Athyreotic Patients Research Articles

Analysis of dose-TSH response effect of levothyroxine soft-gel formulation.

Hypothyroidism is treated with daily levothyroxine (LT4). In recent years, soft gel caps of LT4 (LT4-C) have been commercialized, and their performance has been optimized. Since guidelines recommend dose LT4 according to the tablet preparation efficacy, the present study was undertaken to obtain data about the daily requirement, normalized per body weight, of LT4-C. Patients undergoing LT4-C after total thyroidectomy and radioiodine treatment for differentiated thyroid carcinoma were selected. There was no specific indication of suppression of TSH (i.e., <0.5 or <0.1 mIU/L). Patients were required to maintain a stable LT4 dose during the study period. Patients with interfering factors were excluded from this study. Thirty patients were enrolled (18 females and 12 males; median age, 50 years; median body weight, 71 kg; median LT4-C dose, 1.71 µg/kg/day). The analysis of patient age did not reveal any differences. The LT4-C dose correlated with free-T4 p = 0.03), but not with TSH (p = 0.42) and free-T3 (p = 0.13). TSH was <1.0 mIU/L in 90% of the cases. The LT4-C dose-TSH response effect was analysed by probit regression model: the probability to achieve TSH <1.0 mIU/l was 99% with a dose of 1.84 (95%CI 1.57-2.12) µg/kg/day, 75% with a dose of 1.38 µg/kg/day (95%CI 1.17-1.59), and 50% with a dose of 1.20 (95%CI 0.96-1.43). At ROC curve analysis, the most accurate cut-off of LT4-C dose to achieve TSH <1.0 mIU/l was 1.53 ug/kg/day with 70% sensitivity and 100% specificity. Athyreotic patients can be initially treated with an LT4-C dose lower than previously stated. Therefore, further prospective studies are warranted.

Current status of the thyroid hormone measurement items in patients receiving levothyroxine monotherapy by the management based on the thyroid tissue volume.

We and other investigators reported that mild TSH suppression with levothyroxine (LT4) was needed to achieve normal free triiodothyronine (FT3) levels and metabolic euthyroid state in athyreotic patients. Consequently, management methods based on thyroid tissue volume have been implemented for patients receiving LT4 at the Kuma Hospital. This retrospective study examined the composition of the thyroid hormone measurement items (serum-free thyroxine [FT4], FT3, and FT4 + FT3) in patients receiving LT4 monotherapy. According to the etiology of hypothyroidism, 36% of the 25,523 patients included in this study underwent total thyroidectomy (TT). Thirteen percent and 14% had undergone 131I treatment for hyperthyroidism (RIT) and partial thyroidectomy (PT), respectively. Moreover, 37% of patients had received non-invasive treatment (NIT). The proportion of patients who underwent only FT3 measurements was higher (TT, 93%; RIT, 61%) in the first two groups, whereas the proportion of patients who underwent only FT4 measurements was higher (PT, 50%; NIT, 65%) in the remaining two groups. Only FT3 measurements were performed in 58% of patients. Only FT4 measurements were performed in 34% of patients. The serum TSH levels were suppressed in nearly half of the patients (46%). Thus, FT3 was the major thyroid hormone measured in patients receiving LT4 treatment, and the serum TSH levels were suppressed in nearly half of the patients. This may be attributed to the management guidelines at our hospital, a specialized facility for thyroid disease, wherein half of the patients present are athyreotic or have atrophic thyroid glands after TT or RIT.

A Clinical Audit of Thyroid Hormonal Replacement After Total Thyroidectomy.

Background Thyroid hormone replacement (THR) in athyreotic patients post-thyroidectomy due to thyroid cancer might seem like a straightforward clinical issue to address. To investigate the impact of THR on enhancing thyroid-stimulating hormone (TSH) levels, we conducted a clinical audit, tailoring the dosage based on patient weight and aligning with the standards outlined by the National Institute for Health and Care Excellence and the American Thyroid Association guidelines. Methodology This retrospective and prospective audit analyzed outpatient clinic records for hormone replacement therapy (HRT) post-total thyroidectomy. Retrospective data from March to May 2022 were collected, followed by prospective data after interventions adjusting HRT based on patient weight to digitize clinic notes. The second phase involved changes for 20 scheduled thyroidectomy patients among the total 37 included in the study. Results The thyroid profiles of both groups in the initial and subsequent cycles, treated with adjusted doses of THR, exhibited normal levels of thyroid hormones and calcium. No substantial differences were observed between the groups. On multivariate logistic regression analysis, we found that older age, male sex, body mass index, and preoperative TSH level were the only significant predictors of the need for hormonal therapy. Conclusions Optimal dose of THR after total thyroidectomy had a positive effect on TSH levels in hypothyroidism patients. Hence, THR should be prescribed according to patient weight based on standards and guidelines.

How Should I Take My Levothyroxine?

How Should I Take My Levothyroxine?

Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management.

Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves’ ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.

Selpercatinib-Induced Hypothyroidism Through Off-Target Inhibition of Type 2 Iodothyronine Deiodinase.

The development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid. Thyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases. Upon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels. An off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Proportion of serum thyroid hormone concentrations within the reference ranges in athyreotic patients on levothyroxine monotherapy: a retrospective study

BackgroundIn patients receiving thyroid-stimulating hormone (TSH) suppressive therapy with levothyroxine (LT4) after total thyroidectomy for thyroid cancer, thyroid function tests should be performed to adjust the LT4 dose. Specifically, serum TSH concentrations are commonly measured because TSH suppression is necessary according to thyroid cancer risk. The aim of the present study was to elucidate whether free thyroxine (FT4) or free triiodothyronine (FT3) indicates better for adjusting the dose in athyreotic patients on LT4 monotherapy after total thyroidectomy.MethodsWe retrospectively studied the compatibility of free thyroid hormone (FT4 and FT3) concentrations with reference ranges in athyreotic patients on LT4 monotherapy after total thyroidectomy.ResultsWe identified 2210 consecutive patients from their medical records. Of these patients, 250 had both FT4 and FT3 concentrations in addition to TSH. Two hundred seven had serum TSH concentrations below the reference range (0.5–5.0 μIU/mL), while 43 had them within the reference range. In the 207 patients with TSH concentrations below the reference range, 61 patients (29.5%) had FT4 concentrations within the reference range (0.9–1.7 ng/dL) and 146 patients (70.5%) had FT4 concentrations above the reference range. In contrast, 10 patients (4.8%) had FT3 concentrations below the reference range (2.3–4.0 pg/mL) and 8 (3.9%) had FT3 concentrations above the reference range; 189 patients (91.3%) had concentrations within the reference range. Of the 43 patients with TSH concentrations within the reference range, 25 (58.1%) had FT4 concentrations within the reference range and 18 (41.9%) had FT4 concentrations above the reference range. While, 11 patients (25.6%) had FT3 concentrations below the reference range and one (2.3%) had FT3 concentrations above the reference range; hence, 31 patients (72.1%) had FT3 concentrations within the reference range.ConclusionThis study showed that measuring FT3 concentrations rather than FT4 concentrations as the subsequent parameter of thyroid function might be more useful for disease management in terms of the proportion of serum thyroid hormone concentrations within the reference ranges. Furthermore, FT3 measurement could be useful in providing more detailed treatments, including avoiding more aggressive TSH suppressive therapy and identifying the presence of low T3 syndrome in the background.

Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Abstract #1004012: Nivolumab-Associated Exacerbation of Hypothyroidism in an Athyreotic Patient

Immune checkpoint inhibitor therapy (ICI) can cause various endocrinopathies, including thyroid dysfunction. Hypothyroidism following ICI therapy has been reported in individuals with intact thyroid. We present a case of worsening hypothyroidism in an athyreotic patient following nivolumab therapy.

High-Dose Thyroid Hormone Replacement in Bexarotene-Induced Central Hypothyroidism

Background: Central hypothyroidism is a rare disorder characterized by a defect in thyroid hormone production by an otherwise normal thyroid gland due to decreased stimulation by TSH. Medications are an uncommon cause. Case Presentation: A 72-year-old man was referred for evaluation of a low TSH. He had a long history of hypothyroidism, euthyroid on levothyroxine, and was diagnosed with cutaneous T cell lymphoma (CTCL). Due to disease progression on dapsone, PUVA and TAR baths, he was started on bexarotene. Soon after, he developed recurrent symptoms of hypothyroidism including fatigue, cold intolerance, dry skin, and myalgias. Workup revealed a TSH of <0.01 ulU/mL (0.27-4.20) with a free T4 of 0.6 ng/dl (0.9-1.7). After evaluation, his levothyroxine dose was increased. Repeat labs 3 months later showed a TSH of <:0.01 with a free T4 0.8 ng/dl and T3 43 ng/dl (80-200). Over several months, levothyroxine titration to a supraphysiologic dose of 800 mcg daily was required, despite optimal administration, to normalize FT4. Given persistent hypothyroid symptoms and a low T3 level, liothyronine 5 mcg BID was added and resulted in clinical and biochemical euthyroidism. Clinical Lessons: Unlike in primary thyroid disorders, the TSH assay is unreliable in central hypothyroidism since values can be low, normal, or even mildly elevated; regardless, TSH has subnormal bioactivity. Ineffectual TSH leads to a low T4, which is a required for diagnosis. Bexarotene, a derivative of Vitamin A, is a retinoid X receptor (RXR) selective ligand approved for the treatment of CTCL. The exact mechanism of bexarotene-induced thyroid dysfunction is not clear, although it involves both central and peripheral effects. Bexarotene inhibits TSH gene expression by decreasing the activity of the thyrotropin β subunit gene promoter in a dose-dependent and thyroxine-independent manner; TSH levels drop as early as 4-8 hours after exposure. Bexarotene also directly lowers T4 and T3 levels, even in athyreotic patients, by negatively impacting deiodinase activity and hepatic conjugation. Stopping bexarotene is often not possible given its effectiveness in CTCL. Therefore, thyroid hormone should be initiated with the goal of achieving a normal FT4, although as the current case demonstrates, massively supraphysiologic doses and/or the addition of liothyronine may be necessary to achieve clinical euthyroidism.

Association between serum thyroid hormone balance and thyroid volume in patients treated with levothyroxine monotherapy for hypothyroidism.

Many previous studies including ours have reported that athyreotic patients on levothyroxine (LT4) have relatively low serum free triiodothyronine (FT3) levels, whereas patients with large goitrous diseases often have high serum FT3 levels. Here we investigated Hashimoto thyroiditis (HT) patients on LT4 to study the relationship between thyroid volume (TV) and thyroid hormone status in hypothyroid patients on LT4. We retrospectively studied 408 euthyroid HT patients treated with LT4 for hypothyroidism; divided them as per TV and compared serum levels of free thyroxine (FT4) and FT3 and the FT3/FT4 ratio in each patient group with those in euthyroid matched control group. We also evaluated the association between serum FT3 level and FT3/FT4 ratio and TV among HT patients on LT4. In patients with TV <15 mL, serum FT3 levels were significantly lower than those in controls. In patients with TV 15-80 mL, serum FT3 levels were equivalent to those in controls. In patients with TV ≥80 mL, the serum FT3 levels were significantly higher than those in controls. The serum FT3 level (r = 0.35, p < 0.01) and FT3/FT4 ratio (r = 0.42, p < 0.01) showed a positive correlation with TV. TVs in HT patients on LT4 caused differences in serum thyroid hormone balance, as increasing volume increases the serum FT3 level and FT3/FT4 ratio. Serum thyroid hormone balance in HT patients with smaller thyroids was similar to that in athyreotic patients. Mild thyrotropin suppression with LT4 is needed to achieve normal FT3 levels in such patients.

SUN-420 Spontaneous Changes in TSH Levels After Thyroidectomy During Long-Term Follow-Up

