Correlation Between Glycemic Control and Serum Thyroglobulin Levels in a Patient With RAI-Refractory Thyroid Cancer.

Diabetes is a risk factor for thyroid cancer development. Serum thyroglobulin (Tg) levels are useful as sensitive and specific tumor markers for monitoring radioiodine (RAI)-refractory thyroid cancer; however, the impact of glycemic control on serum Tg levels is poorly understood. Here, we present a case of a female patient with lung metastases of RAI-refractory thyroid cancer in whom glycemic control may have influenced the serum Tg levels. Despite receiving thyroid-stimulating hormone suppression therapy, her serum Tg levels remained elevated. Subsequently, she developed type 2 diabetes and was administered antidiabetic medications for 6 years. Throughout the course of diabetes management, her serum Tg levels fluctuated according to the level of glycemic control, showing a strong correlation with her hemoglobin A1c levels (r = 0.92, P < .01). Similar to the serum levels of other tumor markers, such as the carcinoembryonic antigen and carbohydrate antigen 19-9, the serum levels of Tg can be influenced by glycemic control. Therefore, serum Tg levels in patients with RAI-refractory thyroid cancer and diabetes should be monitored with attention to glycemic control.

Recovery from insulin dependence in immune checkpoint inhibitor-associated diabetes mellitus: A case report.

Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare immune-related adverse event and is usually considered permanent. Here, we report the first case of a 54-year-old man with ICI-DM who recovered from insulin dependence. He was diagnosed with lung cancer and started pembrolizumab therapy. After seven cycles, he developed ICI-associated secondary adrenal insufficiency and started hydrocortisone supplementation. Subsequently, he complained of fatigue, and blood examinations showed hyperglycemia with ketosis. A glucagon challenge test indicated insulin dependence. He was diagnosed with ICI-DM and insulin therapy was initiated. Pembrolizumab therapy was discontinued due to concomitant ICI-associated hepatitis. Six months later, a glucagon challenge test result showed an improvement in insulin secretion, and insulin therapy was discontinued. The lung cancer lesions continued to shrink. Even if ICI-DM develops, it might be possible to control the underlying cancer while avoiding lifelong insulin therapy through early discontinuation of ICI.

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study.

BACKGROUND: The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test. METHODS: We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 µg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 µg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 µg/dL and peak ACTH increase

Influence of Levothyroxine With Recombinant Human Thyroid-Stimulating Hormone on Urinary Iodine Excretion Before Radioactive Iodine Administration.

OBJECTIVE: Stimulation with recombinant human thyroid-stimulating hormone (rhTSH) before radioactive iodine administration for patients with thyroid cancer may increase the body iodine pool in the presence of continued levothyroxine; however, the precise significance of its influence remains unclear. METHODS: This was a prospective observational study conducted between March 2017 and August 2020. We measured the 24-hour urinary iodine excretion and urinary iodine-to-creatinine ratio in patients with thyroid cancer stimulated by rhTSH or thyroid hormone withdrawal (THW) before radioactive iodine administration. Oral iodine intake was controlled by a 7-day self-managed low iodine diet, followed by a strict 3-day low iodine diet while in the hospital. RESULTS: Overall, 343 subjects were included (rhTSH: n = 181; THW: n = 162). The mean levothyroxine dose in the rhTSH group was 115.2 µg daily. The median 24-hour urinary iodine and urinary iodine-to-creatinine ratio in the rhTSH group (71.0 [interquartile range, 57.5-88.0] µg/day and 80.0 [59.0-97.5] µg/gCr, respectively) were significantly higher than those in the THW group (42.0 [30.0-59.0] µg/day and 39.0 [28.0-61.3] µg/gCr, respectively; both P < .001). After propensity score matching by age, sex, body weight, and renal function (rhTSH: n = 106; THW: n = 106), consistent results for both values were observed for both methods. The increase in urinary iodine with the rhTSH method was smaller than the expected value calculated from the amount of levothyroxine. CONCLUSION: Urinary iodine excretion was significantly higher among patients with rhTSH stimulation than those with THW, indicating that the rhTSH method slightly increases the body iodine pool.

[Prostate Cancer Diagnosed during Androgen Replacement Therapy for Late-Onset Hypogonadism Treatment: A Case Report].

We report a 60-year-old man with prostate cancer diagnosed during androgen replacement therapy (ART) for late onset hypogonadism after surgery for pituitary adenoma. He was refered to the department of urology since prostate specific antigen values were elevated after 6 months of ART. After the diagnosis of prostate cancer, ART was discontinued, and robot-asssited laparoscopic radical prostatectomy with pelvic lymphadenoctomy was performed. Pathological examination revealed Gleason score 4 + 5 prostate adenocarcinoma with seminal vesicle invasion and lymph node metastasis(pT3bN1). He has stayed biochemically and radiologically disease-free 33 months postoperatively.

Hyponatremia in an Elderly Patient due to Isolated Hypoaldosteronism Occurring after Licorice Withdrawal.

Hyponatremia is one of the most common electrolyte disorders encountered in the elderly. We present the case of an 81-year-old man who developed hyponatremia due to isolated hypoaldosteronism occurring after licorice withdrawal. He had severe hypokalemia with hypertension and was diagnosed with pseudoaldosteronism. He had been taking a very small dose of licorice as a mouth refresher since his early adulthood. Five months after licorice withdrawal, he developed hypovolemic hyponatremia, which was resolved with administration of fludrocortisone acetate. Our experience with this case suggests that isolated hypoaldosteronism occurring after licorice withdrawal should be considered as a potential cause of hyponatremia in elderly patients.

Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients.

Measuring the levels of the plasma free metanephrines (PFMs) represents a recently developed and promising test for the diagnosis of pheochromocytoma in the United States and Europe. As this test has not yet been evaluated in Japan, it is necessary to evaluate the diagnostic efficacy of measuring the levels of PFMs compared with the standard measurement of the urinary excretion of metanephrines (uMNs) whose reliability is well established to detect of pheochromocytoma. A total of 101 Japanese subjects clinically suspected of having pheochromocytoma in were included in this study. Subsequently, we prospectively measured the PFMs levels in all patients, compared with those of biochemical markers of the catecholamine secretion and metabolisms in the plasma and urine. All subjects with adrenal tumors underwent tumor excision. Data were available for 84 of the 101 patients, 47 of whom had histopathologically proven pheochromocytoma and 37 were finally diagnosed with non-pheochromocytoma. The results of comparisons in the accuracy of measurement for diagnosis of pheochromocytoma between PFMs and the urinary excretion of metanephrines (uMNs) were 0.980 VS 0.951 for AUC of receiver operatorating characteristic (ROC) curve, 0.957 VS 0.894 for sensitivity, and 0.973 VS 0.946 for specificity, respectively. Although the differences were small, the results of our study definitely demonstrated that measurement of PFMs was not inferior to standard urinary metanephrines (uMNs) measurement, which is established to be the most reliable biochemical method to detect pheochromocytoma. This study clearly shows measuring the PFMs levels to be a reliable and efficient method for diagnosing pheochromocytoma in Japanese patients, as demonstrated in previous reports.

Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients.

BACKGROUND: The interactions between kidney and thyroid functions have been known for many years; however, there are few studies on the extent of the improvements and long-term changes of renal function after thyroid hormone replacement therapy (THRT) in chronic kidney disease (CKD) patients. The purpose of this study was to determine how THRT affects the estimated glomerular filtration rate (eGFR) in CKD patients with primary hypothyroidism. METHODS: A retrospective investigation was performed on 51 Japanese patients (15 men and 36 women) with primary hypothyroidism. The changes in eGFR after THRT were examined according to the existence of CKD and severity of thyroid function. RESULTS: eGFR increased rapidly over the first 6 months after THRT in CKD patents, which was followed by a plateau. There was a correlation between eGFR and the severity of hypothyroidism, which was independent of age, and eGFR in severely hypothyroid patients significantly increased up to levels that were similar to mildly hypothyroid patients after THRT. eGFR improved more in the lower initial eGFR group and increased about 30 % in CKD patients (47.5 ± 7.7 vs. 62.1 ± 9.5 ml/min/1.73 m(2), P < 0.01). Moreover, eGFR in CKD patients with mild to moderate hypothyroidism was significantly increased compared to that in non-CKD patients. CONCLUSION: Our data suggested that hypothyroidism contributed to the reduction in eGFR, especially in CKD patients; therefore, patients with CKD should positively be examined for thyroid function, and appropriate THRT should be started if needed.

A case of neurofibromatosis type 1 coinciding with bilateral pheochromocytomas, multiple gastrointestinal stromal tumors, and malignant peripheral nerve sheath tumor.

Neurofibromatosis type 1 (NF1) is associated with benign and malignant neoplasms, but the coincidence of abdominal neoplasms is rare. A 65-year-old woman with NF1 had episodes of nausea, tachycardia, hypertension, and loss of consciousness. Bilateral adrenal tumors were detected by abdominal computed tomography, and plasma and urinary catecholamine levels were elevated. Open bilateral adrenalectomy and histological findings revealed bilateral pheochromocytomas (PCCs). Furthermore, malignant peripheral nerve sheath tumor (MPNST) and multiple gastrointestinal stromal tumors (GISTs) were incidentally found in the abdominal cavity. Early diagnosis of abdominal neoplasms in NF1 patients is important because of the risk of malignancy, organic complications and hemorrhagic-obstructive complications.

A case of hepatitis C-associated osteosclerosis with xanthogranulomatous cholecystitis.

A 62-year-old woman presented with a markedly increased serum ALP level of skeletal origin during a regular follow-up of chronic hepatitis C. Serum calcium, phosphorus, and intact-PTH levels were normal and bone turnover markers were increased. Her generalized bone density was diffusely increased. These findings were consistent with hepatitis C-associated osteosclerosis (HCAO). She underwent cholecystectomy, as gallbladder cancer was suspected; however, histopathological findings demonstrated xanthogranulomatous cholecystitis. After cholecystectomy, serum ALP level and bone turnover markers were gradually decreased. This may indicate the existence of a novel osteogenic factor in the gallbladder in HCAO.

A case of Marinesco-Sjögren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial.

Investigation into the efficacy and safety of octreotide LAR in Japanese patients with acromegaly: Shizuoka study.

The efficacy and safety of the long-acting repeatable formulation of octreotide (OCT-LAR) treatment in patients suffering from acromegaly was investigated retrospectively in Shizuoka prefecture, Japan. Thirty patients (11 male, 19 female; average age, 48.9 years old), 29 of whom had undergone transsphenoidal surgery previously, were treated with OCT-LAR. OCT-LAR was injected i.m. every 4 weeks with an intended protocol of 20 mg over 24 months, however, 46.7% of patients required the dose of OCT-LAR to be increased. The final average dose of OCT-LAR was 25.0 +/- 6.8 mg. Administering OCT-LAR significantly decreased serum GH and insulin-like growth factor 1 (IGF-1) levels (from 13.7 +/- 11.9 to 5.8 +/- 7.3 microg/L and from 585 +/- 263 to 339 +/- 193.7 microg/L after 3 months, respectively). Among patients treated with OCT-LAR, 56.7% expressed

A case of subclinical hypothyroidism developing marked pleural effusions and peripheral edema with elevated vascular endothelial growth factor.

A 69-year-old woman was admitted for the treatment of marked pleural effusions and peripheral edema. Analytical studies of the pleural effusion revealed exudates. Culture for bacterial organisms and tuberculosis were negative, and cytology was normal. She had a mediastinal tumor at the age of 61 and regular follow-up showed no evidence of malignancy. She underwent the mediastinal tumor resection, because we thought this was the cause of her symptoms. However, her clinical symptoms persisted after surgery. Next, we noticed subclinical hypothyroidism, in which serum TSH level was elevated with concomitant normal thyroid hormone levels. In addition, serum vascular endothelial growth factor (VEGF) levels, which have been reported to be related to the pathophysiology of the extravascular volume overload, were elevated. Although her TSH level was slightly elevated (15.4 microU/ml), we started thyroid hormone replacement therapy. This therapy gradually ameliorated her clinical manifestation and abnormal laboratory data, including elevated VEGF levels. These observations indicate that even subclinical hypothyroidism may cause severe clinical manifestations. Furthermore, elevated VEGF may be a contributing factor in the pathogenesis of extravascular volume overload in hypothyroid patients.

Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription.

CONTEXT: Methimazole (MMI) and propylthiouracil (PTU) are widely used as antithyroid drugs (ATDs) for the treatment of Graves' disease. Both MMI and PTU reduce thyroid hormone levels by several mechanisms, including inhibition of thyroid hormone synthesis and secretion. In addition, PTU decreases 5'-deiodination of T(4) in peripheral tissues. ATDs may also interfere with T(3) binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T(3) mediated by TRs has not been studied. OBJECTIVE: The present study was undertaken to determine whether ATDs have an effect on the gene transcription regulated by T(3) and TRs in vitro. METHODS: Transient gene expression experiments and GH secretion assays were performed. To elucidate possible mechanisms of the antagonistic action of ATDs, the interaction between TR and nuclear cofactors was examined. RESULTS: In the transient gene expression experiments, both MMI and PTU significantly suppressed transcriptional activities mediated by the TR and T(3) in a dose-dependent manner. In mammalian two-hybrid assays, both drugs recruited one of the nuclear corepressors, nuclear receptor corepressor, to the TR in the absence of T(3). In addition, PTU dissociated nuclear coactivators, such as steroid receptor coactivator-1 and glucocorticoid receptor interacting protein-1, from the TR in the presence of T(3). Finally, MMI decreased the GH release that was stimulated by T(3). CONCLUSIONS: ATDs inhibit T(3) action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T(3) action at the transcriptional level.

A case of type 2 diabetes mellitus developing hypothyroidism discovered as a result of a discrepancy between glycated hemoglobin and glycated albumin values.

We report a case of type 2 diabetes mellitus presenting hypothyroidism due to overeating of seaweed that was noticed as a result of a discrepancy between glycated albumin (GA) and glycated hemoglobin (GHb). A 71-year-old woman was undergoing managed treatment with oral medicines and insulin for diabetes mellitus with no sign of thyroid disease. Her thyroid function was euthyroid without aid of thyroid hormone. All of the patient's thyroid autoantibodies were negative. Fifteen weeks prior to indications of hypothyroidism, she had started to consume large amounts (100-200 g dry weight equivalent) of cooked "wakame" seaweed every morning. Just before admission to our hospital, her GA was 26.9%, while GHb and fasting plasma glucose remained within normal ranges (less than 5.6%, and 106 mg, respectively). This discrepancy between GA and GHb drew our attention to the development of complications. Naive interview of the patient led us to believe a thyroid hormone deficiency existed, though without any related complaints or findings, such as non-pitting edema, cold intolerance, or easy fatiguing. Seaweed consumption was stopped and periodic observation of thyroid function started. As thyroid hormone levels moved into normal range, GA and GHb returned to their normal relative ratio after 3 months. Thus, measurement of the relative ratio of GA and GHb may be useful for glycemic monitoring, with the potential as a readily available glycemic control marker for patients with changeable complications.

Genomic structure and characterization of the 5'-flanking region of the human ghrelin gene.

Ghrelin, an endogenous ligand for the GH secretagogue receptor, induces GH secretion, food intake, and positive energy balance. Although ghrelin exhibits a variety of hormonal actions, the mechanisms regulating ghrelin expression and secretion remain unclear. To understand regulation of human ghrelin gene expression, we examined the genomic structure of approximately 5,000 bp of the 5'-flanking region of the human ghrelin gene. We performed rapid amplification of cDNA ends to estimate transcriptional start sites, indicating that there are two transcriptional initiation sites within the human ghrelin gene. Both transcripts were equally expressed in the human stomach, whereas the longer transcript was mainly expressed in a human medullary thyroid carcinoma (TT) cell line. Functional analysis using promoter-reporter constructs containing the 5'-flanking region of the gene indicated that the sequence residing within the -349 to -193 region is necessary for human ghrelin promoter function in TT cells. Within this region existed several consensus sequences for a number of transactivating regulatory proteins, including an E-box site. Destruction of this site decreased to 40% of the promoter activity. The upstream region of the promoter has two additional putative E-box sites, and site-directed mutagenesis suggested that these are also involved in promoter activation. Electrophoretic mobility shift assays demonstrated that the upstream stimulatory factor specifically bound to these E-box elements. These results suggest a potential role for upstream stimulatory factor transcription factors in the regulation of human ghrelin expression.

Transgenic mice producing major histocompatibility complex class II molecules on thyroid cells do not develop apparent autoimmune thyroid diseases.

The expression of major histocompatibility complex (MHC) class II molecules on thyrocytes has been demonstrated in autoimmune thyroid diseases. However, the role of this aberrant MHC class II in disease development is controversial. In particular, it remains unknown whether MHC class II expression on thyrocytes, which are nonprofessional antigenpresenting cells, plays a role in inducing autoimmune processes. To clarify this issue, we have produced transgenic mice harboring an MHC class II gene ligated to the promoter of the rat TSH receptor. We obtained three lines of transgenic mice, and the expression of MHC class II by the thyrocytes was demonstrated by immunofluorescence staining and flow cytometry. Our examination revealed no obvious abnormalities in thyroid histology or in thyroid autoantibody production in these transgenic mice. Although serum-free T(4) levels were slightly lower than those of their nontransgenic littermates, no transgenic mouse suffered from clinical hypothyroidism or hyperthyroidism. Furthermore, thyroid lymphocytic infiltration was absent, and MHC class II-expressing thyrocytes obtained from transgenic mice failed to stimulate the proliferation of autologous T cells in vitro. Taken together, these results show that transgenic mice with MHC class II molecules on their thyrocytes do not develop apparent autoimmune thyroid diseases, suggesting that aberrant MHC class II expression alone is not sufficient to induce thyroid autoimmunity.

Alterations of plasma ghrelin levels in rats with lipopolysaccharide-induced wasting syndrome and effects of ghrelin treatment on the syndrome.

Ghrelin not only strongly stimulates GH secretion, but is also involved in energy homeostasis by stimulating food intake and promoting adiposity through a GH-independent mechanism. These effects of ghrelin may play an important role in the pathophysiology of inflammatory wasting syndrome, in which both the somatotropic axis and energy balance are altered. In this study we investigated plasma ghrelin concentrations after lipopolysaccharide (LPS) administration to rats, a model of the wasting syndrome and critical illness. In addition, the therapeutic potential of the antiwasting effects of ghrelin was explored using LPS-injected rats. A single LPS injection suppressed plasma ghrelin levels 6 and 12 h later. Maximal reduction was observed 12 h after LPS injection, in a dose-dependent manner. In contrast, plasma ghrelin levels were elevated after repeated LPS injections on d 2 and 5. Peripheral administration of ghrelin twice daily (10 nmol/rat) for 5 d increased body weight gain in repeated LPS-injected rats. Furthermore, both adipose tissue weight and plasma leptin concentrations were increased after ghrelin administration in these rats. In conclusion, plasma ghrelin levels are altered in LPS-injected rats, and ghrelin treatment may provide a new therapeutic approach to the wasting syndrome and critical illness.

Thyroid hormone action is disrupted by bisphenol A as an antagonist.

Bisphenol A (BPA), a monomer of polycarbonate plastics, has been shown to possess estrogenic properties and act as an agonist for the estrogen receptors. Although an epidemiologically based investigation has suggested that some chemicals could disrupt thyroid function in animals, the effects on thyroid hormone receptors (TRs) are unknown. We show here that BPA inhibits TR-mediated transcription by acting as an antagonist. In the transient gene expression experiments, BPA suppressed transcriptional activity that is stimulated by thyroid hormone (T(3)) in a dose-dependent manner. The inhibitory effects were observed in the presence of physiological concentrations of T(3). In contrast, in the case of negatively regulated TSHalpha promoter, BPA activated the gene transcription that is suppressed by T(3). To elucidate possible mechanisms of the antagonistic action of BPA, the effects on T(3) binding and cofactor interaction with TR were examined. The K(i) value for BPA was 200 micro M when assessed by inhibition of [(125)I]T(3) binding to rat hepatic nuclear TRs. In a mammalian two-hybrid assay, BPA recruited the nuclear corepressor to the TR. These results suggest that BPA could displace T(3) from the TR and recruit a transcriptional repressor, resulting in gene suppression. This is the first report that BPA can antagonize T(3) action at the transcriptional level. BPA may disrupt the function of various types of nuclear hormone receptors and their cofactors to disturb our internal hormonal environment.