Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Scientific Information, Inc.  

BACKGROUND Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder characterized by central adrenal insufficiency (AI) but normal secretion of pituitary hormones other than adrenocorticotropic hormone. IAD usually presents with unspecific symptoms of AI, such as anorexia and fatigue, but some patients present with a variety of atypical manifestations. Rhabdomyolysis is a potentially life-threatening clinical syndrome caused by skeletal muscle injury with the release of muscle cell contents into the circulation. A wide variety of disorders can cause rhabdomyolysis. Herein, we report an unusual case of IAD presenting with hyponatremia and rhabdomyolysis. CASE REPORT A 67-year-old Japanese woman with a 2-month history of anorexia and fatigue was diagnosed with severe hyponatremia (serum sodium, 118 mEq/L) and rhabdomyolysis (serum creatine phosphokinase, 6968 IU/L), after 2 days of vomiting and muscle weakness. Physical and laboratory findings did not show dehydration or peripheral edema. Her rhabdomyolysis resolved with normalization of serum sodium levels during administration of sodium chloride. However, her anorexia and fatigue remained unresolved. After reducing the amount of sodium chloride administered, the patient still had hyponatremia. Detailed endocrinological examinations indicated IAD; her hyponatremia was associated with inappropriately high plasma arginine vasopressin levels. The patient received corticosteroid replacement therapy, which resolved her anorexia, fatigue, excessive arginine vasopressin, and hyponatremia. CONCLUSIONS This case highlights the importance of considering the possibility of central AI in patients with hyponatremia and excessive arginine vasopressin levels. In addition, rhabdomyolysis associated with hyponatremia can be an important manifestation of IAD.

DOI： 10.12659/ajcr.918427

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

A 59-year-old non-obese Japanese woman developed diabetes mellitus with a negative glutamic acid decarboxylase autoantibody (GADA) test result. Her hyperglycemia was initially well controlled by oral hypoglycemic agents; however, despite continued treatment the hyperglycemia gradually worsened. As she had endogenous insulin deficiency and tested positive for insulin autoantibody (IAA), insulin therapy was initiated. Few studies have investigated GADA-negative patients with slowly progressive type 1 diabetes mellitus (SPT1D). Our IAA-positive SPT1D patient progressed from the clinical onset of diabetes mellitus to starting insulin therapy relatively quickly (1.5 years), similarly to other previously reported non-obese patients with GADA-positive SPT1D.

DOI： 10.2169/internalmedicine.1008-18

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Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.

DOI： 10.2188/jea.JE20160151

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.

DOI： 10.2169/internalmedicine.9074-17

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. Case presentation: An 83-year-old Japanese man developed acute anterior hypopituitarism
he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Conclusions: Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

DOI： 10.1186/s13256-017-1371-7

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Aims/Introduction: The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies. Materials and Methods: An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method. Results: Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12–1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91–1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09). Conclusions: Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association.

DOI： 10.1111/jdi.12623

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.56.8304

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders Ltd  

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by heterozygous germline mutations in the tumor suppressor gene MEN1, which encodes a nuclear protein, menin. MEN1 is characterized by the combined occurrence of tumors involving the pituitary gland, pancreatic islets, and parathyroid glands. Additionally, patients with MEN1 often exhibit adrenal tumors. Although most MEN1-associated tumors are benign, malignant lesions arising in these endocrine organs have been reported. Additionally, malignant diseases of non-endocrine organs concomitant with MEN1 have also been reported. Here, we report a rare case of a MEN1 patient who exhibited adrenocortical carcinoma (ACC) and lung adenocarcinoma (LAC). A 53-year-old Japanese woman was diagnosed with genetically proven MEN1 that initially manifested as parathyroid, pancreatic, and adrenal tumors. During the course of the disease, she developed LAC harboring the epidermal growth factor receptor gene mutations and cortisol-secreting ACC. Both tumors were surgically resected. The tumor cells were immunohistochemically negative for menin. Studies have suggested a causative link between MEN1 gene mutations and ACC, and menin expression may decrease in MEN1-related ACCs. In contrast, there are few reports suggesting a specific role of MEN1 gene mutations in LAC. Menin is often inactivated in the LACs of patients without MEN1. Thus, our patient's ACC probably occurred as part of MEN1, whereas the latter had no evident etiological association with her LAC. This case demonstrates the need for physicians to consider the potential development of malignant diseases originating from both endocrine and non-endocrine organs in MEN1 patients.

