Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.
Herman Verloop, Olaf M Dekkers, Robin P Peeters, Jan W Schoones and Johannes W A Smit
Robbert B T Verkooijen, Daphne Rietbergen, Jan W Smit, Johannes A Romijn and Marcel P M Stokkel
Background: This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation.
Methods: We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSH×24-h I-131 uptake).
Results: We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. ± 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSH×24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not.
Conclusion: High Tg/(TSH×24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.
Robbert B T Verkooijen, Jan W A Smit, Johannes A Romijn and Marcel P M Stokkel
Objective: The aim of the present study is to assess the prevalence of second primary tumors in patients treated for thyroid cancer. Furthermore, we wanted to assess the standardized risk rates for all second primary tumors, but especially for breast cancer, as data in the literature indicate an excessive risk in differentiated thyroid cancer (DTC) patients for this tumor.
Materials and methods: We included consecutive patients, who received ablation treatment with I-131 at the Leiden University Medical Center between January 1985 and December 1999 (n = 282). The mean period of follow-up was 10.6 ± 4.1 years.
Results: Thirty-five of the 282 patients (12.4%) had a second primary tumor (SPT), either preceding or following the diagnosis of thyroid cancer. Five other patients had three primary tumors, including DTC. As a result, 40 additional tumors were found in this group, revealing an overall prevalence of 14.2%. Twenty tumors (7.1%) preceded the thyroid cancer with a mean interval of 5.7 years (range: 0.5–22.0 years), whereas 20 tumors (7.1%) occurred after this tumor with a mean interval of 6.7 years (range: 1.0–15.0 years). In 13 female patients, breast cancer was found as SPT. The standardized incidence rate (SIR) for all cancers after the diagnosis of DTC in this study population was not increased (1.13; confidence interval (CI): 0.68–1.69). However, we found an increased SIR of 2.26 (CI: 1.60–3.03) for all cancers either following or preceding DTC, which is mainly caused by a SIR of 3.95 (CI: 2.06–6.45) for breast cancer.
Conclusion: Patients with DTC have an overall increased standardized incidence rate for second primary tumors, but not for second primary tumors following I-131 therapy. These findings suggest a common etiologic and/or genetic mechanism instead of a causal relation.
Xander G Vos, Natalie Smit, Erik Endert, Jan G P Tijssen and Wilmar M Wiersinga
Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves' hyperthyroidism (GH).
Cross-sectional multicentre observational study.
Two hundred and sixty-three consecutive untreated patients (mean age (±s.d.) 42.6±12.4 years; range 16–79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD.
The peak incidence for the diagnosis of GH was 2–3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trend=0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (P=0.01) while age at onset was lower (P=0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism.
Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves' disease. We have found supporting evidence for the existence of genetic anticipation in Graves' disease by means of a lower age of onset in the group with the highest FHS.
Xander G Vos, Natalie Smit, Erik Endert, Jos F Brosschot, Jan G P Tijssen and Wilmar M Wiersinga
The evidence that stress may provoke Graves' hyperthyroidism in genetically susceptible subjects is substantial. Whether exposure to stress is related to the severity of thyrotoxicosis has not been studied. Advancing age is associated with not only less severe Graves' hyperthyroidism but also self-reported stress. We tested the hypothesis whether advancing age is associated with less exposure to stress, resulting in a lower immunological response, and less severe Graves' hyperthyroidism.
Cross-sectional multicenter study.
Two hundred and sixty-three consecutive untreated patients with a first episode of Graves' hyperthyroidism were included. The severity of Graves' hyperthyroidism was evaluated biochemically (freeT4-index and freeT3-index, thyrotropin-binding inhibitory immunoglobulin (TBII)) and clinically by the hyperthyroid symptom scale score (HSS score). Stress exposure was quantitated by three questionnaires.
Advancing age was associated with less severe Graves' hyperthyroidism, both biochemically by lower serum freeT3-index and freeT4-index (P<0.01), lower serum TBII (P=0.05), and clinically by lower HSS scores (P=0.04) and smaller goiter size (P<0.01). FreeT3-index and freeT4-index were directly associated with HSS scores (P<0.01). Stress scores were associated with HSS scores (P<0.01) but not with biochemical severity of Graves' hyperthyroidism. Advancing age was associated with lower scores for stress exposure. Multivariate regression analysis showed that HSS score was independently related to the tendency to report negative feelings (P<0.01) but not to other stress scores and also not to age.
Advancing age is associated with less exposure to stress, lower serum TBII and less severe clinical and biochemical Graves' hyperthyroidism. Because no direct relationship exists between stress exposure and TBII or freeT3-index and freeT4-index, we reject our hypothesis that less stress is causally related to biochemically less severe Graves' hyperthyroidism in old age. HSS score is primarily determined by negative feelings and not by age.
Robbert B T Verkooijen, Frederik A Verburg, Johannes W van Isselt, Cornelis J M Lips, Jan W Smit and Marcel P M Stokkel
The aim of the study was to compare the success rate of an uptake-related ablation protocol in which the dose depends on an I-131 24-h neck uptake measurement and a fixed-dose ablation protocol in which the dose depends on tumour stage.
All differentiated thyroid carcinoma patients with M0 disease who had undergone (near-) total thyroidectomy followed by I-131 ablation were included. In the uptake-related ablation protocol, 1100 (uptake >10%), 1850 (uptake 5–10%) and 2800 MBq (uptake <5%) were used. In the fixed-dosage ablation strategy, 3700 (T1–3, N0 stage) and 5550 MBq (N1 and/or T4 stage) were applied. We used I-131 uptake on whole-body scintigraphy and thyroglobulin-off values to evaluate the ablation 6–12 months after treatment.
In the uptake-related ablation protocol, 60 out of 139 (43%) patients were successfully treated versus 111 out of 199 for the fixed-dose ablation protocol (56%) (P=0.022). The differences were not statistically significant for patients with T4 (P=0.581) and/or N1 (P=0.08) disease or for patients with T4N1 tumour stage (P=0.937).
The fixed-dose I-131 ablation protocol is more effective in ablation of the thyroid remnant in differentiated thyroid carcinoma patients than an uptake-related ablation protocol. This difference is not observed in patients with a N1 and/or T4 tumour stage.
Karen A Heemstra, Rene E Toes, Jan Sepers, Alberto M Pereira, Eleonora P Corssmit, Tom W J Huizinga, Johannes A Romijn and Johannes W Smit
Conventional therapies for Graves' disease, consisting of medical therapy or radioiodine are unsatisfactory, because of limited efficacy and adverse events. Interventions aimed at the underlying autoimmune pathogenesis of Graves' disease may be worthwhile to explore. We therefore performed a prospective, 26-week phase II study with open-ended observational extension to assess the efficacy of rituximab in patients with recurrent Graves' disease.
We performed a prospective, 26-week phase II study with open-ended observations.
Thirteen patients with relapsing Graves' disease (9 females and 4 males, age 39.5±9.5 years) received 2 dosages of rituximab 1000 mg i.v. with a 2-week interval. Before administration and on several periods after the administration of TSH, free thyroxine (FT4), thyrotropin binding inhibitory immunoglobulins (TBII) and the proportion of CD19 and MS4A1 positive peripheral blood mononuclear cells were measured.
The proportion of MS4A1 positive lymphocytes decreased in all patients from 5.8% at baseline to 1.4% at 26 weeks (P=0.007). Four patients with high initial FT4 levels did not respond to treatment. All remaining patients had a decrease in FT4 levels at 26 weeks (P=0.001) and an increase in TSH levels (P=0.011). TBII decreased in all remaining patients (P=0.003). At a follow-up time of 14–27 months, nine of these patients were still euthyroid with normal FT4 (P<0.001) and TSH levels (P=0.008).
The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.
