The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing’s syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.
Mutations in DUOXA2, encoding dual oxidase maturation factor 2, is a rare genetic cause of congenital hypothyroidism. Only four biallelic DUOXA2 mutation carriers have been described to date. This study was conducted to report the clinical and genetic findings of a DUOXA2 mutation-carrying family, and to review the previously reported cases. The proband was a 4-year-old girl, who was diagnosed as having congenital hypothyroidism in the frame of newborn screening. She had a high serum TSH level (138 mU/L) and a low free T4 level (0.4 ng/dL). Ultrasonography revealed goiter. She was immediately treated with levothyroxine. At age 3 years, reevaluation of her thyroid function showed a slightly elevated serum TSH level (11.0 mU/L) with normal free T4 level. Screening of the eleven congenital hypothyroidism-related genes demonstrated a previously reported nonsense DUOXA2 mutation (p.Tyr138*) in the homozygous state. Unexpectedly, we also found that the elder brother of the proband, who had no significant past medical history, had the identical homozygous mutation. Using expression experiments with HEK293 cells, we confirmed that p.Tyr138* was a loss-of-function mutation. In the literature, clinical courses of three patients were described, showing characteristic age-dependent improvement of the thyroid function. In conclusion, The proband showed comparable clinical phenotype to previously reported cases, while her brother was unaffected. The phenotypic spectrum of DUOXA2 mutations could be broader than currently accepted.
Subclinical hypothyroidism (SCH) patients have normal thyroid hormone levels but increased thyroid stimulating hormone (TSH) level in serum. It has been reported that high TSH is related to abnormal skeletal development in mice with hypothyroidism. However, the cellular mechanism is not fully understood. In the present study, we aim to investigate the direct effects of TSH stimulation on chondrocytes, and the putative role of autophagy in this process. By using EdU incorporation assay and flow cytometry for mitochondrial membrane potential assay, we demonstrated deceased proliferation and promoted apoptosis in TSH stimulated primary mouse chondrocytes. And the balance of Bcl-2 and BAX expression on protein level was broken. More interestingly, the expression of autophagic markers Beclin-1 and LC3II was reduced in TSH stimulated chondrocytes, accompanied by less autophagosomes and accumulated p62 protein, indicating an impaired autophagic flux. More interestingly, mTOR was upregulated and AMPK activity was decreased in TSH stimulated PMCs, suggesting that mTOR/AMPK pathway is get involved in the regulation of TSH on autophagy in PMCs. Collectively, we found an increased apoptosis and suppressed autophagy in TSH stimulated primary chondrocytes, which is meaningful in understanding the effects of increased TSH level on articular cartilage and the role of autophagy in this process, and thus provide a potential novel therapeutic target in related cartilage damages.
According to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), cyst fluid only (CFO) cases are classified in the non-diagnostic category. To date, no large study focusing on CFO has been conducted. To reassess the diagnostic significance of CFO, we compared CFO nodules with non-diagnostic nodules excluding CFO (ND-other). We reviewed the conventional thyroid smears of 715 CFO and 766 ND-other nodules. We compared the timing of and findings at re-aspiration, the histology of resected specimens, and the proportion of malignant nodules between the two groups. Re-aspiration was performed in 9.0% of CFO and 23.8% of ND-other cases. In 12.5% of CFO and 49.4% of ND-other cases, the interval between the first and second aspirations was <3 months. Despite this, there were no cases in which cytological interpretation was complicated by the first aspiration. Overall, 77 CFO nodules (10.8%) were surgically resected; 14 were malignant. In all cases in which re-aspiration cytology revealed malignancy, the initial ultrasound interpretation was a high or intermediate suspicion pattern. The proportion of malignancies subsequently diagnosed in nodules initially classified as CFO and ND-other was 2.0% and 5.6%, respectively (p<0.01). As CFO and ND-other thyroid nodules have different clinical management and malignancy rates, we would like to assert that CFO and ND-other nodules should be separated, and that the former should be considered diagnostic. In terms of clinical management, we recommend that only CFO cases with concerning features on ultrasound undergo re-aspiration.
