and mood in older persons. The Editors The advent of automated sensitive assays for thyroid hormones and thyroid-stimulating hormone (TSH) and the increasingly widespread use of such tests have led to a substantial increase in the identification of mild thyroid dysfunction, especially in elderly patients. This, in turn, has led many physicians to treat subclinical (also known as mild) dysfunction. However, the clinical significance of mild thyroid dysfunction remains uncertain, and evidence on the efficacy or safety of treatment is limited (13). Subclinical thyroid dysfunction is characterized by an abnormal serum level of TSH in association with normal serum levels of thyroid hormone. Subclinical hypothyroidism is defined biochemically as an increased serum TSH level with a normal serum free thyroxine (T4) level, and subclinical hyperthyroidism as a decreased serum TSH level with normal levels of free T4 and free triiodothyronine. One postulated consequence of minor abnormalities of thyroid function, especially subclinical hypothyroidism, is an effect on cognitive functioning and mood. The association between overt hypothyroidism and cognitive dysfunction is well established (4, 5), although more recent evidence suggests that this association is confounded by mood (6). Whether a similar association exists with mild or subclinical hypothyroidism is uncertain. Some studies report no association between subclinical hypothyroidism and measures of cognition (5, 79), whereas others have identified between-group differences in cognitive functioning when patients with subclinical hypothyroidism were compared with euthyroid controls (10). A recent study (11) with a case-matched design demonstrated no differences in cognitive functioning between subclinically hypothyroid and euthyroid patients, although the criteria for defining subclinical hypothyroidism were atypical (an upper TSH limit of 3.5 mIU/L) and external validity was reduced by the exclusion of patients with serious illness or a history of cardiovascular disease. Associations between subclinical hypothyroidism and depression have also been described (6, 10, 12, 13), but many of these studies were based on small samples and were subject to selection and recruitment bias. An association between subclinical dysfunction and anxiety has also been demonstrated (14). Nevertheless, the largest reported study to date (30589 patients) (15) showed no association between subclinical hypothyroidism and depression or anxiety, findings that have been reported elsewhere (9, 11). A recent systematic review that aimed to determine any association between thyroid dysfunction and cognitive function and mood concluded that evidence is insufficient to confirm or refute an association with subclinical hypothyroidism or subclinical hyperthyroidism (1). We used standard diagnostic criteria to examine these possible associations in a large community-based cohort of persons 65 years of age or older (the Birmingham Elderly Thyroid Study). We recorded measures of thyroid function, cognitive functioning, depression, and anxiety and report on associations after controlling for the confounding effects of comorbid illness and medication use. Methods Recruitment and Participants Participants were recruited from 20 primary care practices in central England. The sample was selected to encompass patients from a range of socioeconomic backgrounds. To maximize generalizability to the primary care population, all patients who did not have an active diagnosis of thyroid disease were included. Patients were excluded if they had received antithyroid treatment within the previous 12 months or were currently receiving treatment for a thyroid disorder, or if their family physician deemed that contact was inappropriate (for example, because of recent bereavement or inability to give informed consent). All other patients 65 years of age or older were eligible and were invited to participate by letter. Because the uptake rate was only 14.6% among the first 699 patients older than 85 years of age who were contacted, recruitment was subsequently limited to patients 65 to 84 years of age (inclusive) for the remainder of the study, although previously contacted patients who were older than 84 years of age remained eligible. Patients who accepted the invitation received an appointment with a research or trained primary care nurse at their usual primary care practice or their home. Ethical approval was obtained from the Multi-Centre Research Ethics Committee (Scotland), and local approval was confirmed before commencement of the study. Written informed consent was obtained from all