High FT4 Concentrations Research Articles

Association between thyroid function and osteoarthritis: a population-based cohort study

ObjectivesPrevious genetic and animal studies indicated a causal role of thyroid hormones in osteoarthritis (OA), which has not been observed in the general population. We aimed to investigate whether thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were associated with hand, hip, or knee OA. MethodsParticipants from the Rotterdam Study with baseline TSH, FT4, and joint radiographs were included. We used multivariable regression models to investigate the association of thyroid function with the prevalence, severity, incidence, and progression of OA. We conducted stratified analyses by sex, age, body mass index (BMI) and weight-bearing physical activity. ResultsAmong 9054 participants included (mean age 65 years, 56.3% women), higher FT4 concentrations were associated with an increased risk of prevalent knee OA (OR 1.04 per pmol/L, 95% CI 1.01-1.06, corresponding to an OR of 1.62 across the reference range [i.e., 14pmol/L changes] of FT4) and more severe knee OA. There was a positive association between FT4 and overall progression of knee OA (OR 1.03 per pmol/L, 1.00-1.07). No association of TSH with hand, hip, or knee OA was identified. Stratified analysis revealed an association between FT4 and prevalent knee OA among individuals with BMI≥30 kg/m2 (OR 1.05 per pmol/L, 1.01-1.08) and those with high levels of weight-bearing physical activity (OR 1.05 per pmol/L, 1.01-1.10). ConclusionsOur study indicated that higher FT4 concentrations may increase the risk of knee OA. This association might be greater in individuals with extra joint loading, such as those with obesity.

Hyperthyroidism, hypothyroidism, thyroid stimulating hormone, and dementia risk: results from the NHANES 2011-2012 and Mendelian randomization analysis.

As the world ages, dementia places a heavy burden on society and the economy, but current methods of diagnosing dementia are still limited and there are no better therapies that target the causes of dementia. The purpose of this work is to explore the relationship between thyroid disease, thyroid stimulating hormone (TSH) concentrations, free tetraiodothyronine (FT4) concentrations and cognitive function. This study utilized cognitive function and thyroid data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) to assess the relationship between different groups of TSH and FT4 concentrations and cognitive function using weighted logistic regression and restricted cubic spline (RCS), and then used two-sample Mendelian Randomization (MR) to assess the causal relationship between hyperthyroidism, hypothyroidism, TSH and FT4 concentrations with dementia. Our analysis of the 2011-2012 NHANES data showed that the individuals with low TSH concentrations had higher Alzheimer's Disease Word List Registry Consortium1 (CERAD1) and CERAD.delay.recall scores than individuals with high TSH concentrations, and individuals with low FT4 concentrations had higher CERAD3 and Animal Fluency Test scores than individuals with high FT4 concentrations. Our results also showed a non-linear relationship between serum TSH and FT4 concentrations and the Animal Fluency Test. The TSH concentrations within the range of 1.703 to 3.145 mIU/L exhibit a positive correlation with Animal Fluency Test, whereas concentrations outside this range are negatively correlated with Animal Fluency Test. The FT4 concentrations exhibited a positive correlation with Animal Fluency Test to the left of the FT4 concentrations inflection point (0.849 ng/L), whereas to the right of this inflection point, correlation was negative. MR analysis results further indicate that genetic predisposition to hyperthyroidism may be associated with a reduced risk of dementia and vascular dementia(VaD). Conversely, genetic predisposition to hypothyroidism appears to be linked with an increased risk of dementia and VaD. Additionally, genetic predisposition to elevated TSH concentrations may be correlated with a heightened risk of risk of Alzheimer's disease (AD). This study provides evidence of a nonlinear relationship between TSH and FT4 concentrations and cognitive function, with hyperthyroidism decreasing the risk of dementia and VaD, hypothyroidism increasing the risk of dementia and VaD, and elevated serum TSH concentrations increasing the risk of AD. Furthermore, prioritizing early detection, diagnosis, and treatment through the assessment of thyroid function in individuals at high risk for developing dementia is of paramount importance. This strategy has the potential to significantly contribute to the prevention and deceleration of dementia progression.

