This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin resistance syndrome is defined as a condition characterized by severe attenuation of insulin action due to functional impairment of the insulin receptor or its downstream signaling molecules. This syndrome is classified into two types: genetic insulin resistance syndrome, caused by gene abnormalities, and type B insulin resistance syndrome, caused by autoantibodies to the insulin receptor. Genetic insulin resistance syndrome includes type A insulin resistance as well as Donohue and Rabson-Mendenhall syndromes, all of which are caused by abnormalities of the insulin receptor gene; conditions such as SHORT syndrome caused by abnormalities of PIK3R1, which encodes a regulatory subunit of phosphatidylinositol 3-kinase; conditions caused by abnormalities of AKT2, TBC1D4, or PRKCE; and conditions in which a causative gene has not yet been identified. Type B insulin resistance syndrome is characterized by severe impairment of insulin action due to the presence of insulin receptor autoantibodies. Cases in which hypoglycemia alone is induced by autoantibodies that stimulate insulin receptor were not included in Type B insulin resistance syndrome.

17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by pathogenic mutations in CYP17A1. Impaired 17α-hydroxylase and 17,20-lyase activities typically induce hypertension, hypokalemia, sexual infantilism, and amenorrhea. Most patients with 17OHD are diagnosed in adolescence. Here, we report a female (46, XX) patient with 17OHD who was diagnosed at the age of 67 years. Genetic analysis was performed using direct DNA sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) analysis. Direct DNA sequencing revealed a homozygous c.1039C>T in CYP17A1, corresponding to a p.R347C amino acid change. MLPA probe signals showed that the CYP17A1 mutation was present in the homozygous carrier state. The patient’s dehydroepiandrosterone sulfate and androstenedione levels were extremely low, despite elevated adrenocorticotropic hormone (ACTH) and normal cortisol levels. A corticotropin-releasing hormone (CRH) test showed no response of cortisol, despite a normal response of ACTH. Rapid ACTH injection resulted in elevations in the deoxycorticosterone, corticosterone, aldosterone, and 17-hydroxypregnenolone levels, but not in the cortisol level. These results suggested that 17α-hydroxylase/17,20-lyase activities were partially impaired. Computed tomography revealed bilateral adrenal hyperplasia and a hypoplastic uterus. A high basal plasma ACTH level and a discrepancy between ACTH and cortisol responses in a CRH test may provide a definitive diagnostic clue for this disease.

Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

Posterior recurrent laryngeal nerve (RLN) lymph node dissection remains controversial in the operation of thyroid cancer, especially in cases of papillary thyroid microcarcinoma (PTMC). The present study aimed to evaluate the risk factors for posterior RLN lymph node metastasis in patients with PTMC. Two hundred and thirty-nine patients pathologically diagnosed with PTMC after surgery between June 2016 and June 2017 were included. Risk factors including age, sex, tumor diameter, multiple tumor focus, membrane invasion and lateral cervical lymph node metastasis condition, were analyzed, and their corresponding OR values were calculated. The results indicated that posterior RLN lymph node metastasis was pathologically identified in 27/239 patients. Membrane invasion (p = 0.024), VIa lymph node metastasis (p < 0.01), and lateral cervical lymph node metastasis (p < 0.01) were considered to be risk factors for posterior RLN lymph node metastasis. It is concluded that membrane invasion, VIa lymph node metastasis, and lateral cervical lymph node metastasis significantly increased the incidence of posterior RLN lymph node metastasis. Complete dissection of the posterior RLN lymph node was essential for patients with these risk factors.

The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes the pathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience of Japanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In this edition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studies of thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, and globalization of the pathological diagnosis of thyroid tumors.

Peripheral arterialdisease (PAD) can result in diabetic foot ulcers, gangrene, and even amputation. Since most cases of PAD in diabetic patients are associated with peripheral neuropathy, the symptoms of vascular disease are easily concealed by the symptoms of neuropathy and are ignored by people, so it is critical for health care providers to screen PAD for the diabetes patients. This study was carried out to identify theprevalence and related factors of PAD in diabetes mellitus inpatients. This was a cross-sectional observational study. A total of 855 patients were enrolled in the study from December 2018 to December 2019. The patients were divided into a non-PAD group (ABI = 0.9–1.3) and a PAD group (ABI <0.9). Logistic multivariate regression analysis showed that age, LDL-C, dorsalis pedis artery pulsation (left foot), and sensory-current threshold (right foot) were related factors for peripheral arterial disease. Patients who are older and have a higher LDL-C level, abnormal dorsal foot pulse, and abnormal sensory-current threshold must be vigilant, and receive early screening for PAD diagnosis and treatment to avoid a malignant outcome. In clinical work, medical staff should actively apply PAD screening to diabetic patients, identify risk factors as early as possible, conduct early interventions, reduce the risk of PAD in patients, and avoid the occurrence of adverse outcomes.

