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Biomedical subjects

Jayne A Franklyn

Publications and source records attributed to Jayne A Franklyn.

At least 19 recordsLinked to original sources
PubMed2006

Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study.

OBJECTIVES: This study sought to prospectively evaluate the prevalence of cardiovascular abnormalities in patients with overt hyperthyroidism before and after antithyroid therapy. BACKGROUND: Overt hyperthyroidism is associated with recognized cardiovascular effects believed to be reversed by antithyroid therapy; however, increasing data suggest significant long-term cardiovascular mortality. METHODS: A total of 393 (312 women, 81 men) consecutive unselected patients with overt hyperthyroidism were recruited and compared with 393 age- and gender-matched euthyroid control subjects. Hyperthyroid patients were re-evaluated after antithyroid therapy. Findings in patients and matched control subjects were compared at presentation, after treatment when patients had subclinical hyperthyroidism biochemically, and when patients were rendered biochemically euthyroid. All had a structured cardiovascular history and examination, including measurements of blood pressure (BP) and pulse rate. All had resting 12-lead electrocardiogram and 24-h digital Holter monitoring of cardiac rhythm. RESULTS: A higher prevalence of cardiovascular symptoms and signs, as well as abnormal hemodynamic parameters, was noted among hyperthyroid patients at recruitment compared with control subjects. Cardiac dysrhythmias, especially supraventricular, were more prevalent among patients than among control subjects. Palpitation and dyspnea, postural decrease in systolic pressure, and atrial fibrillation (AF) remained more prevalent in treated hyperthyroid subjects with subclinical hyperthyroidism compared with control subjects, and remained more prevalent after restoration of euthyroidism. Predictors for successful reversion to sinus rhythm in those with AF associated with hyperthyroidism were lower BP measurements at recruitment and an initial hypothyroid state induced by antithyroid therapy. Mortality was higher in hyperthyroid subjects than in control subjects after a mean period of follow-up of 66.6 months. CONCLUSIONS: Cardiovascular abnormalities are common in patients with overt hyperthyroidism at presentation, but some persist despite effective antithyroid therapy.

Adolescent↗
PubMed2006

Association of PTPN22 haplotypes with Graves' disease.

CONTEXT: A recent study reported associations of a series of single nucleotide polymorphisms (SNPs) within PTPN22, including rs2476601, with rheumatoid arthritis. OBJECTIVE: Having previously reported significant association of the T allele of rs2476601 in a Graves' disease (GD) cohort, we sought to determine whether novel rheumatoid arthritis-associated SNPs were also contributing to susceptibility to GD. DESIGN: Case control and family-based studies of five PTPN22 tag SNPs were performed. SETTING: An United Kingdom academic department of medicine was the setting for the study. PATIENTS OR OTHER PARTICIPANTS: A total of 768 GD patients, 768 control subjects, and 313 families with autoimmune thyroid disease participated. MAIN OUTCOME MEASURE: Tests for association with disease were the main outcome measure. RESULTS: No association with disease of any of the individual SNPs and no correlation between genotype and clinical phenotype were seen. However, haplotype analysis of the SNP markers with addition of rs2476601 did reveal a strong association of a haplotype containing the T allele, in both the case control (chi2 = 29.13; P = 6.77 x 10(-8)) and family data sets (chi2 = 5.24; P = 0.02). Furthermore, a novel protective effect of a haplotype containing all six SNPs was observed (chi2 = 17.02; P = 3.7 x 10(-5)). CONCLUSIONS: These data suggest that the association of SNPs within the PTPN22 region differs between autoimmune diseases, occurring individually and/or as part of a haplotype, indicating that the mechanisms by which PTPN22 confers susceptibility to GD may, in part, be disease specific.

Arthritis, Rheumatoid↗
PubMed2006

131I activity for remnant ablation in patients with differentiated thyroid cancer: A systematic review.

