The relationship between isolated TSH deficiency and hypophysitis was studied. Six patients (five women and one man) with idiopathic isolated TSH deficiency were longitudinally investigated with an interval of 31 to 60 months. Clinical symptoms, laboratory results and endocrine function were investigated as well as pituitary magnetic resonance imaging (MRI) at the start and the end of the study. Clinically, initial symptoms due to hypothyroidism were ameliorated by the thyroid hormone replacement in all patients. Oligomenorrhea newly appeared during the study in three patients, although no other symptoms appeared. Serum fT3 and fT4 levels were within the reference ranges, and serum TSH level and its response to TRH stimulation remained low in all patients. Peak plasma GH level during GRH stimulation was significantly (p<0.03) decreased, at the end of the study as compared with the start. Peak plasma FSH level to LHRH stimulation was significantly (p<0.03) decreased as well as basal FSH level. In contrast, peak of prolactin during TRH stimulation was significantly (p<0.03) increased at the end of the study as compared with the start as well as basal prolactin level. Endocrine features at the end of the study were compatible with those of lymphocytic adenohypophysitis (LAH). MRI of the pituitary gland showed empty sella in one patient and slight swelling in two patients. These findings remained unchanged during the study period. One patient underwent pituitary biopsy, with histological examination showing atypical form of LAH. LAH can cause idiopathic isolated TSH deficiency and can functionally progress to combine dysfunction of the pituitary gland.

View full abstract

The appropriate period of antithyroid drug (ATD) discontinuation before radioiodine therapy is the most critical problem in Graves' disease patients under going treatment with ATD. To determine the optimal period that does not alter the outcome of radioiodine therapy or exacerbate hyperthyroidism, we compared serum FT4 levels at radioiodine uptake (RAIU) and therapy outcomes between a 2-day withdrawal group and 7-day withdrawal group. We prospectively recruited 43 patients for the 2-day withdrawal protocol and retrospectively reviewed 49 patients treated with radioiodine following the protocol of 7-day withdrawal. There was no significant difference in RAIU between the 2 groups. The mean serum FT4 level measured on the first day of 24-h RAIU of the 7-day group was significantly higher than that in the 2-day group. There were no significant differences in the outcomes at each point (6 months, 1 year, and 2 years after therapy) between the 2 groups. Our results indicated that withdrawal of ATD for 2 days is superior to 7 days in that 2 days discontinuation did not exacerbate hyperthyroidism. In order to prevent serum thyroid hormone increase after ATD withdrawal and radioiodine therapy, a 2-day ATD withdrawal period before radioiodine therapy may be useful for high-risk patients such as the elderly and patients with cardiac complications. We believe that the 2-day ATD withdrawal method may be useful for patients undergoing treatment with ATD who are to undergo radioiodine therapy.

View full abstract

We describe a case of adrenocortical adenoma with preclinical Cushing's syndrome demonstrating diurnal rhythms of ACTH and cortisol in blood. A 50-year-old man was admitted to the hospital for the evaluation of incidental right adrenal mass with hyperglycemia and hypertension. On admission, there were no signs of clinical manifestation of hypercortisolism. The basal levels of cortisol (9.3 μg/dl) and ACTH (9.4 pg/ml) at 0800 h were not elevated and these diurnal rhythms were maintained. One or 8 mg of dexamethasone given orally overnight suppressed the plasma ACTH but not serum cortisol. Ultrasonogram, CT and scintiscan of ¹³¹I adosterol all demonstrated an enlarged adrenal mass in the right adrenal gland. The right adrenal gland was subsequently resected by laparoscopic surgery. Histopathological findings of resected adrenal tumor were consistent with adrenocortical adenoma. Adjacent non-neoplastic adrenal tissue demonstrated adrenocortical atrophy but DHEA-sulfotransferase immunoreactivity in the zona reticularis was detected.

View full abstract

The MAPK signaling pathway plays a crucial role in tumorgenesis and cell proliferation in human papillary thyroid carcinoma (PTC). Ret/PTC rearrangements, RAS and BRAF mutations, the main non-overlapping genetic alterations all leading to MAPK cascade activation, are cumulatively identified in 60-80% of PTCs. In approximately one-fourth of the cases, oncogenic background potentially contributing to MAPK activation in PTC might be different. We therefore attempted to evaluate the mutational status of genes encoding other members of RAF family known to act upstream of MAPKs, ARAF and CRAF (RAF-1). In addition we also analyzed the MET gene that encodes hepatocyte growth factor/scatter factor receptor overexpressed in most of PTCs and a MAPK cascade contributor. In 129 Japanese patients with PTC, BRAF^T1799A was detected in 65 cases (50.4%), and the remaining 64 tumor specimens were subjected to mutation analysis of kinase domains of ARAF, CRAF and MET genes, and hotspots of K- and N-RAS genes. No ARAF, CRAF, MET, K- and N-RAS mutations were revealed. Based on these observations, we concluded that despite the fact that ARAF, CRAF and MET are actively expressed, alterations of these genes are rare in PTC and unlikely to play a perceptible role in the molecular pathogenesis of this type of human malignancy.

View full abstract

Acromegalic arthropathy is one of the most frequent manifestations occurring in acromegaly patients. In contrast, rheumatoid arthritis (RA) is a rare clinical complication in acromegaly patients. Here, we report a 70-year-old Japanese woman with acromegaly, who complained of bilateral finger stiffness and polyarthralgia two months after transsphenoidal surgery of a growth hormone (GH)-secreting pituitary adenoma. Postoperative levels of serum GH and insulin-like growth factor-1 (IGF-1) were markedly decreased without any secretory deficiency of other anterior pituitary hormones. Hand X-ray did not show typical RA changes; however, erosive changes in carpal bones were clearly detected by magnetic resonance imaging with gadolinium enhancement. Based on the levels of serological markers in the patient following surgery including C-reactive protein, rheumatoid factor and matrix metalloproteinase-3, anti-rheumatic therapy was subsequently commenced. Regardless of the levels of GH and IGF-1, acromegaly patients frequently complain about joint-related symptoms even after remission. Therefore, careful observation of bone erosive changes and immunological activity in acromegaly patients is required when joint-related symptoms persist.

View full abstract

The incidence of thyroid microcarcinoma is rising due to the frequent use and improvement of fine-needle aspiration biopsy and ultrasonography. Since the recent update of the TNM (Tumor, Node, Metastasis) staging system for thyroid cancer, the importance of lymph node metastasis became more prominent. In the present study, we evaluated the prognostic factors and extension of thyroid microcarcinomas in Korean patients. The clinical and pathological findings in patients with thyroid microcarcinomas in a Korean hospital from January through December 2004 were evaluated. A total of 302 (50.2%) out of 601 cases of thyroid cancers were microcarcinomas. Evaluation of the histology revealed that nearly all of the cases (300 of 302) were of the papillary type. Analyzing patients of papillary thyroid microcarcinomas, 273 (91.0%) out of 300 patients of papillary microcarcinomas were women. Seventy-eight (26.0%) cases contained multiple tumor masses (≥2), including 49 (16.3%) cases that were bilateral. There were 84 (28.0%) cases of extrathyroidal extensions and 89 cases (29.7%) of lymph node metastasis, but no cases of distant metastases. Application of the new staging system revealed 7 (2.3%) cases that changed from stage III to stage IVA. Thyroid microcarcinomas were also associated with poor prognostic factors and appear to exist at relatively higher cancer stages. Therefore, it is important to treat them as early and as vigorously as possible with extensive surgery, radioactive iodine therapy, and thyroxine suppression.

View full abstract

We recently encountered a 66-year-old Japanese man who had suffered from acute hyperglycemia following flu-like symptoms during treatment of type 2 diabetes. Despite significantly increased plasma glucose levels, HbA1c was only slightly elevated. The possibility of autoimmune type 1 diabetes was excluded because of negative islet-related autoantibodies. Serum levels of pancreatic exocrine enzymes, amylase, lipase, and elastase-l were elevated. However, the insulin-secreting function of his islets was not severely damaged. This case is particularly notable for two reasons. First, it showed a fulminant type 1 diabetes-like clinical onset, but his beta cell function was fairly preserved. Second, it developed during the treatment of type 2 diabetes in an elderly patient.