participants. Measurements and Sample Size Patients were placed under no restrictions on eating or medication use before serum samples were obtained for testing. Serum samples were obtained during normal office hours and were treated and collected according to the practices usual procedure for blood collection. Serum TSH and free T4 were measured by using a chemiluminescent immunoassay (Adiva Centaur [Bayer Diagnostics, Newbury, United Kingdom]) in the Regional Endocrine Laboratory of the University Hospital Birmingham National Health Service Trust. Interassay coefficients of variation were 4.4% to 10.9% over 0.41 to 24.5 mIU/L for the TSH assay and 8.2% to 9.8% over 8.2 to 54.9 pmol/L for the free T4 assay. The laboratory reference range was 0.4 to 5.5 mIU/L for TSH and 9.0 to 20.0 pmol/L for free T4. Serum free triiodothyronine was measured by chemiluminescent assay (Avida Centaur) in all cases in which the TSH level was less than 0.4 mIU/L or a within-range TSH level was accompanied by an elevated free T4 level. The reference range for the triiodothyronine assay was 3.5 to 6.5 pmol/L, and the interassay coefficient of variation was 4.2% to 6.9% over 4.0 to 16.0 pmol/L. The Index of Multiple Deprivation 2004 (16) was calculated for each participant on the basis of his or her postal code. This proxy measure of socioeconomic deprivation encompasses 7 domains: income; employment; health and disability; education, skills, and training; barriers to housing and services; living environment; and crime. All major current or previous medical diagnoses and current drug therapies were recorded on the basis of patient reporting and validation from primary care records. Diagnoses were categorized in line with recognized disease groupings. Medications that are known to interact with thyroid function, anxiety, depression, or cognition were coded under generic headings. Cognition was assessed by using the Folstein Mini-Mental State Examination (MMSE) (17), which is widely used to determine cognitive status in clinical and research settings, and the Middlesex Elderly Assessment of Mental State (MEAMS) (18), which was developed as a screening test to detect gross impairment of specific cognitive skills in elderly persons and systematically surveys the major areas of cognitive performance. Aspects covered by MEAMS include orientation, learning, memory, numeracy, perception, attention, and language skills. Both tests comprise a range of tasks that all elderly persons without cognitive impairment should be able to complete, regardless of intelligence. Possible scores on the MMSE range from 0 to 30. Subtests in MEAMS can be used alone, or a combined score can be produced (range, 0 to 12). In both tests, higher scores indicate less dysfunction. Nurses were trained in the administration of all tests to the required standard. Symptoms of depression and anxiety were self-reported by using the Hospital Anxiety and Depression Scale (HADS) (19), which consists of 7 items for depression and 7 for anxiety. Each item is scored from 0 to 3, and the maximum total score on each scale is 21. Scores of 8 to 10 indicate mild disorder, scores of 11 to 14 indicate moderate disorder, and scores of 15 or greater indicate severe anxiety or depression. Assuming a prevalence of 9% for subclinical hypothyroidism and 6% for subclinical hyperthyroidism, a planned sample size of 6200 patients was sufficient to detect a difference between the subclinical and euthyroid groups of 0.4 unit (SD, 2.2) in MMSE score (20) and 0.7 unit (SD, 3.6) in HADS score (21), with 90% power and 5% significance. Data Management and Coding Participants were classified according to serum free thyroid hormone and TSH levels into 1 of 5 categories: overt hypothyroidism, subclinical hypothyroidism, euthyroidism, subclinical hyperthyroidism, and overt hyperthyroidism. Euthyroidism was further subdivided into quartiles before analysis. Participants who could not be categorized on the basis of thyroid function results were excluded from analyses. Table 1 shows details of criteria for classification. Table 1. Values Used to Categorize Thyroid Status In cases where only 1 item per scale was missing on the HADS data, the missing value was imputed by using mean scores. Missing values on MEAMS and MMSE were not imputed because of the heterogeneity of individual tests (which measured distinct aspects of cognitive processing) and the fact that some processes are assessed by only 1 or 2 items. Participants for whom data were incomplete were excluded from corresponding analyses. Statistical Analysis Analyses were done by using SAS software, version 9.1 (SAS Institute, Inc., Cary, North C

