Over- and Undertreatment With Levothyroxine.

BACKGROUND: Levothyroxine is a very commonly prescribed drug, and treatment with it is often insufficient or excessive. Nonetheless, there have been only a few reports on the determinants of inadequate levothyroxine treatment. METHODS: Data from 2938 participants in the population-based Rhineland Study were analyzed. Putative determinants of inadequate levothyroxine treatment (overtreatment, thyrotropin level <0.56 mU/L; undertreatment, thyrotropin level >4.27 mU/L) were studied with logistic regression. The determinants of the levothyroxine dose were assessed with linear regression. RESULTS: Overall, 23% of the participants (n = 662) stated that they were taking levothyroxine. Among these participants, 18% were overtreated and 4% were undertreated. Individuals over 70 years of age and above were four times as likely to be overtreated (OR = 4.05, 95% CI [1.20; 13.72]). Each rise in the levothyroxine dose by 25 µg was associated with an increased risk of overtreatment (OR = 1.02, 95% CI [1.02; 1.03]) and of undertreatment (OR = 1.02, 95% CI [1.00; 1.03]). Well-controlled participants (normal thyrotropin levels 0.56-4.27 mU/L) received a lower levothyroxine dose (1.04 ± 0.5 µg/kg/d) than overtreated (1.40 ±0.5 µg/kg/d) or undertreated (1.37 ±0.5 µg/kg/d) participants. No association was found between sociodemographic factors or comorbidities and the levothyroxine dose. Iodine supplementation was associated with a lower daily dose (ß = -0.19, 95% CI [-0.28; -0.10]), while three years or more of levothyroxine exposure was associated with a higher daily dose (ß = 0.24, 95% CI [0.07; 0.41]). CONCLUSION: Levothyroxine intake was high in our sample, and suboptimal despite monitoring. Our findings underscore the need for careful dosing and for due consideration of deintensification of treatment where appropriate.

Asymmetrical Transport of Thyroxine Across Human Term Placenta.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Binding Characteristics of Thyroid Hormone Distributor Proteins to Thyroid Hormone Metabolites.

Background: In contrast to the thyroid hormones (THs) 3,3',5-triiodothyronine (T3) and 3,3',5,5'-tetraiodothyronine (thyroxine or T4), the binding characteristics of the thyroid hormone distributor proteins (THDP), thyroxine-binding globulin (TBG), albumin, and transthyretin in relation to TH metabolites are mostly lacking. In this study, we determined the distribution and binding affinity of TH metabolites to THDP, which is important for adequate interpretation of TH metabolite concentrations. Methods: Distribution of 125I-3,3'-diiodothyronine (3,3'-T2), -T3, -3,3',5'-triiodothyronine (rT3), -3,3',5-triiodothyroacetic acid (TA3), and -3,3',5,5'-tetraiodothyroacetic acid (TA4) to TBG, transthyretin, and albumin was determined by agar gel electrophoresis. The rank order of affinity (IC50) of TBG and transthyretin to thyronine (T0), 3-monoiodothyronine (3-T1), 3,5-diiodothyronine (3,5-T2), 3,3'-T2, T3, rT3, T4, TA3, and TA4 was determined with a radioligand, competitive binding assay. In healthy subjects, associations of serum TBG, transthyretin, and albumin with TH and its metabolites were analyzed using multiple linear regression models, adjusted for sex and age. Results: While T3 and T4 are predominantly bound to TBG, we demonstrated that the predominant THDP of 3,3'-T2 and rT3 is albumin, of TA3 is transthyretin and albumin, and of TA4 is transthyretin. With the radioligand binding assay, we showed that the rank order of affinity was T4>TA4 = rT3>T3>TA3 = 3,3'-T2 > 3-T1 = 3,5-T2>T0 for TBG (IC50-range: 0.36 nM to >100 µM) and TA4>T4 = TA3>rT3>T3 > 3,3'-T2 > 3-T1 > 3,5-T2>T0 for transthyretin (IC50-range: 0.94 nM to >100 µM). TBG, transthyretin, and albumin were not associated with T0, 3-T1, 3,3'-T2, rT3, and TA4. Conclusions: Differences in serum TBG, transthyretin, and albumin concentrations within the reference interval do not influence serum concentrations of T0, 3-T1, 3,3'-T2, rT3, and TA4. Distribution of TH metabolites between THDP differs from T4 and T3, which predominantly bind to TBG. The results from our study have potential clinical importance for adequate interpretation of TH metabolism in (patho)physiology.

