Search

Subclinical autoimmune thyroiditis exacerbates after delivery through immune rebound mechanism and may result in five types of thyroid dysfunction. Overall, the prevalence is around 5% in most countries. Typically, an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism, defined as postpartum thyroiditis. Late development of permanent hypothyroidism is found frequently and patients should have thyroid function testing once every 1 to 2 years. Destructive thyrotoxicosis in postpartum thyroiditis should carefully be differentiated from postpartum Graves’ disease. Onset time of postpartum thyroiditis is 1–6 months after parturition but Graves’ disease typically develops at 3–12 months postpartum. Anti-TSH receptor antibodies are raised and thyroid blood flow is increased in Graves’ disease but not in postpartum thyroiditis. Postpartum Graves’ disease should be treated with antithyroid drugs.

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.

Subclinical autoimmune thyroiditis exacerbates after delivery through immune rebound mechanisms and results in 5 types of thyroid dysfunction. The prevalence of postpartum thyroid dysfunction is around 5% in mothers in the general population. Typically, an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism, known as postpartum thyroiditis. Late development of permanent hypothyroidism is found frequently and patients should be followed up once every one to two years. Destructive thyrotoxicosis in postpartum thyroiditis should carefully be differentiated from post-partum Graves' disease. Postpartum thyroiditis typically occurs 1-4 months after parturition whereas Graves' disease develops at 4-12 months postpartum. Anti-TSH receptor antibodies (TRAb) are typically positive and thyroid blood flow is high in Graves' disease, whereas these features are absent in postpartum thyroiditis. Postpartum Graves' disease should be treated with antithyroid drugs.

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.

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

It is generally believed that the detection of thyroid peroxidase antibodies (TPOAb) is superior to that of thyroglobulin antibodies (TgAb) for the diagnosis of Hashimoto's thyroiditis. However, limited data are available on the comparison of TgAb and TPOAb prevalence as a diagnostic measurement for Hashimoto's thyroiditis using sensitive immunoassays. We herein used five different current immunoassay kits (A-E) to compare the prevalence of TgAb and TPOAb in Hashimoto's thyroiditis (n = 70), Graves' disease (n = 70), painless thyroiditis (n = 50), and healthy control subjects (n = 100). In patients with Hashimoto's thyroiditis, positive TgAb was significantly more frequent than positive TPOAb in kits A-D (mean ± SD of the four kits: 98.6 ± 1.7 vs 81.4 ± 2.0%). In patients with Graves' disease, TgAb prevalence was almost equivalent to that of TPOAb in five kits. Patients with painless thyroiditis exhibited positive TgAb significantly more frequently than positive TPOAb in kits A-D (73.5 ± 4.1 vs 33.0 ± 3.4%). The prevalence of TgAb alone was significantly higher than that of TPOAb alone in both Hashimoto's thyroiditis and painless thyroiditis in kits A-D. In kit E, TgAb and TPOAb prevalence did not differ significantly for any disease, and TgAb distribution was different from other kits. In conclusion, the prevalence of TgAb was higher than that of TPOAb in patients with Hashimoto's thyroiditis and painless thyroiditis using commercially available kits. We suggest that TgAb immunoassay is the first choice of screening test for thyroid autoimmune abnormalities in Japan.

ObjectiveWe 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.MethodsWe retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplementall-T4(+l-T4) group (n=103); the HT+l-T4group (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/FT4ratio in individual patients with those of controls matched by serum TSH levels.ResultsThe TT+l-T4group had significantly higher FT4(P3(P3/FT4(Pl-T4group had FT4, FT3and FT3/FT4levels equivalent to those of the controls. The HT-alone group had significantly lower FT4(P3(P=0.083), and significantly higher FT3/FT4(PConclusionsThe presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3levels.

A 54-year-old woman with subclinical hypothyroidism developed liver dysfunction after increasing dose of levothyroxine (L-T4) in tablet form (Thyradin S(®)) from 25μg to 50μg. Viral hepatitis, autoimmune hepatitis and NASH were ruled out with examinations. After cessation of levothyroxine in 50μg tablet form, liver enzymes gradually returned to normal. She was diagnosed levothyroxine-induced liver injury, based on criteria proposed in DDW-J 2004 workshop. Thyradin S(®) powder 0.01% (here in after referred to as L-T4 in powder form) was tried as an alternative, and liver enzymes have remained within normal range. As for Thyradin S(®) tablet, additives are different for each type of levothyroxine sodium content. The difference of additive is whether Fe2O3 is contained or not: it is not included in Thyradin S(®) 50μg tablet and powder form. Although there are two case reports in the Japanese literature and three case reports in the English literature of liver dysfunction suspected due to L-T4, we cannot find past reports about cases of drug induced liver dysfunction due to Fe2O3 free levothyroxine tablet form. This is a rare case report of drug induced liver injury due to Fe2O3 free levothyroxine tablet form, and administration of L-T4 in powder form may be useful for treatment of cases similar to this one.

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.

Background The cytological findings in conventional specimens (C-S) and liquid-based cytology specimens (LBC-S) are not quite same. The aim of this article is to clarify the cytological findings of papillary thyroid carcinoma (PTC) characteristic of LBC-S. Methods Out of 5,971 cases diagnosed in a single institution from March to September in 2012, 161 PTC cases with both C-S and LBC-S were reviewed. Additionally, we compared the findings with those in LBC-S of 55 adenomatous or hyperplastic nodule (AN) and 21 follicular neoplasm (FN) cases. Results Compared to C-S, the incidences of trabecular and hobnail patterns, collagenous stroma, naked capillaries, intercellular spaces, convoluted nuclei, eosinophilic nucleoli, and perinucleolar halo were increased. Pale nuclei were observed in only one of 161 PTC cases. Specificity of convoluted nuclei and perinucleolar halo were 97.4% and 96.1%, respectively. Conclusion Convoluted nuclei and perinucleolar halo might become a new indicator of PTC in LBC-S. Contrarily, we should be aware that pale nuclei are rarely observed in LBC-S. Diagn. Cytopathol. 2015;43:108–113. © 2014 Wiley Periodicals, Inc.

Postpartum thyroid dysfunction occurs in approximately 5-10% of women in the general population within one year of delivery. Differentiation of postpartum Graves' thyrotoxicosis (PPGr) from postpartum destructive thyrotoxicosis (PPDT) is essential because of the difference in treatment measures between the two. However, it is sometimes difficult because radioactive iodine uptake is contraindicated when patients are lactating. We examined the usefulness of determining the time of onset postpartum and measurement of antithyrotropin (anti-TSH) receptor antibodies and thyroid blood flow.Forty-two patients with newly developed thyrotoxicosis after delivery were examined: 18 had Graves' disease and 24 had destructive thyrotoxicosis. Serum free thyroxine (fT4), free triiodothyronine (fT3), and TSH were measured by chemiluminescent immunoassays. Anti-TSH receptor antibodies (TRAb), antithyroglobulin antibodies (TgAb), and antithyroid peroxidase antibodies (TPOAb) were measured by the Elecsys electrochemiluminescence immunoassay. Thyroid volume and blood flow (TBF) were measured quantitatively by color flow Doppler ultrasonography.Onset of thyrotoxicosis was distributed from 2 to 12 months postpartum. Twelve (85.7%) of 14 patients who developed thyrotoxicosis at three months or earlier after delivery had PPDT. On the other hand, all 11 patients who developed thyrotoxicosis at 6.5 months or later had PPGr. All patients with PPGr had positive TRAb (14.9±14.9 IU/L, mean±standard deviation (SD)) and all patients with PPDT had negative TRAb (0.1±0.3 IU/L, p0.0001). Fifteen (83.3%) of 18 PPGr patients had high TBF of more than 4.0% (8.9±4.4), and all PPDT patients had low TBF of4.0% (1.6±1.0, p0.0001). The fT3/fT4 ratio was higher in PPGr (64.0±23.9) than in PPDT (38.9±13.1, p0.0002), but absolute values overlapped between the two.Early onset of thyrotoxicosis postpartum was associated mainly with PPDT, and a late onset was suggestive of PPGr. Positive TRAb and high TBF4.0% are indicators of postpartum onset of Graves' disease.

Oral glucocorticoids are administered in moderate and severe cases of subacute thyroiditis (SAT), providing dramatic relief from pain and fever. However, there have been no reports regarding the optimal dose of prednisolone (PSL) for treatment of SAT. In this study, we used 15 mg/day of PSL as the initial dosage and tapered it by 5 mg every 2 weeks. We assessed the effectiveness of this treatment protocol.We examined 384 consecutive and untreated patients with SAT who visited our thyroid clinic between February 2005 and December 2008. We excluded patients who did not fit our protocol, and the final number of subjects was 219. When patients complained of pain in their neck or C-reactive protein (CRP) was still high, physicians were able to extend the tapering of the dose of PSL or increase it at 2-week intervals. The endpoint of the study was the duration of the PSL medication. We also compared the severity of thyrotoxicosis and rate of hypothyroidism after SAT between the short medication group (patients who recovered within 6 weeks) and long medication group (patients who recovered in 12 weeks or more).The number of patients whose thyroiditis improved within 6 weeks and did not recur was 113 (51.6%), and 61 (27.9%) improved within 7 to 8 weeks and did not have a recurrence. The longest duration was 40 weeks. Seven patients (3.2%) needed increases in the dosage of PSL. Thyroid hormone (free thyroxine and free triiodothyronine) levels measured at the initial visit in the short medication group were significantly higher than those in the long medication group (p0.05). Serum CRP, male-to-female ratio, body weight, and age showed no differences between the two groups. There were no differences in the rate of hypothyroidism after SAT between the two groups (p=0.0632).The treatment protocol that we employed had 15 mg/day of PSL as the initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks, and was effective and safe for Japanese patients. However, 20% of patients with SAT needed longer than 8 weeks to recover from the inflammation.

Dr. Hakaru Hashimoto (Figure 1), born 5 May 1881, was the third son of a prominent family who had practiced medicine for generations in Iga Ueno, Mie Prefecture, Japan. He was one of the first graduates to receive a bachelor’s degree from the Fukuoka Medical College of Kyoto Imperial University in 1907. Hakaru Hashimoto received tutelage and training from Professor Miyake of the Department of Surgery of Fukuoka Medical College. Professor Miyake also instructed Dr. Hashimoto on the technique of assessing excised thyroid glands microscopically. In 1912, at the age of 30, Hakaru Hashimoto reported a distinct new disease in ‘Archiv fur Klinische Chirurgie”, a German journal of clinical surgery. His paper, which consisted of 30 pages and 5 illustrations and centered on histological changes in thyroid tissue, discussed the results of his examination of thyroid tissue samples taken from four women. Hakaru Hashimoto further explained in his report that the new pathological characteristics he had identified, namely infiltration of lymphoid and plasma cells, formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen, were histologically similar to those of Mikulicz’s disease. He expressed confidence that he had discovered a new disease, which he named “struma lymphomatosa”, emphasizing the lymphoid cell infiltration and formation of lymphoid follicles with germinal centers, neither of which had previously been reported.

Graves' disease often occurs after delivery. However, it has been difficult to predict who will develop Graves' hyperthyroidism. We attempted to predict postpartum onset of Graves' disease by measuring anti-TSH receptor antibodies (TRAb) and thyroid-stimulating antibodies (TSAb) in early pregnancy. TRAb was measured by a third generation assay and TSAb was measured by a newly developed sensitive bioassay. In 690 early pregnant women, 2 showed borderline TRAb positive reactions. However, none of them developed Graves' disease after delivery. Thirty-eight of 690 pregnant women were positive for anti-thyroid peroxidase antibodies (TPOAb) and 4 were positive for TSAb. Two of these 4 women developed postpartum Graves' hyperthyroidism. These findings indicate that the third generation TRAb assay was not useful, but that the sensitive TSAb bioassay was moderately useful for predicting the postpartum onset of Graves' hyperthyroidism.

Background A germline mutation of KEAP1 gene was reported as a novel genetic abnormality associated with familial multinodular goiter. That report was limited, and the pathogenic features were not well established. Patient findings We report a 47-year-old Japanese woman who presented with hyperthyroidism and a large multinodular goiter. The family history was notable for a paternal history of goiter. Graves’ disease was diagnosed based on positive TRAb, but scintiscan imaging showed that the patient’s radioiodine uptake was restricted in the non-nodular areas, indicating largely cold nodules. A total thyroidectomy was performed. The resected thyroid tissue weighed 209 g, and subsequent pathological findings were benign. The patient had a germline heterozygous KEAP1 mutation, c. 1448 G > A, resulting in an amino acid substitution (p.R483H). A next-generation sequencing analysis covering all known genes associated with multinodular goiter showed no additional germline mutation. The nuclear accumulation of NRF2, a protein associated with KEAP1, was shown at much higher rates in the patient’s nodules compared with nodules obtained from four unrelated patients with multinodular goiters. Conclusion A novel germline mutation (R483H) of KEAP1 gene was associated with the development of a non-toxic multinodular goiter.

Aim: It is difficult to differentiate follicular carcinomas (FC) from follicular adenomas (FA) because ultrasonography and cytology provide very similar findings. FC is histopathologically diagnosed to have capsular and/or vascular invasion. In a few patients, tumor protrusions are observed by preoperative ultrasonography as large forms of capsular invasion of follicular carcinomas. The aim of the study was to clarify the predictive value of tumor protrusions on preoperative ultrasonography for follicular carcinomas. Material and methods: A total of 531 patients (FC: 184 patients, FA: 347 patients) undergoing thyroid surgery were included in this study. A tumor protrusion on ultrasonography was defined as follows: 1) a solid tumor extending beyond a marginal line of capsular zone of the main tumor on B-mode ultrasonography; 2) intensive blood signals observed within the protrusion area on Doppler ultrasonography. The large form of capsular invasion was defined if the protrusion lesion was histopathologically diagnosed to be a capsular invasion of follicular carcinoma. Results: The sensitivity of tumor protrusion was 0.071, specificity 0.994, positive predictive value 0.867, and negative predictive value 0.669 for FC diagnosis. For the large form of capsular invasion in FC the sensitivity of tumor protrusion was 0.813, specificity 0.982, positive predictive value 0.684, and negative predictive value 0.982. Conclusions: A tumor protrusion with intensive blood signals extending from the main tumor on ultrasonography strongly suggests a large form of capsular invasion of follicular carcinoma.

Objective: The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). Evidence: This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. Conclusions: Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.