Large method differences for free thyroid hormone assays in the hyperthyroid range can affect assessment of hyperthyroid status: Comparison of Abbott Alinity to Roche Cobas, Siemens Centaur and equilibrium dialysis LC-MS/MS

BackgroundFree T4 (FT4) determination is one of the most commonly performed biochemical tests in endocrinology. Treatment of thyroid dysfunctions is adjusted based on the severity of symptoms and biochemical test results. For Graves’ hyperthyroidism, clinical guidelines recommend using FT4 as a (rough) guide to dose antithyroid drugs, together with other clinical information. It is well known that different platforms and methods give different FT4 results; however, large non-linear method differences at high FT4 concentrations are less well recognized. Current clinical guidelines do not make it clear that method differences in the hyperthyroid range can affect recommendations. MethodSerum samples from patients with very low (biochemically hypothyroid) to very high (hyperthyroid) concentrations of FT4 and/or free T3 (FT3) were analyzed using Abbott Alinity and compared to concentrations measured using Roche Cobas, Siemens ADVIA Centaur (FT4 only) and an in-house equilibrium dialysis liquid chromatography tandem mass spectrometry (LC-MS/MS) method. ResultsAlinity measured markedly lower FT4 and FT3 concentrations compared to the other methods, particularly at high FT4 concentrations. Regression analysis indicated that Alinity FT4 had a non-linear (curved) relationship to FT4 measured by the other methods. The method differences affected guideline-recommended treatments for hyperthyroidism. ConclusionMeasured free thyroid hormone concentrations are highly method-dependent, especially at high FT4 concentrations. Clinicians treating hyperthyroid patients should be aware that patients appear much less hyperthyroid from FT4-measurements performed using Alinity compared to Cobas or Centaur. Guideline-recommended antithyroid drug dosages based on FT4 (including multiples of the upper reference range) have to be adjusted to the FT4 method used. FT4 results from different methods should be clearly distinguished (e.g. separate lines) in medical records.

Higher free thyroxine associated with PFAS exposure in first trimester. The Odense Child Cohort.

BackgroundPerfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings. ObjectivesTo investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH). MethodsIn the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status. ResultsA doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses. ConclusionExposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified.

Offspring conceived through ART have normal thyroid function in adolescence and as young adults.

STUDY QUESTIONAre there differences in thyroid function between adolescents and young adults conceived with and without ART?SUMMARY ANSWERThis study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART.WHAT IS KNOWN ALREADYStudies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential.STUDY DESIGN, SIZE, DURATIONThe Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13–20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14- or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population.PARTICIPANTS/MATERIALS, SETTING, METHODSThyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on individual thyroid hormone concentrations, was compared: euthyroidism, subclinical and overt hypo- and hyperthyroidism and thyroid autoimmunity. Outcomes were compared between the cohorts, and univariately between fresh embryo transfers (ET) and frozen ET (FET) within the GUHS. The correlation between maternal peak E2 concentrations (pE2) and fT4 was assessed within the GUHS.MAIN RESULTS AND THE ROLE OF CHANCEAll mean thyroid function outcomes fell within the normal range. At both ages, we report no differences in TSH concentrations. At age 14 years, lower fT3 concentrations (4.80 versus 5.35 pmol/L, P < 0.001) and higher fT4 concentrations (12.76 versus 12.19 pmol/L, P < 0.001) were detected in the GUHS adolescents compared to Gen2 adolescents. At age 20 years, higher fT3 and fT4 concentrations were reported in GUHS adolescents (4.91 versus 4.63 pmol/L, P = 0.012; 13.43 versus 12.45 pmol/L, P < 0.001, respectively) compared to Gen2 participants. No differences in the prevalence of subclinical and overt hypo- and hyperthyroidism or thyroid autoimmunity were demonstrated between the cohorts at age 14 and 20 years. Thyroid function did not differ between ET and FET, and no correlation between pE2 and fT4 was reported.LIMITATIONS, REASONS FOR CAUTIONThe observational nature of the study limits the ability to prove causation. Furthermore, the comparison of ET and FET offspring at age 20 years may be lacking power. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI) owing to the low number of ICSI cycles at the time of study. As ART laboratory and clinic data were collected contemporaneously with the time of treatment, no other data pertaining to the ART cycles were sought retrospectively; hence, some factors could not be accounted for.WIDER IMPLICATIONS OF THE FINDINGSThis study does not support previous findings of clinically relevant differences in thyroid function when comparing a cohort of adolescents conceived after ART to counterparts conceived without ART. The minor differences detected in fT3 and fT4 were considered not biologically relevant. Although these findings appear reassuring, they warrant reinvestigation in adulthood.STUDY FUNDING/COMPETING INTERESTSThis project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director and a shareholder of PIVET Medical Centre, Perth, Western Australia.TRIAL REGISTRATION NUMBERN/A.

