Current status of diabetes treatment in Miyazaki Prefecture, Japan: Results of a questionnaire survey conducted in 2016 and 2020.

AIMS/INTRODUCTION: The Japanese diabetes treatment guidelines do not specify the first choice of hypoglycemic agents, unlike those of Western countries. Furthermore, the current situation in diabetes treatment is that the choice of hypoglycemic agents is determined by each physician. Therefore, we aimed to determine the current situation in Miyazaki Prefecture, Japan, in this context. For this, we carried out a questionnaire survey among physicians twice regarding the target value of glycated hemoglobin and the choice of hypoglycemic agents in various cases. MATERIALS AND METHODS: We administered an unsigned questionnaire to physicians in Miyazaki Prefecture, Japan, in July 2016 and March 2020. We divided responses into those of diabetologists and those of non-diabetologists, and analyzed each response. We then compared the results between both years. RESULTS: In total, 18 diabetologists and 142 non-diabetologists responded in 2016, and 21 diabetologists and 134 non-diabetologists responded in 2020. Many diabetologists chose biguanide as the first-line drug for obese type 2 diabetes patients. In addition, the rate of choice of sodium-glucose cotransporter 2 inhibitor (SGLT2i) among physicians almost increased in 2020. Some non-diabetologists, and even a few diabetologists, inappropriately chose SGLT2i and biguanide for patients with severe renal dysfunction. CONCLUSIONS: Because SGLT2i became available in 2016 and a few years have passed, both diabetologists and non-diabetologists seemed to refrain from prescribing SGLT2i. However, with the emergence of various lines of firm evidence regarding the use of SGLT2i, physicians started to prescribe it. However, some diabetologists and non-diabetologists chose hypoglycemic agents inadequately; therefore, there is a need for novel and precise information.

Nasogastric administration of lenvatinib solution in a mechanically ventilated patient with rapidly growing anaplastic thyroid cancer.

SUMMARY: A 54-year-old woman was referred to our hospital with a cervical tumor. CT revealed a cervical tumor extending to the upper mediastinum, tracheal deviation and tumor infiltration in the cervical vessels. She was followed-up because no diagnosis of malignancy was made by cytology. However, 2 months later, a CT scan showed enlargement of the tumor and tracheal stenosis, and a surgical biopsy was performed and she was diagnosed with anaplastic thyroid cancer (ATC). The tracheal tube with tracheal stenosis could not be removed due to the rapid growth of the tumor, necessitating management by mechanical ventilation. Due to the difficulty of surgical resection, she was treated with lenvatinib. A lenvatinib solution was made and administered via a nasogastric tube. After lenvatinib treatment, the tumor volume decreased and the tracheal stenosis improved. The tracheal tube was removed and oral intake became possible. She was discharged and received ambulatory lenvatinib therapy. The tumor was significantly reduced in size, but gradually grew and was exposed through the cervical wound 6 months later. Esophageal perforation occurred 10 months after the start of treatment. Lenvatinib was re-administered via a nasogastric tube. Eleven months later, the patient died of massive bleeding from the exposed cervical tumor. Patients with advanced ATC may require management with mechanical ventilation for airway stenosis or with a nasogastric tube for esophageal stenosis and perforation. We experienced a case in which lenvatinib was safely administered via a nasogastric tube while performing mechanical ventilation. LEARNING POINTS: An anaplastic thyroid cancer patient under mechanical ventilator management was treated with lenvatinib via a nasogastric tube. The lenvatinib solution can easily be prepared and administered via a nasogastric tube. The lenvatinib solution was effective for a patient with difficulty in oral intake. Lenvatinib could also improve the prognosis of an anaplastic thyroid cancer patient with severe airway and esophageal trouble.

Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab.

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.

Fulminant hepatitis and elevated levels of sIL-2R in thyroid storm.