View full abstract

Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure.

View full abstract

Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (ΔL130 in exon 4 and W610X in exon 16) in the remaining four patients. ΔL130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, ΔL130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.

View full abstract

Subclinical hypothyroidism (SH), defined as an asymptomatic state characterized by normal serum concentrations of free thyroxine and elevated serum concentrations of TSH. The aim of this study is to investigate the complex interplay between insulin resistance and low grade chronic inflammation in Kuwaiti women with subclinical hypothyroidism. Thirty four women with subclinical hypothyroidism (SH) and 20 healthy women as controls matched to the patient group for sex, age and body mass index (BMI), were enrolled in this prospective study. TSH, FT4, C reactive protein, glucose, insulin, Homeostasis Model assessment (HOMA), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) were estimated. Total cholesterol and LDL-C were significantly higher in patients with SCH as compared with control subjects, however triglyceride and HDL-C were not statistically different. CRP was not statistically different between the SCH patients and control group (3.64 ± 0.94 Vs 3.18 ± 0.71 P>0.05). Insulin levels were significantly higher in the SCH group comparable to the control (12.5 ± 2.67 Vs 10.80 ± 2.01 p<0.05), however HOMA-IR was not statistically different (2.85 ± 0.64 Vs 2.54 ± 0.64 P>0.05). Patients with subclinical hypothyroidism exhibited elevated atherogenic parameters (hyperinsulinemia, total cholesterol, LDL-C). Therefore screening and treatment for subclinical hypothyroidism may be warranted due to its adverse effects on lipid metabolism.

View full abstract

Adenoid cystic carcinoma is a tumor of exocrine glands originating primarily from the minor and major salivary glands, lacrimal gland, bronchus, breast, and intestinal and genital tracts. Intracranial remote metastasis from adenoid cystic carcinoma in salivary gland is quite rare. The authors encountered a case of intrasellar remote metastasis from an adenoid cystic carcinoma of parotid gland origin, presenting with hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). To our knowledge, this is the first reported case of metastasis from an adenoid cystic carcinoma to intrasellar area. A 78-year-old woman had an adenoid cystic carcinoma in the left parotid gland, which was resected surgically followed by local radiation therapy of 60 Gy. After 4 years, the patient presented with general malaise, followed by disturbed consciousness caused by hyponatremia. The clinical data showed severe hyponatremia induced by SIADH. An intrasellar heterogenous mass lesion compressing the optic chiasm was resected subtotally via an endonasal transsphenoidal approach. Histopathological examination of the tumor specimens revealed adenoid cystic carcinoma, which had identical histological findings as those of the painful superficial cervical lymph nodes resected in the same operation. Tumors such as the present case are easily confused with pituitary adenoma or craniopharyngioma. Although rare, metastasis from tumors including those of salivary gland origin should be considered in the differential diagnosis of unusual pituitary tumors.

View full abstract

The oxidative modification of low-density lipoproteins (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Iron plays a part in the formation of highly toxic free radicals such as hydroxide and superoxide anions, which can induce lipid peroxidation. We investigated whether serum iron status was associated with circulating oxidized LDL (oxLDL) levels in type 2 diabetic patients, in whom oxidative stress and susceptibility to lipid oxidation were supposedly increased. Serum ferritin levels were significantly correlated with plasma oxLDL concentrations in both male and female patients (p<0.02 and p<0.05, respectively). No correlation was detected between ferritin and LDL-cholesterol (LDL-C) concentrations despite the close correlation between LDL-C and oxLDL concentrations (p<0.0001). Stepwise regression analysis showed that ferritin concentration was an independent positive determinant of oxLDL level, in addition to triglyceride concentration, body mass index and sex. This is the first report to show that serum ferritin is associated with circulating oxLDL levels in patients with type 2 diabetes. Further work is required to establish a causative link between iron excess and the development of diabetic vascular complications.

View full abstract

Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.

