Kristien Boelaert

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.

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.

Lack of association between serum TSH or free T4 and body mass index in euthyroid subjects.

Background  There is ongoing debate regarding the influence of minor changes in thyroid status within the normal range and body mass index (BMI). Overt thyroid dysfunction is well recognized to affect weight, but the influence of minor perturbations of thyroid function remains unclear.

The association between serum TSH concentration and thyroid cancer

There is mounting evidence that the serum concentration of TSH is an independent predictor for the diagnosis of thyroid malignancy in patients with nodular thyroid disease. Furthermore, preoperative serum TSH concentrations are higher in patients with more aggressive tumours, suggesting a potential role for TSH in the progression of differentiated thyroid cancer. Based on these observations, patients with higher serum TSH concentrations and borderline cytological results may require more aggressive investigation and treatment when compared with those with lower baseline TSH levels. The mechanisms underlying the finding of higher serum TSH in patients with thyroid cancer remain unexplained. In this issue of Endocrine-Related Cancer, Fiore et al. have analysed the relationship between serum TSH and diagnosis of papillary thyroid cancer in 10 178 patients with nodular thyroid disease who were investigated by fine-needle aspiration biopsy. They found significantly higher TSH concentrations in patients who were subsequently diagnosed with thyroid cancer compared with those with benign disease. In addition, they found that the development of autonomous thyroid function (TSH<0.4 muU/ml) was associated with a reduction in the risk of papillary thyroid carcinoma. In this commentary, the evidence regarding the association between serum TSH and thyroid cancer is discussed placing these new findings into context.

A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer.

Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.

Differences in the Recurrence and Mortality Outcomes Rates of Incidental and Nonincidental Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-Analysis of 21 329 Person-Years of Follow-up

CONTEXT There is controversy as to whether papillary thyroid microcarcinoma (PTMC) represents more than one disease entity with different outcomes, requiring different treatment. OBJECTIVES To compare characteristics, outcomes, and factors associated with prognosis of incidental and nonincidental PTMC. SETTING AND DESIGN Two reviewers performed searches of online databases (1966-2012), reference lists, and conference abstract books. Longitudinal studies of subjects >16 years old receiving any treatments for papillary thyroid cancer ≤10 mm in size were included. Two reviewers independently screened abstracts and articles, extracted data, and assessed quality of studies using National Institute of Clinical Excellence and PRISMA criteria. RESULTS Of 1102 abstracts identified, 262 studies were reviewed and 17 studies included, comprising 3523 subjects, with mean follow-up of 70 months and total follow-up of 21 329 person-years. This included 854 subjects with incidental PTMC (follow-up, 4800 person-years; mean tumor size, 4.6 mm [range 3.3-6.7 mm]) and 2669 nonincidental PTMC cases (follow-up, 16 529 person-years; mean tumor size, 6.9 mm [range 5.6-8.0 mm]). The recurrence rate in the incidental group (0.5%; 95% confidence interval [CI], 0-1%, P < .001) was significantly lower than that in the nonincidental group PTMC (7.9%; 95% CI, 5-11%), with an OR of recurrence of 14.7 (95% CI, 5.6-54.8, P < .001) for nonincidental PTMC, compared with incidental PTMC. Lymph nodes were involved in 80% (126/157) of recurrences. On meta-regression, age, sex, size, tumor multifocality, lymph node involvement, and treatment modality were not significantly associated with recurrence. CONCLUSIONS Our meta-analysis strongly suggests the existence of at least two distinct entities of PTMC. Incidental PTMC has different clinical characteristics and a much lower recurrence rate than nonincidental PTMC, suggesting that management protocols should be re-considered. Additional studies with standardized data collection are required to explore potential differences between subgroups of nonincidental PTMC.

Prediction of cure and risk of hypothyroidism in patients receiving 131I for hyperthyroidism

Context  There is little consensus regarding the most appropriate dose of radioiodine (131I) to be administered to patients with hyperthyroidism.

Abnormal expression of 11 beta-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11β-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11β-HSD2 was readily demonstrable. Here we have used real-time RT–PCR to quantify expression of mRNA for 11 β-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11β-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11β-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11β-HSD2 activity (71.9±22.3 pmol/h/mg protein (mean±s.d.)) but no detectable 11β-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11β-HSD2 inhibitor) resulted in a 30.3±7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11β-HSDl to 11β-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11β-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours.

objective Thyroid hormones (THs) perform essential roles in pituitary function. They regulate anterior pituitary hormone secretion and are also key determinants of pituitary cell proliferation and differentiation. The critical role of deiodinase enzymes, which serve as prereceptor regulators of TH action, remains largely unexplored. Three deiodinase enzymes metabolize active and inactive THs and thereby determine tissue concentrations of the biologically active ligand, tri‐iodothyronine (T3). We hypothesized that aberrant expression of deiodinase enzymes and/or altered enzyme activity in pituitary tumours may change tissue concentrations of THs and influence their growth and secretory characteristics.

Optimal management of hypothyroidism, hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy

Normal physiological changes of pregnancy warrant the need to employ gestation specific reference ranges for the interpretation of thyroid function tests. Thyroid hormones play crucial roles in foetal growth and neurodevelopment which are dependent on adequate supply of maternal thyroid hormones from early gestation onwards. The prevention of significant adverse obstetric and neurodevelopmental outcomes from hypothyroidism requires a strategy of empirical levothyroxine dose increases and predictive dose adjustments in pregnancy combined with regular thyroid function testing, starting before pregnancy and until the postpartum period. Subclinical hypothyroidism has been associated with an increased risk of pregnancy loss and neurocognitive deficits in children, especially when diagnosed before or during early pregnancy. Whilst trials of levothyroxine replacement for mild hypothyroidism in pregnancy have not indicated definite evidence of improvements in these outcomes, professional guidelines recommend treatment, especially if evidence of underlying thyroid autoimmunity is present. Studies of isolated hypothyroxinaemia in pregnancy have shown conflicting evidence with regards to adverse obstetric and neurodevelopmental outcomes and no causative relationships have been determined. Treatment of this condition in pregnancy may be considered in those with underlying thyroid autoimmunity. Whilst the evidence for a link between the presence of anti‐TPO antibodies and increased risks of pregnancy loss and infertility is compelling, the results of ongoing randomized trials of levothyroxine in euthyroid women with underlying autoimmunity are currently awaited. Further studies to define the selection of women who require levothyroxine replacement and to determine the benefits of a predictive dose adjustment strategy are required.