SUMMARY: We report the case of a 48-year-old man with thyroid storm associated with fulminant hepatitis and elevated levels of soluble interleukin-2 receptor (sIL-2R). Fatigue, low-grade fever, shortness of breath, and weight loss developed over several months. The patient was admitted to the hospital because of tachycardia-induced heart failure and liver dysfunction. Graves' disease with heart failure was diagnosed. He was treated with methimazole, inorganic iodide, and a ß-blocker. On the day after admission, he became unconscious with a high fever and was transferred to the intensive care unit. Cardiogenic shock with atrial flutter was treated with intra-aortic balloon pumping and cardioversion. Hyperthyroidism decreased over 10 days, but hepatic failure developed. He was diagnosed with thyroid storm accompanied by fulminant hepatitis. Laboratory investigations revealed elevated levels of sIL-2R (9770 U/mL). The fulminant hepatitis was refractory to plasma exchange and plasma filtration with dialysis, and no donors for liver transplantation were available. He died of hemoperitoneum and gastrointestinal hemorrhage due to fulminant hepatitis 62 days after admission. Elevated circulating levels of sIL-2R might be a marker of poor prognosis in thyroid storm with fulminant hepatitis. LEARNING POINTS: The prognosis of thyroid storm when fulminant hepatitis occurs is poor. Liver transplantation is the preferred treatment for fulminant hepatitis induced by thyroid storm refractory to plasma exchange. Elevated levels of soluble interleukin-2 receptor might be a marker of poor prognosis in patients with thyroid storm.

Rapid pleural effusion after discontinuation of lenvatinib in a patient with pleural metastasis from thyroid cancer.

We report a case of rapid pleural effusion after discontinuation of lenvatinib. A 73-year-old woman was diagnosed with poorly differentiated thyroid cancer with right pleural metastasis. Weekly paclitaxel treatment was performed for 18 weeks, but it was not effective. Oral administration of lenvatinib, a multi-target tyrosine kinase inhibitor, reduced the size of cervical and thoracic tumors and lowered serum thyroglobulin levels. Lenvatinib was discontinued on day 28 because of Grade 2 thrombocytopenia and Grade 3 petechiae. Seven days after discontinuation of lenvatinib, the patient was hospitalized because of dyspnea and right pleural effusion. Pleural effusion rapidly improved with drainage and re-initiation of lenvatinib and did not recur. Anorexia caused by lenvatinib led to undernutrition, which resulted in death 13 months after initiation of lenvatinib. Autopsy revealed extensive necrosis with primary and metastatic lesions, suggesting that the patient responded to lenvatinib. Physicians should be aware of the possibility of flare-up in patients with thyroid cancer treated with lenvatinib. Learning points: Autopsy findings revealed that lenvatinib was efficacious in treating poorly differentiated thyroid cancer without primary lesion resection. Flare-up phenomenon may occur in thyroid cancer treated with lenvatinib. Attention should be paid to flare-up phenomenon within a few days of discontinuing lenvatinib.

Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency.

CONTEXT: Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH). OBJECTIVE: The aim of this study was to identify the genetic cause of CHH in a patient and to functionally characterize a KISS1R mutation. DESIGN: The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand-KISS1R mutant complex with those of wild-type KISS1R variants. RESULTS: A homozygous mutation (c.440C>T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket. CONCLUSION: We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket.

Epidemiology of anorexia nervosa in Japanese adolescents.