DOI： 10.1016/j.rmcr.2016.12.002

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DOI： 10.1016/j.annepidem.2016.09.004

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors. Hypertension secondary to pheochromocytoma is often paroxysmal, and patients occasionally present with sudden attacks of alternating hypertension and hypotension. Spontaneous, extensive necrosis within the tumor that is associated with catecholamine crisis is an infrequent complication of adrenal pheochromocytoma, but its pathogenesis remains unclear. Case presentation: A 69-year-old Japanese man developed acute-onset episodic headaches, palpitations, and chest pains. During the episodes, both marked fluctuations in blood pressure (ranging from 40/25 to 300/160 mmHg) and high plasma levels of catecholamines were found simultaneously. Radiological findings indicated a 4-cm left adrenal pheochromocytoma. These episodic symptoms disappeared within 2 weeks with normalization of plasma catecholamine levels. Two months later, the patient underwent adrenalectomy. Microscopic examinations revealed pheocromocytoma with a large central area of coagulative necrosis. The necrotic material was immunohistochemically positive for chromogranin A. Granulation tissue was adjacent to the necrotic area, accompanied by numerous hemosiderin-laden macrophages and histiocytes with vascular proliferation. Viable tumor cells, detected along the periphery of the tumor, demonstrated pyknosis, and the Ki-67 labeling index was 2 % in the hot spot. No embolus or thrombus formation was found in the resected specimen harboring the whole tumor. The Pheochromocytoma of the Adrenal gland Scaled Score was 2 out of 20. The patient's postoperative course was unremarkable for &gt
7 years. Conclusions: Presumed causal factors for the extensive necrosis of adrenal pheochromocytoma in previously reported cases include hemorrhage into the tumor, hypotension induced by a phentolamine administration, embolic infarction, high intracapsular pressure due to malignant growth of the tumor, and catecholamine-induced vasoconstriction. In the present case, histopathological and clinical findings suggest that under conditions of chronic ischemia due to catecholamine-induced vasoconstriction, an acute infarction occurred after sudden attacks of alternating hypertension and hypotension. Over the subsequent 2 weeks, repetitive massive release of catecholamines from the infarcts into circulation likely accelerated infarction progression by causing repeated attacks of alternating hypertension and hypotension and resulted in the large necrosis. This case highlights the need for physicians to consider acute spontaneous tumor infarction accompanying episodic catecholamine crisis as a rare but severe complication of pheochromocytoma.

DOI： 10.1186/s13256-016-1068-3

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Our aim is to examine the dose-response association between cumulative genetic risk and actual risk of type 2 diabetes mellitus (T2DM) and the influence of adjustment for covariates on T2DM risk through a comprehensive meta-analysis of observational studies. METHODS: Electronic literature search using EMBASE and MEDLINE (from 2003 to 2014) was conducted for cross-sectional or longitudinal studies that presented the odds ratio (OR) for T2DM in each group with categories based on the total number of risk alleles (RAs) carried (RAtotal ) using at least two single-nucleotide polymorphisms. Spline regression model was used to determine the shape of the relationship between the difference from the referent group of each study in RAtotal (ΔRAtotal ) and the natural logarithms of ORs (log OR) for T2DM. RESULTS: Sixty-five eligible studies that included 68 267 cases among 182 603 participants were analysed. In both crude and adjusted ORs, defined by adjusting the risk for at least two confounders among age, gender and body mass index, the slope of the log OR for T2DM became less steep as the ΔRAtotal increased. In the analysis limited to 14 cross-sectional and four longitudinal studies presenting both crude and adjusted ORs, regression curves of both ORs in relation to ΔRAtotal were almost identical. CONCLUSION: Using only single-nucleotide polymorphisms for T2DM screening was of limited value. However, when genotypic T2DM risk was considered independently from risk in relation to covariates, it was suggested that genetic profiles might have a supplementary role related to conventional T2DM risk factors in identifying individuals at high risk of T2DM. Copyright © 2015 John Wiley & Sons, Ltd.

