Tim I M Korevaar and Robin P Peeters
Robin P Peeters, Wendy M van der Deure and Theo J Visser
Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.
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.
Georg Brabant, Robin P Peeters, Shiao Y Chan, Juan Bernal, Philippe Bouchard, Domenico Salvatore, Kristien Boelaert and Peter Laurberg
Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.
Layal Chaker, Sanaz Sedaghat, Ewout J Hoorn, Wendy P J Den Elzen, Jacobijn Gussekloo, Albert Hofman, M Arfan Ikram, Oscar H Franco, Abbas Dehghan and Robin P Peeters
Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally.
Prospective cohort study.
Participants aged ≥45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR <60 mL/min/1.73 m2 according to the CKD-EPI formula.
We included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (β): −1.75 mL/min; 95% confidence interval (CI): −2.17, −1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (β: −0.06 mL/min; CI: −0.11, −0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend = 0.04).
Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.
Samer R Khan, Arjola Bano, Marlies Wakkee, Tim I M Korevaar, Oscar H Franco, Tamar E C Nijsten, Robin P Peeters and Layal Chaker
Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results.
We assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis.
8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease.
Within the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27–2.31) for TPO-Ab positivity, 1.25 (CI: 1.14–1.37) for AITD and 1.34 (CI: 1.16–1.54) respectively, and 1.17 (CI: 1.03–1.32) for hypothyroidism and hyperthyroidism.
Our meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.
Mirjana Barjaktarovic, Tim I M Korevaar, Romy Gaillard, Yolanda B de Rijke, Theo J Visser, Vincent W V Jaddoe and Robin P Peeters
The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association.
Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7–8.0 years).
Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan.
FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV.
At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.
Chantal Zevenbergen, Tim I M Korevaar, Andrea Schuette, Robin P Peeters, Marco Medici, Theo J Visser, Lutz Schomburg and W Edward Visser
Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions.
In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT4), tri-iodothyronine (T3), reverse T3, T4, and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models.
Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT4 levels, and positively with T3 levels. Cu was positively associated with T4, T3, and rT3, which was largely dependent on TBG levels.
The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted.
Marloes Louwerens, Bente C Appelhof, Herman Verloop, Marco Medici, Robin P Peeters, Theo J Visser, Anita Boelen, Eric Fliers, Johannes W A Smit and Olaf M Dekkers
Research on determinants of well-being in patients on thyroid hormone replacement therapy is warranted, as persistent fatigue-related complaints are common in this population. In this study, we evaluated the impact of different states of hypothyroidism on fatigue and fatigue-related symptoms. Furthermore, the relationship between fatigue and the TSH receptor (TSHR)-Asp727Glu polymorphism, a common genetic variant of the TSHR, was analyzed.
A cross-sectional study was performed in 278 patients (140 patients treated for differentiated thyroid carcinoma (DTC) and 138 with autoimmune hypothyroidism (AIH)) genotyped for the TSHR-Asp727Glu polymorphism.
The multidimensional fatigue inventory (MFI-20) was used to assess fatigue, with higher MFI-20 scores indicating more fatigue-related complaints. MFI-20 scores were related to disease status and Asp727Glu polymorphism status.
AIH patients scored significantly higher than DTC patients on all five MFI-20 subscales (P<0.001), independent of clinical and thyroid hormone parameters. The frequency of the TSHR-Glu727 allele was 7.2%. Heterozygous DTC patients had more favorable MFI-20 scores than wild-type DTC patients on four of five subscales. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue was found in DTC patients only.
AIH patients had significantly higher levels of fatigue compared with DTC patients, which could not be attributed to clinical or thyroid hormone parameters. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue in DTC patients should be confirmed in other cohorts.
Karen A Heemstra, Wendy M van der Deure, Robin P Peeters, Neveen A Hamdy, Marcel P Stokkel, Eleonora P Corssmit, Johannes A Romijn, Theo J Visser and Johannes W Smit
It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T3), free thyroxine (FT4), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships.
We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma.
We measured BMD of the femoral neck and lumbar spine. FT4, T3, TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay.
We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT4 and T3 levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index.
We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.