Implication of aortic calcification on persistent hypertension after laparoscopic adrenalectomy in patients with primary aldosteronism.

OBJECTIVES: To identify risk factors, including aortic calcification, for persistent hypertension in primary aldosteronism patients undergoing laparoscopic adrenalectomy. METHODS: Between October 2000 and October 2015, we carried out 101 consecutive laparoscopic adrenalectomies for unilateral primary aldosteronism. Of these, 95 cases with at least 1 year of postoperative follow up were included. These were divided into two study groups based on whether they had normal blood pressure without antihypertensive medications (resolved group) or still required medications (unresolved group) at 1 year after surgery. Variables included age, sex, body mass index, history of hypertension, dosage of antihypertensive medication score, presence of type 2 diabetes, subclinical Cushing syndrome, preoperative renal function, aldosteronoma resolution score and abdominal calcification index. Univariate and multivariate logistic regression analyses were used to assess independent risk factors for persistent hypertension 1 year after surgery. RESULTS: The complete resolution of hypertension without antihypertensive medication 1 year after adrenalectomy was 36 out of 95 (38%). The preoperative antihypertensive medication score, systolic blood pressure and abdominal calcification index were significantly higher, and the aldosteronoma resolution score were significantly lower in the unresolved group than in the resolved group. Using multivariate logistic regression analysis, independent risk factors significantly correlating with persistent hypertension 1 year after surgery were aldosteronoma resolution score and abdominal calcification index. CONCLUSIONS: Laparoscopic adrenalectomy for primary aldosteronism is effective in improving blood pressure and reducing the need for antihypertensive medications. Aldosteronoma resolution score and abdominal calcification index represent potential independent risk factors for persistent hypertension 1 year after surgery.

Lower aldosterone-renin ratio is a risk factor for total and cancer death in Japanese individuals: the Takahata study.

OBJECTIVE: A higher plasma aldosterone-renin ratio (ARR) is an established marker for screening for primary aldosteronism (PA). The association between higher ARR and mortality in a general population has not been fully explored. We here examined whether higher ARR is a risk factor for total and cause-specific mortality in a Japanese population. SUBJECTS AND METHODS: A population-based, longitudinal study of 1,310 Japanese individuals (age: 63·9 ± 9·8 years) enrolled in the Takahata study between 2004 and 2006 and followed for up to 8 years. The incidence and causes of death were monitored annually until 10 January 2012 (median follow-up: 2691 days). RESULTS: During the follow-up period, 64 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total and cancer mortality in subjects with lower ARR (log-rank P < 0·001). Cox's proportional hazard model analyses with adjustment for age and gender showed that lower ARR was associated with increased total and cancer mortality in subjects with low (≦72) vs high (>72) ARR (hazard ratios and 95% confidential intervals: 2·56, 1·44-4·56 and 2·78, 1·16-6·65, respectively). CONCLUSIONS: Lower ARR was a significant and independent risk factor for increased total and cancer mortality in this Japanese population. Subjects with higher ARR were not-at-risk for total death in general. These findings increase the necessity for identifying people with PA from those with higher ARR. People with higher ARR without PA may be at very low risk for total and cancer death.

Pathophysiology and treatment of subclinical Cushing's disease and pituitary silent corticotroph adenomas [Review].

Pituitary adrenocorticotropic hormone (ACTH)-secreting tumor presents with a variety of clinical features. We outlined the features of ACTH release and characteristics of corticotroph adenoma cells. We especially focused on the corticotroph adenomas in patients with no clinical features of Cushing's disease. Subclinical Cushing's disease is defined by ACTH-induced mild hypercortisolism without typical features of Cushing's disease. Silent corticotroph adenomas (SCAs) are defined by normal cortisol secretion and ACTH-immunopositive staining without autonomous ACTH secretion. Clinicians who are not well-informed about the disease may sometimes confuse SCAs (because of their clinically silent nature) with "subclinical Cushing's disease". The recent criteria for diagnosing subclinical Cushing's disease in Japan are presented. Cortisol measurement was recently standardized in Japan, so plasma cortisol cutoff level should be reconsidered for the diagnosis. In patients with uncontrolled diabetes and hypertension despite appropriate treatment, subclinical Cushing's disease may be efficiently detected. Subclinical Cushing's disease may be associated with metabolic change. In subclinical Cushing's disease, mild hypercortisolism due to autonomous secretion of ACTH contributes to metabolic change and treatment of subclinical hypercortisolism can reverse this change.

Evaluation of the diagnostic criteria for Cushing's disease in Japan.

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is caused by an ACTH-producing tumor, as is the case with Cushing's disease and ectopic ACTH syndrome (EAS). Diagnosis and differential diagnosis of Cushing's disease from EAS in ACTH-dependent Cushing's syndrome are thus challenging problems in clinical endocrinology. The diagnostic criteria for Cushing's disease in Japan, established by the working group of the Japan Ministry of Health, Labour and Welfare, were originally reported in 2003 and revised in 2007 and 2010. In addition, criteria for subclinical Cushing's disease were established in Japan in 2010. In this review, we evaluate the usefulness and accuracy of the most recent diagnostic criteria. Previous data suggest that as an initial test of Cushing's syndrome, 0.5 mg dexamethasone is more sensitive than 1 mg in the overnight dexamethasone suppression test (DST). Here, we recommend 0.5 mg plus a plasma cortisol cut-off level of 3 µg/dL as a suitable low-dose overnight DST for screening of all cases of ACTH-dependent Cushing's syndrome in Japan. Recently, standardization of cortisol measurements by the ID-LC/MS/MS method using seven assay kits with standard plasma material containing synthetic hydrocortisone-d4 was carried out in Japan. The resulting relative standard deviation was within 10%. The cut-off value remains valid even after standardization of plasma cortisol measurements. Although the recent diagnostic criteria achieve higher diagnostic specificity, care should be taken since data for Cushing's disease partially overlaps with some cases of EAS. Overall, therefore, this review suggests that the accuracy of each diagnostic test should be considered.

Ultrasonographic thyroid nodular findings in Japanese children.

PURPOSE: The Fukushima Health Management Survey conducted after the accident at the Fukushima Nuclear Power Plant included thyroid ultrasound examinations for children aged ≤18 years at the time of the accident. The purpose of this study was to investigate the frequency of thyroid nodular lesions detected using high-quality ultrasonography in a general population of Japanese children, in whom such data have not been previously characterized. METHODS: The current study investigated 4,365 free-living children aged between 3 and 18 years in three Japanese prefectures (Aomori, Yamanashi and Nagasaki). The same ultrasonography equipment as that used in the Fukushima Survey was employed to observe thyroid nodular lesions. The following categories of findings were used-'A', further examinations are not necessary; 'B', the presence of thyroid nodules with a diameter of ≥5.1 mm or thyroid cysts with a diameter of ≥20.1 mm; and 'C', immediate further examinations are required. As a sub-category of 'A', 'A1' was defined as the absence of nodules or cysts, and 'A2' was defined as the presence of thyroid nodules with a diameter of ≤5.0 mm or thyroid cysts with a diameter of ≤20.0 mm. RESULTS: Overall, 4,321 (99 %) of the total participants were classified with a status of 'A' and 44 (1 %) were classified with a status of 'B'. No participants were classified with a status of 'C'. A total of 56.5 % of the total participants was classified with a status of 'A2'. Thyroid nodules were identified in 1.6 % of the total participants and thyroid cysts were identified in 56.9 % of the participants. CONCLUSION: The current study provides data regarding the actual frequency of ultrasonographically detected thyroid nodular lesions among the Japanese children. These results would be useful for evaluating thyroid findings in Japanese children, although careful interpretation is required.

Involvement of nuclear factor-kB and Nurr-1 in cytokine-induced transcription of proopiomelanocortin gene in AtT20 corticotroph cells.

OBJECTIVE: The precise mechanism whereby proinflammatory cytokines activate the hypothalamo-pituitary-adrenal axis is still unclear. We examined whether transcription factors nuclear factor (NF)-kappaB and Nurr-1 are involved in the cytokine-induced proopiomelanocortin (POMC) gene expression. METHODS: The mouse corticotropinoma cell line AtT20 was treated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta). Real-time PCR, luciferase assay and Western blotting were conducted to assess the gene expression, promoter activity and protein expression in various conditions. RESULTS: Intrinsic expression of NF-kappaB was confirmed by RT-PCR. An active component of NF-kappaB (p65) was upregulated in the nuclear fraction by both TNF-alpha and IL-1beta treatment in a dose- and time-related manner. These cytokines potently stimulated the promoter activity of NF-kappaB and Nurr-1. We also found rapid upregulation of the Nurr-1 gene and protein after treatment with these cytokines. Cotreatment of the cells with either of the cytokines and corticotropin-releasing hormone resulted in additive effects. Cytokine-induced Nurr-1 transcription and Nurr-1 transcription induced by overexpression of NF-kappaB were both blunted by mutagenesis within the NF-kappaB responsive element, which implies that Nurr-1 upregulation specifically requires NF-kappaB binding to its own DNA-binding site. Proinflammatory cytokines exert positive effects on POMC gene expression, which were inhibited by pretreatment with a specific NF-kappaB inhibitor. CONCLUSION: These results together imply that Nurr-1 expression is a connecting point between neuroendocrine and immune systems in mediating cytokine-induced POMC gene expression.

The frequency of type 2 diabetic patients who meet the endocrinological screening criteria of subclinical Cushing's disease.

Cushing's syndrome, including its mild form/state of adrenal-dependent subset (subclinical Cushing's syndrome; subCS), is known to enhance glucose intolerance, hypertension and obesity. Recently, subclinical Cushing's disease (subCD) has been identified, but its prevalence and the extent of consequent metabolic derangement are unclear. We screened 90 type 2 diabetic patients hospitalized in our department for subCD, according to the diagnostic guideline proposed by the working group of Japanese Ministry of Health, Welfare and Labor in 2006. Plasma ACTH and cortisol levels in the morning and at midnight were determined, and overnight 0.5 mg dexamethasone suppression test (DST) was performed. Those who showed poor cortisol suppression in DST underwent the desmopressin (DDAVP) test. Fifty-seven patients (63.3%) demonstrated abnormally high midnight cortisol levels (>or=2.5 microg/dL), while only nine of them failed to suppress plasma cortisol levels to <3 microg/dL after DST. Although none of the eight patients who underwent the DDAVP test demonstrated the anticipated paradoxical rise in plasma ACTH, these eight patients (8.9%) endocrinologically met the screening criteria of subCD. Since a considerable percentage of pituitary adenomas causing overt Cushing's disease are not identifiable in magnetic resonance imaging, many of those causing subCD may also be unidentifiable. Further follow-up studies including confirmatory testing and pituitary imaging are necessary.

Evaluation of plasma, salivary, and urinary cortisol levels for diagnosis of Cushing's syndrome.

As a screening test for Cushing's syndrome, the evaluation of late-night cortisol levels is indispensable. We evaluated the usefulness and accuracy of plasma, urinary, and salivary cortisol levels measured late at night for the diagnosis of Cushing's syndrome. High cortisol levels (> 5 microg/dL) during the night are indicative of Cushing's syndrome, although night plasma cortisol levels are not readily reproducible because of the stressful situation. There was no correlation between plasma and urinary cortisol levels late at night, and late-night urinary cortisol levels provided weak information for the diagnosis of Cushing's syndrome. By contrast, late-night plasma and salivary cortisol levels showed a positive correlation, and salivary cortisol sampling was found to be useful for the diagnosis of Cushing's syndrome, because more than 0.4 microg/dL of late-night salivary cortisol levels gave a sensitivity of 86% and a specificity of 100% in our hospital. This method is also useful for the diagnosis of early or mild stage Cushing's syndrome, so-called subclinical Cushing's syndrome. Inherent differences between assays make it difficult to define optimal diagnostic criteria. However, the relative levels of salivary cortisol ratio, which is presented as a relative level, compared with the mean levels of healthy subjects in each institute, is useful for the screening of Cushing's syndrome as the cut-off level of 1.5 shows both high sensitivity and specificity in subclinical and overt Cushing's syndrome. Late-night salivary cortisol measurement is therefore a primary method of choice in the screening of patients suspected of having Cushing's syndrome.