CONTEXT: Radioiodine ablation of the thyroid remnant after thyroidectomy is commonly performed in the management of patients with differentiated thyroid cancer. Although many centers administer an activity of 100 mCi, there is uncertainty over using a lower activity. OBJECTIVE: A systematic review of the published literature was used to compare the success rates of remnant ablation using approximately 30 mCi with approximately 100 mCi (1.1 vs. 3.7 GBq). DATA SOURCES: Data were obtained from MEDLINE and EMBASE for the years 1966 to March 2006. STUDY SELECTION: All studies that reported rates of successful ablation associated with approximately 30 or approximately 100 mCi of radioiodine were reviewed. DATA EXTRACTION: Studies were based on reviews of patient case notes (n = 41), prospective cohorts (n = 12), and randomized trials (n = 6). We obtained the success of thyroid remnant ablation according to different administered activities of radioiodine. Where a study reported on two or more activities, the risk ratio of having a successful ablation (approximately 30 vs. approximately 100 mCi) was calculated and combined in a meta-analysis. DATA SYNTHESIS: Observational studies confirmed the high ablation success rate ( approximately 80%) using approximately 100 mCi, although 22% of studies reported a rate of 90% or greater. The pooled ablation success rate in these studies was 10% lower using 30 mCi compared with 100 mCi (95% confidence interval, 3-17%; P = 0.01). The meta-analysis of the randomized trials produced equivocal results. For example, the rate of successful ablation in patients given 30 mCi was 8% lower compared with 100 mCi (95% confidence interval, 29% lower or up to 20% greater, P = 0.58), consistent with there being no difference or that 30 mCi is much less effective. CONCLUSIONS: From the published data, it is not possible to reliably determine whether ablation success rates using 30 mCi are similar to using 100 mCi. Large randomized trials are needed to resolve the issue and guide clinical practice.

Humans↗
PubMed2006

Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey.

CONTEXT: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. OBJECTIVE: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. EXCLUSIONS: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. OUTCOME MEASURE: Tests of thyroid function (TSH concentration and free T4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. EXPLANATORY VARIABLES: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004). ANALYSIS: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction. RESULTS: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. CONCLUSIONS: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population.

Aged↗
PubMed2006

How does glucose insulin potassium improve hemodynamic performance? Evidence for altered expression of beta-adrenoreceptor and calcium handling genes.

BACKGROUND: Glucose insulin potassium (GIK) improves hemodynamic performance after coronary artery surgery (CABG). We investigated whether this is associated with changes in gene expression of beta1-adrenergic receptor (ADRB1) or other calcium handling proteins. METHODS AND RESULTS: During a randomized double-blind placebo-controlled trial, 48 patients undergoing on-pump CABG, allocated to receive pre-ischemic placebo (5% dextrose) or GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1); 0.75 mL.kg(-1).h(-1)) continued for 6 hours after the removal of the aortic cross-clamp (AXC), underwent left ventricular biopsy for analysis of specific mRNAs immediately before AXC, before release of AXC, and 10 minutes after reperfusion (placebo n=24, GIK n=24). GIK or placebo was infused for a mean of 79+/-21 minutes or 79+/-18 minutes pre-ischemia respectively. Serial hemodynamic measurements were performed. Biopsy samples were snap-frozen and stored at -80 degrees C, mRNA was extracted and TaqMan real-time polymerase chain reaction was performed to investigate expression of ADRB1, sarcoplasmic reticulum Ca-ATPase (SERCA2a), and phospholamban (PLB). GIK significantly increased cardiac index versus placebo (P=0.037). TaqMan reverse-transcriptase polymerase chain reaction showed significantly greater ADRB1 mRNA expression at all time points (4.9-fold, 7.4-fold, and 15.6-fold increase, respectively; P<0.001), significantly greater SERCA2a mRNA expression after reperfusion (13.2-fold; P<0.001), and increased PLB mRNA expression at pre-ischemia and reperfusion (P<0.001 for both time-points) in GIK groups versus placebo. CONCLUSIONS: The beneficial hemodynamic effects of GIK therapy are associated with increased ADRB1 and SERCA2a mRNA expression. Further work is therefore warranted to investigate these mRNA effects at the protein level.

Aged↗
PubMed2006

Detection and surgical treatment of cervical lymph nodes in differentiated thyroid cancer.

There is considerable controversy regarding the treatment of patients with cervical metastases from differentiated thyroid cancer. Most have papillary carcinoma and the main areas of contention relate to methods of assessment and staging, surgical management and mode of follow up. there is little evidence to support elective anatomical imaging with CT or MRI in those patients with suspected or proven malignancy at the primary site as indicated by fine needle aspiration cytology (FNAC) but who have no clinical evidence of nodal disease. The role of routine ultrasound (US) in the pre-operative assessment of suspected or known malignancy is developing but is largely unproven. When it is performed, high risk areas for metastatic neck disease (levels II-V) should be assessed. Suspicious nodes on US should be further evaluated by FNAC. Suspected or proven neck disease may be further assessed pre-operatively with CT or MRI and then treated surgically. Disease in the central compartment requires a total thyroidectomy and level VI central compartment neck dissection. Suspected or proven lateral compartment cancer should be treated by selective neck dissection (at least levels III, IV, and V) below the accessory nerve. There is no role for 'Berry picking' and clinically node negative high risk patients should have an elective central compartment level VI neck dissection. Sentinel node biopsy lays no role and neither does elective lateral compartment surgery in patients with no clinical or radiological evidence of disease. For follow up, US represents the most sensitive means of detecting neck recurrences and in the presence of an elevated serum thyroglobulin, imaging may also include whole body iodine-131 scanning and anatomical imaging with CT or MRI. The role of PET remains controversial but is likely to develop further as the technique becomes more widely available. In the future, the concentration of patients with this disease in large center can only improve the way we treat differentiated thyroid cancer.

Cell Differentiation↗
PubMed2006

Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American Thyroid Association.

The fetus is totally dependent in early pregnancy on maternal thyroxine for normal brain development. Adequate maternal dietary intake of iodine during pregnancy is essential for maternal thyroxine production and later for thyroid function in the fetus. If iodine insufficiency leads to inadequate production of thyroid hormones and hypothyroidism during pregnancy, then irreversible fetal brain damage can result. In the United States, the median urinary iodine (UI) was 168 microg/L in 2001-2002, well within the range of normal established by the World Health Organization (WHO), but whereas the UI of pregnant women (173 microg/L; 95% CI 75-229 microg/L) was within the range recommended by WHO (150-249 microg/L), the lower 95% CI was less than 150 microg/L. Therefore, until additional physiologic data are available to make a better judgment, the American Thyroid Association recommends that women receive 150 microg iodine supplements daily during pregnancy and lactation and that all prenatal vitamin/mineral preparations contain 150 microg of iodine.

Adolescent↗
PubMed2005

Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells.

Cancer reflects the progressive accumulation of genetic alterations and subsequent genetic instability of cells. Cytogenetic studies have demonstrated the importance of aneuploidy in differentiated thyroid cancer development. The pituitary tumour transforming gene (PTTG), also known as securin, is a mitotic checkpoint protein which inhibits sister chromatid separation during mitosis. PTTG is highly expressed in many cancers and overexpression of PTTG induces aneuploidy in vitro. Using fluorescent intersimple sequence repeat PCR (FISSR-PCR), we investigated the relationship between PTTG expression and the degree of genetic instability in normal and tumorous thyroid samples. The genomic instability index (GI index) was 6.7-72.7% higher in cancers than normal thyroid tissues. Follicular thyroid tumours exhibited greater genetic instability than papillary tumours (27.6% (n=9) versus 14.5% (n=10), P=0.03). We also demonstrated a strong relationship between PTTG expression and the degree of genetic instability in thyroid cancers (R2=0.80, P=0.007). To further investigate PTTG's role in genetic instability, we transfected FTC133 thyroid follicular cells and observed increased genetic instability in cells overexpressing PTTG compared with vector-only-transfected controls (n=3, GI Index VO=29.7+/-5.2 versus PTTG=63.7+/-6.4, P=0.013). Further, we observed a dose response in genetic instability and PTTG expression (GI Index low dose (0.5 microg DNA/ six-well plate) PTTG=15.3%+/-1.7 versus high dose (3 microg DNA) PTTG=50.8%+/-3.3, P=0.006). Overall, we describe the first use of FISSR-PCR in human cancers, and demonstrate that PTTG expression correlates with genetic instability in vivo, and induces genetic instability in vitro. We conclude that PTTG may be an important gene in the mutator phenotype development in thyroid cancer.

Caspase 3↗
PubMed2005

Thyroid function and mortality in patients treated for hyperthyroidism.