Misleading FT4 measurement: Assay-dependent antibody interference

IntroductionCommonly used free thyroxine (FT4) immunoassays can be falsely elevated due to interference causing misinterpreted thyroid function. We present two cases with high FT4 concentrations due to antibody interference. This study’s aim was to investigate the source of the FT4 immunoassay interference and possibility of its removal by two different techniques in order to correct the discrepancy between obtained FT4 values and the patient’s clinical status.Materials and methodsTwo patients presented at their general practitioners’ with elevated FT4 concentrations in combination with a normal and increased thyroid stimulating hormone (TSH) concentrations. Clinical symptoms differed between patients but did not correspond with the hyperthyroid status suggested by the laboratory results. FT4 concentrations from both patients were measured on four common commercial immunoassays and the dialysis method before and after treatment with heterophilic blocking tubes and protein A/G.ResultsRemoval of interfering antibodies using protein A/G resulted in normal FT4 concentrations.ConclusionThis report illustrates falsely elevated FT4 concentrations due to assay interference on the Immulite immunoassay analyser caused by heterophilic antibodies, which were eliminated by protein A/G treatment. We point out the importance of a close collaboration between doctors and the laboratory to avoid unnecessary clinical intervention.

Concentrations of Thyroid Axis Hormones in Psychotic Patients on Hospital Admission: the Effects of Prior Drug Use

The aim of this study was to determine the concentrations of thyroid axis hormones in psychotic patients on hospital admission and to search for the associations between the concentrations of these hormones and prior drug use as well as mental symptoms. MATERIAL AND METHODS. Psychiatric diagnoses, psychotropic drug use, and the severity of psychoses were evaluated using the standard methods on admission. Venous blood from patients and healthy controls was drawn for the analysis of free thyroxin (FT(4)), free triiodothyronine (FT(3)), thyroid-stimulating hormone (TSH), and sex hormone-binding globulin (SHBG) concentrations. RESULTS. Eighty-one psychotic patients, free of a thyroid disorder, were enrolled into the study. Compared with the controls, they displayed the higher FT(4) concentrations in the general group (P=0.003) and the higher SHBG concentrations only in men (P=0.013). The FT(4) concentration was higher in the patients who were not taking an antipsychotic drug on admission (P=0.039). No significant correlation was found between the severity of psychosis and concentrations of thyroid axis hormones. However, the FT(3) concentration in the general group and TSH concentration in women correlated with the factor of the Brief Psychiatric Rating Scale expressing elevated mood. CONCLUSIONS. Our study confirms the higher FT(4) concentrations in a significant proportion of acute psychotic patients. The concentrations of thyroid axis hormones were found to be associated with prior antipsychotic treatment on hospital admission.