Evaluation of diagnostic tests for ACTH-dependent Cushing's syndrome.

We evaluated the usefulness and accuracy of diagnostic tests for adrenocorticotropic hormone (ACTH)- dependent Cushing's syndrome, based on our experience of 88 cases, including 73 cases with Cushing's disease, and 15 cases with ectopic ACTH syndrome (EAS). In our study, 0.5 mg of dexamethasone failed to suppress the morning cortisol secretion in 100% of cases with Cushing's disease and EAS. Plasma ACTH levels were significantly increased by desmopressin (DDAVP) in 86% of cases with Cushing's disease, especially in microadenomas (90%), while these levels were not affected in normal subjects. In EAS, 44% responded to DDAVP. Plasma ACTH levels were increased in response to the human corticotropin-releasing hormone (CRH) test in 100% of microadenomas and 73% of macroadenomas with Cushing's disease, but only in 27% of cases with EAS. A high dose (8 mg) of dexamethasone suppressed the morning cortisol secretion in 89% of microadenomas with Cushing's disease, and in 82% of all cases with Cushing's disease, while it did in only 20% of cases with EAS. Taken together, the 0.5 mg dexamethasone suppression test (DST) and DDAVP test are considerably useful for the screening of ACTH-dependent Cushing's syndrome. The CRH test and 8 mg DST would be effective for the diagnosis of Cushing's diseases, because our study shows a sensitivity of 81% in cases with Cushing's disease when these tests are considered together. These data were submitted to prepare the diagnostic criteria for Cushing's disease, suggested by the working group of the Ministry of Health, Labour, and Welfare of Japan.

Development and validation of a 0.5 mg dexamethasone suppression test as an initial screening test for the diagnosis of ACTH-dependent Cushing's syndrome.

For the diagnosis of Cushing' s syndrome (CS), the overnight 1 mg dexamethasone suppression test (DST) has been widely used as a standard low-dose DST. However, it is evident that 1 mg DST may not be sensitive enough to detect CS when the cortisol cut-off concentration is 5 microg/dL. Therefore, we developed and validated 0.5 mg DST as a new screening method for diagnosis of ACTH-dependent CS. To compare 0.5 mg DST with 1 mg DST, 110 patients with ACTH-dependent CS were enrolled, including 88 with Cushing' s disease (CD), 8 with subclinical CD and 14 with ectopic ACTH syndrome, as well as 134 control subjects. Subjects were given either 0.5 mg or 1 mg dexamethasone orally at 23:00 on different days, with blood samples collected the following morning between 8:00 and 9:00 to determine plasma cortisol concentration. The area under the receiver operator characteristics curve observing the 0.5 mg DST was higher than that of the 1 mg DST. The most sensitive and specific cut-off value of plasma cortisol concentration using 0.5 mg DST was found to be 3.05 microg/dL with 99.1% sensitivity and 98.4% specificity, identical to the 3 microg/dL cut-off currently used in the Japanese guideline for diagnosis of subclinical CD. In conclusion, 0.5 mg DST is a sensitive and specific screening test for diagnosis of ACTH-dependent CS. We recommend 0.5 mg DST with a cortisol cut-off concentration of 3 microg/dL to be used as the initial step in diagnosing ACTH-dependent CS.

Corticotropin-releasing factor (CRF) is involved in the acute anorexic effect of alpha-melanocyte-stimulating hormone: a study using CRF-deficient mice.

Alpha-melanocyte-stimulating hormone (alpha-MSH) and its receptors are critical and indispensable for maintaining appropriate feeding behavior and energy homeostasis in both mice and humans. Corticotropin-releasing factor (CRF) is a candidate for mediating the anorexic effect of alpha-MSH. In the present study, we examined whether CRF and its receptors are involved in the anorexic effect of alpha-MSH, using CRF-deficient (CRFKO) mice and a CRF receptor antagonist. Intracerebroventricular administration of NDP-MSH, a synthetic alpha-MSH analogue, suppressed food intake in wild-type (WT) mice. This effect was abolished by pretreatment with a non-selective CRF receptor antagonist, astressin, suggesting that the effect of alpha-MSH-induced anorexia was mediated by a CRF receptor. In CRFKO mice, administration with NDP-MSH did not affect food intake at an early phase (0-4h). In addition, CRF mRNA levels in the hypothalamus were significantly increased in NDP-MSH-treated mice. Therefore, our findings, using CRFKO, strongly support evidence that CRF is involved in the acute anorexic effect of alpha-MSH. On the other hand, NDP-MSH administered to CRFKO mice led to suppressed food intake at the late phase (4-12h), similar to the effect in WT mice. Further, NDP-MSH similarly reduced food intake during the late phase in all types of mice, including WT, CRFKO, and CRFKO with corticosterone replacement. The results would suggest that alpha-MSH-induced suppression of food intake at late phase was independent of glucocorticoids and CRF.

Predominant role of 25OHD in the negative regulation of PTH expression: clinical relevance for hypovitaminosis D.

Although severe deficiency of bioactive vitamin D (1,25OH2D) causes rickets, mild insufficiency of the hormone, known as hypovitaminosis D, is responsible for the occurrence of secondary hyperparathyroidism and osteoporosis. To clarify the pathophysiology of the disease, we studied the negative feedback effect of 1,25OH2D and its precursor 25OHD on the transcriptional activity of parathyroid hormone (PTH) gene using the PT-r parathyroid cell line. We found that PT-r cells express endogenous 1alpha-hydroxylase as well as PTH mRNAs. We also found the potent suppressive effect of physiological concentration of 25OHD on the transcriptional activity of PTH gene. A similar effect was obtained with 1,25OH2D but only with pharmacological concentration. Interestingly, the effect of 25OHD was completely abolished when the cells were treated with 1alpha-hydroxylase inhibitor ketoconazole. These results suggest that the negative feedback regulation of vitamin D on PTH gene transcription occurs not by the end-product 1,25OH2D but by its prohormone 25OHD via intracellular activation by 1alpha-hydroxylase within the parathyroid cells.

Diagnostic usefulness of the growth hormone-releasing peptide-2 test as a substitute for the insulin tolerance test in hypopituitarism.

Adrenal insufficiency can result from primary disorder of the adrenal gland or occurs secondarily due to deficiency in adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). To prevent adrenal crisis, it is thus important to test the remaining function of the adrenal gland. Tests for the function of the hypothalamic-pituitary-adrenal (HPA) axis are also useful for examining localization of disease causing adrenal insufficiency. Generally, the insulin tolerance test (ITT) is useful for examining the HPA axis in both hypothalamic and pituitary diseases; however, ITT has a number of disadvantages. The growth hormone-releasing peptide (GHRP)-2 test may be a useful tool for diagnosing secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage. In the present study, we examined the diagnostic usefulness of the GHRP-2 test as a substitute for ITT in hypopituitarism. We showed that patients with significant ACTH response to ITT also had significant response to the GHRP-2 test, while patients with no significant ACTH response to ITT also had no significant response to the GHRP-2 test. These data suggest that the GHRP-2 test may be a useful diagnostic tool for secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage.

A male case of nonclassical 21-hydroxylase deficiency first manifested in his sixties with adrenocortical incidentaloma.

