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Herman Verloop, Olaf M Dekkers, Robin P Peeters, Jan W Schoones and Johannes W A Smit

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.

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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.

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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.

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Robbert B T Verkooijen, Frederik A Verburg, Johannes W van Isselt, Cornelis J M Lips, Jan W Smit and Marcel P M Stokkel

Introduction

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.

Methods

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.

Results

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).

Conclusion

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.

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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

Objective

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.

Design

We performed a prospective, 26-week phase II study with open-ended observations.

Methods

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.

Results

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).

Conclusions

The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.

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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

Objective

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.

Results

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.

Conclusions

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.

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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

Objective

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.

Design

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.

Results

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).

Conclusion

One year of rhGH replacement in adults with GHD improves endothelial function and increases the number of circulating CD34+ cells.

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Ilse G C Hermsen, Harm R Haak, Ronald R de Krijger, Thomas M A Kerkhofs, Richard A Feelders, Wouter W de Herder, Hanneke Wilmink, Jan W A Smit, Hans Gelderblom, Noel F C C de Miranda, Ronald van Eijk, Tom van Wezel and Hans Morreau

Background

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.

 The epidermal growth factor receptor (EGFR) has been implicated in the development of one-third of all malignancies. EGFR pathway members in ACC have been investigated, however, without available clinical data and relation to survival.

Methods

In this study, mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue.

Results

One BRAF, two EGFR TK domain (c.2590G>A, p.864A>T) and 11 T P53, but no PIK3CA or KRAS, mutations were found. No relationship was found between mutation status, immunostaining and mitotane response or survival.

Conclusion

In conclusion, our data suggest that the role of EGFR tyrosine kinase inhibitors in ACC is limited. Treatment with EGFR monoclonal antibodies on the other hand might be beneficial for a larger group of patients. The possible efficacy of this therapy in ACC should be evaluated in future trials.