Luca Giovanella, Penelope M Clark, Luca Chiovato, Leonidas Duntas, Rossella Elisei, Ulla Feldt-Rasmussen, Laurence Leenhardt, Markus Luster, Camilla Schalin-Jäntti, Matthias Schott, Ettore Seregni, Herald Rimmele, Jan Smit and Frederik A Verburg
Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.
Mirjam A Lips, Hanno Pijl, Jan B van Klinken, Gerrit H de Groot, Ignace M Janssen, Bert Van Ramshorst, Bart A Van Wagensveld, Dingeman J Swank, Fracois Van Dielen and Johannes W A Smit
Obesity and weight loss influence thyroid hormone physiology. The effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) in obese subjects have not been studied in parallel. We hypothesized that differences in transient systemic inflammation and catabolic state between the intervention types could lead to differential effects on thyroid hormone physiology.
Design and methods
We recruited 12 lean and 27 obese females with normal fasting glucose (normal glucose tolerant (NGT)) and 27 obese females with type 2 diabetes mellitus (T2DM) for this study. Weight loss was achieved by restrictive treatment (gastric banding or high-protein-low-calorie diet) or by RYGB. Fasting serum leptin, TSH, triiodothyronine (T3), reverse T3 (rT3), and free thyroxine (fT4) concentrations were measured at baseline and 3 weeks and 3 months after the start of the interventions.
Obesity was associated with higher TSH, T3, and rT3 levels and normal fT4 levels in all the subjects when compared with the controls. After 3 weeks, calorie restriction and RYGB induced a decline in TSH levels and a rise in rT3 and fT4 levels. The increase in rT3 levels correlated with serum interleukin 8 (IL8) and IL6 levels. After 3 months, fT4 and rT3 levels returned to baseline levels, whereas TSH and T3 levels were persistently decreased when compared with baseline levels. No differences in the effects on thyroid hormone parameters between the interventions or between NGT and T2DM subjects were observed at any time point.
In summary, weight loss directly influences thyroid hormone regulation, independently of the weight loss strategy used. The effects may be explained by a combination of decreased leptin levels and transient changes in peripheral thyroid hormone metabolism.
Agatha A van der Klaauw, Alberto M Pereira, Ton J Rabelink, Eleonora P M Corssmit, Anton-Jan Zonneveld, Hanno Pijl, Hetty C de Boer, Johannes W A Smit, Johannes A Romijn and Eelco J P de Koning
Adult patients with GH deficiency (GHD) are at increased risk for cardiovascular morbidity and mortality. Endothelial function, vascular stiffness, and loss of circulating CD34+ cells are considered biomarkers for cardiovascular disease. The aim of this study was to assess vascular structure and function in relation to circulating CD34+ cells in adults with GHD before and during 1 year of recombinant human GH (rhGH) replacement.
One-year intervention with rhGH.
Patients and methods
Vascular function (flow-mediated dilatation (FMD)) and structure (pulse wave velocity (PWV) and analysis) were assessed in 14 adult patients (nine men) with GHD (mean age 57 years, range 27–71 years). In addition, the number of CD34+ cells was evaluated using flow cytometric analysis. Study parameters were analyzed at baseline, and after 6 months and 1 year of rhGH replacement.
rhGH replacement increased IGF-I levels from 10.4±4.5 mmol/l at baseline to 18.4±10.1 mmol/l, and 20.5±8.0 mmol/l, at 6 months, and 1 year respectively (P=0.001). FMD increased from 3.5±1.8% to 6.0±2.5% and 5.1±2.5% during 1 year of rhGH replacement (P=0.008). There was no beneficial effect on PWV, central pulse pressure, central systolic pressure, and augmentation index. The number of CD34+ cells increased from 794.9±798.8 to 1270.7±580.1 cells/ml and to 1356.9±759.0 cells/ml (P=0.010).
One year of rhGH replacement in adults with GHD improves endothelial function and increases the number of circulating CD34+ cells.