Depressive disorder and thyroid axis functioning during pregnancy

Background. Depression and thyroid dysfunction are prevalent in women, including pregnant women. The aim of this study was to assess the relationship between depression and thyroid function during pregnancy. Methods. One hundred and ninety-nine pregnant women three times during pregnancy were assessed for depressive disorder and for thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations. Results. Prevalence of depressive disorder was 6.5% in early pregnancy, 3.0% in middle pregnancy and 3.5% in late pregnancy. There were no women with overt thyroid dysfunction. Subclinical hyperthyroidism was found in 23% of women in early pregnancy, in 5% of women in middle pregnancy and in 6% of women in late of pregnancy. In late pregnancy depressed women compared to non-depressed women had significantly higher FT4 concentrations and a strong trend towards lower TSH concentrations as well as higher prevalence of subclinical hyperthyroidism. Conclusions. These findings show an association between thyroid dysfunction and depression in late pregnancy. Because gestational depression might interfere with pregnancy outcome, evaluation of thyroid function during gestation is warranted.

Perinatal Outcome of Children Born to Mothers with Thyroid Dysfunction or Antibodies: A Prospective Population-Based Cohort Study

There are only a few large prospective studies involving evaluation of the effect of maternal thyroid dysfunction on offspring and observations are inconsistent. The objective of the study was to investigate the effects of thyroid dysfunction or antibody positivity on perinatal outcome. The study included prospective population-based Northern Finland Birth Cohort 1986 including 9247 singleton pregnancies. First-trimester maternal serum samples were analyzed for thyroid hormones [TSH, free T(4) (fT4)] and antibodies [thyroid-peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab)]. Mothers were classified by their hormone and antibody status into percentile categories based on laboratory data and compared accordingly. Outcomes were perinatal mortality, preterm delivery, absolute and gestational age-adjusted birth weight, and absolute and relative placental weight. The offspring of TPO-Ab- and TG-Ab-positive mothers had higher perinatal mortality, which was not affected by thyroid hormone status. Unadjusted and adjusted (for maternal age and parity) risk for increased perinatal mortality was an odds ratio of 3.1 (95% confidence interval 1.4-7.1) and 3.2 (1.4-7.1) in TPO-Ab- and 2.6 (1.1-6.2) and 2.5 (1.1-5.9) in TG-Ab-positive mothers. TPO-Ab-positive mothers had more large-for-gestational age infants (2.4 vs. 0.8%, P = 0.017), as did mothers with low TSH and high fT4 concentrations vs. reference group (6.6 vs. 2.5%, P = 0.045). Significantly higher placental weights were observed among mothers with low TSH and high fT4 or high TSH and low fT4 levels as well as among TPO-Ab-positive mothers. First-trimester antibody positivity is a risk factor for perinatal death but not thyroid hormone status as such. Thyroid dysfunction early in pregnancy seems to affect fetal and placental growth.

Performance of direct equilibrium dialysis and analogue-type free thyroid hormone assays, and an immunoradiometric TSH method in patients with thyroid dysfunction

Direct equilibrium dialysis and analogue-type radio-immunoassays for free triiodothyronine (FT3) and free thyroxine (FT4) in serum were compared in 168 subjects with various states of thyroid function. A good diagnostic efficacy for FT3 and FT4 by either type of assay was observed in hyperthyroidism. In hypothyroidism the free thyroid hormone assays, particularly the FT3 assays, performed diagnostically less well, partly because patients with mild disease were included in the study. No significant differences in the percentages of misclassifications of thyroid dysfunction patients by corresponding dialysis and analogue assays were found. We observed a good linear correlation between dialysis and analogue methods for FT3 (r = 0.98) and FT4 (r = 0.97) in this study comprising out-patients not suffering from severe non-thyroidal disease, known from earlier studies in this and other laboratories to interfere in these assays. It is concluded that analogue assays may be used on out-patients in whom severe systemic diseases are less frequent than in hospitalized patients. There are, however, other limitations to the use of analogue assays than systemic diseases. We observed two euthyroid patients with thyroxine auto-antibodies causing very high FT4 concentrations as determined by analogue assay; their dialysable FT4 concentrations were normal. We also tested a recently developed immunoradiometric serum TSH assay, which was found to perform well in primary hypo- and hyperthyroidism. Serum TSH was elevated in one patient hyperthyroid because of a TSH-producing pituitary adenoma, and within the reference limits in a patient with secondary hypothyroidism.