Cost effectiveness of initial endoscopy for dyspepsia in patients over age 50 years : a randomised controlled trial in primary care

BACKGROUND Dyspepsia can be managed by initial endoscopy and treatment based on endoscopic findings, or by empirical prescribing. We aimed to determine the cost effectiveness of initial endoscopy compared with usual management in patients with dyspepsia over age 50 years presenting to their primary care physician. METHODS 422 patients were recruited and randomly assigned to initial endoscopy or usual management. Primary outcomes were effect of treatment on dyspepsia symptoms and cost effectiveness. Secondary outcomes were quality of life and patient satisfaction. Total costs were calculated from individual patients use of resources with unit costs applied from national data. Statistical analysis of uncertainty on incremental cost-effectiveness ratio (ICER) was done along with a sensitivity analysis on unit costs with cost-effectiveness acceptability curves. FINDINGS In the 12 months following recruitment, 213 (84%) patients had an endoscopy compared with 75 (41%) controls. Initial endoscopy resulted in a significant improvement in symptom score (p=0.03), and quality of life pain dimension (p=0.03), and a 48% reduction in the use of proton pump inhibitors (p=0.005). The ICER was Pound Sterling1728 (UK Pound Sterling) per patient symptom-free at 12 months. The ICER was very sensitive to the cost of endoscopy, and could be reduced to Pound Sterling165 if the unit cost of this procedure fell from Pound Sterling246 to Pound Sterling100. INTERPRETATION Initial endoscopy in dyspeptic patients over age 50 might be a cost-effective intervention.

Randomised controlled trials in primary care: case study

Editorial by Thomas Although over 90% of patient contacts within the NHS occur in primary care, many of the interventions used in this setting remain unproved.1 The relevance of research undertaken in secondary or tertiary care to general practice is questionable, and more research based in primary care is needed.2 Increasing research in primary care will inevitably increase demand for randomised controlled trials in this setting. Some of the trials will be of health service interventions (pragmatic trials),3 where the focus lies in assessing the cost effectiveness of an intervention rather than efficacy or safety. The difficulties experienced in doing randomised controlled trials in primary care have been reported4–6 and are not restricted to this setting. 7 8 We discuss some of the issues that must be considered when conducting and interpreting the results of trials in primary care using examples generated during a trial of the management of dyspepsia (box). #### Birmingham open access endoscopy study The study aimed to evaluate the effectiveness of two management strategies for patients presenting in primary care with symptoms of dyspepsia. Two randomised controlled trials were conducted concurrently, with eligibility being determined by the patients age at presentation. Randomisation was done at the individual patient level by using sealed opaque, sequentially numbered envelopes during a primary care consultation for dyspepsia. ##### Initial endoscopy trial Eligible patients— 50 years of age or older. Intervention— Referred for open access endoscopy. ##### Test and endoscopy trial Eligible patients— Under 50 years. Intervention —Tested for Helicobacter pylori antibodies with Helisal near patient test. Patients with positive results referred for open access endoscopy; those with negative results received symptomatic treatment only. Control arms (both trials)— Managed according to “usual practice” excluding open access endoscopy. This included antacids, H2 receptor antagonists, proton pump inhibitors, outpatient gastroenterology referral, facilitated or direct access endoscopy (for example, vetted by consultant), …

A Randomized Controlled Trial of the Effect of Thyroxine Replacement on Cognitive Function in Community-Living Elderly Subjects with Subclinical Hypothyroidism: The Birmingham Elderly Thyroid Study

CONTEXT Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit. OBJECTIVE Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function. DESIGN AND SETTING We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care. PATIENTS Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening. INTERVENTION T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr). MAIN OUTCOME MEASURES Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered. RESULTS Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months. CONCLUSIONS This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

Systematic review: the effectiveness of hypnotherapy in the management of irritable bowel syndrome

To systematically review the literature evaluating hypnotherapy in the management of irritable bowel syndrome (IBS).