CONTEXT: Hyperthyroidism has been reported to cause excess all-cause and circulatory mortality. Whether this can be reversed is unknown, as is the influence of mild persisting thyroid dysfunction and treatment-induced hypothyroidism. OBJECTIVES: To determine whether radioiodine treatment is associated with increased mortality and to determine the influences of mild thyroid dysfunction and the development of overt hypothyroidism treated with thyroxine (T(4)). DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2668 individuals aged 40 years or older treated for overt hyperthyroidism with radioiodine in the West Midlands region of England from 1984-2002. MAIN OUTCOME MEASURES: Cause of death compared with age- and period-specific mortality in England and Wales and assessment of the influence of T(4) therapy for radioiodine-induced hypothyroidism and subclinical thyroid dysfunction on mortality. RESULTS: In 15,968 person-years of follow-up, 554 died vs 487 expected deaths (standardized mortality ratio [SMR], 1.14; 95% confidence interval [CI], 1.04-1.24, P=.002). Increased risks of all-cause and circulatory deaths vs age- and period-specific mortality were observed in follow-up in those not requiring, or prior to, T(4) therapy. These increased risks were not observed during follow-up on T(4) therapy (circulatory disease SMR prior to T(4), 1.33; 95% CI, 1.14-1.53 vs SMR, 0.91; 95% CI, 0.70-1.17 during T(4)). Patients receiving T(4) had decreased risk of mortality vs risk in the period not requiring, or prior to, T(4) therapy (all-cause mortality hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; circulatory mortality HR, 0.65; 95% CI, 0.48-0.87). Increased all-cause mortality vs the background population was observed in the period prior to T(4) therapy in follow-up associated with low, normal, and high serum thyrotropin. The SMR for ischemic heart disease increased slightly when analyzed by serum thyrotropin, high serum thyrotropin being the highest SMR (low thyrotropin SMR, 1.06; 95% CI, 0.75-1.45; normal thyrotropin SMR, 1.17; 95% CI, 0.76-1.71; high thyrotropin SMR, 1.48; 95% CI, 0.86-2.37). Comparison within the cohort showed that mild hypothyroidism prior to T(4) therapy was associated with increased risk of mortality from ischemic heart disease vs biochemical euthyroidism (HR, 2.08; 95% CI, 1.04-4.19). CONCLUSIONS: Patients treated with radioiodine for hyperthyroidism had increased mortality vs age- and period-specific mortality in England and Wales, a finding no longer evident during T(4) therapy. This supports treating hyperthyroidism with doses of radioiodine sufficient to induce overt hypothyroidism. The association within the cohort of mortality from ischemic heart disease with subclinical hypothyroidism suggests T(4) replacement should be considered should this biochemical abnormality develop after radioiodine therapy.

Adult↗
PubMed2005

Pituitary tumor transforming gene binding factor: a novel transforming gene in thyroid tumorigenesis.

CONTEXT: There are currently no clear markers for the detection of differentiated thyroid cancer and its recurrence. Pituitary tumor transforming gene (PTTG) is a protooncogene implicated in the pathogenesis of multiple tumor types, which stimulates fibroblast growth factor-2 secretion via PTTG binding factor (PBF). OBJECTIVE: The aim of this study was to ascertain whether PBF expression is associated with thyroid cancer outcome. DESIGN: PBF expression was measured at the mRNA and protein level. Tissue was collected during surgery, with normal samples being taken from the contralateral lobe. In vitro studies ascertained the ability of PBF to transform cells and form tumors in nude mice and its subcellular localization. SETTING: The study was conducted at a primary care/referral center. PATIENTS: Thyroid tumors were collected from a series of 27 patients undergoing surgical excision of papillary and follicular thyroid tumors. INTERVENTION: No intervention was conducted. MAIN OUTCOME MEASURE: The expression of PBF in thyroid cancers compared with normal thyroid, hypothesized before the investigation to be raised in tumors, was the main outcome measure. RESULTS: PBF mRNA expression was higher in differentiated thyroid carcinomas than in normal thyroid (P < 0.001; n = 27) and was independently associated with tumor recurrence (P = 0.002; R(2) = 0.49). PTTG was able to up-regulate PBF mRNA expression in vitro (P < 0.001; n = 12), and stable overexpression of PBF in NIH3T3 cells resulted in significant colony formation (P < 0.001; n = 12). In vivo, stable sc overexpression of PBF induced tumor formation in athymic nude mice. CONCLUSIONS: PBF is an additional prognostic indicator in differentiated thyroid cancer that is transforming in vitro and tumorigenic in vivo.

Adult↗
PubMed2005

Maternal nutrient deprivation induces sex-specific changes in thyroid hormone receptor and deiodinase expression in the fetal guinea pig brain.

Thyroid hormone deprivation during fetal life has been implicated in neurodevelopmental morbidity. In humans, poor growth in utero is also associated with fetal hypothyroxinaemia. In guinea pigs, a short period (48 h) of maternal nutrient deprivation at gestational day (gd) 50 results in fetuses with hypothyroxinaemia and increased brain/body weight ratios. Thyroid hormone action is mediated by nuclear thyroid hormone receptors (TRs) and is dependent upon the prereceptor regulation of supply of triiodothyronine (T3) by deiodinase enzymes. Examination of fetal guinea pig brains using in situ hybridization demonstrated widespread expression of mRNAs encoding TRalpha1, alpha2 and beta1, with regional colocalization of deiodinase type 2 (D2) mRNA in the developing forebrain, limbic structures, brainstem and cerebellum at gd52. With maternal nutrient deprivation, TRalpha1 and beta1 mRNA expression was significantly increased in the male, but decreased in the female fetal hippocampus and cerebellum and other areas showing high TR expression under euthyroid conditions. Maternal nutrient deprivation resulted in elevated D2 mRNA expression in males and females. Deiodinase type 3 (D3) mRNA expression was confined to the shell of the nucleus accumbens, the posterior amygdalohippocampal area, brainstem and cerebellum, and did not change with maternal nutrient deprivation. In conclusion, maternal nutrient deprivation resulted in sex-specific changes in TR mRNA expression and a generalized increase in D2 mRNAs within the fetal brain. These changes may represent a protective mechanism to maintain appropriate thyroid hormone action in the face of fetal hypothyroxinaemia in order to optimize brain development.

Animals↗
PubMed2005

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 1,059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 x 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 1,366 AITD cases and 1,061 controls (GD, P=2 x 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.

Case-Control Studies↗
PubMed2004

Regression mapping of association between the human leukocyte antigen region and Graves disease.

The human leukocyte antigen class II genes DRB1, DQB1, and DQA1 are associated with Graves disease (GD), but, because of strong linkage disequilibrium within this region, the primary etiological variant(s) remains unknown. In the present study, 871 patients with GD and 621 control subjects were genotyped at the DRB1, DQB1, and DQA1 loci. All three loci were associated with GD (P=1.45 x 10(-12), P=3.20 x 10(-5), and P=9.26 x 10(-12), respectively). Stepwise logistic-regression analysis showed that the association could be explained by either DRB1 or DQA1 but not by DQB1. To extend previous results, the amino acid sequence of the exon 2-encoded peptide-binding domain of DRB1 was predicted for each subject, and, by use of logistic regression, each position was analyzed for association with GD. Of 102 amino acids, 70 were uninformative; of the remaining 32 amino acids, 13 were associated with GD (P values ranged from 2.20 x 10(-4) to 1.2 x 10(-12)). The strongest association was at position beta 74. This analysis is consistent with the possibility that position beta 74 of exon 2 of the DRB1 molecule may have a specific and central role in autoantigen presentation by DRB1 to T lymphocytes. However, we cannot yet exclude a primary role for DQA1 or for other polymorphisms that affect DRB1 function or expression.

Case-Control Studies↗
PubMed2004

Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment.

Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.

Adolescent↗
PubMed2004

Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

CONTEXT: Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. OBJECTIVES: To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. DATA SOURCES: MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. STUDY SELECTION AND DATA EXTRACTION: A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. DATA SYNTHESIS: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. CONCLUSIONS: Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

Humans↗
PubMed2004

Polymorphisms of interleukin 4 receptor gene and interleukin 10 gene are not associated with Graves' disease in the UK.

Graves' disease (GD) is an autoimmune disorder of the thyroid gland and both environmental and genetic factors contribute to disease aetiology. Cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10), are involved in the immune response and may be implicated in the autoimmune disease process. Associations have been reported between single nucleotide polymorphisms (SNPs) of IL-10 and the Ile50Val polymorphism of the IL-4 receptor gene (IL-4R) gene and atopy and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The autoimmune diseases cluster within families and susceptibility genes may overlap between the different disorders. Therefore, we investigated 5 SNPs (-592C/A, -657G/A, - 819C/T, -1349A/G, and -2013G/A) in the promoter region of the IL-10 and the Ile50Val polymorphism (A/G) in the IL-4R in a large UK population based case-control dataset with GD. No association was found between the polymorphisms studied and GD and no significant differences were found in genotype or allele frequencies between the patients and control subjects. We conclude these polymorphisms of IL-10 and IL-4R previously associated with other immune mediated diseases, do not confer susceptibility to GD in white Caucasians in the United Kingdom.

Genetic Predisposition to Disease↗