DOI： 10.1002/dmrr.2680

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 64-year-old Japanese man with mild reticular shadows in both lungs developed a lung tumor causing ectopic Cushing's syndrome. He was prescribed an adrenal inhibitor, which controlled his hypercortisolemia. However, he developed acute exacerbation of idiopathic pulmonary fibrosis (IPF) and died within weeks. Previous studies have suggested a dosage reduction of corticosteroids for IPF as a triggering event for acute exacerbation. The present case suggests that IPF coexisting with Cushing's syndrome may have been exacerbated after the correction of hypercortisolemia. Therefore, close monitoring of cortisol levels along with the clinical course of IPF is required in similar cases that require the correction of hypercortisolemia.

DOI： 10.2169/internalmedicine.55.5566

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 73-year-old Japanese woman with untreated Graves' hyperthyroidism developed glucocorticoid-induced adrenal insufficiency (AI) after a supraphysiological dose of prednisolone therapy for bronchial asthma. Days later, she had high plasma adrenocorticotropic hormone (ACTH) levels and was expected to recover from glucocorticoid-induced AI. Her plasma ACTH levels remained high over 3 months during a physiological dose of hydrocortisone replacement. However, she suffered a further decrease in her serum cortisol level and was diagnosed with isolated adrenocorticotropin deficiency (IAD), in which bioinactive ACTH likely caused the high ACTH value. IAD should be considered as an unusual disorder associated with Graves' disease, especially in older patients.

DOI： 10.2169/internalmedicine.55.6599

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Language：English   Publisher：The Japanese Society of Internal Medicine  

A 65-year-old Japanese man presented to our hospital in June 2013 with a 6-day history of fever and fatigue, a 24-h history of thirst, and polyuria. His temperature was 37.8°C and he was alert. However, laboratory tests revealed severe hyperglycemia, undetectable C-peptide levels, and diabetic ketoacidosis. Serum antibody testing confirmed a Coxsackie virus A2 infection. A variety of viral infections are reported to be involved in the development of fulminant type 1 diabetes mellitus (FT1D). Our patient is the first reported case of FT1D associated with Coxsackie virus A2 infection and supports the etiological role of common viral infections in FT1D.

DOI： 10.2169/internalmedicine.55.5292

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Other Link： http://search.jamas.or.jp/link/ui/2017010131

Language：English   Publisher：The Japanese Society of Internal Medicine  

A 59-year-old Japanese woman developed diabetes mellitus without ketoacidosis in the presence of glutamic acid decarboxylase autoantibody (GADA) (24.7 U/mL). After the amelioration of her hyperglycemia, the patient had a relatively preserved serum C-peptide level. Her endogenous insulin secretion capacity remained almost unchanged during 5 years of insulin therapy. The patient's GADA titers normalized within 15 months. The islet-related autoantibodies, including GADA, are believed to be produced following the autoimmune destruction of pancreatic beta cells and are predictive markers of type 1 diabetes mellitus. Therefore, the transient appearance of GADA in our patient may have reflected pancreatic autoimmune processes that terminated without progression to insulin deficiency.

DOI： 10.2169/internalmedicine.55.5398

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Other Link： http://search.jamas.or.jp/link/ui/2017035397

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 39-year-old woman with a 3-year history of a rounded face developed widespread myalgia. Detailed examinations revealed no disorders that could explain the pain other than concomitant Cushing's disease and central hypothyroidism. Both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat Cushing's disease, but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia. Few studies have so far investigated patients with fibromyalgia associated with Cushing's syndrome. In our case, the hypothyroidism caused by Cushing's disease probably played an important role in triggering and exacerbating fibromyalgia. This highlights the need to examine the endocrine function in patients with muscle pain.

DOI： 10.2169/internalmedicine.55.5926

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Language：English   Publisher：The Japanese Society of Internal Medicine  

A 67-year-old woman developed isolated adrenocorticotropin deficiency (IAD), which manifested as lethargy, a 20-kg body weight loss, hypoglycemia, and parkinsonism, and began corticosteroid replacement. Her symptoms resolved rapidly, and her weight returned to normal within six months. However, she then developed slowly progressive type 1 diabetes mellitus (T1D) with co-existing Hashimoto thyroiditis, and commenced insulin therapy. To our knowledge, this is the first reported case of parkinsonism associated with IAD. In addition, because diabetes mellitus, including T1D, could be latent in patients with untreated IAD, careful assessment of glucose metabolism is needed after commencing corticosteroid replacement until weight regain is achieved.<br>

DOI： 10.2169/internalmedicine.54.5022

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Other Link： http://search.jamas.or.jp/link/ui/2016260432

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Results of epidemiologic studies that investigated the significance of pulse pressure (PP) and mean arterial pressure (MAP) in terms of risk of cardiovascular disease (CVD) in patients with diabetes mellitus are inconsistent. We performed a quantitative meta-analysis to estimate CVD risk in relation to PP or MAP. Electronic literature search was conducted for prospective studies providing data on CVD risk for an increment in baseline MAP or PP in patients with diabetes mellitus. The pooled CVD risk for a 10-mm Hg increase in each blood pressure (BP) index was estimated with a random-effects model. There were 17 eligible studies consisting of 52,647 patients and 5,112 CVD cases. The pooled relative risk (95% confidence interval) of CVD for an increment of 10 mm Hg was 1.10 (1.04 to 1.16) for PP and 1.09 (0.98 to 1.21) for MAP. Significant between-study heterogeneity was observed (I2 [p value]; 76.5% [p <0.001] for PP, 67.8% [p = 0.005] for MAP). In studies concurrently investigating CVD risk for the 4 indexes (i.e., PP, MAP, systolic BP, and diastolic BP), the pooled relative risk (95% confidence interval) was 1.17 (1.09 to 1.26) for PP, 1.11 (1.06 to 1.15) for MAP, 1.14 (1.06 to 1.22) for systolic BP, and 1.06 (0.94 to 1.19) for diastolic BP. In conclusion, the current meta-analysis suggested that PP was the strongest indicator among the 4 commonly used BP indexes. However, the large heterogeneity urged cautious interpretation of the study results. © 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjcard.2013.12.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

This meta-analysis quantified the risk of type 2 diabetes mellitus (T2DM) preceded by body weight (BW) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight-gain, which was defined as BW gain from early adulthood (18-24 years of age) to cohort entry (&gt;= 25 years of age), and late weight-gain, which was defined as BW gain from cohort entry. The pooled relative risk (RR; 95% confidence interval [CI]) of T2DM for an increment of BW gain standardized into a 5-kg m(-2) increment in the body mass index (BMI) was 3.07 (2.49-2.79) for early weight-gain and 2.12 (1.74-2.58) for late weight-gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight-gain compared with current BMI (RR [95% CI], 3.38 [2.20-5.18] vs. 2.39 [1.58-3.62]), while there was little difference between late weight-gain (RR [95% CI], 2.21 [1.91-2.56]) and current BMI (RR [95% CI], 2.47 [1.97-3.30]). The meta-analysis suggested that BW gain was a quantifiable predictor of T2DM, as well as current obesity in adults. Particularly, BW gain in early rather than middle-to-late adulthood played an important role in developing T2DM.

DOI： 10.1111/obr.12129

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/hjh.0000000000000019

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/HJH.0000000000000353

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER DIABETES ASSOC  

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(株)先端医学社  

新しい経口2型糖尿病治療薬であるdipeptidyl peptidase-4(DPP-4)阻害薬は、おもに食後高血糖の改善効果に優れ、体重増加や低血糖を起こしにくいことを特徴とする。糖尿病患者に対する血糖管理の脳卒中(脳梗塞)を予防する効果が今まで必ずしも明確となっていないなかで、欧米人においてDPP-4阻害薬を用いた血糖管理による脳梗塞発症予防効果が示されている。日本人2型糖尿病患者と欧米患者とのあいだでは、肥満度の明らかな違いに加えてDPP-4阻害薬の効果にも差がある可能性が示唆されており、DPP-4阻害薬による脳梗塞予防効果について日本人患者での検討も必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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