Randomised controlled trial of Helicobacter pylori testing and endoscopy for dyspepsia in primary care

Abstract Objective: To determine the cost effectiveness of a strategy of near patient Helicobacter pylori testing and endoscopy for managing dyspepsia. Design: Randomised controlled trial. Setting: 31 UK primary care centres. Participants: 478 patients under 50 years old presenting with dyspepsia of longer than four weeks duration. Interventions: Near patient testing for H pylori and open access endoscopy for patients with positive results. Control patients received acid suppressing drugs or specialist referral at general practitioners discretion. Main outcome measures: Cost effectiveness based on improvement in symptoms and use of resources at 12 months; quality of life. Results: 40% of the study group tested positive for H pylori. 45% of study patients had endoscopy compared with 25% of controls. More peptic ulcers were diagnosed in the study group (7.4% v 2.1%, P=0.011). Paired comparison of symptom scores and quality of life showed that all patients improved over time with no difference between study and control groups. No significant differences were observed in rates of prescribing, consultation, or referral. Costs were higher in the study group (£367.85 v £253.16 per patient). Conclusions: The test and endoscopy strategy increases endoscopy rates over usual practice in primary care. The additional cost is not offset by benefits in symptom relief or quality of life. What is already known on this topic Patients younger than 50 without H pylori infection are unlikely to have treatable disease detected at endoscopy Such patients can be managed by acid suppression and reassurance alone Test and endoscopy (referral of patients testing positive for H pyloriin primary care) has been recommended as a way to reduce endoscopic workload What this paper adds Applying a test and endoscopy strategy increased the endoscopy referral rate from 25% to 40% The strategy produced no significant differences in symptoms or quality of life compared with usual management The increased costs of this strategy cannot be justified

The Effects of Exercise upon Symptoms and Quality of Life in Patients Diagnosed with Irritable Bowel Syndrome : A Randomised Controlled Trial

While it seems intuitively appealing to promote participation in regular exercise in the management of irritable bowel syndrome, limited randomised controlled trial evidence exists to support this recommendation. We examined the feasibility and effects of an exercise intervention upon quality of life and irritable bowel symptoms using a randomised controlled trial methodology. Patients with a clinically confirmed diagnosis of irritable bowel syndrome according to Rome II criteria were randomised to either an exercise consultation intervention or usual care for 12 weeks. Outcomes included irritable bowel specific quality of life, symptoms (total symptoms, constipation, diarrhoea and pain) and exercise participation. The recruitment rate of eligible patients identified from hospital records was 18.3% (56/305). Analyses revealed no differences in quality life scores between groups at 12-week follow-up. The exercise group reported significantly improved symptoms of constipation (mean difference=10.9, 95 % CI= -20.1, -1.6) compared to usual care at follow-up. The intervention group participated in significantly more exercise than usual care at follow-up (mean difference=21.6, 95% CI=9.4, 33.8). Recruitment of eligible patients into this study was possible but rates were low. Findings highlight the possibility that exercise may be an effective intervention for symptom management in patients with irritable bowel syndrome; this may be particularly the case for constipation predominant patients.