Background. Spontaneous serum TSH variations during levothyroxine replacement therapy and multiple dose changes in athyreotic patients seem to be frequent in clinical practice. Aim. To describe the rate and extent of spontaneous serum TSH variations in patients after total thyroidectomy for differentiated thyroid cancer (DTC) in real-life practice, and the number of resulting levothyroxine (LT4) dose adjustments. Methods. Data of DTC patients were prospectively collected at a single referral center between January 2005 and May 2019. TSH and fT4 serum levels, LT4 dose and formulation, and concomitant medications were recorded at 1, 3, and 12 months after primary treatment (surgery ± radioiodine therapy), and then yearly; the data were retrospectively evaluated for this study. Visit at one month was used to tailor LT4 dose and was not considered into the data analysis. Patients with structural evidence of disease or during pregnancy were excluded. Results. Data of 2883 evaluations (472 patients) were collected; at baseline, the median age was 49.7 years, 73.5% were females. The LT4 formulation administered at baseline were tablets (84.9%), liquid solution (11.4%), or soft-gel capsule (3.7%). Overall, in 27.5% of clinical evaluation with unchanged levothyroxine dose (341/1243), there were meaningful spontaneous TSH variations (defined as delta TSH > 1.5 mcUI/ml) at yearly follow-up visit. It is clinically significant: in 6.6% of visits, overt thyrotoxicosis was recorded. Furthermore, the treating clinicians decided to change the LT4 dose in 37.1% of cases. These figures were not significantly higher in the first years, and a rate above 25% persist even after ten years of follow-up. The median maintenance dose needed was 1.61 (interquartile range [IQR] 1.41-1.92) mcg/Kg/day for tablets, 1.54 (IQR 1.39-1.79) mcg/Kg/day for liquid solution, and 1.46 (IQR 1.23-1.71) mcg/Kg/day for soft-gel capsules. After correction for daily dose, there was no difference in the rate of TSH variations > 1.5 mcUI/ml, or in the absolute value of median delta of TSH between the three formulations. In 20.1% of patients, the LT4 formulation was changed during the follow-up: it was more common in patients with a known gastroenteric disease (OR 1.76, p=0.03). Conclusions. TSH spontaneous variations and dose adjustments are very common in patients after total thyroidectomy, even during long-term follow-up: wide variations happen in more than 1/4 of all visits, and dose changes are needed in more than 1/3 of all evaluations. We were more inclined to change LT4 formulation in patients with known interference in LT4 absorption: however, no difference in TSH variations was recorded between users of three different formulations, even if soft-gel capsules seem to have a lower maintenance dose.

Serum Thyroid Hormone Balance in Levothyroxine Monotherapy-Treated Patients with Atrophic Thyroid After Radioiodine Treatment for Graves' Disease

Background: Some studies reported that among athyreotic patients on levothyroxine (LT4) after total thyroidectomy, patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum fT3 levels. The reduction of the thyroid volume (TV) after radioiodine treatment for Graves' disease is well known; however, a few studies evaluated thyroidal function including serum triiodothyronine (T3) levels of hypothyroid patients on LT4 after radioiodine treatment in detail.Methods: We retrospectively studied 446 patients treated with LT4 for radioiodine-induced hypothyroidism and who had undergone ultrasonography. We compared serum fT4 and fT3 levels in hypothyroid patients on LT4 who presented an atrophic thyroid change after radioiodine treatment, with those in the euthyroid matched control group with intact thyroids. We also stratified patients with normal TSH levels according to TV and evaluated serum thyroid hormone levels.Results: In 356 of 446 (80%) patients, TV was lower than the lower limit of the 95% reference range of controls. Excluding 43 patients with high serum TSH levels, we assessed thyroid function test results in 313 patients with atrophic thyroid glands. Of these cases, eight patients with strongly suppressed TSH levels had serum fT3 levels that were significantly higher than those in controls (p < 0.001). Overall, 27 patients with mildly suppressed TSH levels had serum fT3 levels equivalent to those in controls (p = 0.386), whereas 278 patients with normal TSH levels had serum fT3 levels that were significantly lower than those in controls (p < 0.001). We also assessed fT3 levels relative to TV in 326 patients with normal TSH levels. Of these cases, in 267 patients with TV less than 5 mL and in 46 patients with TV between 5 and 10 mL, serum fT3 levels were significantly lower than those in controls (p < 0.001). In 13 patients with TV more than 10 mL, serum fT3 levels were equivalent to those in controls (p = 0.844).Conclusions: Serum thyroid hormone balance in most patients on LT4 after radioiodine treatment for Graves' disease was similar to that in athyreotic patients on LT4. Mild TSH suppression with LT4 is needed to achieve normal fT3 levels in such patients.

Variants in MCT10 protein do not affect FT3 levels in athyreotic patients.

Several single-nucleotide polymorphisms in genes encoding for transporters have been associated with serum thyroid hormone concentrations with inconsistent results. The aim of this study was to assess the clinical significance of the rs17606253 in SLC16A10 gene alone and in combination with the DIO2 Thr92Ala variation in athyreotic patients. One-hundred patients submitted to total thyroidectomy and treated with levothyroxine were included. Pre- and post surgical serum TSH levels did not differ by more than ± 0.5 mIU/l. Both patients carrying the wild-type allele or heterozygous for rs17606253 in SLC16A10 gene had a significant reduction in FT3 post surgical levels (p = 0.01 and p < 0.0001, respectively) while Thr92Ala in DIO2 gene was associated with reduced FT3 levels for heterozygous and rare homozygous patients (p < 0.0001 and p = 0.01, respectively). We identified two groups ("FT3 unchanged" and "FT3 reduced") using a cutoff of at least 0.5 pg/ml as a significant variation between pre- and post surgical FT3 values. In this case, the rs17606253 was not statistically associated with reduced FT3 levels at genotype and allele levels. On the contrary, the Thr92Ala in DIO2 gene was confirmed statistically associated with reduced FT3 levels after surgery with a p = 0.035 at genotype level and p = 0.014 at allele level. We confirmed the role of DIO2 Thr92Ala polymorphism on T3 levels. On the contrary, SLC16A1 rs17606253 polymorphism did not impair hormone levels in athyreotic patients treated with levothyroxine therapy.

Changes in TSH levels in athyreotic patients with differentiated thyroid cancer during levothyroxine therapy: influence on dose adjustments.

The aim of the study was to describe the spontaneous TSH level variations and levothyroxine dose adjustments in athyreotic patients with differentiated thyroid cancer (DTC) in real-life practice. Patients with DTC were retrospectively evaluated at a tertiary referral center between October 2006 and November 2013. Hormone measurements (TSH and FT4 serum levels), L-T4 prescription information (dose per kg per day) and other medications were recorded at 1month and 3, 12, 24, 36 and 48months after primary treatment (surgery ± radioiodine therapy). The cohort was composed of 452 patients; about 20% of patients with stable levothyroxine dose have clinically meaningful spontaneous TSH variations (defined as ΔTSH > 2mcUI/mL) at yearly follow-up visit. Furthermore, about 25% of athyreotic DTC patients with stable dose have a ΔTSH > 1.5mcUI/mL and about 40% a ΔTSH > 1mcUI/mL during each follow-up visit. We further investigated whether this TSH variation would lead to subsequent dose changes. About 19.9-37.7% of DTC patients on stable LT4 dose on the previous visit had their levothyroxine dose reduced, while 7.8-14.9% increased due to TSH variations. We further evaluated the decision to change the dose in relation with the age-specific TSH range. Up to 77.2% of patients had their dose adjusted due to TSH falling below the age-specific range. Spontaneous serum TSH variations determine levothyroxine replacement therapy in athyreotic patients with DTC, requiring multiple dose changes.

CGE19-062: The Rs1388378 Polymorphism in the Human DIO2 Gene is Associated with Decreased L-Thyroxine Dose Requirement in Thyroidectomized Patients

Background: Patients with differentiated thyroid cancer (DTC) are usually managed with total thyroidectomy and subsequent radioiodine ablation of the remnant thyroid tissue. L-thyroxine (L-T4) therapy (about 2 µg/kg) is required for life, with a wide variation in patient dose requirements. The iodothyronine deiodinase types I, II, and III (DIO1, DIO2, and DIO3, respectively) regulate the activity of the thyroid hormone via removal of specific iodine moieties from the precursor molecule T4. During LT4 replacement, the active hormone triiodothyronine (T3) levels strictly depend on DIO2-mediated activation of LT4. Therefore, the aims of this study were to investigate the association of DIO1 and DIO2 polymorphisms with DTC and L-T4 dose requirement in the Saudi population. Methods: A total of 1,067 (560 controls and 507 DTC thyroidectomized cases) Saudi Arabs were included. Serum free thyroxine and TSH levels were measured in the cases. We genotyped 1 DIO1 variant rs2294512_G and 3 DIO2 SNPs, rs1388378_T, rs12885300_T, rs225013_T, by TaqMan assay. Results: The DIO1 and DIO2 genotyping revealed an association between L-T4 dose requirement and rs1388378_T. Patients carrying the rs1388378_T allele required a lower l-T4 dose (145.91±33.31; P=.035). No significant association was found for these SNPs with cancer risk. Conclusions: Our study identified 1 DIO2 variant associated with L-T4 dose requirement. Thyroidectomized patients carrying T allele of rs1388378 need lower L-T4 dose to maintain normal TSH level thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.

Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients.

Previous reports by us and other investigators showed that among athyreotic patients on levothyroxine (LT4) following total thyroidectomy patients with normal serum thyroid-stimulating hormone (TSH) levels had mildly low serum free triiodothyronine (FT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum FT3 levels and patients with strongly suppressed serum TSH had elevated serum FT3 levels. The objective of this study was to clarify which of these three patient groups are closer to their preoperative euthyroid condition based on reported subjective symptoms. We prospectively studied 148 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy. Symptoms reflecting thyroid function documented preoperatively and following 12 months of LT4 after thyroidectomy were compared. In 65 patients with strongly suppressed TSH levels significant changes in symptoms with tendencies towards thyrotoxicosis were seen with regards to heat and cold tolerance (p < 0.01), bowel movements (p < 0.05), and hand tremors (p < 0.05). In 33 patients with normal TSH levels, significant changes in symptoms with tendencies towards hypothyroidism were seen with regards to heat and cold tolerance (p < 0.05) and activity (p < 0.05). Lastly, in 50 patients with mildly suppressed TSH levels and FT3 levels equivalent to preoperative levels, all symptom items remained equivalent to their preoperative levels. Symptoms reflecting thyroid function in patients on LT4 following total thyroidectomy suggested that patients with mildly suppressed TSH levels were closest to a euthyroid status. These data provide useful findings regarding the management of patients following total thyroidectomy.

The association between thyroid hormone balance and thyroid volume in patients with Hashimoto thyroiditis.

While patients with large goitrous thyroid diseases often have a relatively high serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio, athyreotic patients have a relatively low FT3/FT4 ratio. Here we investigated the relationship between thyroid hormone status and thyroid volume (TV) among a large number of euthyroid Hashimoto thyroiditis (HT) patients. We retrospectively enrolled 2,603 untreated HT patients who visited the Kuma hospital from 2012 to 2016, and divided them into four groups as per the TV: normal TV (<20 mL), slight goiter (20 ≤ TV < 50 mL), moderate goiter (50 ≤ TV < 80 mL), and the large goiter group (≥80 mL). Baseline characteristics and laboratory data of each group were compared to those of 1,554 control subjects. The association between FT3/FT4 ratio and TV among HT patients was then analyzed. We observed a change in laboratory parameters among 13 patients in the large goiter group who were prescribed levothyroxine (LT4) for reducing TV. Compared to normal subjects, the moderate and large goiter groups exhibited significantly higher serum FT3 levels, while all HT groups exhibited lower serum FT4 levels. Serum FT3/FT4 ratios showed a positive correlation with TV (r = 0.35, p < 0.01), which was independent of age, sex, body mass index, and TgAb and TSH levels. LT4 treatment lowered serum FT3 levels and FT3/FT4 ratios significantly. Our results indicated that HT patients with increased TV tended to present with high serum FT3, low FT4, and high FT3/FT4 ratios. The elevation of deiodinase activity may be an important factor affecting thyroid hormonal balance in such patients.

Comparison of Thyroid Hormones in Euthyroid Athyreotic Patients Treated with Levothyroxine and Euthyroid Healthy Subjects

Comparison of Thyroid Hormones in Euthyroid Athyreotic Patients Treated with Levothyroxine and Euthyroid Healthy Subjects

Decreased sensitivity of thyrotropin-thyroid hormone feedback control in hypothyroid and athyreotic patients treated with levothyroxine. Is serum triiodothyronine involved?

ObjectivesThe search for optimal therapy for hypothyroidism is challenging and complex and is still going on. We investigated TSH-thyroid hormone feedback control in hypothyroid and athyreotic patients properly treated with levothyroxine (LT4), based on normal TSH values. Material and methodsWe randomly selected 150 hypothyroid, 110 athyreotic and 210 euthyroid subjects, determined their serum T4, T3 and TSH values and calculated T4/TSH and T3/T4 ratios. ResultsThe TSH distribution in hypothyroidism was significantly shifted to the higher and that in athyreosis to the lower values from the normal distribution in euthyroid controls. This TSH-thyroid hormone dissociation in hypothyroidism was characterized with higher T4 and higher matched TSH values. We found 5% hypothyroid and 10% athyreotic patients normalize TSH only with hyperthyroxinemia. Serum T3 was lower in both hypothyroid groups and unaffected by a higher LT4 dose and higher serum T4 in athyreosis. ConclusionOur results suggest that the decreased serum T3 is a major cause of impaired TSH-thyroid hormone feedback control in hypothyroidism treated with LT4.