Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Interference against a newly labeled substance with ruthenium sulfonate complexes showing discrepant thyroid function test results.

We report here two patients exhibiting a combination of falsely elevated serum levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin receptor antibodies (TRAb), measured using Elecsys assay kits (Roche Diagnostics GmbH). The first patient was a 74-year-old man misdiagnosed with Graves' disease and treated with methimazole. The second patient was a 48-year-old woman whose serum FT4 and FT3 concentrations were found to be high during a blood test. These patients denied taking biotin or any other supplements. Further detailed examination, including a heterophilic blocking tube test, revealed the presence of serum antibodies. The abnormal reactions were observed only using the improved assay kits using ruthenium (Ru) sulfonate instead of Ru as a chemiluminescent agent. Therefore, serum antibodies to the Ru sulfonate complex caused the pseudo-high levels of FT4, FT3, and TRAb. To our knowledge, this is the first report showing that antibodies to the Ru sulfonate complex in the electrochemiluminescence immunoassay can cause falsely elevated levels of the combination, leading to discrepant thyroid function test results. We emphasize that in cases of abnormal test results, alternative assay methods should be considered for further examination; unusual test results should not be impulsively interpreted, even when using revised assay kits.

Long-Term Outcomes of Active Surveillance and Immediate Surgery for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma: 30-Year Experience.

Background: It has been 30 years since the initiation of active surveillance (AS) for adult patients with low-risk papillary thyroid microcarcinoma (PTMC). This study compared the long-term oncological outcomes of patients who underwent AS or immediate surgery (IS). Methods: This is a retrospective review of extended follow-up data from patients enrolled in a single-center, prospective observational study in Japan. In total, 5646 patients diagnosed with low-risk PTMC at Kuma Hospital between 1993 and 2019 were enrolled in this study. Of these, 3222 patients underwent AS (AS group), whereas 2424 underwent IS (IS group). The patients were followed up regularly, at least once per year. Descriptive outcome data were presented according to the treatment group. Results: In the AS group, 124 patients (3.8%) had tumor enlargement of ≥3 mm, and the 10- and 20-year enlargement rates were 4.7% and 6.6%, respectively. Novel lymph node metastases occurred in 27 patients (0.8%), and the 10- and 20-year nodal metastasis occurrence rates were 1.0% and 1.6%, respectively. In the IS group, 13 patients (0.5%) experienced lymph node recurrence postoperatively, and the 10- and 20-year nodal recurrence rates were 0.4% and 0.7%, respectively. Eighteen (1.4%) of the 1327 patients who underwent hemithyroidectomy experienced recurrence in the residual thyroid. The rate of lymph node metastasis was significantly higher in the AS group than in the IS group (1.1% vs. 0.4% and 1.7% vs. 0.7% at 10 and 20 years, respectively; p = 0.009), but the differences were small. However, the proportion of patients who underwent one or more and two or more surgeries was significantly higher in the IS group than in the AS group (100% vs. 12.3% and 1.07% vs. 0.09%, p < 0.01). Distant metastatic recurrence was observed in one patient after AS and conversion surgery and another after IS; however, they were alive (18.4 and 18.8 years after diagnosis, respectively). None of the patients in this study died of thyroid carcinoma. Conclusions: Long-term oncological outcomes of patients with PTMC generally did not differ clinically significantly between those undergoing AS and IS. AS is a viable initial management option for patients with low-risk PTMC.

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

BACKGROUND: In 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. METHODS: We retrospectively studied the compatibility of free thyroid hormone (FT4 and FT3) concentrations with reference ranges in athyreotic patients on LT4 monotherapy after total thyroidectomy. RESULTS: We 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. CONCLUSION: This 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.

Serum thyroglobulin evaluation on LC-MS/MS and immunoassay in TgAb-positive patients with papillary thyroid carcinoma.

Objective: This study aimed to elucidate disproportionately low serum thyroglobulin (Tg) values in Tg antibody (TgAb)-positive patients with structural recurrence of papillary thyroid carcinoma (PTC) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Design: A retrospective study was performed on 176 patients in whom Tg and TgAb levels were measured between 2016 and 2021. Several comprehensive analyses of Tg-LC-MS/MS with an electrochemiluminescence immunoassay for Tg (Tg-ECLIA) were conducted using serum samples. Methods: TgAb-positive patients who underwent total thyroidectomy with multiple lung metastases due to PTC were evaluated using Tg-LC-MS/MS and Tg-ECLIA. Tg expression in lymph node metastases and metastatic lesions was evaluated by immunohistochemistry and Tg levels of aspiration washouts were also evaluated. Two in vitro assays were performed to elucidate TgAb interference. Results: Tg concentrations of negative TgAb in both assays were similar (R2 = 0.99; n = 52). Patients with structural recurrence showed higher Tg values with Tg-LC-MS/MS than with Tg-ECLIA. The undetectable proportion was significantly lower with Tg-LC-MS/MS (31.6%, 6/19) than with Tg-ECLIA (68.4%, 13/19; P = 0.023). The spike-recovery rate and Tg concentrations determined by the serum mixture text (n = 29) were significantly reduced to 75.0% (118.3-88.7%) and 81.3% (107.0-87.0%), respectively, with TgAb using Tg-ECLIA (both P > 0.001) confirming assay interference but not using Tg-LC-MS/MS (91.8-92.3%, P = 0.77 and 98.4-100.8%, P = 0.18, respectively). Conclusions: TgAb had no effect on the Tg-LC-MS/MS assay but yielded 19-25% lower values in Tg-ECLIA. Tg-LC-MS/MS is preferable for monitoring serum Tg levels in TgAb-positive patients, although those with structural recurrence often had disproportionally low Tg values.

The magnitude of increased Levothyroxine dose during pregnancy in patients on thyroid-stimulating hormone (TSH) suppression treatment after total thyroidectomy for papillary carcinoma.

The dose of L-T4 replacement for hypothyroidism often needs to be increased after pregnancy. In our institution, patients are instructed to double the dose 2 days a week after pregnancy. However, there is scarce evidence supporting the need for a dose increase after pregnancy in patients with preconception thyroid-stimulating hormone (TSH) suppression (TSH <0.3 µIU/mL). This study aimed to determine the need for a dose increase in L-T4 among women with a TSH-suppressive dose of L-T4 before pregnancy. In this retrospective observational study, between January 2008 and December 2018, we analyzed 166 pregnancies in 134 patients on TSH suppression treatment after total thyroidectomy for papillary carcinoma. Thyroid function tests were performed before and in the first trimester of pregnancy. The dose was adjusted and maintained during the first trimester of pregnancy in 76 pregnancies (group A) and 90 pregnancies (group B), respectively. The median serum TSH level was significantly lower in group A than that in group B (0.014 µIU/mL (IQR, 0.005-0.071) vs. 0.155 µIU/mL (IQR, 0.021-0.657), p < 0.001). TSH suppression could not be maintained after pregnancy in 15.8% and 38.9% of the pregnancies in groups A and B, respectively. Increasing the post-pregnancy dose by an average of 27.4% resulted in maintenance of TSH suppression after pregnancy in 84.2% of pregnancies. In conclusion, this study suggests that increasing the L-T4 dose after pregnancy may be appropriate in postoperative thyroid cancer patients whose serum TSH levels should be suppressed.

Hypothyroidism due to nephrotic syndrome: a notable clinical entity.

Nephrotic syndrome (NS) is characterized by massive urinary protein leakage and associated hypoproteinemia due to increased protein permeability caused by impaired renal glomerular connections. Although there have been several sporadic reports regarding the relationship between NS and thyroid dysfunction, a consensus has yet to be reached. The mechanism of hypothyroidism in NS is attributed to the loss of protein-bound thyroid hormones, such as thyroxine-binding globulin, transthyretin, and albumin, into the urine. Herein, we report four adults with hypothyroidism that developed or worsened due to the onset of NS. The patients' underlying thyroid status was post-total thyroidectomy with supplemental levothyroxine (L-T4) in two patients, hypothyroidism with supplemental L-T4 due to Hashimoto's disease in one patient, and Hashimoto's disease with normal thyroid function in one patient. Our results suggest that the presence of a reduced thyroid reserve may predispose patients to hypothyroidism in NS. We conclude that NS may cause or exacerbate hypothyroidism. In such cases, an NS assessment, including a urine test, is required.

Prevalence and Treatment Outcomes of Marine-Lenhart Syndrome in Japan.

INTRODUCTION: Marine-Lenhart syndrome (MLS) is now understood to be a combination of Graves' disease and autonomously functioning thyroid nodule(s) (AFTNs). The prevalence of the syndrome and suitable treatments for those living in iodine-sufficient areas are uncertain. OBJECTIVES: We aimed to investigate the prevalence, treatment, and prognosis of MLS in Japan, an iodine-sufficient area. METHODS: This study involved patients who visited our hospital between February 2005 and August 2019. Among patients with both thyrotoxicosis and thyroid nodule(s) larger than 10 mm, MLS and isolated AFTNs were diagnosed based on serum thyroid-stimulating hormone receptor antibody levels and scintigraphy using radioiodine or technetium-99m and thyroid uptake. RESULTS: Twenty-two patients were found to have MLS, compared to 372 with isolated AFTNs and 8,343 with Graves' disease, during the period. Therefore, the rate of MLS cases was 0.26% among all patients with Graves' disease (22/8,343). Treatments and outcomes were assessed for cases of MLS (n = 18) and isolated AFTNs (n = 269). Antithyroid drugs (ATDs) were withdrawn in 27.8% of cases in the MLS group and 10.3% in the isolated AFTN group. There was no significant difference in the clinical outcome after ATD withdrawal between the 2 groups. However, the rate of hypothyroidism after radioactive iodine (RAI) administration was significantly higher in the MLS group than in the isolated AFTN group (42.9 vs. 9.0%, p = 0.005) despite similar doses of RAI. CONCLUSIONS: The prevalence of MLS among patients with Graves' disease was 0.26% in Japan. RAI therapy induces hypothyroidism more frequently than in those with AFTNs probably because RAI is taken up in the surrounding Graves' tissues.

Autoimmune thyroid disease and thyroid function test fluctuations in patients with resistance to thyroid hormone.

OBJECTIVE: Resistance to thyroid hormone beta (RTHß) is an inherited syndrome caused by mutations in the thyroid hormone receptor ß (THRB) gene. Patients with RTHß typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHß patients and further to explore their association with THRB gene mutations. DESIGN AND METHODS: We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHß patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital. RESULTS: Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHß patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHß. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD. CONCLUSIONS: The frequency of AITD in male RTHß patients was significantly higher compared to unaffected relatives. More than 20% of RTHß patients temporarily showed laboratory findings atypical of RTHß during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Poorly Differentiated Thyroid Carcinoma Coexisting with Graves' Disease Involving T3 Thyrotoxicosis due to Increased D1 and D2 Activities.

Background: Poorly differentiated thyroid carcinoma is rare and patients are typically euthyroid. We report a novel rare case of poorly differentiated thyroid carcinoma with triiodothyronine (T3) thyrotoxicosis. Patient's Findings: A 77-year-old man presented to Kuma Hospital due to a neck tumor. A thyroid ultrasonography revealed a 220-mL mass in the right lobe. Laboratory data showed low serum thyrotropin (TSH), low free thyroxine (fT4), and high free T3 (fT3) levels. Anti-TSH receptor antibodies and thyroid-stimulating antibodies were positive. 131I scintigraphy showed diffuse uptake only in the left thyroid lobe. The patient underwent a total thyroidectomy and histological examination identified as poorly differentiated thyroid carcinoma. He was diagnosed with poorly differentiated thyroid carcinoma coexisting with Graves' disease. The tumor showed elevated type 1 iodothyronine deiodinases (D1) and type 2 iodothyronine deiodinases (D2) activities compared with that of the left thyroid lobe. Summary and Conclusions: Increased D1 and D2 activities in poorly differentiated carcinoma resulted in T3 toxicosis with a high serum fT3/fT4 ratio.

Favorable outcomes of papillary thyroid microcarcinoma concurrent with Graves' disease after radioactive iodine therapy.

Graves' disease (GD) may coexist with papillary thyroid microcarcinoma (PTMC). The main purpose of this study was to evaluate whether treatment with radioactive iodine (RAI) may cause acute exacerbation of PTMC concurrent with GD or not. From the medical records of 10,257 GD patients who underwent RAI therapy between 2000-2017, 12 subjects with concurrent PTMC were retrieved. Further, 49 patients with concurrent GD and PTMC who underwent no RAI administration throughout their clinical course were enrolled as controls. Size of the PTMC nodules was evaluated based on maximal diameter and tumor volume-doubling rate (TV-DR). Among the 12 subjects who underwent RAI therapy (median dose, 13 mCi), 2 showed tumors >10 mm in maximal diameter with slow growth for more than 10 years, while the other 10 showed tumors with maximal diameter ≤10 mm. No subject showed any clinical findings of nodal or distant metastasis during the follow-up periods (0.4-11.5 years) before surgery or during active surveillance. No significant differences were observed in the TV-DR values (median, 0.044/year; range, -0.81-1.40) between the study subjects and controls (median, 0.025/year; range, -0.70-1.29; p = 0.69). When comparing the TV-DR before and after RAI administration in 3 individuals in particular, in whom PTMC were cytologically confirmed before RAI administration and whose prospective follow-up data were available, tumor progression was observed to be stable or decreased after RAI administration. There were no acute exacerbations or unfavorable outcomes of concurrent PTMC and GD after low-dose RAI administration.

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.

Papillary thyroid carcinomas are highly obscured by inflammatory hypoechoic regions caused by subacute thyroiditis: a longitudinal evaluation of 710 patients using ultrasonography.

Subacute thyroiditis is a self-limited inflammatory disease and very few patients undergo ultrasonographic re-examination if no nodules are found at the initial examination. The objective of the study was to assess the diagnostic accuracy of ultrasonography in detecting nodular lesions in patients with subacute thyroiditis. We conducted a longitudinal study involving 710 patients with subacute thyroiditis who underwent ultrasonographic examinations in a single center between 2008 and 2018. These examinations were performed at initial diagnosis and during follow-up, with subsequent evaluation of nodules using fine needle aspiration cytology. Ultrasonographic examination used for the initial screening of thyroid nodules in patients with subacute thyroiditis showed a sensitivity of 72.4%, specificity of 89.0%, positive predictive value of 80.4%, and negative predictive value of 83.8%. Twenty-two patients (3.1%) had concomitant papillary thyroid carcinoma, 10 of whom underwent thyroidectomy while the remaining 12 opted for active surveillance owing to having low-risk microcarcinomas. Approximately 30% of papillary carcinomas (7/22) were identified during follow-up ultrasonography, but not during the initial scan. All tumors in this false-negative group were latently localized in the bilateral hypoechoic regions of the thyroid and showed no calcified components. Of the 15 tumors that were detected during both initial and follow-up examinations, 7 exhibited calcified components and 5 were located in unaffected areas apart from the inflammatory hypoechoic region. Subacute thyroiditis highly obscures any coexisting papillary carcinoma when inflammatory hypoechoic regions are present. Ultrasonographic re-examination after a sufficient interval is indispensable for patients with subacute thyroiditis.

Quality of Life in Patients with Low-Risk Papillary Thyroid Microcarcinoma: Active Surveillance Versus Immediate Surgery.

OBJECTIVE: This study aimed to compare the quality of life (QoL) and psychological issues of patients with papillary thyroid microcarcinoma (PMC) who were under active surveillance (AS) and those who underwent immediate surgery (OP). METHODS: This was a cross-sectional study conducted on 347 patients with low-risk PMC who were under AS (n = 298) or who underwent OP (n = 49). They were asked to complete two questionnaires (thyroid cancer-specific health-related QoL [THYCA-QoL] and the Hospital Anxiety and Depression Scale [HADS]). The results between the AS and OP groups were compared. RESULTS: The mean ages of patients in the AS and OP groups were 58.6±12.5 and 58.4±13.1 years (P =.94), respectively, and the male ratios were 34/298 (11%) and 2/49 (4.1%) (P =.14), respectively. The median follow-up periods from diagnosis in the AS and OP groups were 56.5 months (interquartile range [IQR], 32 to 88 months) and 84 months (IQR, 64 to 130 months) (P<.001), respectively. In the THYCA-QoL questionnaire, the OP group had more complaints about "voice" (P<.001), "psychological" (P =.025), "problems with scar" (P<.001), and "gained weight" (P =.047) than the AS group. Other scales of the THYCA-QoL were comparable in the two groups. In the HADS questionnaire, the AS group had significantly better anxiety (P =.020), depression (P =.027), and total scores (P =.014) than the OP group. CONCLUSION: PMC patients in the OP group had more complaints and were more anxious and depressed than the AS group. These findings suggest that AS is a reasonable alternative to surgery for patients with low-risk PMC from the point of view of QoL and psychology. ABBREVIATIONS: AS = active surveillance; CI = confidence interval; HADS = Hospital Anxiety and Depression Scale; LT4 = levothyroxine; OP = immediate surgery; PMC = papillary microcarcinoma; PTC = papillary thyroid carcinoma; QoL = quality of life; STAI = State-Trait Anxiety Inventory; THYCA-QoL = thyroid cancer-specific health-related quality of life; TSH = thyrotropin.

Moderate Frequency of Anti-Thyroglobulin Antibodies in the Early Phase of Subacute Thyroiditis.

BACKGROUND: Subacute thyroiditis is generally believed to be induced by viral infection, and little attention has been paid to anti-thyroid antibodies. OBJECTIVES: Our study aimed to assess the prevalence of anti-thyroid antibodies in patients with subacute thyroiditis. METHODS: Anti-thyroglobulin (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were measured with 4 different immunoassay kits currently used in 40 patients in the early phase of subacute thyroiditis. RESULTS: The proportion of samples positive for TgAb was 52.5 ± 13.7% (mean of 4 kits), which was significantly (p < 0.05) higher than that positive for TPOAb (15.6 ± 6.5%). The prevalence of positive TgAb alone (negative TPOAb) was also significantly higher than that of TPOAb alone (negative TgAb). TgAb titers decreased or disappeared within 4 months to 6 years in 6 patients. CONCLUSIONS: Patient samples were moderately positive for TgAb initially, but the titer decreased or disappeared afterwards in subacute thyroiditis.

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.

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.

Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with huge goitrous Hashimoto's thyroiditis.

PURPOSE: The serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio in patients with huge goitrous Hashimoto's thyroiditis (HG-HT) is relatively high. We investigated the cause of high FT3/FT4 ratios. METHODS: We measured the serum FT3, FT4, and thyrotropin (TSH) levels of seven patients with HG-HT who had undergone a total thyroidectomy. Eleven patients with papillary thyroid carcinoma served as controls. The activities and mRNA levels of type 1 and type 2 iodothyronine deiodinases (D1 and D2, respectively) were measured in the thyroid tissues of HG-HT and perinodular thyroid tissues of papillary thyroid carcinoma. RESULTS: The TSH levels in the HG-HT group were not significantly different from those of the controls. The FT4 levels in the HG-HT group were significantly lower than those of the controls, whereas the FT3 levels and FT3/FT4 ratios were significantly higher in the HG-HT group. The FT3/FT4 ratios in the HG-HT group who had undergone total thyroidectomy and received levothyroxine therapy decreased significantly to normal values. Both the D1 and D2 activities in the thyroid tissues of the HG-HT patients were significantly higher than those of the controls. However, the mRNA levels of both D1 and D2 in the HG-HT patients' thyroid tissues were comparable to those of the controls. Interestingly, there were significant correlations between the HG-HT patients' D1 and D2 activities, and their thyroid gland volume or their FT3/FT4 ratios. CONCLUSIONS: Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT3/FT4 ratio in patients with HG-HT.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.