View full abstract

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

View full abstract

Here we report the case of a 65-year-old woman with acromegaly complicated with monoclonal gammopathy of undetermined significance (MGUS). The patient visited Shimane University Hospital for treatment of spinal canal stenosis, and was diagnosed as acromegaly with GH 43.1 ng/ml, insulin-like growth factor (IGF)-I 510 ng/ml and the detection of a pituitary adenoma by MRI. She was also diagnosed as MGUS with IgG 2208 mg/dl, the existence of IgG-κ type monoclonal protein, and 5.6% plasma cells in bone marrow. After a pituitary adenoma was operatively removed by transsphenoidal approach, IgG levels, as well as GH and IGF-I levels, decreased spontaneously and simultaneously. We suspect a pathogenetic link between acromegaly and MGUS in this case, because both GH and IGF-I are known to directly promote immunoglobulin production from plasma cells, thus inducing the proliferation of the cells in vitro.

View full abstract

The aim of this study was to assess the association between high sensitivity-C-reactive protein (hs-CRP), a sensitive marker of inflammation, and early-stage carotid atherosclerosis, in patients with early-state type 2 diabetes mellitus. The study subjects were 75 patients with type 2 diabetes mellitus without obvious diabetic vascular complications, who were not on any medication, and whose HbA_1c level was less than 6.5%. We evaluated the mean intima-media thickness (IMT) of the common carotid artery (CCA) by ultrasound B-mode imaging. Then, we investigated various factors associated with CCA-IMT including hs-CRP. Serum hs-CRP levels correlated well with factors strongly associated with insulin resistance such as homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin level, and body mass index. Serum hs-CRP also correlated with mean CCA-IMT and serum levels of soluble intercellular adhesion molecule-1. Multivariate regression analysis using mean CCA-IMT as the dependent variable identified only age, hs-CRP, and diastolic blood pressure as independent determinants of mean CCA-IMT. While hs-CRP associates with insulin resistance and subclinical atherosclerosis in ealy-state type 2 diabetes, our data suggest that hs-CRP is a useful marker of subclinical atherosclerosis in early-state type 2 diabetes mellitus independent of factors that directly reflect insulin resistance.

View full abstract

Turner syndrome is a common sex chromosome anomaly. Human growth hormone (hGH) is effective for treating short stature, which is a major characteristic of the disease. In this report, we analyzed the results of low-dose GH treatment for short stature in 212 Turner syndrome patients with growth hormone deficiency. These patients were enrolled in KIGS Japan. After 5 years of treatment, change in height was more than the mean growth curve in many patients, and the standard deviation (SD) for stature improved by +1.22 SDS. As the treatment progressed, the weight-for-height index (WHI) decreased in patients aged 8.1 years or older but not more than 14.8 years at the commencement of the treatment.

View full abstract

A 58-year-old woman complaining of finger tremor was referred to our hospital. The diagnosis of Graves' disease was made based on increased free triiodothyronine (18.88 pg/ml) and free thyroxine (7.47 ng/dl), low TSH (<0.005 μIU/ml) and increased TSH receptor binding antibody activity (70.9%). Serum level of AST (62 U/l) and ALT (93 U/l) were increased and liver biopsy revealed linkage of adjacent portal areas by lymphoplasmacytic infiltrates and fibrosis with piecemeal necrosis. Although antinuclear antibody was negative, these findings indicated that she had autoimmune hepatitis (AIH) according to the criteria of the International Autoimmune Hepatitis Scoring System. Slowly progressive type 1 diabetes mellitus (DM) was confirmed by a diabetic response pattern due to 75 g-oral glucose tolerance test, and seropositivity towards anti-glutamic acid decarboxylase (725 U/ml) and islet cell (80 JDF Units) antibodies. This case exhibited an extremely rare combination of three different autoimmune diseases, including Graves' disease, slowly progressive type 1 DM and AIH, and had no known sensitive human leukocyte antigen (HLA) typing or haplotype for these disorders. Alhough it is common for patients with Graves' disease to exhibit abnormal liver function, it is important to make an accurate diagnosis of AIH because of this life-threatening disorder.

View full abstract