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

A 28-year-old Japanese woman positive for TSH receptor antibody and anti-nuclear antibody complained of difficulty seeing nearby objects, severe throbbing retro-orbital pain, diplopia, blepharoptosis and upward gaze palsy when she became hypothyroid during treatment with 30 mg methylmercaptoimidazole for Graves’ hyperthyroidism. Brain magnetic resonance imaging revealed slightly swollen bilateral inferior rectus muscles, suggesting the external ophthalmoplegia due to the muscle pathology commonly encountered in Graves’ disease. The retro-orbital pain was associated with marked accommodation failure and the pupillary abnormalities. The left and/or right eye showed intermittent, asymmetric and fluctuating mydriasis, being unresponsive to ordinary light but slowly responsive to strong sunlight and slowly responsive in a dark room. During the 5-year period, mydriasis was observed 9 times on both sides, 11 times only on the right side and 4 times only on the left side. Internal ophthalmoplegia with tonic pupils and accommodation failure affecting both the pupillary sphincter muscle and ciliary muscle due to damage to the parasympathetic outflow to these muscles was suggested. Autoimmune mechanism and/or the mechanism underlying channelopathy affecting the ciliary ganglion or short ciliary nerves might be responsible for this fluctuating complication. This very rare panophthalmopathy affecting both external and internal muscles occurred when the patient was suffering from iatrogenic hypothyroidism during the 30 mg methylmercaptimidazole treatment for Graves’ disease.

Resistance to thyroid hormone beta (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor beta (TRβ) is a rare disorder. Little information is available regarding the clinical experience of this syndrome in Japan. We retrospectively reviewed the records of 34 patients with RTHβ (21 adult females and 13 adult males) with positive TRβ mutations identified at our division between 2000 and 2020. Of the 24 patients with available clinical history, 10 (41.7%) received inappropriate treatments such as antithyroid drugs, thyroidectomy, or radioactive iodine. Diagnostic delay and inappropriate management of RTHβ are still present in Japan. Every patient except one demonstrated thyroid hormone profiles indicative of syndrome of inappropriate secretion of thyrotropin (SITSH), characterized by a hormonal profile of hyperthyroxinemia with a non-suppressed TSH concentration. Since the most common forms of hyperthyroidism including Graves’ disease feature elevated thyroid hormone levels with suppressed TSH concentrations, early diagnosis of SITSH is critical for preventing inappropriate management. One patient positive for anti-thyroglobulin antibody (Tg-Ab) and anti-thyroperoxidase antibody (TPO-Ab) showed remarkably elevated TSH (>200 μIU/mL) despite thyroid hormone concentrations within the reference ranges. At least one thyroid autoantibody (Tg-Ab, TPO-Ab, or thyrotropin receptor antibodies) was identified in 37.9% (11/29) of the patients tested. One patient developed overt Graves’ disease nine years after RTHβ diagnosis. These findings suggest that RTHβ is frequently comorbid with additional autoimmune thyroid disorders. Further research is required to identify the most appropriate treatments for RTHβ patients who develop a second thyroid disorder.

The receptors of chemokines play a significance role in the aggressiveness of tumor. CXCR4/CXCR7 promote metastasis of papillary thyroid carcinoma (PTC). This study examined the expresssion of chemokine receptors CXCR4/CXCR7 in human tissue specimens of PTC and peritumoral nonmalignant tissues. The correlation between CXCR4/CXCR7 and the clinicopathological factors in PTC was also determined. CXCR4/CXCR7 were examined in 115 PTC tissues from 115 patients using immunohistochemistry. Staining intensity was compared with patients and tumor characteristics including gender, age, tumor size, capsule invasion, multifocality, lymph node metastasis, and nature of paracancerous tissue. [Statistics: rank sum test, Spearman rank order correlation test; p < 0.05]. Higher expression rates of CXCR4/CXCR7 exhibited in PTC compared with peritumoral nonmalignant tissues. The expression of them was correlated in cancer and paracancerous specimens. A trend toward higher CXCR4/CXCR7 expression was found among tumors showing positive lymph nodes and capsule invasion, while no association with sex, age, tumor size, and nature of paracancerous tissue. Number of lymph nodes was associated with higher intensity IHC staining for CXCR4/CXCR7. Intense staining for CXCR4 was also associated with multifocality. Expression of CXCR4/CXCR7 by PTCs was correlated with lymph node metastasis and capsule invasion. Although multiple bias, they were thought to play a significance role in the aggressiveness of PTC, which provides potential targets for therapeutic interventions.