A multicenter, open-label, phase 2 study was conducted to investigate the efficacy and safety of long-acting pasireotide formulation in Japanese patients with acromegaly or pituitary gigantism. Medically naïve or inadequately controlled patients (on somatostatin analogues or dopamine agonists) were included. Primary end point was the proportion of all patients who achieved biochemical control (mean growth hormone [GH] levels<2.5μg/L and normalized insulin-like growth factor-1 [IGF-1]) at month 3. Thirty-three patients (acromegaly, n=32; pituitary gigantism, n=1) were enrolled and randomized 1:1:1 to receive open-label pasireotide 20mg, 40mg, or 60mg. The median age was 52 years (range, 31-79) and 20 patients were males. At month 3, 18.2% of patients (6/33; 90% confidence interval: 8.2%, 32.8%) had biochemical control (21.2% [7/33] when including a patient with mean GH<2.5μg/L and IGF-1< lower limit of normal). Reductions in the median GH and IGF-1 levels observed at month 3 were maintained up to month 12; the median percent change from baseline to month 12 in GH and IGF-1 levels were -74.71% and -59.33%, respectively. Twenty-nine patients completed the 12-month core phase, 1 withdrew consent, and 3 discontinued treatment due to adverse events (AEs; diabetes mellitus, hyperglycemia, liver function abnormality, n=1 each). Almost all patients (97%; 32/33) experienced AEs; the most common AEs were nasopharyngitis (48.5%), hyperglycemia (42.4%), diabetes mellitus (24.2%), constipation (18.2%), and hypoglycemia (15.2%). Serious AEs were reported in 7 patients with the most common being hyperglycemia (n=2). Long-acting pasireotide demonstrated clinically relevant efficacy and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.
In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.
The purpose of this study was to determine whether treatment using the active form of vitamin D (1,25(OH)2D3) could protect against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats and ameliorate oxidative stress. Male Sprague-Dawley rats were divided into three groups and treated with standard chow, HFD, or HFD plus intraperitoneal injection of 1,25(OH)2D3 (5 μg/kg body weight, twice per week), respectively, for 16 weeks. Serum lipid profiles, hepatic function, intrahepatic lipid, and calcium levels were determined. Hepatic histology was examined using hematoxylin/eosin, Masson’s trichrome, and Oil Red O staining. Oxidative stress was assessed by measuring hepatic malondialdehyde (MDA) and F2α-isoprostane content. Expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) and downstream target genes was analyzed using quantitative RT-PCR. 1,25(OH)2D3 treatment improved the serum lipid profile, reduced intrahepatic lipid levels, and attenuated hepatic steatosis and inflammation in HFD rats. Furthermore, MDA and F2α-isoprostane levels in liver tissue were reduced by 1,25(OH)2D3 administration. Although 1,25(OH)2D3 did not regulate the expression of Nrf2 mRNA, it did induce Nrf2 nuclear translocation. The expression of Nrf2 target genes, including Gclc, Nqo1, Sod2, and Cat, was up-regulated by 1,25(OH)2D3. We conclude that 1,25(OH)2D3 protects against HFD-induced NAFLD by attenuating oxidative stress, inducing NRF2 nuclear translocation, and up-regulating the expression of genes encoding antioxidant enzymes.
To explore the role of NF-κB activation in the development of insulin resistance and investigate whether or not that the inhibition of NF-κB activation by PDTC will improve the insulin resistance of L6 cells exposed to H2O2. L6 cells were treated with H2O2, PDTC or both H2O2 and PDTC for 4 hours. The uptake of glucose with stimulation of insulin, the expression of P38-MAPK, p- P38-MAPK, NF-κBp65, p- NF-κBp65, IRS-1, IRS-2, p-IRS-2, PI3K, IκBα, p- IκBα, caspase-8 and GLUT4, the production of ROS, TNF-α, IL-6 and IL-1β as well as the apoptosis rate of L6 cells were determined and compared in L6 treated with H2O2 alone or both H2O2 and PDTC. Compared with the L6 cells treated with H2O2 alone, the L6 cells treated with both H2O2 and PDTC showed (1) significantly lower production of ROS, TNF-α, IL-6 and IL-1β; (2) significantly decreased expression of P38-MAPK, p- P38-MAPK and NF-κBp65, p- NF-κBp65, p- IκBα and caspase-8; (3) significantly lower rate of apoptosis; (4) significantly higher expression of IRS-2, p-IRS-2 (Tyr 612), PI3K and GLUT4; (5) significantly higher uptake of glucose with stimulation of insulin; (6) significantly increased expression of Bcl2 and decreased ratio of Bax to Bcl2. Based on the findings of the present study, inhibition of NF-κB activation by PDTC would improve the insulin resistance of L6 cells exposed to H2O2.
We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients’ data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.
Diabetes mellitus is associated with an increased risk of falls, which increases the incidence of osteoporotic fractures and accordingly decreases quality of life. However, the association between fall risk and diabetic complications is not completely understood. Therefore, the aim of this study was to examine the association between fall risk and osteoporotic fractures in patients with type 2 diabetes mellitus (T2DM). We enrolled 194 Japanese patients with T2DM and assessed their fall risk using a brief interview form that included five items covering physical and social aspects of functioning and environmental factors. We examined the associations between fall risk and the presence of diabetic complications, such as neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease (PAD), and osteoporotic fractures (including any fracture and vertebral fractures only). In the multivariate logistic regression analysis, a longer history of T2DM, the presence of neuropathy and PAD, and a history of any fractures were significantly and positively associated with the risk of falls. On the other hand, a lower body mass index, the presence of neuropathy, and the risk of falls were independently and positively associated with the risk of any fracture. When fractures were limited to vertebral fractures only, the association with the risk of falls remained significant. We found that the risk of falls and osteoporotic fractures were associated in patients with T2DM and that a brief screening test of the risk of falls was useful for assessing the risk of osteoporotic fractures.
Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 μIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 μg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.
The prognosis for autoimmune thyroid diseases (AITDs), such as Hashimoto’s disease (HD) and Graves’ disease (GD), varies among patients. Interleukin (IL)-12 and IL-18 also induce Th1 differentiation, and SOCS1 (Suppressor of cytokine signaling 1) and TIM-3 (T cell immunoglobulin and mucin domain-3) are known to be negative regulators of Th1 cells. To clarify the association of functional polymorphisms in the IL12, IL12Rβ1, IL18, SOCS1 and TIM3 genes with the intractability and severity of autoimmune thyroid disease (AITD), we genotyped these polymorphisms in 151 GD patients, including 61 patients with intractable GD and 51 patients with GD in remission, in 140 HD patients, including 59 patients with severe HD and 55 patients with mild HD, and in 74 healthy controls. The frequency of the IL18 -607CC genotype which correlates with a high production of IL-18, was significantly higher in patients with GD in remission than in those with intractable GD (p=0.0178). The -607C allele was significantly higher in patients with severe HD than in those with mild HD (p=0.0050). The -607CC genotype in IL18 gene may be protective against the intractability of GD, and the -607C allele may enhance the severity of HD.
G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.
Patients with aldosterone-producing adenomas are treated using surgery, and patients with idiopathic hyperaldosteronism receive medical treatment using mineralocorticoid receptor antagonists (MRAs). However, the outcomes of surgical and medical treatment for primary aldosteronism (PA) remain unclear. Therefore, we compared the outcomes of surgical and medical treatment for PA and aimed to identify a specific subgroup that might benefit from medical treatment. We identified 269 patients who were treated for PA (unilateral excess: 221 cases; bilateral excess: 48 cases) during 2000-2015 at the Seoul National University Hospital and two other tertiary centers. The main outcomes were the amelioration of hypertension and hypokalemia. Treatment improved hypertension in the surgical treatment group (78.2%) and the medical treatment group (55.6%) (p = 0.001). At the last follow-up, hypokalemia was normalized in the surgical treatment group (97.1%) and the medical treatment group (93.7%; p = 0.046). Among patients with unilateral aldosterone excess, surgery provided advantages in resolving hypertension without worsening renal function. Among patients who were >60 years old or had impaired renal function, surgical and medical treatment provided similar amelioration of hypokalemia and hypertension. Three patients developed hyperkalemia after surgery, and no patients developed hyperkalemia after initiating medical treatment. The surgical treatment group exhibited a lower postoperative estimated glomerular filtration rate (eGFR) and higher serum potassium levels, compared to the medical treatment group. Surgical treatment provided better hypertension and hypokalemia outcomes among patients with PA, compared to medical treatment. However, MRAs may be appropriate for elderly patients with impaired renal function.
Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians’ awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians’ poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.
Uridine diphosphate-glucuronosyltransferase 2B15 (UGT2B15) conjugates 5α-androstane-3α, 17β-diol (3α-diol) to 3α-diol glucuronide (3α-diol G) in steroid target tissues. The present study investigated the regulation of UGT2B15 expression during the ovulatory process in the rat. Real-time PCR analysis revealed that treatment of immature rats with equine chorionic gonadotropin followed by human chorionic gonadotropin transiently stimulated UGT2B15 gene expression in granulosa cells of preovulatory follicles within 6 h. The progesterone receptor antagonist RU486 suppressed the gonadotropin-induced UGT2B15 expression. The expression of UGT2B15 and the levels of 3α-diol G were transiently increased by luteinizing hormone (LH) treatment in cultured preovulatory follicles. The LH-stimulated UGT2B15 mRNA level in cultured preovulatory follicles was inhibited by inhibitors of adenylyl cyclase, phosphoinositide 3-kinase and mitogen-activated protein kinase. Furthermore, a vitamin D receptor agonist (calcitriol) suppressed the LH-stimulated UGT2B15 expression in a dose-dependent manner. Taken together, these results indicate that gonadotropins transiently stimulate UGT2B15 expression and activity in preovulatory follicles, and UGT2B15 mRNA levels are regulated by the progesterone receptor and vitamin D receptor.
Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.
There have been reports of the use of levothyroxine or levothyroxine plus liothyronine for consumptive hypothyroidism caused by hepatic hemangiomas. Administration of levothyroxine without liothyronine can be inadequate to maintain normal levels of both free T3 and free T4 in some patients. However, there is no report of treatment with liothyronine plus propranolol. We herein present a case in which we used liothyronine therapy for multifocal hepatic hemangiomas in a Japanese patient with low free T3 and normal free T4 levels. A 2-month-old Japanese male was referred to our hospital because of jaundice. Abdominal computed tomography showed multifocal hemangiomas in both lobes of the liver. TSH level was elevated, free T3 level was low, free T4 level was normal, and hypothyroidism due to hepatic hemangiomas was diagnosed. In addition to propranolol, liothyronine was started. We used liothyronine without levothyroxine for hypothyroidism because only free T3 level had decreased, whereas free T4 level remained in the normal range. The TSH and free T3 levels normalized in this patient in less than 1 month. The liothyronine dose was gradually reduced with regression of the hemangiomas, and liothyronine administration was discontinued at the age of 5 months. At the age of 11 months, growth and neurological development of the patient met age-specific norms, and he was euthyroid at that time. This is the first report demonstrating the use of liothyronine with propranolol for treatment of this type of consumptive hypothyroidism.
We report a 27-year-old pregnant woman with polyuria, polydipsia and headache in the third trimester of pregnancy. Hypernatremia (153 mEq/L), high plasma osmolality (300 mOsm/kgH2O) and low urinary osmolality (92 mOsm/kgH2O) were observed at the admission to our hospital. Plasma arginine vasopressin (AVP) level was inappropriately low (2.2 pg/mL) compared to the high plasma osmolality. Plasma AVP responses to hypertonic-saline infusion were blunted, and her urine osmolality increased in response to desmopressin. The diagnosis of central diabetes insipidus was made from these results. Magnetic resonance imaging (MRI) of hypothalamic-pituitary region demonstrated a significant enlargement of the pituitary stalk, suggesting the presence of hypophysitis. In addition, serum anti-rabphilin-3A antibodies that have been recently reported as a biomarker of lymphocytic infundibulo-neurohypophysitis, were positive. Diabetes insipidus continued after delivery, suggesting that polyuria was not mainly due to excessive vasopressinase activity or reduced renal sensitivity to AVP by prostaglandin E2 that can cause temporal polyuria during pregnancy. We therefore clinically diagnosed central diabetes insipidus due to lymphocytic infundibulo-neurohypophysitis, without performing invasive transsphenoidal pituitary biopsy. This case suggested the usefulness of anti-rabphilin-3A antibodies for the etiological diagnosis of central diabetes insipidus during pregnancy.
