Quetiapine and Valproic Acid-induced Central Hypothyroidism in a Patient with Autism Spectrum Disorder and Intractable Epilepsy: A Case Report.

OBJECTIVES: Patients with an autism spectrum disorder (ASD) are prone to disruptive behaviors and aggression. Atypical antipsychotics are used to treat these difficult ASD conditions. Several psychotropic drugs have been linked to hypothyroidism. The clinical manifestation of hypothyroidism is indistinguishable from that of an antipsychotic's general adverse effect, which can lead to a delayed or missed diagnosis. Conversely, thyroid dysfunction can exhibit an impact on mood, anxiety, depression, and cognitive functions. CASE STUDY: We present a case of central hypothyroidism caused by long-term use of valproic acid (VPA) and adding quetiapine to risperidone. The current case had a history of hyperprolactinemia and subclinical hypothyroidism caused by risperidone and VPA, respectively, before the administration of quetiapine. CONCLUSION: This is the first report of quetiapine-induced central hypothyroidism in a patient with ASD, as determined by a thyrotropin-releasing hormone (TRH) loading test. TRH loading test may be useful in elucidating the pathogenesis of hypothyroidism in patients receiving quetiapine and VPA. Thyroid function monitoring in patients taking quetiapine and VPA may provide an opportunity to begin replacement therapy.

Autoimmune Thyroiditis Shifting from Hashimoto's Thyroiditis to Graves' Disease.

In 15-20% of cases, Graves' disease (GD) shifts to Hashimoto's thyroiditis (HT), while the shift from HT to GD is rare. We present a case of a patient in whom HT shifted to GD, along with a literature review. A 50-year-old woman with myxedema was diagnosed with Hashimoto's disease due to hypothyroidism and the presence of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb); she also had thyroid stimulating antibodies (TSAb) without any signs of GD. Although thyroid hormone replacement therapy improved her thyroid function, 2 months later, hyperthyroidism appeared and did not improve after discontinuation of the replacement therapy. The patient was diagnosed with GD, which improved with antithyroid agent administration. To date, only 50 cases regarding conversion from HT to GD have been reported. The median age is 44 years (range, 23-82 years), and the median time of conversion is 7 years (range, 0.1-27 years). The male-to-female ratio of HT conversion to GD is 1:9, closer to that of regular GD (1:10) than that of general HT (1:18). All patients received thyroid hormone replacement therapy for hypothyroidism due to HT. Continuous evaluation of TSAb levels is recommended in HT, particularly in cases of TSAb-positive and those under replacement, since it may help predict conversion to GD. Evaluating the clinical characteristics of patients with HT preceding GD is crucial to ensure appropriate treatment and reduce the risk of adverse events.

Development of a sensitive liquid chromatography-tandem mass spectrometry method for quantification of human plasma arginine vasopressin.

BACKGROUND AND AIMS: Direct measurement of arginine vasopressin (AVP) via immunoassays is not widely conducted, mainly because of technical constraints. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) has been widely used as the gold standard in clinical chemistry. Here, we aimed to develop an MS-based assay to determine human plasma AVP and compare the results with those obtained using a conventional immunoassay. MATERIALS AND METHODS: We developed a protocol using triple quadrupole MS coupled with LC for the measurement of human plasma AVP. Analytical evaluations of the method were performed, and the results obtained using LC/MS/MS and radioimmunoassay (RIA) were compared. RESULTS: The lower limit of quantification (LLOQ) for plasma AVP obtained using LC/MS/MS and RIA were 0.2 and 0.4 pg/mL, respectively. Although there was a weak overall correlation between the results obtained using the two different methods, the RIA results did not agree with the LC/MS/MS results, particularly at low concentrations. CONCLUSIONS: AVP detection through RIA is not satisfactory compared with that using LC/MS/MS. Diagnostic values of direct AVP measurements must be evaluated based on the results obtained via sensitive and accurate MS-based methods rather than those obtained through RIA.

Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review.

BACKGROUND: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition. CASE PRESENTATION: A 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing's syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2-63.3 pg/mL), cortisol (73.1 µg/dL; 6.4-21.0 µg/dL) and 24-h urinary free cortisol (UFC) (6160 µg/day; 11.2-80.3 µg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case. CONCLUSION: MTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.

Urinary ß-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection.

Adefovir dipivoxil (ADV) is effective for hepatitis B virus (HBV) infection; however, ADV may provoke renal injury resulting in osteomalacia, and this side effect is seldom recognized until bone fractures emerge. We herein present a 66-year-old woman with HBV infection who received ADV for 6 years. Although she exhibited no sign of bone fractures, her urinary ß-2 microglobulin (ß2MG) level increased to 83,837 µg/L and scintigraphy revealed minimal fractures of the third rib. ADV was subsequently reduced and her urinary ß2MG rapidly fell to 3,637 µg/L. Conversely, her urinary N-acetyl-ß-D-glucosaminidase, and serum phosphate, alkaline phosphatase levels did not respond.

Histologic study of age-related change in the posterior pituitary gland focusing on abnormal deposition of tau protein.

We studied histologic findings of age-related change in the posterior pituitary gland focusing specifically on abnormal deposition of tau protein. Posterior pituitary glands from a total of 201 patients with mean age of 72, range 15 to 100 years, were dissected at autopsy, and semiquantitative analysis of tau protein deposition in the posterior pituitaries was performed. We confirmed that tau protein deposition in the posterior pituitary appears histologically as either a 'thread-like' or 'dot' form. In double staining using an anti-neurofilament antibody and Gallyas-Braak staining, Gallyas-Braak-positive structures were located in the neurite. The grade and the frequency of tau protein deposition were increased in accord with aging. An interrelation was observed between tau protein deposition in the brain and that in the posterior pituitary. In tauopathy diseases, tau protein deposition in the posterior lobe is advanced compared to that in non-tauopathy diseases. The level of tau protein deposition in the hypothalamus was compared semi-quantitatively with that in the posterior pituitary, and the levels correlated well. We suggest that in the posterior pituitary of elderly people, high frequency of occurrence of deposition of abnormal tau protein in the neurites may cause dysfunction of the pituitary gland.

Glucose intolerance in Japanese patients with obstructive sleep apnea.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) often accompanies obesity and diabetes mellitus. This study was performed to investigate the prevalence of glucose intolerance and to determine independent predictors for insulin resistance in patients with OSAS. METHODS: A cross-sectional study of 679 OSAS patients with an apnea-hypopnea index (AHI)>or=5/h and 73 controls subjects (AHI<5/h) was done in a tertiary university-based medical center. They were assessed by nocturnal polysomnography and underwent an oral glucose tolerance test. RESULTS: The prevalence of diabetes mellitus in OSAS patients was higher than that of the control group (25.9% vs. 8.2%, p<0.001) and 424 patients (62.4%) received a new diagnosis of impaired glucose tolerance or diabetes mellitus. The very severe OSAS group (AHI >or=45/h) had significantly higher homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA beta-cell function than the other OSAS groups (AHI<45/h) and the control group. In a logistic regression model adjusting for potential confounders: age, AHI, minimum SpO(2) and body mass index (BMI), only BMI was associated with insulin resistance (HOMA-IR>3) (odds ratio: 1.272, 95% confidence interval 1.206-1.343, p<0.0001). CONCLUSION: Glucose intolerance was more common in patients with OSAS. Insulin resistance was associated not with AHI but rather with BMI.

Metabolic syndrome in Japanese patients with obstructive sleep apnea syndrome.

We investigated the prevalence of metabolic syndrome in patients with obstructive sleep apnea syndrome (OSAS) referred to a tertiary university-based medical center. A cross-sectional study of patients with a definite diagnosis of OSAS was performed using new diagnostic criteria for metabolic syndrome that were designed for the Japanese population. Clinical features and comorbidities related to metabolic syndrome were compared between 819 patients with OSAS (719 men and 100 women) and 89 control subjects without OSAS. Metabolic syndrome was significantly more common in the patients with OSAS than in the controls (49.5% vs. 22.0% for men, p < 0.01; 32.0% vs. 6.7% for women, p < 0.01). Men with OSAS (apnea-hypopnea index [AHI] > or =5/h) had a higher risk of metabolic syndrome compared with controls (odds ratio [OR]: 3.47; 95% confidence interval [CI]: 1.84-6.53). There was a significantly increased risk of metabolic syndrome in men with moderate OSAS (AHI: 15-29.9/h) (OR: 2.83; 95% CI: 1.42-5.66) and men with severe OSAS (AHI > or =30/h) (OR: 5.09; 95% CI: 2.67-9.71). Women with OSAS (AHI> or =5/h) also had an increased risk of metabolic syndrome (OR: 6.59; 95% CI: 1.47-29.38), and the risk was significantly higher in women with severe OSAS (AHI > or =30/h) (OR 14.00; 95% CI: 2.93-66.82). Risk factors for metabolic syndrome differed by gender: in men, age, body mass index (BMI), and OSAS (AHI > or =15/h) were significantly associated with metabolic syndrome, whereas, in women, BMI was the only risk factor for metabolic syndrome. The increase of metabolic syndrome in Japanese OSAS patients suggests that this patient population is burdened with multiple risk factors for cardiovascular disease.

Multiple endocrine neoplasia type I and Cushing's syndrome due to an aggressive ACTH producing thymic carcinoid.

Thymic carcinoid in multiple endocrine neoplasia type 1 (MEN 1) is previously reported as a non-ACTH producing tumor. The present case is a 39-year-old man with mortal outcome from thymic carcinoid and Cushing's syndrome with high plasma ACTH. The symptom was first observed at age 29 and was relieved after extended thymectomy, with reduction of ACTH level. The tumor was positive for ACTH, Grimelius silver staining and Chromogranin A. The finding of primary hyperparathyroidism, pituitary adenoma, and a novel germline nonsense mutation (W423X) established the diagnosis of MEN 1. Cushing's syndrome due to ACTH producing thymic carcinoid should be also considered as one phenotype of the MEN 1 spectrum.

[Sleep apnea syndrome].

Obstructive sleep apnea syndrome (OSAS) is strongly associated with cardiovascular disease which means these patients could suffer sudden death from these cardiovascular diseases, but it is a rare case that common OSAS itself causes sudden death directly. On the other hand, we never wrongly diagnose serious sleep-related breathing disorders (SBDs) such as sleep hypoventilation syndrome, OSAS patients with cardiovascular disease (i.e. ischemic heart disease, cardiac arrhythmia and cardiac failure) and bilateral vocal cord paralysis caused by multiple system atrophy as common OSAS. This section describes how to distinguish these SBDs from common OSAS.

Sleep-disordered breathing in patients with idiopathic cardiomyopathy.

BACKGROUND: Sleep-disordered breathing may adversely affect heart function, and thereby contribute to the progression of heart failure. A study was undertaken in patients with idiopathic cardiomyopathy to document the characteristics of sleep-disordered breathing. METHODS AND RESULTS: Thirty-five patients with a diagnosis of idiopathic cardiomyopathy, comprising 20 patients with dilated cardiomyopathy (DCM) and 15 patients with hypertrophic cardiomyopathy (HCM), underwent overnight polysomnography. Of these 35, 16 (80%) of the DCM patients and 7 (47%) of the HCM patients had sleep-disordered breathing. Central sleep apnea-hypopnea syndrome (CSAHS) was seen in 10 DCM patients, but not in the HCM patients, and obstructive sleep apnea-hypopnea syndrome (OSAHS) was seen in 6 DCM patients and 7 HCM patients. CSAHS was seen in DCM patients with a low left ventricular ejection fraction. HCM patients with OSAHS had a significantly greater body mass index (BMI) than those without OSAHS and CSAHS (27.6 +/- 3.8 vs 22.0 +/- 4.0 kg/m2, p<0.05). DCM patients with OSAHS had a larger BMI than those with CSAHS (29.3 +/- 5.8 vs 24.2 +/- 4.0 kg/m2, p<0.05) and those without OSAHS and CSAHS (29.3 +/- 5.8 vs 21.3 +/- 3.1 kg/m2, p<0.05). CONCLUSIONS: Sleep-disordered breathing is common in patients with idiopathic cardiomyopathy; half of DCM patients had CSAHS, which was closely associated with obesity.