Evaluation of the Birmingham IBS symptom questionnaire

BackgroundIrritable Bowel Syndrome (IBS) is a chronic/common condition that causes a significant effect on the individual (reduced quality of life), society (time lost off work) and health services. Comparison of studies evaluating the management of IBS has been hindered by the lack of a widely adopted validated symptom score. The aim of this study was to develop and validate a disease specific score to measure the symptoms of patients with IBS.MethodsA self-administered 14-item symptom questionnaire (based on Rome II criteria) was mailed to 533 persons included in a prevalence study of IBS. The reliability of each underlying dimension identified was measured by Cronbachs α. Validity was assessed by comparing symptom scores with concurrent IBS specific quality of life (QoL) scores. Reproducibility was measured by the test-retest method and responsiveness measured by effect size.Results379 (71%) questionnaires were returned. The underlying dimensions identified were pain, diarrhoea and constipation. Cronbachs α was 0.74 for pain, 0.90 for diarrhoea and 0.79 for constipation. Pain and diarrhoea dimensions had good external validity (r = -0.3 to -0.6), constipation dimension had moderate external validity (r = -0.2 to -0.3). All dimensions were reproducible (ICCs 0.75 to 0.81). Effect sizes of 0.27 to 0.53 were calculated for those with a reported improvement in symptoms.ConclusionThe Birmingham IBS Symptom Questionnaire has been developed and tested. It has been shown to be suitable for self-completion and acceptable to patients. The questionnaire has 3 internal dimensions which have good reliability, external validity and are responsive to a change in health status.

A randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome

BackgroundIrritable Bowel Syndrome (IBS) is a common condition characterised by pain, distension and altered bowel habit. Evidence suggests functional foods containing probiotics improve gastrointestinal transit, however, data are limited by short follow-up periods and evaluation in selected populations.MethodsA multi-centre, randomized, double blind, controlled trial to evaluate the effect of a probiotic vs non-probiotic dairy product on symptoms in IBS with a constipation element (IBS – Constipation or IBS – Mixed profile). Set in 13 general practices within central England. Individuals meeting the ROME III criteria for IBS, aged 18–65 completed a pre-study diary. Eligible individuals were randomized to consume dairy ‘yoghurt’ products which either did or did not contain active probiotics twice daily and to complete a daily diary. Primary outcome was subjective global assessment of symptom relief at week 4. Other outcomes comprised, IBS symptom scores, pain, bloating and flatulence levels, stool frequency, stool consistency, ease of bowel movement and quality of life.Results179 were randomized (91 active, 88 placebo). 76 (43 active, 33 placebo) completed the study. No significant between group differences existed at 4 weeks (57% active vs 53% placebo, reported adequate relief (p = 0.71)). By week 8, 46% active vs 68% placebo reported adequate relief (p = 0.03). This was sustained at week 12.ConclusionsSignificant improvements were reported for most outcomes in all trial participants but improvement did not differ by group. This trial does not provide evidence for effectiveness of a probiotic in IBS, in variance with a body of published literature and review conclusions. Differential drop out may however cloud interpretation of data.UK Trial registrationISRCTN78863629

Treatments for irritable bowel syndrome: patients' attitudes and acceptability

BackgroundIrritable Bowel Syndrome, a highly prevalent chronic disorder, places significant burden on the health service and the individual. Symptomatic distress and reduced quality of life are compounded by few efficacious treatments available. As researchers continue to demonstrate the clinical efficacy of alternative therapies, it would be useful to gain a patient-perspective of treatment acceptability and identify patients attitudes towards those modalities considered not acceptable.MethodsSix hundred and forty-five participants identified from an earlier IBS-prevalence study received a postal questionnaire to evaluate preferences and acceptability of nine forms of treatment. Proportions accepting each form of treatment were calculated and thematic analysis of qualitative data undertaken.ResultsA total of 256 (39.7%) of 645 potential respondents completed the questionnaire (mean age 55.9 years, 73% female). Tablets were most acceptable (84%), followed by lifestyle changes (diet (82%), yoga (77%)). Acupuncture (59%) and suppositories (57%) were less acceptable.When explaining lack of acceptability, patient views fell into four broad categories: dislike treatment modality, do not perceive benefit, general barriers and insufficient knowledge. Scepticism, lack of scientific rationale and fear of CAM were mentioned, although others expressed a dislike of conventional medical treatments. Past experiences, age and health concerns, and need for proof of efficacy were reported.ConclusionMost patients were willing to accept various forms of treatment. However, the reservations expressed by this patient-population must be recognised with particular focus directed towards allaying fears and misconceptions, seeking further evidence base for certain therapies and incorporating physician support and advice.