We often recommend total thyroidectomy for patients with Graves' disease who wish to have a child in the near future in order to prevent fetal or neonatal hyperthyroidism, especially if the patients' serum thyrotropin receptor antibody (TRAb) values are high. The aim of this study was to analyze changes in serum TRAb values using a quantitative third-generation assay after total thyroidectomy and the half-lives of serum TRAb values to estimate the postoperative time needed to achieve the safe TRAb value for mothers. We retrospectively examined the records of 45 Graves' disease patients who underwent a total thyroidectomy and had high serum TRAb values. We also evaluated factors that prolonged the postoperative reduction of serum TRAb values. The serum TRAb values decreased rapidly in most of the patients, especially within the early postoperative (3-month) period. The presence of Graves' ophthalmopathy (GO) (p=0.001), smoking (p=0.004), and serum thyroglobulin values > 0.5 ng/mL at postoperative 12 months (p=0.039) were significantly associated with prolonged half-lives of the serum TRAb values. The median TRAb value half-life was 93.5 days in the patients without GO or smoking, 162.5 days in the patients with GO or smoking, and 357.4 days in the patients with both GO and smoking. Our findings indicate that using the half-life of patients' serum TRAb values determined by this third-generation assay would be effective to evaluate the reduction of serum TRAb values after total thyroidectomy and to estimate the postoperative time needed to achieve the maternal safe value.

Title The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. Author(s) Yamashita, Shunichi; Amino, Nobuyuki; Shong, Young Kee Citation Thyroid, 21(6), pp.577-580; 2011 Issue Date 2011-06 URL http://hdl.handle.net/10069/25511 Right © Mary Ann Liebert, Inc. NAOSITE: Nagasaki University's Academic Output SITE

Tumor thrombus in the thyroid vein or the internal jugular vein may be caused by thyroid malignancies. Therefore, a tumor thrombus is very suspicious for malignancy. Total thyroidectomy should be performed in such patients if there is a primary thyroid tumor, and a high probability of pulmonary metastasis seems likely as there is direct exposure of malignant cells to the circulation. Our study was performed to determine whether ultrasonography is an effective preoperative modality to detect tumor thrombi of thyroid malignancies and whether tumor thrombi are associated with pulmonary metastases.Between 2004 and 2009, all thyroid surgery patients at Kuma Hospital had preoperative neck ultrasonography to look for tumor thrombi in the thyroid veins and the internal jugular veins as well as thyroid masses and abnormal lymph nodes. We looked for solid masses with an echogenic "tongue" in the internal jugular vein and masses with a projection from thyroid tumor to the thyroid vein on grayscale ultrasonography. We also used Doppler ultrasonography to look for the absence of blood flow.Among 7754 patients who had thyroid surgery, there were 9 patients with tumor thrombi. In seven of the patients, tumor thrombi were detected by preoperative ultrasound, and in the remaining two patients, tumor thrombi were detected during surgery. Tumor thrombi were identified in the internal jugular vein in six patients and in the thyroid vein in three patients. Pulmonary metastases were present in three patients (50% of the patients with thyroid carcinoma). The patients with tumor thrombi were more likely (33.3%) to have pulmonary metastasis than those without (0.9%) tumor thrombi (p 0.0001). In four patients with papillary carcinoma, projection-like lesions of irregularly shaped tumors were misdiagnosed to be tumor thrombi in the thyroid veins on preoperative ultrasound. These four patients did not have pulmonary metastases.The preoperative detection of a tumor thrombus on ultrasonography has important clinical significance. Therefore, preoperative neck ultrasound in patients with thyroid masses should attempt to determine whether there are signs of tumor thrombi as well as to characterize the nature and location of abnormal thyroid and extrathyroid masses.

Objective3,5,3′-triiodothyronine-predominant Graves' disease (T3-P-GD) is characterized by a persistently high serum T3 level and normal or even lower serum thyroxine (T4) level during antithyroid drug therapy. The source of this high serum T3 level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T3 level in T3-P-GD.MethodsWe measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T3-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy.ResultsThyroidal D1 activity in patients with T3-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P3-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P3-P-GD and CT-GD and the serum FT3-to-FT4 ratio (r=0.370, P3-to-FT4 ratio (r=0.676, PConclusionsOur results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT3-to-FT4 ratio in T3-P-GD.

Recent advances in ultrasonography and fine needle aspiration biopsy (FNAB) have facilitated accurate diagnosis of thyroid carcinomas that require treatment. However, we often encounter nodules evaluated as malignant on ultrasonography but diagnosed as benign on cytology, for which the optimal treatment strategy remains uncertain. A 28-year-old female had solitary and solid thyroid nodule measuring 6 cm in maximal diameter in February 1994. The lesion was cytologically diagnosed as benign. From September 1998, the nodule spontaneously decreased in size but ultrasonographic findings suspicious of malignancy such as peripheral and intra-tumoral calcification, low internal echo and irregular border gradually appeared. In July 2010, the volume of her nodule showed 97% decrease but was evaluated as papillary carcinoma on ultrasonography. FNAB was performed again and the nodule was diagnosed as benign. When we encounter a nodule showing ultrasonographic findings suggestive of malignancy with negative cytology, we should consider the possibility of a benign nodule degenerating over time.

Multiple cysts of the thyroid gland have not been recognized as one of the causes of hypothyroidism. Here we present six patients from a region with relatively high iodine intake in whom multiple cysts of the thyroid were associated with hypothyroidism or the development of hypothyroidism.All patients were women and ranged in age from 49 to 71. Their thyroids were mildly enlarged, tests for thyroid autoantibodies were negative, and multiple cysts were detected in the thyroid by ultrasonography. By dietary questionnaire their iodine intake was estimated to range from 2 to 10 mg of iodine daily. Otherwise, there was no evidence for disorders or factors associated with hypothyroidism. All four patients who agreed to dietary iodine restriction became euthyroid at approximately 1 month after a low-iodine diet (less than 0.5 mg iodine per day) was started.Although these patients were from a region with high-iodine intake and had a relatively high intake compared with most regions of the world, this amount of iodine intake is not associated with hypothyroidism in otherwise healthy persons. Therefore, we propose that multiple thyroid cysts, which we have termed polycystic goiter, is probably a cause of hypothyroidism in patients with a relatively high iodine intake.

Summary Objective Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. Design and patients A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation. Measurements Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography. Results After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P

Objective: To gain an insight into risk factors for hypothyroidism after subacute thyroiditis (SAT), we examined the correlation between initial laboratory and ultrasonographic findings and sequential thyroid dysfunction among treatment modalities. Patients: We reviewed retrospectively the medical records of 252 patients (26 men and 226 women) with SAT who consecutively visited our thyroid clinic at Kuma Hospital for at least 6 months from 1996 through 2004. Results: Throughout the course, 135 patients (53.6%) developed transient or permanent hypothyroidism. Levels of TSH were most often elevated (greater than 5 IU/ml) 2 months after SAT onset regardless of treatment, and 97.0% of patients who showed transient or permanent hypothyroidism clustered within 6 months from onset. During follow-up, patients treated with prednisone (PSL) were more likely to have normal thyroid function than patients not treated or those receiving anti-inflammatory drug therapy. In patients who developed hypothyroidism with PSL treatment or without treatment, the rates of bilateral hypoechogenic areas (HEA) were 6-fold higher than those of unilateral HEA. Moreover, permanent hypothyroidism occurred in 5.9% of patients, and all patients with permanent hypothyroidism presented initially with bilateral HEA and had consequently small thyroid size with or without abnormal autoimmunity. Conclusions: The rates of thyroid dysfunction after SAT were significantly lower in patients receiving PSL. Extent of HEA in the thyroid, but not laboratory findings, may be a possible marker for developing thyroid dysfunction after SAT.

Background: Borna disease virus (BDV) infection of humans has not been widely accepted due to the low titer of the antibody and lack of reliable diagnostic tools. Objectives: To examine exposure to BDV or a related virus in Japanese psychiatric and general population by detecting the specific IgG, IgM, and IgA. Study design: Sera from 304 psychiatric and 378 control subjects were examined for IgG, IgM, and IgA against BDV nucleoprotein (N) and phosphoprotein (P) using highly specific and sensitive radioligand assay. The avidity was also examined. Results: The specific IgG, IgM, and IgA against both BDV-N and -P were detected and the seropositivity was not significantly different between patients and controls. The avidity of the specific IgG was low to moderate, and the specific IgM did not disappear for several years. Conclusions: Our results suggested common exposure to BDV or a related virus in the general Japanese population. Low avidity IgG and persistent IgM suggested delayed immune response against BDV or a related virus. The specific IgA indicated mucosal involvement.

Some patients with massive metastatic thyroid carcinoma exhibit T(3) thyrotoxicosis. We investigated the prevalence and cause of T(3) thyrotoxicosis and the clues to the diagnosis.Serum free T(3) (FT(3)), free T(4) (FT(4)), and TSH were measured in patients with massive metastases from papillary, follicular, or medullary thyroid carcinomas (31, 20, and seven patients, respectively). Patients without recurrence served as controls. Thyrotoxic patients were reexamined 1 wk after withdrawal of levothyroxine. Type 1 and type 2 iodothyronine deiodinase (D1 and D2) activities were measured in three tumor tissues from thyrotoxic patients.The serum FT(3) level and FT(3)/FT(4) ratio in the follicular carcinoma (FC) group were significantly higher than those in the papillary carcinoma group or patients without recurrence. Four patients (20%) in the FC group but none in the other groups demonstrated T(3) thyrotoxicosis or a FT(3)/FT(4) ratio greater than 3.5. One week after withdrawal of levothyroxine, both FT(3) and FT(4) levels decreased. Retrospective measurements of FT(3) in frozen stored sera demonstrated that FT(3) exceeded the upper normal limit when FT(4) began to decrease but remained within the normal range. Tumor tissues showed high D1 and D2 activities.Twenty percent of patients with massive metastatic FC exhibited T(3) thyrotoxicosis, most likely due to increased conversion of T(4) to T(3) by tumor expressing high D1 and D2 activities. Occasional measurement of serum FT(3) in addition to FT(4) and TSH is recommended in patients with massive metastatic FC, especially when serum FT(4) decreases on fixed doses of levothyroxine.

Among thyroid nodules arising from follicular cells, benign nodular goiter is thought not to metastasize to regional or distant organs. However, we encountered five cases that were pathologically diagnosed as benign nodular goiter but showed metastasis. The prevalence of benign nodular goiter showing metastasis was 0.17% (5 of 2978 patients). On pathology, there were no detectable signs of carcinoma or follicular adenoma lesions. Two patients showed lymph node metastasis that was pathologically confirmed as metastasis of nodular goiter. One was preoperatively and another was postoperatively detected by ultrasonography. These patients also showed distant metastases that could be ablated by radioiodine. One patient preoperatively showed lung metastasis and the remaining two showed lung and bone metastases and bone metastasis postoperatively. Pathological diagnosis of thyroid nodules has limitations, and cases diagnosed as benign nodular goiter should still undergo careful follow-up.

Although transient thyrotoxicosis occurring after antithyroid drug (ATD) withdrawal in patients with Graves' hyperthyroidism has been reported, the prevalence of transient thyrotoxicosis after ATD therapy is as yet unknown. When patients with transient hyperthyroidism are mistakenly regarded as recurrences, they receive unnecessary therapy. The aim of this study was to investigate the prevalence of transient thyrotoxicosis after ATD withdrawal.We selected 110 consecutive patients with Graves' disease whose ATD therapy was stopped from December 2002 to September 2004 prospectively. Patients were observed for more than 1 year after ATD withdrawal, and 12 patients dropped out. Serum levels of free thyroxine (FT(4)), thyrotropin, and thyrotropin-binding inhibitor immunoglobulin were measured at ATD withdrawal, and 3, 6, and 12 months after withdrawal. When the patients showed mild thyrotoxicosis (serum FT(4) level of less than 3.00 ng/dL), we followed them up for 1 month without medication.The remission rate of the study group was 61.8% (68/110). Twenty-eight patients became euthyroid after transient thyrotoxicosis, equivalent to 41.2% of the remission patients. Eight of 28 patients showed overt thyrotoxicosis, and the rest subclinical thyrotoxicosis. Transient thyrotoxicosis occurred mostly 3-6 months after ATD withdrawal.Transient thyrotoxicosis after ATD withdrawal in patients with Graves' disease is not a rare phenomenon. Clinicians should be aware that the recurrence of Graves' disease after the withdrawal of ATD may be transient.

Ultrasonography is the most useful tool for detection and evaluation of thyroid nodules. In this study, we present our classification system for ultrasonographic evaluation, which has been routinely performed since 1995. Of 1244 nodules identified by ultrasonography in 900 patients, 1145 nodules demonstrating adequate specimens on fine-needle aspiration biopsy were enrolled in the study. We stratified these nodules into classes 1 to 5 with intermediate steps of 0.5 for classes 2 to 5. Nodules classified as 3.5 or greater were evaluated as malignant, those classified as 3 were evaluated as borderline, and those classified as 2.5 or lower were evaluated as benign. Of 233 nodules evaluated as malignant, 179 (76.8%) were cytologically confirmed as malignant. Furthermore, 145 of 159 nodules (91.2%) classified as 4 or greater were cytologically diagnosed as carcinoma. Of 710 nodules evaluated as benign, 683 (96.1%) were cytologically confirmed as benign. Two hundred fifty-five nodules of 210 patients were surgically resected and pathologically examined. In this series, the positive predictive value of ultrasonographic evaluation of malignancy was 97.2%. These findings suggest that our classification system is simple and useful to facilitate ultrasonographic evaluation of thyroid nodules.

Objective: The objective is to provide clinical guidelines for the management of thyroid problems present during pregnancy and in the postpartum. Participants: The Chair was selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society. The Chair requested participation by the Latin American Thyroid Society, the Asia and Oceania Thyroid Society, the American Thyroid Association, the European Thyroid Association, and the American Association of Clinical Endocrinologists, and each organization appointed a member to the task force. Two members of The Endocrine Society were also asked to participate. The group worked on the guidelines for 2 yr and held two meetings. There was no corporate funding, and no members received remuneration. Evidence: Applicable published and peer-reviewed literature of the last two decades was reviewed, with a concentration on original investigations. The grading of evidence was done using the United States Preventive Services Task Force system and, where possible, the GRADE system. Consensus Process: Consensus was achieved through conference calls, two group meetings, and exchange of many drafts by E-mail. The manuscript was reviewed concurrently by the Society’s CGS, Clinical Affairs Committee, members of The Endocrine Society, and members of each of the collaborating societies. Many valuable suggestions were received and incorporated into the final document. Each of the societies endorsed the guidelines. Conclusions: Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Care requires coordination among several healthcare professionals. Avoiding maternal (and fetal) hypothyroidism is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery. Maternal hyperthyroidism and its treatment may be accompanied by coincident problems in fetal thyroid function. Autoimmune thyroid disease is associated with both increased rates of miscarriage, for which the appropriate medical response is uncertain at this time, and postpartum thyroiditis. Fine-needle aspiration cytology should be performed for dominant thyroid nodules discovered in pregnancy. Radioactive isotopes must be avoided during pregnancy and lactation. Universal screening of pregnant women for thyroid disease is not yet supported by adequate studies, but case finding targeted to specific groups of patients who are at increased risk is strongly supported. (J Clin Endocrinol Metab 92: S1–S47, 2007)

Summary Objective Differentiation between destruction-induced thyrotoxicosis and Graves’ thyrotoxicosis is important for selection of proper therapy. It is, however, often difficult to make this distinction without measurement of radioactive iodine uptake. We investigated the possibility that assessment of thyroid blood flow would allow differentiation between the two entities. Patients and measurements One hundred and fourteen untreated patients with thyrotoxicosis (56 Graves’ disease, 28 painless thyroiditis, 30 subacute thyroiditis) and 25 normal controls were examined. Serum levels of freeT4 (FT4), freeT3 (FT3) and TSH were measured by chemiluminescent immunoassay, and anti-TSH receptor antibodies (TSH-binding inhibitory immunoglobulin, TBII) were measured by enzyme-linked immunosorbent assay. Thyroid volume and blood flow (TBF) were measured quantitatively by ultrasonography. Results TBF was significantly higher in Graves’ disease (mean ± 1SD: 14·9 ± 6·4%, P

Medullary thyroid carcinoma (MTC) is a thyroid malignancy originating from C cells. To date, serum calcitonin measurement and fine-needle aspiration biopsy (FNAB) have been prominent diagnostic approaches to these lesions. Although an elevated serum calcitonin level strongly suggests the presence of MTC, this examination cannot identify the origin of the calcitonin overexpression, especially in patients demonstrating multiple thyroid nodules. For the treatment planning, it is important to know which nodule is MTC, especially in nonhereditary MTC. In this study, we propose calcitonin measurement in the washout of FNAB needles after sampling each tumor (FNAB-CT) as a new approach to diagnosis of MTC. We performed FNAB-CT for five MTC cases. Although only one of these cases was definitively diagnosed as having MTC by FNAB cytology, FNAB-CT values ranged from 17,000 to 560,000 pg/mL, which were exceedingly higher than those of 11 controls (seven papillary carcinomas, two adenomatous nodules, one chronic thyroiditis, and one normal thyroid), which showed values ranging from

We encountered a 55-year-old female patient with Hashimoto's thyroiditis who showed persistent fever, and could not find any source of fever other than the large nontender goiter. Her fever continued with positive CRP for 6 months. Although we did not assume that the inflammation was related to Hashimoto's thyroiditis, total thyroidectomy was performed for cosmetic reasons; however, fever was resolved immediately after thyroidectomy. Pathological diagnosis was Hashimoto's chronic thyroiditis. Immunohistochemical staining showed that the follicular cells were positive for IL-1alpha, IL-1beta, and TNF-alpha. We believed that fever was induced by inflammatory cytokines produced in thyroid. The case indicated that Hashimoto's thyroiditis with nontender goiter could cause idiopathic fever.

A 54-year-old woman with subclinical hypothyroidism developed liver dysfunction after increasing dose of levothyroxine (L-T4) in tablet form (Thyradin S(®)) from 25μg to 50μg. Viral hepatitis, autoimmune hepatitis and NASH were ruled out with examinations. After cessation of levothyroxine in 50μg tablet form, liver enzymes gradually returned to normal. She was diagnosed levothyroxine-induced liver injury, based on criteria proposed in DDW-J 2004 workshop. Thyradin S(®) powder 0.01% (here in after referred to as L-T4 in powder form) was tried as an alternative, and liver enzymes have remained within normal range. As for Thyradin S(®) tablet, additives are different for each type of levothyroxine sodium content. The difference of additive is whether Fe2O3 is contained or not: it is not included in Thyradin S(®) 50μg tablet and powder form. Although there are two case reports in the Japanese literature and three case reports in the English literature of liver dysfunction suspected due to L-T4, we cannot find past reports about cases of drug induced liver dysfunction due to Fe2O3 free levothyroxine tablet form. This is a rare case report of drug induced liver injury due to Fe2O3 free levothyroxine tablet form, and administration of L-T4 in powder form may be useful for treatment of cases similar to this one.

Background Patients with metastases to the thyroid from renal cell carcinoma (RCC) that need surgical management are not many and unfamiliar to clinicians and thyroid endocrinologists. Therefore, little information is available on ultrasonographic features of metastatic carcinoma in the thyroid. The strategic value of ultrasound in preoperative surgical planning for patients with thyroid nodules has become increasingly appreciated. The purposes of this article are to clarify the ultrasound characteristics of metastatic carcinoma to the thyroid from RCC by evaluating many patients in one institute, and to investigate the role of ultrasonography in preoperative diagnosis. Methods Ten patients with these carcinomas who had undergone surgical management were investigated clinically and ultrasonographically. Ultrasonographic features to be evaluated were the form of involvement in the thyroid, size, shape, pattern, calcifications, vascularity, and tumor thrombus. Clinical features were previous history of RCC, serum thyroglobulin levels, cytology, preoperative diagnosis, and surgery. Results Ultrasonographic features of these carcinomas were more likely to involve a solitary, irregular, and solid without calcifications, and prominent intra-tumoral vascularity and tumor thrombus in the vein. These patients tended to be older, and to have relatively late recurrence in the thyroid, RCC in the right kidney as the primary site, and relatively low serum thyroglobulin levels. Conclusions Metastatic carcinomas to the thyroid from RCC presented highly characteristic features on ultrasonography. These ultrasonographic features combined with cytological findings and previous medical history of RCC can provide the optimal process for the preoperative diagnosis of such patients.

Background: Thyroid-stimulating antibodies (TSAb) are known to be responsible for hyperthyroidism in Graves' disease (GD). The conventional methods to measure TSAb depend on cell-based assays that require cumbersome procedures and a sterilized tissue culture technique. The aim of the present study was to develop a ready-to-use cell-based assay for measuring TSAb activity without requiring sterilized conditions. Methods: We developed a new assay kit using a frozen Chinese hamster ovary cell line expressing the thyroid-stimulating hormone receptor, cyclic adenosine monophosphate (cAMP)-gated calcium channel and aequorin, tentatively named the aequorin TSAb assay. Activated stimulatory G-protein-coupled adenylate cyclase increases intracellular cAMP, which then binds to the cyclic nucleotide-gated calcium channel. Activation of this channel allows Ca2+ to enter the cell, and the influx of Ca2+ can be measured with aequorin, which is quantified by a luminometer. Results can be obtained in only 4 h without sterilized conditions. TSAb activities were expressed by international units using the NIBSC 08/204 standard. Results: Positive results of aequorin TSAb were obtained in 197 of 199 (98.9%) of untreated patients with GD. Only 1 of 42 (2.3%) patients with painless thyroiditis had a weakly positive aequorin TSAb. All 45 patients with subacute thyroiditis and 185 normal subjects showed negative aequorin TSAb. As for chronic thyroiditis, all 52 euthyroid patients showed negative aequorin TSAb, but 8 of 50 (16.0%) hypothyroid patients had a positive reaction. However, these positive reactions were not induced by serum thyroid-stimulating hormone (TSH) and were thought to be induced by the stimulating activity of anti-TSH receptor immunoglobulins. Conventional porcine TSAb and Elecsys thyroid-stimulating hormone receptor antibodies were positive in 69.3 and 95.5% of GD, respectively. Conclusion: The aequorin TSAb assay was positive in 98.9% of GD and was more sensitive than the conventional assay. This assay can be conducted in only 4 h without sterilized conditions and is practically useful in general clinical laboratories.

BackgroundIgG4-related disease is a novel disease entity characterized by diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells and fibrosis into multiple organs. There is still controversy over whether some thyroid diseases are actually IgG4-related disease. The objective of this study was to elucidate the clinicopathological features of Graves' disease with diffuse lymphoplasmacytic infiltration in the thyroid.Patients and methodsAmong 1,484 Graves' disease patients who underwent thyroidectomy, we examined their histopathological findings including the degree of lymphoplasmacytic and fibrotic infiltration and levels of IgG4-positive plasma cells in the thyroid. Their clinical pictures were defined by laboratory and ultrasonographic evaluation.ResultsA total of 11 patients (0.74%) showed diffuse lymphoplasmacytic infiltration in the stroma of the thyroid gland. Meanwhile, other patients showed variable lymphoid infiltration ranging from absent to focally dense but no aggregation of plasma cells in the thyroid gland. Based on the diagnostic criteria of IgG4-related disease, 5 of the 11 subjects had specifically increased levels of IgG4-positive plasma cells in the thyroid. Fibrotic infiltration was present in only 1 patient developing hypothyroidism after anti-thyroid drug treatment for 4 years, but not in the other 10 patients with persistent hyperthyroidism. Obliterative phlebitis was not identified in any of the 11 subjects. Thyroid ultrasound examination showed 1 patient developing hypothyroidism who had diffuse hypoechogenicity, but the other hyperthyroid patients had a coarse echo texture.ConclusionsIn our study, Graves' disease patients with persistent hyperthyroidism who had diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells in the thyroid showed no concomitant fibrosis or obliterative phlebitis.

Recently, non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total cholesterol minus HDL-C, has emerged as a predictor of cardiovascular disease.We evaluated the effect of L-T4 replacement on non-HDL-C levels in patients with primary hypothyroidism.Thirteen patients with overt hypothyroidism and 26 patients with subclinical hypothyroidism participated in the study. The lipid profiles, including non-HDL-C, were measured in patients with hypothyroidism before and 3 months after L-T4 replacement was started.After L-T4 replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with overt hypothyroidism. In patients with subclinical hypothyroidism, the serum concentrations of total cholesterol, non-HDL-C, remnant-like particle cholesterol, and apolipoprotein B (Apo B) were significantly decreased, whereas no significant changes in the serum concentrations of low-density lipoprotein cholesterol, HDL-C, triglycerides, apolipoprotein A-I, and Lp(a) were observed. In all 39 patients, the reduction in the non-HDL-C levels correlated with the reduction in the low-density lipoprotein cholesterol, remnant-like particle cholesterol, and Apo B levels. However, the reduction in the non-HDL-C levels did not correlate with the reduction in the HDL-C, Lp(a), and apolipoprotein A-I levels.This study is the first to show that L-T4 replacement may reduce serum concentrations of non-HDL-C in patients with hypothyroidism. The study also suggests that such altered serum concentrations of non-HDL-C in hypothyroidism may be related to the disturbed metabolism of low-density lipoprotein, remnant lipoprotein, and Apo B.