Lipoprotein lipase activator NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin-induced diabetic rats.

NO-1886 is a lipoprotein lipase (LPL) activator. Administration of NO-1886 results in an increase in plasma high-density lipoprotein cholesterol (HDL-C) and a decrease in plasma triglyceride (TG) levels. The aim of this study was to ascertain whether NO-1886 improves fatty liver caused by high-fat feeding in streptozotocin (STZ)-induced diabetic rats. Administration of NO-1886 resulted in increased plasma HDL-C levels and decreased TG levels without affecting total cholesterol and glucose levels in the diabetic rats. NO-1886 dose-dependently decreased liver TG contents and cholesterol contents, resulting in improvement of fatty liver. NO-1886 also reduced plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that accompany fatty liver. The liver cholesterol contents were inversely correlated with plasma HDL-C levels (r = -0.5862, P <.001) and were positively correlated with plasma TG levels (r = 0.4083, P <.003). The liver TG contents were inversely correlated with plasma HDL-C levels (r = -0.6195, P <.001) and were positively correlated with plasma TG levels (r = 0.5837, P <.001). There was no correlation between plasma cholesterol levels, and cholesterol and TG contents in liver. These results indicate that reducing plasma TG levels and elevating in HDL-C levels may result in improving fatty liver.

Growth hormone insensitivity syndrome associated with syringomyelia and type I Chiari malformation.

A 49-year-old man with syringomyelia and a Type I Arnold-Chiari malformation (Chiari-I) was diagnosed with growth hormone insensitivity syndrome (GHIS). He was short in stature, had high circulating levels of GH, and low circulating levels of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). His GH responses to the administration of growth hormone-releasing hormone (GHRH) and L-DOPA were normal, but his levels of IGF-I and IGFBP-3 did not increase after the administration of exogenous GH. Direct genomic DNA sequencing revealed neither a mutation nor deletion in this patient's GH receptor (GHR) gene, though one polymorphism was detected, indicating that his GHR gene was normal. This is the first reported case of an association of GHIS with syringomyelia and Chiari-I malformation.

Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers.

BACKGROUND: It has been shown that restless legs syndrome (RLS) in adults may be linked to abnormalities in iron stores. Whether reduced iron stores play a role in children is not clear. METHODS: We evaluated the status of iron stores and sleep in three teenagers who presented with severe sleep onset insomnia, subjective sleep latency exceeding 60 min and excessive daytime sleepiness. RESULTS: The three teenagers were found to have RLS and laboratory evaluation confirmed reduced body stores of iron with a low percent iron saturation (mean value 9.7%) and a low serum ferritin level (mean value 17 microg/l). None had marked anemia. The three patients were treated with oral iron for 4-5 months. As a group they had an increase in percent iron saturation (from a mean of 9.7 to 22.7%) and serum ferritin (from a mean of 17 to 27 microg/l) and a marked reduction of the symptoms of RLS, with mean subjective sleep latency decreasing from 143 to 23 min, sleep efficiency increasing from 75.7 to 84.0% and the number of periodic movements per hour of sleep decreasing from 20.5 to 10.5. INTERPRETATION: These findings support the hypothesis that abnormal iron stores or metabolism may result in RLS causing insomnia in teenagers. We recommend evaluation of iron status including serum iron, total iron binding capacity and ferritin levels in teenagers with chronic insomnia of unexplained origin even when anemia is mild or absent.