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.

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.

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.

Characteristics and natural course of hypoechoic thyroid lesions diagnosed as possible thyroid lymphomas by fine needle aspiration cytology.

BACKGROUND: There is little information regarding the natural course of hypoechoic thyroid lesions that are probable or possible thyroid lymphoma based on fine needle aspiration cytology (FNAC) results. METHODS: Sixty-five patients who were diagnosed as probable or possible thyroid lymphoma by ultrasonography (US) and FNAC were investigated. Forty-three patients with strong suspicion underwent thyroid surgery for the diagnosis at our hospital, and 22 patients were followed up with periodic US examination. Thyroid lymphoma was definitely diagnosed in 41 out of 43 patients who underwent thyroid surgery, and such patients were defined as Group A. The outcomes of 22 patients who were followed up without an immediate therapy were analyzed. Their hypoechoic lesions decreased in size (n = 10) or disappeared (n = 2) in 12 of 22 patients, and such patients were defined as Group B. Patients in Group A and B were compared using the Kuma Hospital-US classification (USC), the diagnostic categories of the Bethesda System for Reporting Thyroid Cytopathology, and the κ/λ deviation of the immunoglobulin light chain in the FNAC specimens. Mann-Whitney U-test and chi-squared test (with Yate's continuity correction) were used to compare the two groups. RESULTS: The USC of < 3.5 [9/12 (75.0%) in Group B; 10/41 patients (24.4%) in Group A] and the κ/λ deviation ratio of < 3.40 [11/12 (91.7%) in Group B; 17/41 patients (41.5%) in Group A] were significantly more frequent (p < 0.01), and the FNAC of 'benign' or 'atypia of undetermined significance or follicular lesion of undetermined significance (AUS)' with a comment of possible lymphoma [9/12 (75.0%) in Group B; 12/41 patients (29.3%) in Group A] was significantly more frequent (p < 0.05) in Group B than Group A. CONCLUSIONS: Our study suggests that some hypoechoic thyroid lesions that are possible thyroid lymphoma based on US and FNAC might decrease in size or disappear during the careful observation.

Comparative frequency of four different types of pregnancy-associated thyrotoxicosis in a single thyroid centre.

BACKGROUND: Pregnancy and delivery markedly influence thyroid function. However, the comparative prevalence of gestational thyrotoxicosis (GT), new onset of Graves' disease during pregnancy (GD during pregnancy), postpartum destructive thyrotoxicosis (PPT), and postpartum Graves' thyrotoxicosis (PPGD) has not yet been determined. METHODS: We prospectively registered and performed a review of 4127 consecutive non treated female patients with thyrotoxicosis, seen between August 2008 and December 2013 in our outpatient clinic of Kuma Hospital. 187 out of the 4127 women had new diagnosis of thyrotoxicosis during pregnancy or in the postpartum period. We investigated the prevalence of new diagnosis of GT, GD during pregnancy, PPT and PPGD and compared the characteristics of these types of thyrotoxicosis. The postpartum period is defined as twelve months after delivery. RESULTS: Out of 187 pregnant or postpartum women, we identified 30 (16.0%) with GT, 13 (7.0%) with GD during pregnancy, 42 (22.5%) with PPT, and 102 (54.5%) with PPGD. The onset time of thyrotoxicosis during pregnancy, i.e., both GT and GD during pregnancy, was delayed by a couple of weeks when hCG peaked at 10 gestational weeks. Seventy-six percent of patients with PPT developed thyrotoxicosis between delivery and 4 months postpartum; on the other hand, 83.3% of patients with PPGD developed thyrotoxicosis at 6 months postpartum or later. CONCLUSIONS: We named gestational thyrotoxicosis, new onset of Graves' disease during pregnancy, postpartum destructive thyrotoxicosis, and postpartum Graves' thyrotoxicosis as pregnancy-associated thyrotoxicosis. A clinically significant number of women developed Graves' disease in the postpartum period in a single thyroid centre.

Biochemical Markers Reflecting Thyroid Function in Athyreotic Patients on Levothyroxine Monotherapy.

BACKGROUND: Some investigators reported that among athyreotic patients on levothyroxine (LT4) monotherapy following total thyroidectomy, the patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas the patients with mildly suppressed serum TSH levels had normal serum fT3 levels, and the patients with strongly suppressed serum TSH had elevated serum fT3 levels. The objective of the present study was to clarify which of these three patient groups is closer to their preoperative euthyroid condition. METHODS: A total of 133 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy were prospectively studied. The patients' serum levels of lipoproteins, sex hormone-binding globulin, and bone metabolic markers measured preoperatively were compared with the levels measured at postoperative LT4 therapy 12 months after the thyroidectomy. RESULTS: The postoperative serum sex hormone-binding globulin (p < 0.001) and bone alkaline phosphatase (p < 0.01) levels were significantly increased in the patients with strongly suppressed TSH levels (≤0.03 µIU/mL). The postoperative serum low-density lipoprotein cholesterol levels were significantly increased (p < 0.05), and the serum tartrate-resistant acid phosphatase-5b levels were significantly decreased (p < 0.05) in the patients with normal TSH (0.3 < TSH ≤5 µIU/mL). In the patients with mildly suppressed TSH (0.03 < TSH ≤0.3 µIU/mL) and fT3 levels equivalent to their preoperative levels, all metabolic markers remained equivalent to their preoperative levels. CONCLUSIONS: The serum biochemical markers of thyroid function in patients on LT4 following total thyroidectomy suggest that the patients with mildly suppressed TSH levels were closest to euthyroid, whereas those with normal TSH levels were mildly hypothyroid and those with strongly suppressed TSH levels were mildly hyperthyroid. These data may provide novel information on the management of patients following total thyroidectomy for thyroid cancer or benign thyroid disease.

Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients.

OBJECTIVE: We and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (L-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established. METHODS: We retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental L-T4 (+L-T4) group (n=103); the HT+L-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels. RESULTS: The TT+L-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+L-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls. CONCLUSIONS: The presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels.