Treatment plan for neonates with borderline hypothyroidism (persistent hyperthyrotropinemia with normothyroxinemia) has not been established. In this study, changes in thyroid function after discontinuation of low-dose L-thyroxine (L-T4) supplement in infants with the condition were evaluated. Fourteen infants with hyperthyrotropinemia at neonatal screening had repeated hyperthyrotropinemia (>8 mU/L) with normothyroxinemia. TSH response was exaggerated at TRH testing. The subjects were treated with low-dose L-T4 (3 to 9 μg/kg/day) for 2.2 to 6 years, and euthyroid status was maintained. After discontinuation of therapy, mild hyperthyrotropinemia persisted up to 24 months, while serum FT4 remained within the lower half of the normal range. TSH response to TRH stimulation, which tended to be exaggerated 1 month after discontinuation, became lower 6 to 12 months later. RAIU and thyroid scintigraphy were normal in all subjects. No patient developed hypothyroxinemia, although mild elevation of TSH lasted rather long after discontinuation of low-dose L-T4 therapy. Administration of L-T4 was not resumed provided the subjects were followed at regular interval. Further long-term investigation is needed to define whether re-administration is necessary or not.
We report two cases of monostotic Paget's disease which were effectively treated with bisphosphonate. Case 1 was a 60-year-old female. Medical examination revealed high alkaline phosphatase (ALP) levels making her visit our clinic. Hematological examination showed high levels of ALP isozyme 3 and bone metabolism markers, and bone scintigraphy demonstrated strong accumulation of 99mTc on the skull. With the diagnosis of monostotic Paget's disease of the skull, treatment with bisphosphonate (etidronate) was started. The response to etidronate was good and after 12 weeks of treatment, the ALP levels decreased to about 26% of the levels before treatment, without the appearance of any symptoms or lesion development. One year and three months later, ALP increased again, and etidronate administration was resumed. However, four years after the diagnosis of the disease, etidronate became ineffective and oral administration of alendronate, a stronger bisphosphonate, was started at 5 mg/day. The patient responded favorably to the bisphosphonate and is still under observation. Case 2 was a 71-year-old female. High ALP levels were found during the follow-up of type 2 diabetes, and the case was diagnosed as monostotic Paget's disease of the pelvis based on bone metabolism markers and bone scintigraphy. Etidronate treatment at 200 mg/day resulted in the improvement of bone metabolism markers and bone scintigraphy findings. When she died of colon cancer twelve months later, with no marked progress of the Paget's disease of bone observed clinically.
The association of the ACE gene I/D polymorphism with type 2 diabetes (DM) was examined in a population-based Japanese sample. A total of 902 individuals (490 females and 412 males, age 58.8 ± 12.2 yr) from a cohort population (n = 3,706) of the Funagata diabetes study were divided into three groups according to genotype: D/D (n = 104), I/D (n = 436) and I/I (n = 362). Chi-square test and ANOVA were used for association studies and to assess the differences in the traits' values, respectively. More individuals with the genotypes D/D and I/D were diabetic (8.7% and 4.1%, respectively) than those with the genotype I/I (2.8%, p = 0.008 and p=0.032, respectively). The genotype D/D was a risk factor for DM (relative risk (RR) 3.13, 95% CI 1.31-7.51), and also for DM and IGT (RR 1.78, 95% CI 1.14-2.76). Multiple logistic regression analysis also showed that the genotypes with the D allele were risk factors for DM and IGT even when adjusting for age, sex, hypertension and serum total cholesterol levels (odds ratio 1.49, 95% CI 1.01-2.21). The D allele of the ACE gene I/D polymorphism is a risk factor for DM.
Subclinical Cushing's syndrome (SCS) is being detected with increased frequency in patients with adrenal incidentaloma. In the current study, we evaluated the prevalence of SCS in 70 patients with adrenal incidentaloma and compared the main findings on them with other patients with nonfunctional adrenal incidentaloma (NFA). Overnight 3 mg dexamethasone (DXM) suppression test to exclude cortisol hypersecretion, and high dose DXM suppression test to find out patients with SCS, were applied to all subjects. Afterwards, biochemical and clinical findings of patients with SCS were compared with the other patients with NFA. Four of the 70 patients with adrenal incidentaloma were found to have SCS, with a prevalence of 5.7%. Basal ACTH and DHEA-S levels were significantly lower (p<0.05 and p<0.01, respectively), and midnight cortisol and 24-hour urinary free cortisol levels were significantly higher in patients with SCS (p<0.001 and p<0.05, respectively). Biochemical and metabolic bone parameters were similar in patients with SCS and in patients with NFA. Hypertension, diabetes mellitus, and obesity were more common in patients with SCS. One of the patients with SCS developed adrenocortical insufficiency following unilateral adrenalectomy which lasted for about 6 months. Suppressed ACTH and DHEA-S levels, and high midnight cortisol levels may be some clues for SCS in patients with adrenal incidentaloma. Since patients with SCS frequently have risk factors for atherosclerosis such as hypertension, diabetes, and obesity, and the surgical management of SCS with adrenalectomy may offer an advantage. Patients undergoing adrenalectomy should be followed for the development of adrenal insufficiency.
Thyroid hemiagenesis is a very rare abnormality, in which one thyroid lobe fails to develop. Most of the patients diagnosed have an associated thyroidal disease. The true prevalence of thyroid hemiagenesis is not known, but it is estimated to be 0.02% in normal children. We report a forty-five year-old female patient with a multinodular goiter in left lobe, associated with hemiagenesis of right lobe and isthmus.
Sheehan's syndrome is thought to be caused by pituitary necrosis associated with massive hemorrhage at delivery. We report here on a patient with Sheehan's syndrome, showing a rare type of panhypopituitarism suggesting dysfunction of both the hypothalamus and the pituitary. Although the basal level of plasma ACTH was normal, that of plasma cortisol was low. ACTH showed a delayed high response to CRH and a low response to insulin-induced hypoglycemia, while plasma cortisol showed a low response to CRH and no response to insulin-induced hypoglycemia. In the standard ACTH test, a normal rise of plasma cortisol was found. These results indicate that the primary site responsible for hypothalamic-pituitary-adrenocortical hypofunction may be the hypothalamus. In addition, the dysfunction of the pituitary itself is suggested by the hyposecretion of other pituitary hormones with impaired responses in their provocative tests and partially empty sella.
To clarify the mechanism of leptin resistance during pregnancy, we measured plasma leptin concentrations, free to total leptin ratio (percent free leptin) and soluble leptin receptor concentrations in pregnant women, and compared the results with those in non-pregnant women. We collected plasma samples from 23 non-pregnant and 31 pregnant women in the third trimester. Plasma samples from 5 pregnant women were collected longitudinally in each trimester. Plasma leptin concentrations in pregnant women in the second trimester (17.4 ± 3.2 ng/ml) were higher than those in the first trimester of pregnancy (11.0 ± 2.8 ng/ml, n = 5), as previously reported. However, percent free leptin did not change significantly throughout pregnancy. Percent free leptin correlated with total leptin concentrations (ng/ml) in non-pregnant women (r = 0.727, P<0.0001), but not in women in the third trimester of pregnancy (r = 0.006). Constant percent free leptin during pregnancy despite increased leptin concentrations indicates increased leptin binding capacity in pregnant women, that might partly contribute to the establishment of leptin resistance. On the other hand, soluble leptin receptor concentrations showed significant negative correlation with BMI and plasma leptin concentrations in pregnant women (r = −0.470, P<0.01 and r = −0.493, P<0.01, respectively) but not in non-pregnant women. These data suggest the possibility that soluble leptin receptor is a minor component of leptin binding capacity in the plasma of pregnant women.
A nationwide epidemiologic survey of familial Graves' disease (GD) was conducted in 2001. "Familial GD" was defined as a patient who had at least one Graves' patient within the proband's first-degree relatives. The primary survey was performed for estimating the prevalence of patients among a random selection of 2367 departments/hospitals of internal medicine, endocrinology, thyroidology and pediatrics. Of those receiving the primary questionnaire, 1361 (57.5%) responded, and 902 familial GD patients who visited them in 2000 were reported. The total number of patients was estimated to be 2850 (95% confidence intervals: 2100-3600). Based on the nationwide survey concerning the prevalence of hyperthyroidism in 1999, 2.1-3.1% of hyperthyroidism appeared to be familial GD and the relative risk of familial GD was roughly estimated to be 19-42. Subsequently, a second survey was carried out for obtaining the clinico-epidemiologic features of those patients. Of 902 patients, 487 (54%) were reported. No significant differences between familial and non-familial GD were found in age and sex distributions, clinical features or laboratory findings. Familial GD possessed the highest association with Hashimoto's thyroiditis, approximately 8% within the first-degree relatives, suggesting a shared genetic predisposition. These findings confirm the familial clustering of GD in the Japanese population, indicating the importance of environmental factors, genetic factors or both in the development of the disease.