Nonclassical form of 21-hydroxylase deficiency (NC 21OHD) as a frequent variant on the milder end of the disease spectrum has been widely acknowledged, but its potential contribution to adrenocortical tumorigenesis has not been fully elucidated. We report a 66-year old male case of bilateral adrenocortical incidentaloma, associated with partial 21OHD without any episodes of hypoadrenocorticism in his past history. He was demonstrated to be a compound heterozygous mutant of CYP21A2 gene (IVS2-13A/C>G/I172N). The two tumors in the left adrenal, which were interpreted as myelolipoma by imaging studies, were followed by sequential observation, whereas the contralateral large solid tumor associated with inhomogeneous radiological appearance was subsequently removed. The resected tumor was diagnosed an adrenocortical adenoma, which was devoid of P450c21 immunoreactivity. 21OHD is often associated with benign adrenocortical tumors, but bilateral adrenal tumors with heterogeneous components in both adrenals have not been reported to the best of our knowledge.

Inhibitory effects of glucocorticoids on urocortin-mediated increases in interleukin-6 gene expression in rat aortic smooth muscle cells.

Urocortin (Ucn) 1, Ucn2, and Ucn3 have potent effects on appetite and the cardiovascular system. Endogenous Ucns in combination with CRF receptor type 2beta may have a physiological role in the cardiovascular system. We previously demonstrated that both Ucn1 and Ucn2 increased IL-6 output levels in A7r5 aortic smooth muscle cells. In the present study, we extended observations on stress or hormone-induced changes in IL-6 gene expression in the cardiovascular system, and determined the effects of glucocorticoids on Ucn-mediated increases in IL-6 mRNA levels, protein levels, and gene transcription activity in A7r5 cells. Ucn1, Ucn2, and Ucn3 all increased IL-6 mRNA levels via CRF receptor type 2. Dexamethasone blocked the ability of Ucn1 to increase IL-6 mRNA and protein levels, while it failed to attenuate the Ucns-mediated changes in cyclic AMP (cAMP)-response element binding protein or extracellular signal-related kinases phosphorylation. Dexamethasone also suppressed Ucn1- or cAMP-stimulated IL-6 gene transcription via a glucocorticoid receptor. Together, these findings demonstrate that glucocorticoids suppress IL-6 gene transcription via Ucn-induced cAMP-dependent pathways in A7r5 cells.

High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro.

Diabetes mellitus is frequently associated with coagulation disorders such as coronary heart disease and stroke. We aimed to clarify the molecular mechanism whereby hyperglycemia causes the procoagulant state. HuH7 human hepatocyte cells were treated with high glucose alone or in combination with proinflammatory cytokines, and the effects on the activity of the transcription factor nuclear factor kappa-B (NF-kappaB), which mediates the expression of acute-phase and coagulation-related genes, were examined. The results showed that increasing the medium glucose concentration from 3 to 24 mM significantly enhanced NF-kappaB-luciferase activity by 40% in the presence of insulin. The effect was promoter specific and not mimicked by comparable hyperosmolality with L-glucose. Proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) also stimulated NF-kappaB-dependent transcription and showed an additive effect with high glucose. Similar effects were obtained on acute-phase or coagulation/fibrinolysis-related gene promoters such as fibrinogen or plasminogen activator inhibitor-1, all of which are shown to have NF-kappaB-mediated transcription. Finally, pretreatment of the cells with an antioxidant PDTC completely abolished the effect of high glucose and markedly attenuated that of TNF-alpha, suggesting the involvement of reactive oxygen species. These results suggest that (1) high glucose as well as proinflammatory cytokines have positive effects on NF-kappaB-mediated transcription in an additive manner and enhance coagulation-related gene expression and (2) the effects are mediated, at least partly, by the generation of oxidative stress and may be responsible for the high prevalence of thrombotic disorders in the metabolic syndrome with diabetes, hyperinsulinemia, obesity, and/or inflammation.

Expression of adrenocorticotropic hormone, prolactin and transcriptional factors in clinically nonfunctioning pituitary adenoma.

