Jayne A. Franklyn

Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study

BACKGROUND Low serum thyrotropin, in combination with normal concentrations of circulating thyroid hormones, is common, especially in elderly people and in individuals with a history of thyroid disease. We aimed to assess the long-term effects of subclinical hyperthyroidism on mortality. METHODS We did a population-based study of mortality in a cohort of 1191 individuals not on thyroxine or antithyroid medication. All participants were aged 60 years or older. We measured concentration of thyrotropin in serum at baseline in 1988-89. We recorded vital status on June 1, 1999, and ascertained causes of death for those who had died. We compared data for causes of death with age-specific, sex-specific, and year-specific data for England and Wales. We also compared mortality within the cohort according to initial thyrotropin measurement. RESULTS During 9733 person-years of follow-up, 509 of 1191 people died, the expected number of deaths being 496 (standardised mortality ratio [SMR] 1.0, 95% CI 0.9-1.1). Mortality from all causes was significantly increased at 2 (SMR 2.1), 3 (2.1), 4 (1.7), and 5 (1.8) years after first measurement in those with low serum thyrotropin (n471). These increases were largely accounted for by significant increases in mortality due to circulatory diseases (SMR 2.1, 2.2, 1.9, 2.0, at years 2, 3, 4, and 5 respectively). Increases in mortality from all causes in years 2-5 were higher in patients with low serum thyrotropin than in the rest of the cohort (hazard ratios for years 2, 3, 4, and 5 were 2.1, 2.2, 1.8, and 1.8, respectively). This result reflects an increase in mortality from circulatory diseases (hazard ratios at years 2, 3, 4, and 5 were 2.3, 2.6, 2.3, 2.3), and specifically from cardiovascular diseases (hazard ratios at years 2, 3, 4, and 5 were 3.3, 3.0, 2.3, 2.2). INTERPRETATION A single measurement of low serum thyrotropin in individuals aged 60 years or older is associated with increased mortality from all causes, and in particular mortality due to circulatory and cardiovascular diseases.

Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom.

Increasing use of assays for TSH with improved sensitivity as a first‐line test of thyroid function has raised questions regarding prevalence and clinical significance of abnormal results, especially values below normal. We have assessed the thyroid status of 1210 patients aged over 60 registered with a single general practice by measurement of serum TSH using a sensitive assay. High TSH values were more common in females (11.6|X%) than males (2.9|X%). TSH values below normal were present in 6.3|X% of females and 5.5|X% of males, with values below the limit of detection of the assay present in 1.5|X% of females and 1.4|X% of males. Anti‐thyroid antibodies were found in 60|X% of those with high TSH but only 5.6|X% of those with subnormal TSH. Eighteen patients were hypothyroid (high TSH, low free thyroxine) and one thyrotoxic (low TSH, raised free thyroxine) at initial testing. Seventy‐three patients with elevated TSH but normal free T4 were followed for 12 months; 13 (17.8|X%) developed low free T4 levels and commenced thyroxine, TSH returned to normal in four (5.5|X%) and 56 (76.7|X%) continued to have high TSH values. Sixty‐six patients with TSH results below normal were followed. Of the 50 subjects with low but detectable TSH at initial testing, 38 (76|X%) returned to normal at 12 months; of those 16 with undetectable TSH followed, 14 (87.5|X%) remained low at 12 months. Only one subject (who had an undetectable TSH) developed thyrotoxicosis. In view of the marked prevalence of thyroid dysfunction in the elderly, we suggest that screening of all patients over 60 should be considered. It is important that those with high TSH are followed in view of the risk of progression to overt hypothyroidism, but the risk of thyrotoxicosis in those with TSH values below normal appears small.

Parameters for reliable results in genetic association studies in common disease

It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.

Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence

Objectives To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women. Design Systematic review and meta-analysis. Data sources Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth. Study selection Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes. Data synthesis Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model. Results 30 articles with 31 studies (19 cohort and 12 case-control) involving 12 126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12 566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P<0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P=0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P=0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90). Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.

Iodine status of UK schoolgirls: a cross-sectional survey

BACKGROUND Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50-99 μg/L, moderate if 20-49 μg/L, and severe if less than 20 μg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. METHODS In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14-15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June-July, 2009, and November-December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. FINDINGS 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 μg/L (IQR 56·9-109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). INTERPRETATION Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. FUNDING Clinical Endocrinology Trust.

Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study

BACKGROUND Radioiodine is used increasingly as first-line treatment for hyperthyroidism, but concerns remain about subsequent risk of cancer, especially in those treated at a young age. We investigated cancer incidence and mortality in patients treated with radioiodine for hyperthyroidism. METHODS We did a population-based study in 7417 patients treated in Birmingham, UK, between 1950 and 1991. We compared details of all cancer diagnoses and deaths in 1971-91 from the UK Office for National Statistics with data on cancer incidence and mortality for England and Wales specific for age, sex, and period. FINDINGS During 72,073 person-years of follow-up, 634 cancer diagnoses were made, compared with an expected number of 761 (standardised incidence ratio [SIR] 0.83 [95% CI 0.77-0.90]). The relative risk of cancer mortality was also decreased (observed cancer deaths 448, expected 499; standardised mortality ratio [SMR] 0.90 [0.82-0.98]). Incidence of cancers of the pancreas, bronchus, trachea, bladder, and lymphatic and haemopoietic systems was lowered. Mortality from cancers at all these sites was also reduced but findings were significant only for bronchus and trachea. There were significant increases in incidence and mortality for cancers of the small bowel (SIR 4.81 [2.16-10.72], SMR 7.03 [3.16-15.66]) and thyroid (SIR 3.25 [1.69-6.25], SMR 2.78 [1.16-6.67]), although absolute risk of these cancers was small. INTERPRETATION The decrease in overall cancer incidence and mortality in those treated for hyperthyroidism with radioiodine is reassuring. The absolute risk of cancers of the small bowel and thyroid remain low, but the increased relative risk shows the need for long-term vigilance in those receiving radioiodine.

Long-term thyroxine treatment and bone mineral density

Studies of the effect of thyroxine replacement therapy on bone mineral density have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that prescribed doses of thyroxine should be reduced. We have examined the effect of long-term thyroxine treatment in a large homogeneous group of patients; all had undergone thyroidectomy for differentiated thyroid cancer but had no history of other thyroid disorders. The 49 patients were matched with controls for age, sex, menopausal status, body mass index, smoking history, and calcium intake score; in all subjects bone mineral density at several femoral and vertebral sites was measured by dual-energy X-ray absorptiometry. Despite long-term thyroxine therapy (mean duration 7.9 [range 1-19] years) at doses (mean 191 [SD 50] micrograms/day) that resulted in higher serum thyroxine and lower serum thyrotropin concentrations than in the controls, the patients showed no evidence of lower bone mineral density than the controls at any site. Nor was bone mineral density correlated with dose, duration of therapy, or cumulative intake, or with tests of thyroid function. There was a decrease in bone density with age in both groups. We suggest that thyroxine alone does not have a significant effect on bone mineral density and hence on risk of osteoporotic fractures.

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

Association of the TSHR gene with Graves' disease: the first disease specific locus

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD ‘blocks’ and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 × 10−6, OR 1.7) with Graves’ disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1366 AITD cases and 1061 controls (GD, P=2 × 10−6, OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.

Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor‐2 (FGF‐2) in human pituitary adenomas: relationships to clinical tumour behaviour

objective Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor‐2 (FGF‐2). Given this background, we have determined the expression of PTTG, PBF, FGF‐2 and its receptor FGF‐R‐1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour.