Abstract
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The first article, entitled “Seasonal rhythms: the role of thyrotropin and thyroid hormone,” is written by Drs. Nakayama and Yoshimura (1). Dr. Yoshimura is a biologist, and his main research interest is focusing on mechanisms of seasonal adaptation by animals. Therefore, he was originally not involved in thyroid research. However, while pursuing the mechanisms regulating the gonadal size of the Japanese quail (Coturnix japonica), which dramatically increase when the season changes from the short-day (SD) to the long-day (LD) phase, he found that locally generated triiodothyronine (T3) by the action of type 2 iodothyronine 5′-deiodinase (Dio2) within the mediobasal hypothalamus (MBH) induces dynamic morphological changes between nerve terminals and glial endfeet in the median eminence, resulting in the increase in the secretion of gonadotropin-releasing hormone, which then results in dramatic enlargement of the testes. Furthermore, Dr. Yoshimura's group identified a factor that induces the expression of Dio2 in the MBH upon switching from SD to LD. Surprisingly, the factor was thyrotropin (TSH), a very well-known hormone to endocrinologists. However, the identified TSH was not the one we know, which is secreted by the pars distalis (PD) in the anterior pituitary gland. The TSH involved in this process is secreted by the pars tuberalis (PT), which consists of thin layers of cells that surround the median eminence and pituitary stalk. The PT-derived TSH and well-known PD-generated pituitary TSH are immunologically identical but differ in their carbohydrate moieties. Moreover, the secretion of the PT-derived TSH is neither regulated by thyroid hormone nor does it stimulate thyroid hormone synthesis. Because the PT-derived TSH is a key hormone that regulates seasonal reproduction in quail, it is indeed a “springtime hormone.” Dr. Yoshimura's group also elucidated why the PT-derived TSH does not stimulate thyroid hormone synthesis by the thyroid gland. These findings, demonstrating that TSH is not only a “thyroid-stimulating hormone” but also a “springtime hormone,” are a big surprise for many thyroidologists. Of note, because of the outstanding achievements in the field of thyroid research, the American Thyroid Association (ATA) awarded the Van Meter Prize to Dr. Takashi Yoshimura in 2015. He is the third Japanese recipient of the prize. Previous Japanese Van Meter awardees include Drs. Takashi Yamada and Kenjiro Inoue.
The second article is entitled “Insights into the management of papillary microcarcinoma of the thyroid” by Drs. Akira Miyauchi, Yasuhiro Ito, and Hitomi Oda (2). Because the detection of thyroid carcinomas has been much improved, we encounter patients with thyroid cancer much more frequently than before. Several groups of researchers have reported that the increase in the incidence in thyroid cancer is mostly due the increase in detection of small papillary thyroid carcinomas (PTCs), while mortality from thyroid cancer remains largely unchanged. Because of the usually favorable outcomes in patients with small PTCs, concerns have been raised about the increased detection (“overdiagnosis”) and overtreatment of small PTCs. Importantly, the majority of thyroid cancers detected by advanced imaging technologies are papillary microcarcinomas (PMCs) <10 mm in diameter. Therefore, defining how to manage PMCs appropriately has become a very important healthcare issue.
In 1993, Dr. Miyauchi hypothesized that most PMCs remain small, that surgery is in general not necessary, and that surgery can still be performed safely at a later time in the few PMCs showing progressive growth. With this hypothesis, Dr. Miyauchi et al. at Kuma hospital, as well as a group in the Cancer Institute Hospital in Tokyo, performed a prospective cohort study called “active surveillance” for patients with low-risk PMCs without lymph node or distant metastasis, signs or symptoms of invasion to the recurrent laryngeal nerve or trachea, or high-grade cytology. Patients with low-risk PMCs were asked to choose either active surveillance or immediate surgery. If patients chose active surveillance, they were followed with ultrasound examination six months after the diagnosis and once per year thereafter. Patients who had signs of progression such as size enlargement and/or the novel appearance of lymph node metastasis during the active surveillance were surgically treated.
In Kuma hospital, 1179/2153 (55%) patients with PMCs chose active surveillance, whereas 45% patients underwent immediate surgery. It is somewhat surprising that >50% of the patients chose active surveillance, despite the fact that they may have felt some threat after having been diagnosed with a malignancy. The results of this longitudinal study are impressive. During a 10-year period of active surveillance, an increase in the tumor size by >3 mm was observed in only 8% of patients. Second, only 3.8% of all patients developed a novel lymph node metastasis, which then prompted a “rescue surgery” when indicated. Similar results were obtained at the Cancer Institute Hospital in Tokyo, and none of the patients who underwent active surveillance or received “rescue surgery” showed distant metastasis or died of thyroid cancer.
On the other hand, two patients who received immediate surgery had permanent vocal cord paralysis, even though the surgeries were performed by highly experienced endocrine surgeons. Taken together, these findings indicate overdiagnosis and overtreatment for PMCs should be avoided—recommendations that are now reflected in the 2015 ATA management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer (3). Of note, the Nagataki-Fujifilm prize was awarded to Dr. Miyauchi by the Asia and Oceania Thyroid Association in 2015 for his remarkable achievements and contributions in the management of thyroid cancer.
The third article, entitled “Thyroid storm: a Japanese perspective,” has been written by Dr. Takashi Akamizu (4). Thyroid storm (TS) is defined as life-threating thyrotoxicosis requiring emergency treatment. However, peer-reviewed diagnostic criteria have not been available. In addition, the exact incidence or epidemiology for TS remained uncertain. Based on these observations, the Guideline Committee for Thyroid Storm was established in 2006 as one of the main clinical topics sponsored by the JTA. The mission of the committee was to develop diagnostic and management criteria for TS and to better characterize its epidemiology. The committee identified and reviewed 99 published and seven unpublished cases in the period 1983–2006 in Japan. Then, it created the first edition of diagnostic criteria for TS in 2008. After evaluation of the nationwide survey, the final edition of the diagnostic criteria of TS was published in 2012 (5). In the diagnostic criteria, the involved experts clearly stated that thyrotoxicosis is an absolute criterion for the diagnosis of TS, whereas thyrotoxicosis is just implied in the criteria defined by the Burch–Wartofsky Point Scale (BWPS) (6). Also, the committee avoided the scoring system that was used in the BWPS because the committee judged that it was not possible to introduce a scoring system based on a retrospective study.
Since the publication of the first edition of the diagnostic criteria, the number of reported TS cases has risen due to increased awareness of TS among Japanese endocrinologists. Subsequently, the committee created detailed management and treatment recommendations for TS (7). There are several particularly important aspects in these recommendations. One is addressing the question whether propylthiouracil (PTU) is more beneficial than methimazole (MMI) in TS. It had been recommended that PTU is the first choice for the treatment of thyrotoxicosis in TS. This concept is based on the fact that PTU is not only inhibiting the de novo synthesis of thyroid hormones, but also inhibits the action on type 1 iodothyronine 5′-deiodinase (Dio1), thereby acutely decreasing circulating levels of the active thyroid hormone, T3. However, based on accumulating evidence and/or observations, the committee members concluded that MMI may not be disadvantageous compared to PTU for the treatment of thyrotoxicosis in TS.
Another aspect is the timing of inorganic iodide administration. Several textbooks, as well as guidelines published by the ATA and other organizations, recommend that inorganic iodide should be given at least one hour after the administration of antithyroid drugs (ATD) (8). However, two large prospective studies performed in Japan demonstrated that concurrent administration of MMI and inorganic iodide are not associated with any adverse effect, and that the combined administration of the ATD and iodide lowered free thyroxine levels significantly faster than treatment with MMI alone. Therefore, the committee is now recommending that inorganic iodide should be administered concurrently with ATDs to patients with TS. Thus, relevant for clinical purposes, Akamizu et al. clarified the clinical features, prognosis, and incidence of TS and established detailed recommendations for the diagnosis and treatment of TS (7).
The last article, entitled “Lessons from Fukushima: latest findings of thyroid cancer after the Fukushima Nuclear Power Plant Accident,” is written by Shunichi Yamashita et al. (9). Studies on atomic bomb survivors in Hiroshima and Nagasaki have clearly demonstrated that external radiation exposure increases the risk for thyroid cancer in a dose- and age-dependent manner. As for internal radiation exposure, it also became evident from epidemiological studies after the Chernobyl nuclear power plant accident that internal exposure to radioactive iodine increases PTC risk in a dose-dependent manner in individuals aged <18 years at the time of an accident.
Most unfortunately, a serious accident occurred at the Fukushima Daiichi Nuclear Power Plant after the Great East Japan Earthquake, followed by the giant tsunami on March 11, 2011. At that time, a vast majority of people expressed concerns about an increase in thyroid cancer risk from the dispersed radioactive materials, especially radioactive iodine, from the melted reactors. In response to their concern, the Fukushima Health Management Survey was launched soon after the disaster, in July 2011. Subsequently, thyroid ultrasound screening began from October 9, 2011, to March 31, 2014, for a baseline examination, followed by a second evaluation performed between April 1, 2014, and March 31, 2016, and a third round beginning in April 2016 that is still ongoing.
As a result of the first screening, 116 out of approximately 300,000 subjects were diagnosed as having suspicious or malignant lesions. Similar results were obtained in the second screening: 71 out of approximately 270,000 subjects were found to have suspicious or malignant nodules. Considering that mass thyroid screening using ultrasound and fine-needle aspiration biopsy has revealed that thyroid cancer was detected in 3.5% of otherwise healthy Japanese women aged >30 years old (10), it is highly unlikely that the incidence in thyroid cancer in the Fukushima Prefecture detected through screening can be attributed to the nuclear accident. Moreover, we now know that the exposure activities in Fukushima were much lower than those in Chernobyl (11). However, it may be too early to conclude definitely whether radiation exposure subsequent to the Fukushima accident has an impact on thyroid cancer incidence. At this point, we need to await the results of future epidemiological studies, and further characterize genetic abnormalities and pathological features of the identified carcinomas. At this moment, we expect that further follow-up and characterization of the Fukushima cohort, in which the authors of this review and their groups are taking an active part, will provide important information and insights into the incidence and natural history of radiation-associated thyroid cancers in children, adolescents, and young adults.
Before closing, we would like to express our deep regret about the passing of Professor Shigenobu Nagataki (12). He had been an eminent leader in thyroid research in Japan. Moreover, he always emphasized the importance of international contributions of the JTA and interactions with the world at large. Therefore, we are very saddened that he could not contribute or read this special issue of Thyroid. We are convinced that he would have been absolutely thrilled by these contributions, perhaps more than anybody else in the world.