A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy.

Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient's symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis. LEARNING POINTS: HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.

Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion].

This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 µg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 µg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.

Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma.

UNLABELLED: Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 µg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended. LEARNING POINTS: There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases.Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear.When total thyroidectomy is performed in patients with RTH, a large amount of thyroxine is needed to maintain their thyroid function.There is no consensus regarding the management of thyroid carcinoma in patient with RTH, but effective treatments such as total thyroidectomy followed by RAI and TSH suppression therapy are recommended.

A case of cortisol producing adrenal adenoma associated with a latent aldosteronoma: usefulness of the ACTH loading test for the detection of covert aldosteronism in overt Cushing syndrome.

A 36-year-old woman with Cushing syndrome was evaluated for coexisting hyperaldosteronism, which was suggested by an abnormal response of the aldosterone-to-cortisol ratio in peripheral blood to the ACTH-administration despite a low basal aldosterone-to-renin ratio. Computed tomography revealed two independent tumors in the left adrenal gland, and adrenal venous sampling indicated hyperaldosteronism in addition to hypercortisolism in the same side. Postsurgical study including immunohistochemical analysis of steroidogenic enzymes suggested one adenoma to be cortisol-producing and the other, aldosterone-producing. The comorbidity of these different hormone-producing adenomas is not rare and careful pre-surgical evaluation is necessary to avoid post-surgical exacerbation of latent hyperaldosteronism.

An acylic polyisoprenoid derivative, geranylgeranylacetone protects against visceral adiposity and insulin resistance in high-fat-fed mice.

Induction of heat shock protein (HSP)72 improves insulin resistance and obesity in diabetic animal models. Geranylgeranylacetone (GGA), known as an antiulcer drug, induces HSP72 and protects organs against several cellular stresses. This study investigated whether GGA administration would induce HSP72 in liver and render physiological protection against high-fat feeding in mice. A single and 4-wk oral administration of 200 mg/kg GGA was performed in high-fat diet (HFD)-fed mice. Metabolic parameters, cytokines, and gene expressions related to insulin signaling were evaluated. A single administration of GGA induced HSP72 in liver of normal chow-fed and HFD-fed mice. Insulin resistance after HFD was slightly ameliorated. Four weeks of GGA administration also increased HSP72 in liver and significantly improved insulin resistance and glucose homeostasis upon glucose challenge. Activation of c-jun NH2-terminal kinase (JNK) was attenuated, and insulin signaling was improved in the liver of HFD mice. Visceral adiposity was decreased in GGA-treated mice, accompanied by reduced leptin and increased adiponectin levels. GGA can be a novel therapeutic approach to treat metabolic syndrome as well as type 2 diabetes by improving insulin signaling and reducing adiposity. These beneficial effects of GGA could be mediated through HSP72 induction and JNK inactivation in the liver.

Nifedipine induces peroxisome proliferator-activated receptor-gamma activation in macrophages and suppresses the progression of atherosclerosis in apolipoprotein E-deficient mice.

OBJECTIVE: Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice. METHODS AND RESULTS: In macrophages, nifedipine increased peroxisome proliferator-activated receptor-gamma (PPARgamma) activity without increasing PPARgamma-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPARgamma activity, suggesting that nifedipine does not activate PPARgamma via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPARgamma2-Ser112 phosphorylation and induced PPARgamma activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPARgamma2-Ser112 phosphorylation, and mutating PPARgamma2-Ser112 to Ala abrogated nifedipine-mediated PPARgamma activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPARgamma2-Ser112 phosphorylation, leading to PPARgamma activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPARgamma. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPARgamma2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta. CONCLUSIONS: Nifedipine unlike amlodipine inhibits PPARgamma-Ser phosphorylation and activates PPARgamma to suppress monocyte chemoattractant protein-1 expression and induce ATP-binding cassette transporter A1 expression in macrophages. These effects may induce antiatherogenic effects in hypertensive patients.

Plasma renin activity and aldosterone concentration are not altered by the novel calcium channel antagonist, azelnidipine, in hypertensive patients.

OBJECTIVE: In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC. METHODS: 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks. RESULTS: Azelnidipine treatment in drug-naïve (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values. CONCLUSION: These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

Heat shock treatment with mild electrical stimulation safely reduced inflammatory markers in healthy male subjects.