BACKGROUND: No epidemiologic survey examining eating disorders in Japan has been done at a national level since 1992. The prevalence of anorexia nervosa, as assessed by questionnaires to hospitals, is thought to be underestimated because patients with anorexia nervosa tend to avoid consultations. In conformity with the School Health and Safety Act of Japan, schools are required to have physicians perform a medical examination of students every year. The teachers in charge of health education and school physicians determine the height, weight, and health condition, and examine the medical records of each student. Therefore, we as members of the Survey Committee for Eating Disorders of the Japanese Ministry of Health, Labour, and Welfare conducted an epidemiologic survey using questionnaires sent to schools in seven prefectures to determine the current prevalence of anorexia nervosa among adolescents. METHODS: We sent a questionnaire to elementary, junior high, and senior high schools. Questionnaires contained items on the number of students, patients with anorexia nervosa in each grade who were diagnosed by specialists, and students who the school physician strongly suspected to have anorexia nervosa but who did not undergo a clinical examination in a medical institution. RESULTS: We found patients of both sexes with anorexia nervosa aged 9-10 years in elementary schools. The point prevalence of anorexia nervosa for girls, including strongly suspected cases, in the three grades of junior high school and three grades of senior high school were 0-0.17 %, 0-0.21 %, 0.17-0.40 %, 0.05-0.56 %, 0.17-0.42 % and 0.09-0.43 %, respectively. We also confirmed a prominent sex difference in the prevalence of anorexia nervosa. The prevalence of boys was one third that of girls in some prefectures. One third to one half of diagnosed and strongly suspected students with anorexia nervosa had not received medical consultation or treatment. CONCLUSIONS: Although the prevalence of anorexia nervosa had regional differences in Japan, it has reached levels comparable to those in Western societies. Because no eating disorder center exists and the treatment environment is poor, national action to address this disease is a pressing need in Japan.

A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting. Dentin matrix protein 1 (DMP1), a noncollagenous extracellular protein, plays critical roles in bone mineralization and phosphate homeostasis. Recently, loss-of-function mutations in DMP1 gene have been identified as the molecular cause of ARHR. Here, we describe a Japanese family that includes two ARHR-affected siblings carrying a novel mutation of the DMP1 gene. The patients were a 53-year-old woman and a 50-year-old man with short stature and skeletal deformities who were the offspring of a first-cousin marriage. Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D. Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR. Sequence analysis of peripheral leukocytes from the patients revealed that they carried a novel homozygous nonsense mutation in the DMP1 gene (98G>A, W33X), which leads to a truncated DMP protein with no putative biological function. Unaffected family members were heterozygous for the mutation. This is the first report of a Japanese family with ARHR carrying a novel mutation of the DMP1 gene.

Myasthenia gravis complicated with primary aldosteronism and hypokalemic myopathy.

A 34-year-old Japanese man was admitted to an outside hospital with an elevated creatinine kinase level and suspected myositis. He was treated with high dose methylprednisolone, which caused severe aggravation of muscle weakness. He was transferred to our hospital at that time. On admission, chest computed tomography (CT) and the presence of anti-acetylcholine receptor antibodies supported a diagnosis of myasthenia gravis and thymoma. Laboratory findings showed hypokalemia, low plasma renin activity and high serum aldosterone. Further studies, including abdominal CT and adrenal venous sampling suggested primary aldosteronism. At first, thymectomy was performed, and one month later, he was treated with laparoscopic adrenalectomy. Immediately after this procedure, he suffered from myasthenic crisis, which was successfully managed with mechanical ventilation and steroid pulse therapy followed by oral prednisolone. This case presented a serious difficulty in differentiating from various myopathies and giving proper treatment because of a rare combination of independent diseases and their masquerading clinical features.

[A case of lung cancer with hyperthyroidism].

We here report a case of metastasis from lung cancer to the thyroid. On presentation, this patient showed painful anterior cervical swelling and right supraclavicular lymph node swelling. Laboratory data showed primary hyperthyroidism. Although subacute thyroiditis was suspected, echo-guided needle aspiration biopsy and lymph node biopsy revealed poorly differentiated squamous cell carcinoma. As a result, primary lung cancer with thyroid metastasis was diagnosed based on mediastinal enlargement on chest X ray films and normal findings in organs other than the lung and thyroid. Chemotherapy for lung cancer induced a decrease in the size of tumor and the normalization of thyroid function. However, 2 months after the normalization, cervical swelling enlarged and a lung mass in right upper lobe and skin tumor appeared. Despite treatment with chemotherapy, she died. Postmortem revealed that the right upper lung carcinoma was the primary lesion and immunohistochemical staining for surfactant protein was positive in the thyroid, skin tumor and lymph node, which revealed these carcinomas had metastasized from lung cancer. To the best of our knowledge, thyrotoxicosis induced by thyroid metastasis of lung cancer is an uncommon case.