Change in Thyroid Hormone Metabolite Concentrations Across Different Thyroid States.

Background: In contrast to the thyroid hormones (TH) 3,3',5-triiodothyronine (T3) and thyroxine (T4), current literature on thyroid hormone metabolite concentrations in the hypothyroid and hyperthyroid states is inconclusive. It is unknown how thyroidectomy affects thyroid hormone metabolite concentrations and if levothyroxine (LT4) replacement therapy after thyroidectomy restores thyroid hormone metabolite concentrations in those without a thyroid gland. The treatment of patients with differentiated thyroid cancer (DTC) covers the euthyroid, hypothyroid, and (subclinical) hyperthyroid states and therefore provides a unique model to answer this. Here, we prospectively studied nine TH and its metabolites (THM) across different thyroid states in a cohort of patients treated for DTC. Also, three potentially important determinants for THM concentrations were studied. Methods: We prospectively included patients aged 18 to 80 years who were scheduled for DTC treatment at the Erasmus MC. Peripheral blood samples were obtained before surgery (euthyroid, endogenous TH production), after surgery just before radioactive iodine therapy (hypothyroid), and six months later on LT4 therapy ([subclinically] hyperthyroid, exogenous T4 supplementation). Nine THMs were quantified in serum with an established liquid chromatography/tandem mass spectrometry method. Repeated measurement analysis was used to compare the three different thyroid states with each other for each THM, while linear regression was used to determine the association between THM concentrations and age, sex, and kidney function. Results: In total, 77 patients (mean age 49 years; 65% women) were eligible for the study. 3,5-diiodothyronine and 3,3',5-triiodothyroacetic acids were below the lower limit of detection. Compared with the euthyroid state, all THMs were significantly decreased in the hypothyroid state and significantly increased in the (subclinically) hyperthyroid state, with T3 concentrations remaining within the reference interval. Higher age was associated with higher 3-monoiodothyronine (3-T1) concentrations (p < 0.001). Women had higher L-thyronine concentrations than men (p = 0.003). A better kidney function was associated with lower 3-T1 concentrations (p < 0.001). Conclusions: All THMs decrease after a thyroidectomy and increase under thyrotropin (TSH)-suppressive LT4-therapy, suggesting that formation of thyroid hormone metabolites is dependent on peripheral extrathyroidal metabolism of T4. This is also reflected by T3 concentrations that remained within the reference interval in patients receiving TSH-suppressive LT4-therapy as T3 has some thyroidal origin.

A Mass Spectrometry-Based Panel of Nine Thyroid Hormone Metabolites in Human Serum.

BACKGROUND: While thyroxine (T4), 3,3',5-triiodothyronine (T3), and 3,3',5'-triiodothyronine (rT3) have routine methods available for evaluating patients with suspected thyroid disease, appropriate methods for the measurement of other thyroid hormone metabolites (THMs) are lacking. The effects of other iodothyronines or iodothyroacetic acids are therefore less explored. To better understand the (patho)physiological role of THMs, a robust method to measure iodothyronines and iodothyroacetic acids in serum in a single analysis is needed, including associated reference intervals. METHODS: Clinical and Laboratory Standards Institute guidelines, European Medicines Agency guidelines, and the National Institute of Standards and Technology protocol were used for the method validation and reference intervals. Reference intervals were determined in 132 healthy males and 121 healthy females. Serum samples were deproteinized with acetonitrile, followed by anion-exchange solid phase extraction and analysis with LC-MS/MS, using eight 13C6-internal standards. RESULTS: The analytical method validation was performed for all nine THMs. Reference intervals (2.5th to 97.5th percentile) were determined for L-thyronine (4.9-11.3 ng/dL), 3-monoiodothyronine (0.06 --0.41 ng/dL), 3,5-diiodothyronine (<0.13 ng/dL), 3,3'-diiodothyronine (0.25--0.77 ng/dL), T3 (66.4--129.9 ng/dL), rT3 (15.0--64.1 ng/dL), T4 (4.3--10.0 µg/dL), triac/3,3',5-triiodothyroacetic acid (not detected), and tetrac/3,3',5,5'-tetraiodothyroacetic acid (2.2--27.2 ng/dL). CONCLUSIONS: A broad dynamic concentration range exists among the nine THMs. This method should help to develop a better understanding of the clinical relevance of other THMs, as well as an understanding of thyroid hormone metabolism in health and disease.