Vitamin D is a modulator of both the innate and adaptive immune system. As vitamin D deficiency was a risk factor for some autoimmune diseases, we aimed to evaluate the serum vitamin D levels in autoimmune thyroid diseases (AITD) including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) and investigated the association between serum vitamin D levels and AITD. 175 AITD patients including 51 GD, 61 euthyroid HT (mild HT), 63 euthyroid HT patients with hypothyroidism receiving hormone therapy (treated HT) were recruited from the outpatient department. 51 controls were from the physical checkup center of the hospital. 25-Hydroxyvitamin D levels, thyroid function, antithyroid antibodies, IL-4, IL-17, and TNF-α were determined. Compared with the controls, treated and mild HT patients had significantly lower 25(OH)D levels (45.77±3.48 vs. 83.49±6.24 nmol/L, P<0.001) and (55.25±3.88 vs. 83.49±6.24 nmol/L, P<0.001), respectively. However, GD patients had similar 25(OH)D levels (81.77±5.60 vs. 83.49±6.24 nmol/L P=0.808). Compared to 24.1% controls with prevalent vitamin D deficiency, mild HT and treated HT patients were significantly different (55.4%, p<0.001) and (70.3%, p<0.001), respectively; no difference was seen in the GD patients (22.9%, P=0.797). Serum 25(OH)D levels were not associated with thyroid function, antithyroid antibodies, and serum cytokines IL-4, IL-17, and TNF-α in patients with AITD. We observed relatively low vitamin D level in mild and treated HT patients, while GD patients had similar 25(OH)D levels to those of healthy individuals. Further studies are imperative to explore the complex etiology of vitamin D deficiency in AITD.
Retinoic acid (RA) is converted from retinal by retinaldehyde dehydrogenases (RALDHs) and is an essential signaling molecule in embryonic and adult tissue. We previously reported that RALDH1 was produced in the rat anterior pituitary gland and hypothesized that RA was generated in the gland. Midkine (MK) is an RA-inducible growth factor, and MK production in the rat anterior pituitary gland was recently reported. However, the mechanism that regulates gene expression of MK in the pituitary gland has not been determined. To investigate regulation of MK production in the anterior pituitary gland, we analyzed changes in MK mRNA in cultured rat anterior pituitary cells. We identified MK-expressing cells by double-staining with in situ hybridization and immunohistochemical techniques for RALDH1. MK mRNA was expressed in RALDH1-producing cells in the anterior pituitary gland. Using isolated anterior pituitary cells of rats, we examined the effect of RA on gene expression of MK. Quantitative real-time PCR revealed that 72 h exposure to a concentration of 10-6 M of retinal and all-trans retinoic acid increased MK mRNA levels by about 2-fold. Moreover, the stimulatory effect of all-trans retinoic acid was mimicked by the RA receptor agonist Am80. This is the first report to show that RA is important in regulating MK expression in rat anterior pituitary gland.
Vitamin D-dependent rickets type 2A (VDDR2A) is a rare inherited disorder with decreased tissue responsiveness to 1,25-dihydroxyvitamin D [1,25(OH)2D], caused by loss of function mutations in the vitamin D receptor (VDR) gene. Approximately 50 types of mutations have been identified so far that change amino acids in either the N-terminal DNA binding domain (DBD) or the C-terminal ligand binding domain (LBD) of the VDR protein. The degree of responsiveness to 1,25(OH)2D varies between patients with VDDR2A, which may depend on their residual VDR function. In this report, we describe a female patient with VDDR2A caused by an early stop codon (R30X) in the VDR gene that resulted in a severely truncated VDR protein. She developed alopecia and bowed legs within a year after birth and was diagnosed with rickets at the age of 2. She had been treated with active vitamin D and oral calcium supplementation until 22 years of age, when she developed secondary hyperparathyroidism and high bone turnover. The genetic diagnosis of VDDR2A promoted the discontinuation of active vitamin D treatment in favor of monotherapy with oral calcium supplementation. We observed amelioration of the secondary hyperparathyroidism and normalization of bone metabolic parameters within 6 years.
Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.
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