Takumi Kudo

Prognostic Impact of Serum Thyroglobulin Doubling-Time Under Thyrotropin Suppression in Patients with Papillary Thyroid Carcinoma Who Underwent Total Thyroidectomy

BACKGROUND Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time. METHODS Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were <0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling-time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months. RESULTS Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were <1 year (17 patients), those that were 1-3 years (21 patients), and those that were ≥ 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of <1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg-DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis. CONCLUSIONS Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC.

A Novel Homozygous Missense Mutation of the Dual Oxidase 2 (DUOX2) Gene in an Adult Patient with Large Goiter

OBJECTIVE To describe the first adult case of large goiter associated with a novel R1110Q mutation in the dual oxidase 2 (DUOX2) gene. She was initially euthyroid, and developed hypothyroidism later in her forties. DUOX2 is an essential enzyme in iodine organification of thyroid hormone biosynthesis. Only infant cases of congenital hypothyroidism due to mutations of the DUOX2 gene have been reported. Biallelic mutation of DUOX2 is thought to lead to total iodine organification defect. PATIENTS AND MEASUREMENT: This 57-year-old woman became first aware of goiter around the age of 20 years. Since the goiter had enlarged gradually, she consulted us at the age of 32 years. Goiter was soft, and thyroid function was normal. Antithyroid antibodies were negative. Both physical and mental development was normal. Three of her nine siblings and her mother had large goiters. At the age of 44 years, thyroid function demonstrated subclinical hypothyroidism. She started to take levo-thyroxine at a dose of 100 mug/day to reduce goiter. At the age of 56 years, goiter size remained the same. The perchlorate discharge rate was 72.8%, suggesting partial iodine organification defect. Thus, thyroid peroxidase (TPO) gene and DUOX2 gene were analyzed. RESULTS There was no mutation in the TPO gene, but a novel homozygous mutation (R1110Q) in the DUOX2 gene was identified. The same heterozygous mutation was detected in her two sons and two grandchildren. This mutation was not detected in 104 control alleles and was located at a site differing from any other reported mutations in the DUOX2 gene. CONCLUSIONS This homozygous missense mutation can be associated with thyroid dysfunction and goiter formation of an enlarged thyroid gland.

Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves' disease.

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.

Initial Treatment with 15 mg of Prednisolone Daily Is Sufficient for Most Patients with Subacute Thyroiditis in Japan

BACKGROUND 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. METHODS 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). RESULTS 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 (p<0.05). 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). CONCLUSIONS 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.

Multiple Thyroid Cysts May Be a Cause of Hypothyroidism in Patients with Relatively High Iodine Intake

BACKGROUND 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. SUMMARY 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. CONCLUSIONS 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.

Estimation of the lifetime probability of disease progression of papillary microcarcinoma of the thyroid during active surveillance

Background. We reported that a minority of patients with low‐risk papillary microcarcinoma of the thyroid showed disease progression during active surveillance and that older patients had significantly lower disease progression rates than younger patients. Here, we estimated lifetime (≤85 years old) probabilities of disease progression during active surveillance according to the age at presentation based on age decade‐specific disease progression rates. Methods. From 1993–2013, 1,211 low‐risk papillary microcarcinoma patients aged 20–79 years underwent active surveillance at Kuma Hospital. We calculated the disease progression rate at the 10‐year point of active surveillance for each age‐decade group (20s to 70s) with the Kaplan‐Meier method. The lifetime disease progression probability for each age group was calculated as (1 − cumulative probability of progression‐free survival calculated with age decade‐specific disease progression rates) until the patients reached their 80s (i.e., 85 years on average). Results. The age decade‐specific disease progression rates at 10 years of active surveillance were 36.9% (20s), 13.5% (30s), 14.5% (40s), 5.6% (50s), 6.6% (60s), and 3.5% (70s); the respective lifetime disease progression probabilities were 60.3%, 37.1%, 27.3%, 14.9%, 9.9% and 3.5% according to the age at presentation. Conclusion. The estimated lifetime disease progression probabilities of papillary microcarcinoma during active surveillance vary greatly according to the age at presentation.

Reference values of serum calcitonin with calcium stimulation tests by electrochemiluminescence immunoassay before/after total thyroidectomy in Japanese patients with thyroid diseases other than medullary thyroid carcinoma.

Calcitonin is a very sensitive tumor marker of medullary thyroid carcinoma (MTC). MTC patients usually have very high values of serum calcitonin that can be used to diagnose the disease. To improve the diagnostic sensitivity in family members with small MTCs and to evaluate the postoperative biochemical cure status, a calcium stimulation test is widely used. Serum calcitonin has been measured using several methods, but in Japan, only an electrochemiluminescence immunoassay (ECLIA) is currently performed to determine serum calcitonin. Reference values for the calcium stimulation test using an ECLIA have not been reported. Here we conducted a calcium stimulation tests in 26 patients without MTC before and after total thyroidectomy. Preoperatively, the basal calcitonin values of all patients were within normal limits and increased to a mean of 14.4 pg/mL after calcium stimulation. We transformed the peak values before total thyroidectomy to a logarithmic distribution and calculated the normalized mean ± 1.96× standard deviation; the reference upper limit was thus expressed. In the female patients with non-MTC, the reference upper limit was 67.6 pg/mL. In all patients, the calcium stimulation test results after total thyroidectomy showed undetectable basal and stimulated calcitonin values (<0.5 pg/mL). This is the first study to determine reference values to be used for the calcium stimulation test along with an ECLIA in non-MTC patients. We propose that female patients are regarded as biochemically cured or normal when the stimulated calcitonin values by ECLIA are <67.6 pg/mL before surgery and <0.5 pg/mL after total thyroidectomy.

The Prevalence of Polycystic Thyroid Disease in Hypothyroid Patients with Negative Thyroid Autoantibodies

BACKGROUND We previously reported that multiple thyroid cysts may be a cause of hypothyroidism in patients with a relatively high iodine intake and we termed it polycystic thyroid disease (PCTD). The aim of this study was to investigate the prevalence of PCTD in patients who visited our thyroid center. We hypothesized that patients with PCTD are not rare in a region with a high iodine intake. METHODS We retrospectively studied the cause of hypothyroidism based on medical histories and ultrasonography in new patients to our hospital from April 2008 to March 2009 whose serum tests for antithyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb) were negative. Serum thyroid hormones, thyrotropin (TSH), TgAb, and TPOAb were measured in 8243 patients. Patients with four or more thyroid cysts, negative tests for TgAb and TPOAb, no evidence for thyroid diseases other than their thyroid cysts, and no exposure to thyroid-perturbing influences were defined as having PCTD. RESULTS Three hundred seven patients had overt hypothyroidism (TSH level above 10.0 μU/mL and free thyroxine level below 0.7 ng/dL), of whom 71 patients were both TgAb and TPOAb negative. There were 546 patients with subclinical hypothyroidism (TSH level above 5.0 μU/mL and normal free thyroxine), of whom 193 patients were both TgAb and TPOAb negative. There were 24 patients with overt hypothyroidism and PCTD, accounting for 7.8% (24/307) of all causes of overt hypothyroidism. There were 42 patients with subclinical hypothyroidism and PCTD, accounting for 7.7% (42/543) of all causes of subclinical hypothyroidism. PCTD was more common among elderly people than young people. CONCLUSIONS PCTD appears to be a minor but not negligible cause of hypothyroidism, at least in iodine-rich regions. PCTD with hypothyroidism may have been misdiagnosed as thyroid antibody-negative Hashimotos thyroiditis in many reports.

Benign thyroid teratomas manifest painful cystic and solid composite nodules: three case reports and a review of the literature.

Benign thyroid teratomas are rare in adolescents and adults. We report on three cases of benign thyroid teratomas that presented as painful tumors in the neck after puberty. The tumor adjacent to the thyroid in each case showed rapid enlargement with predominant cystic lesions within several months. Ultrasonography and computed tomography revealed few findings suggesting the origin of the tumor. Cytological examination and culture of the aspirate failed to show cells originating from the thyroid or infectious findings, but revealed a small population of columnar epithelial cells or squamous epithelial cells. Chemical analysis of the aspirate showed levels of pancreatic enzymes higher than those in serum. The accumulation of cystic fluid in each case was refractory to drainage treatment or percutaneous thanol injection therapy. The patients subsequently underwent resection of the tumor, and microscopic examination revealed various types of tissue including pancreas, adipose, cartilage, muscle, and skin, and the cystic wall was lined by gastric, intestinal, respiratory, and stratified squamous epithelium. Surgical resection was curative, and subsequent histologic examination revealed mature benign teratomas of the thyroid. The main characteristic of our cases presented the painful tumors due to the enlarged cystic formation lined by a variety of different types of epithelium, which agreed with previous cases of benign thyroid teratomas in adolescents and adults.

Serial Changes in Liver Function Tests in Patients with Subacute Thyroiditis

Liver function test abnormalities are well known in untreated patients with thyrotoxicosis (1). Recently, our studies clarified that these abnormalities in hyperthyroid Graves’ disease and painless thyroiditis were mainly induced by the metabolic effects of excess thyroid hormone (2). Subacute thyroiditis also induces thyrotoxicosis due to thyroid destruction; however, little is known about the abnormalities of liver function tests. We prospectively studied liver biochemical tests during the clinical course in 36 patients with subacute thyroiditis in order to clarify the prevalence and nature of liver function abnormalities. Patients with evidence of cardiovascular complications, past histories of hepatobiliary disorders, excess alcohol consumption, and positive for hepatitis B surface antigen and=or anti-hepatitis C virus antibodies were excluded. As previously described (2), we measured serum levels of albumin (ALB), total bilirubin (BIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (g-GTP), lactic dehydrogenase (LDH), creatinine phosphokinase (CK), TSH, FT4, and FT3 at the first visit and 1, 2, and 3–5 months later. The initial laboratory results in subacute thyroiditis are summarized in Table 1. The initial mean values of AST, ALT, ALP, and g-GTP were significantly higher than those of normal controls. On the other hand, the initial mean values of ALB, BIL, and CK were significantly lower than those of normal controls. Eighteen (50.0%) untreated patients were found to have at least one liver function test abnormality. Serial changes in the values of serum AST, ALT, and ALP are shown in Figure 1. The mean values of AST, ALT, and ALP decreased and had normalized by 3–5 months. There were no significant correlations between initial values of ALT or ALP and FT4, FT3, or C reactive protein (CRP). In order to clarify the source of increased ALP, isoenzymes were analyzed (Table 2). Total ALP activities were significantly higher than those of normal controls in subacute thyroiditis and Graves’ disease, but were normal in painless thyroiditis. In the electrophoresis study, the distribution pattern was normal in Graves’ disease and painless thyroiditis, but ALP2 (liver type) was significantly increased in subacute thyroiditis. These data suggest that biochemical abnormalities are induced by liver damage. On the other hand, only in Graves’ disease, bone ALP concentration, measured by ELISA, was significantly higher than that of normal controls. In Graves’ disease, we observed that serum AST and ALT were high and had further increased by 1 month after treatment. Moreover, the increase of ALP continued until 3–5 months after treatment (2). Similar, but mild, changes in liver function tests were also observed in patients with painless thyroiditis (2). These changing patterns are different from those in thyrotoxicosis induced by subacute thyroiditis (Fig. 1). In summary, liver function test abnormalities were found in half of all patients with subacute thyroiditis and returned to normal within a few months. These changes are not associated with other hepatitis disease. Liver-type ALP increase suggested that biochemical abnormalities are induced by transient liver damage, different from biochemical abnormalities, which are induced by dynamic changes in thyroid hormones in Graves’ thyrotoxicosis.