We investigated whether growth hormone (GH) treatment could accelerate the onset of puberty in patients with isolated GH deficiency (GHD). Of the 135 boys and 89 girls who started GH treatment before the onset of puberty and were followed up at Tanaka Growth Clinic, 83 boys and 51 girls who started GH treatment sufficiently earlier than the average age at onset of puberty of GHD patients (<10 years vs. 11.7 years for boys; <9.5 years vs. 11.4 years for girls) were analyzed. Age at onset of puberty significantly positively correlated to age at the start of GH treatment (boys: r = 0.427, p < 0.0001; girls: r = 0.302, p < 0.05). When the subjects were divided into two groups each: for boys, Groups A (n = 45) and B (n = 39), treatment was started at age <8 and 8 to <10 years, respectively; for girls, Groups A (n = 26) and B (n = 21), treatment was started at age <7 and 7 to <9.5 years, respectively, age at the onset of puberty was significantly lower in Groups A than in Groups B by the Mann-Whitney U test (boys: p < 0.01; girls: p < 0.05) and Kaplan-Meier log-rank test (boys: p < 0.01; girls: p < 0.05). These results indicate that GH treatment accelerates the delayed onset of puberty in patients with GHD. Heights at the onset of puberty in Groups A and B were not significantly different, suggesting that early treatment does not increase adult height.

Opioids are widely used for treatment of acute and chronic pain. However, opioids have several well-known clinical adverse effects such as constipation, nausea, respiratory depression and drowsiness. Endocrine dysfunctions are also opioid-induced adverse effects but remain under-diagnosed in clinical settings, especially opioid-induced adrenal insufficiency (OIAI). A 46-year-old woman was treated with transdermal fentanyl at a dose of 90–120 mg daily morphine milligram equivalent for non-malignant chronic pain for four years. Fatigue, loss of appetite and decrease in vitality began about two years after starting fentanyl. Subsequently, constipation and abdominal pain appeared and became worse, which led to suspicion of adrenal insufficiency. Clinical diagnosis of OIAI was established based on laboratory findings of secondary adrenal insufficiency, including corticotropin-releasing hormone stimulation test, clinical history of long-term fentanyl use, and exclusion of other hypothalamic-pituitary diseases. Oral corticosteroid replacement therapy was unable to relieve her abdominal pain and constipation; opioid-rotation and dose-reduction of fentanyl were not feasible because of her persistent pain and severe anxiety. While her clinical course clearly suggested that long-term, relatively high-dose transdermal fentanyl treatment may have contributed to the development of secondary adrenal insufficiency, the symptoms associated with OIAI are generally non-specific and complex. Together with under-recognition of OIAI as a clinical entity, the non-specific, wide range of symptoms can impede prompt diagnosis. Thus, vigilance for early symptoms enabling treatments including corticosteroid replacement therapy is necessary for patients taking long-term and/or high dose opioid treatment.

Di-(2-ethylhexyl) phthalate (DEHP) is extensively used in many personal care and consumer products, which results in widespread human exposure. Limited studies have suggested that exposure to DEHP may affect thyroid function, but little is known about the effect and mechanisms of DEHP exposure on the hypothalamic-pituitary-thyroid axis (HPTA). The present study was conducted to elucidate the potential mechanisms underlying DEHP disrupting the function of the HPTA. DEHP was administered to Wistar rats by gavage at 0, 5, 50, and 500 mg/kg/day for consecutive 28 days and then the rats were sacrificed within 24 h following the last dose. The hormone levels of HPTA were quantified with radioimmunoassay and enzyme-linked immunosorbent assay, the protein levels of thyrotropin-releasing hormone receptor (TRHR) and thyroid-stimulating hormone receptor (TSHR) were analyzed by Western blot and immunohistochemistry, and the expression levels of TRHR and TSHR mRNA were measured by quantitative real-time PCR. The low dose of DEHP increased the body weights of rats. Serum levels of T3, T4, FT3 and FT4 as well as protein and mRNA levels of TSHR decreased in rats treated with 50 mg/kg or 500 mg/kg DEHP compared with those of controls. Although the protein levels of TRH in the hypothalamus or protein and mRNA levels of TRHR in pituitary were up-regulated, serum levels of TSH did not change statistically in rats treated with DEHP. Therefore, DEHP can produce thyroid toxicity and may interfere with the secretion of pituitary TSH. In conclusion, DEHP could interfere with the balance of HPTA of adolescent rats, and disturb the homeostasis of thyroid related hormones and the expression levels of receptors.