We describe here a case of a clinically nonfunctioning pituitary adenoma, but with expression of ACTH and PRL. A 42-year-old woman was referred to our department for further evaluation of pituitary tumor. She had no acromegaloid features, and no typical Cushingoid features. She had no galactorrhea, and had regular menses. GH, IGF-I, LH, FSH, TSH, ACTH and cortisol levels in blood were all within the normal ranges, while PRL levels were mildly elevated. Both ACTH and cortisol levels were adequately increased in response to CRH, and both were suppressed by a small dose of dexamethasone. Plasma ACTH and cortisol levels were decreased at night, suggesting the circadian rhythms for plasma ACTH levels were undisturbed. Based on these findings we did not clinically suspect ACTH-producing tumor, however immunohistochemistry revealed ACTH immunoreactivity in the pituitary adenoma. Therefore, the tumor was considered a silent corticotroph adenoma. PRL was co-expressed in a significant subpopulation of ACTH-immunoreactive tumor cells. Ptx1, Neuro D1, and T pit were densely expressed and Pit-1 was sparsely expressed in the nuclei of adenoma cells. It is therefore possible that a tumor originating in an immature or uncommited adenohypophysial stem cell may later differentiate into different cell types due to a combination of certain specific transcriptional factors.

Acute mesenteric ischemia and hepatic infarction after treatment of ectopic Cushing's syndrome.

SUMMARY: Patients with Cushing's syndrome and excess exogenous glucocorticoids have an increased risk for venous thromboembolism, as well as arterial thrombi. The patients are at high risk of thromboembolic events, especially during active disease and even in cases of remission and after surgery in Cushing's syndrome and withdrawal state in glucocorticoid users. We present a case of Cushing's syndrome caused by adrenocorticotropic hormone-secreting lung carcinoid tumor. Our patient developed acute mesenteric ischemia after video-assisted thoracoscopic surgery despite administration of sufficient glucocorticoid and thromboprophylaxis in the perioperative period. In addition, our patient developed hepatic infarction after surgical resection of the intestine. Then, the patient was supported by total parenteral nutrition. Our case report highlights the risk of microthrombi, which occurred in our patient after treatment of ectopic Cushing's syndrome. Guidelines on thromboprophylaxis and/or antiplatelet therapy for Cushing's syndrome are acutely needed. LEARNING POINTS: The present case showed acute mesenteric thromboembolism and hepatic infarction after treatment of ectopic Cushing's syndrome.Patients with Cushing's syndrome are at increased risk for thromboembolic events and increased morbidity and mortality.An increase in thromboembolic risk has been observed during active disease, even in cases of remission and postoperatively in Cushing's syndrome.Thromboprophylaxis and antiplatelet therapy should be considered in treatment of glucocorticoid excess or glucocorticoid withdrawal.

Adipsic hypernatremia without hypothalamic lesions accompanied by autoantibodies to subfornical organ.

Adipsic (or essential) hypernatremia is a rare hypernatremia caused by a deficiency in thirst regulation and vasopressin release. In 2010, we reported a case in which autoantibodies targeting the sensory circumventricular organs (sCVOs) caused adipsic hypernatremia without hypothalamic structural lesions demonstrable by magnetic resonance imaging (MRI); sCVOs include the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which are centers for the monitoring of body-fluid conditions and the control of water and salt intakes, and harbor neurons innervating hypothalamic nuclei for vasopressin release. We herein report three newly identified patients (3- to 8-year-old girls on the first visit) with similar symptoms. The common features of the patients were extensive hypernatremia without any sensation of thirst and defects in vasopressin response to serum hypertonicity. Despite these features, we could not detect any hypothalamic structural lesions by MRI. Immunohistochemical analyses using the sera of the three patients revealed that antibodies specifically reactive to the mouse SFO were present in the sera of all cases; in one case, the antibodies also reacted with the mouse OVLT. The immunoglobulin (Ig) fraction of serum obtained from one patient was intravenously injected into wild-type mice to determine whether the mice developed similar symptoms. Mice injected with a patient's Ig showed abnormalities in water/salt intake, vasopressin release, and diuresis, which resultantly developed hypernatremia. Prominent cell death and infiltration of reactive microglia was observed in the SFO of these mice. Thus, autoimmune destruction of the SFO may be the cause of the adipsic hypernatremia. This study provides a possible explanation for the pathogenesis of adipsic hypernatremia without demonstrable hypothalamus-pituitary lesions.