We studied the efficacy and safety of oral 1-deamino-8-D-arginine-vasopressin (DDAVP) tablets in 9 patients, aged 17-36 years, with central diabetes insipidus (DI). The tablet contained 100 μg of desmopressin acetate. Maximum plasma concentration was obtained at 90 min after a single oral administration of 100 μg DDAVP with a mean plasma level of 14.7 ± 5.4 (range: 5.3-50.9) pg/ml. The onset of action was observed 2 h after oral administration, while the maximum effect was obtained at 4 h. Mean urine volume in patients decreased significantly from 402 ± 52 to 26 ± 3 ml/hr and urine osmolality increased from 91 ± 8 to 732 ± 21 mosm/kg at 4 h after the intake of oral DDAVP. Plasma osmolality level and serum sodium concentration remained unchanged throughout the study. Long-term treatment for 5 years with oral DDAVP resulted in control of diuresis in 8 of the 9 patients. The average oral DDAVP dose required to obtain this control was 19 ± 2 (range: 15-30) times more than that of prior intranasal treatment. No adverse effects were observed during this follow-up period. These results indicate that oral DDAVP is a safe therapeutic agent that may be a good alternative treatment of central DI, particularly in patients who have chronic rhinitis and visual disturbances.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) behaves predominantly as an oxoreductase converting the receptor-inactive glucocorticoids to their active forms in vivo, while the type 2 isoform (11β-HSD2) possesses only dehydrogenase activity and inactivates cortisol in human or corticosterone in rat. We determined enzyme activity of 11β-HSD in rat lungs from fetus to adult, and examined whether 11β-HSD1 exists in alveolar type II cells, the most important site for the synthesis of pulmonary surfactant in mature lungs, by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Enzyme activity of 11β-HSD1 and 2 in lung tissue homogenate were determined as NADP+- and NAD+-dependent conversion of corticosterone to 11-dehydrocorticosterone, respectively. We found that 11β-HSD1 activity was increased progressively from 21 days gestation to 7 weeks after birth. 11 β-HSD2 activity was significantly lower than that of 11β-HSD1 throughout gestation and after birth. Immunoreactivity for 11β-HSD1 was detected in the cytoplasm of the cells in the alveolar region of adult rats. Some of these expressing 11β-HSD1 were considered to be alveolar type II cells, because of their cuboid shape and localization at the corner of the alveoli. RT-PCR demonstrated 11 β-HSD1 mRNA in isolated alveolar type II cells. Our results suggest that alveolar type II cells enhance intracellular glucocorticoid availability via 11β-HSD1. 11β-HSD1 in alveolar type II cells is thought of as an autocrine amplifier of glucocorticoid action in the lung.
Total thyroidectomy was performed in 455 patients with differentiated thyroid carcinoma between 1978 and 1999. Serum calcitonin (CT) was determined preoperatively in all patients using polyclonal antibodies. Among the subjects, 25 patients showed elevated serum calcitonin levels preoperatively. Pathological diagnoses of 18 patients were confirmed as medullary thyroid carcinoma (MTC) postoperatively. Eight patients were diagnosed as papillary thyroid carcinoma (PTC) in the final pathological diagnosis without evidence of minimal foci of MTC or C cell hyperplasia, and they showed elevated CT levels preoperatively. Hypercalcitoninemia in 8 patients with PTC continued through out the 24 follow-up months with normal CEA levels. Extrathyroidal CT-producing diseases were all neglected, and precise pathological examination showed negative evidence of minute MTC or C cell hyperplasia in these 8 patients. Serum CT levels were simultaneously determined by a different CT assay kit using the same blood samples in 7 of 8 patients. Serum CT levels were all within normal values in another CT kit applying a different polyclonal antibody, although elevated CT values continued in the routine CT kit. The recognition of polymeric or fragmented CT by polyclonal antibody was thought to be the causative factor for the hypercalcitoninemia after total thyroidectomy in the patients with PTC. Knowledge of the false positive CT determination makes it important to employ different CT assay kits, especially the new generation of two-site immunoassays using two monoclonal antibodies against distinct epitopes of human CT, although the new generation kits are not clinically available in Japan.
Thyrotropin releasing hormone receptor 1 (TRHR1) and 2 (TRHR2) mRNAs were examined using reverse transcription polymerase chain reaction (RT-PCR). These data were then correlated with endocrinological and histological characteristics in 65 human pituitary adenomas including one non tumorous pituitary gland, to clarify the role of TRHR1 and 2 gene expression in human pituitary adenomas, especially as it relates to the paradoxical stimulatory effects of TRH found in pituitary adenomas. TRHR mRNA was not identified in four ACTH cell adenomas, whereas TRHR mRNA expression was found in 12/23 acromegaly specimens, 7/8 prolactinomas, 3/3 TSH cell adenomas, and 22/27 clinically nonfunctioning adenomas. Specimens obtained from patients expressing the TRHR gene were found to express TRHR1 and TRHR2 or TRHR1 alone, whereas no cases were identified in which TRHR2 alone was expressed. In examining the relationship between GH, PRL, TSH, or gonadotropin subunit response to TRH administration and TRHR gene expression, TRHR mRNA was found to be absent in 9 out of 10 GH cell adenomas without paradoxical GH response to TRH (non-responder), whereas TRHR genes were shown to be expressed in 10 out of 12 GH cell adenomas with paradoxical GH response to TRH (responders) (χ2 = 11.73, p = 0.0009). However, there was no significant correlation between TRHR gene expression and responsiveness to PRL or gonadotropins to TRH administration in PRL cell adenomas (χ2 = 0.16, p = 0.87) or gonadotroph cell adenomas (χ2 = 0.0006, p = 1), respectively. We concluded that the existence of the TRH receptor in adenoma cells plays an important role in the paradoxical GH response to TRH administration in GH cell adenomas. It should be noted that the PRL response to TRH in prolactinoma or an abnormal response of gonadotropin and/or its subunits to TRH in gonadotroph cell adenomas is considered to be due to a mechanism other than direct TRH action in adenoma cells. However, further studies are required to elucidate the role of TRHR2 in pituitary adenomas.
We report a 12-year-old girl with aplastic anemia accompanied by chromosome 8 trisomy during growth hormone (GH) therapy. When she was six years old she was diagnosed as idiopathic isolated GH deficiency, and GH therapy (0.175 mg/kg/week) was initiated. At the age 12, she began to exhibit petechiae in both lower limbs. Platelet count was 11,000/μL; serum hemoglobin level 11.8 gr/mL; white blood cell count 3,400/μL, with 37% neutrophils, 58% lymphocytes, 4% monocytes and 1% basophils. Bone marrow examination showed that total nucleated cell count and megakaryocyte were 17,000/μL and 0/μL, respectively, suggesting low formation. In addition, 13% of bone marrow cells contained the 3 signals of chromosome 8 marker (trisomy 8). She was diagnosed as aplastic anemia accompanied with chromosome 8 trisomy. GH therapy was stopped immediately, and simultaneous administration of methylprednisolone and anti-thymocyte globulin was initiated. Platelet count improved with treatment, and the 3-signal chromosome 8 abnormality disappeared from the bone marrow cells. The fact that a hematological adverse effect other than leukemia exists in conjunction with GH therapy warrants further investigation into possible hematological changes occurring during or after GH therapy.
We identified two novel mutations of the aquaporin-2 (AQP2) gene in a sporadic Japanese patient diagnosed with an autosomal recessive nephrogenic diabetes insipidus (NDI). The patient, a Japanese boy, was referred to our clinic at the age of 5 months because of unexplained recurrent fever. He was diagnosed with NDI by clinical, biochemical and endocrine findings. Molecular analysis demonstrated that he was a compound heterozygote for two mutations. One mutation consisted of a two base deletion in exon 1 (197, 198 delCA). This deletion caused a frameshift in the open reading frame, resulting in a premature stop codon 186 bases downstream in exon 1. The second mutation was a G to A transition of the terminal exon splice site (1502-1G→A). To date, several mutations in the AQP2 gene have been described, however no splicing mutation in the AQP2 gene has been identified. The deletion mutation described in this case study was inherited paternally and the splicing site mutation was inherited maternally, indicating an autosomal recessive inheritance. In the present case study, we identified two new mutations in the AQP-2 gene. Previous studies have shown that there is no hot spot for mutations in the AQP-2 gene, and thus genetic analysis for individual patients is helpful for genetic counseling and early diagnosis.
The incidence of parathyroid carcinoma is rare. We recently encountered a case of double carcinoma, located in the right and left upper parathyroid glands. A 67-year old man came to the Teikyo University Hospital because of his bilateral parathyroid masses with hypercalcemia and high parathyroid hormone (PTH). Preoperative diagnoses were parathyroid adenoma in the left lobe and papillary thyroid carcinoma or parathyroid carcinoma in the right lobe. First, the left tumor was removed; however, iPTH was still high. The right mass was then resected and iPTH fell to normal range. Histological examination revealed both tumors were parathyroid carcinoma. To the best of our knowledge, this is the first report of double parathyroid carcinoma confirmed histologically.