OBJECTIVE: Obesity induces chronic inflammation, which contributes to the development and progression of insulin resistance, diabetes and atherosclerosis. We have recently shown that induction of heat shock protein 72 by mild electric current and thermo (MET) treatment in mouse model of type 2 diabetes ameliorated glucose homeostasis and insulin resistance accompanied by reduced adiposity. For clinical application of MET, we confirmed its safety in healthy subjects. METHODS: MET was applied for 10 healthy Japanese male (12 V, 55 pulses/s, 30 min at 42 °C) twice a week for 8 weeks. Fat volume was measured by CT scan and several parameters were investigated. RESULTS: MET did not induce any adverse effects nor muscle contraction/pain. There were no significant alterations in glucose homeostasis or insulin resistance. Visceral and subcutaneous fat volume showed a trend of decrease without significant difference (-3.9% and -4.3%, respectively), which were restored 8 weeks after withdrawal of MET. Interestingly, serum tumor necrosis factor-α (TNF-α: 0.91 ± 0.05 pg/mL vs. 0.67 ± 0.06 pg/mL; p = 0.006) and high sensitivity C-reactive protein (hs-CRP: 521.9 ± 73.9 ng/mL vs. 270.8 ± 43.7 ng/mL; p = 0.023) levels, both of which are associated with chronic inflammation, were significantly decreased. CONCLUSION: MET may be beneficial for the reduction of an inflammatory response observed in diabetes and metabolic syndrome.

Predictors of coronary heart disease in Japanese patients with type 2 diabetes: Screening for coronary artery stenosis using multidetector computed tomography.

UNLABELLED: Aims/Introduction: Multidetector computed tomography (MDCT) coronary angiography has been applied as a tool for non-invasive evaluation of the coronary arteries. The purpose of the present study was to evaluate the effectiveness of MDCT in screening for coronary artery disease (CAD), and to identify the indications for screening in diabetes patients with CAD. MATERIALS AND METHODS: The study population consisted of 52 Japanese type 2 diabetes patients who underwent examination with a 64-slice MDCT scanner, electrocardiogram (ECG), echocardiography and ultrasonographic scanning of the carotid arteries. Regression analysis was carried out to assess the correlation between MDCT results and CAD risk factors. RESULTS: Stenosis of the coronary artery was detected in 19/52 patients. Of the 19 patients, 7 patients had no symptoms, including chest pain, and no ischemic changes in ECG. Significant differences between patients with stenosis and those without stenosis were detected by mean IMT (1.21 vs 0.95 mm), and duration of diabetes (20 vs 13 years). Two-tailed χ(2)-test showed that a duration of diabetes of more than 20 years (odds ratio 6.222) and more than 1.1 mm of mean-IMT (odds ratio 4.600) significantly correlated with the stenosis. CONCLUSIONS: It was shown that MDCT is useful in detecting coronary artery stenosis in diabetic patients without symptoms of CAD or ECG abnormality, and the predictors of CAD are mean IMT and duration of diabetes. It is recommended that patients with more than 1.1 mm mean IMT at the carotid artery and/or more than 20 years duration of diabetes should be screened for CAD by carrying out MDCT.

A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases.

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.

A case of primary thyroid squamous cell cancer: transformation from benign tumour associated with chronic thyroiditis?

Primary squamous cell cancer of the thyroid gland (SCT) is a rare malignant tumour and is associated with a high mortality. A female patient who suffered from primary SCT is described in this report. The cancer was identified with acute painful swelling of the thyroid gland, when the patient was under periodical observation for her chronic thyroiditis at our outpatient's clinic. In spite of the highly malignant potential of the cancer as indicated by histological examinations, including p53 and MIB-1 index analyses, the patient has been successfully treated so far with surgery and radiation therapy, surviving for more than 34 months with no sign of recurrence or metastasis. Early diagnosis and prompt treatment might have been essential for the successful management of this patient. Further observations and investigations are necessary to clarify the mechanisms of the long survival and to find a better treatment for the disease.

Possible relevance of alpha lipoic acid contained in a health supplement in a case of insulin autoimmune syndrome.

The insulin autoimmune syndrome is characterized as producing polyclonal or monoclonal anti-insulin autoantibodies in a patient with no previous history of exposure to exogenous insulin. The patient is 44-year-old Japanese woman and she had symptoms of hypoglycaemia without exposure to exogenous insulin. The patient was considered to have IAS because high titre of anti-insulin autoantibodies (96-98%: bound/total) were found in her serum. Her HLA DR beta1 DNA sequences analysis revealed that she has the DRB1(*)0406 and DRB1(*)0901. Our patient have been taken alpha lipoic acid (ALA) before onset. SH group compounds are known to play an important role in the pathogenesis of IAS, and ALA contains SH. From these data, we propose the possibility of the correlation between pathogenesis of IAS and ALA, and it will be important to pay attention for ALA as a cause of hypoglycemia in such cases.

A case of slowly progressive type 1 diabetes with unstable glycemic control caused by unusual insulin antibody and successfully treated with steroid therapy.

A 75-year-old man with type 1 diabetes and history of insulin therapy for previous 3 years using only human recombinant ones was suffering from unstable glycemic control. He had a high level of total insulin and a high titer of insulin antibodies (IA) (bound/total ratio: 89.8%). Low affinity constant (k(1): 0.0312 x 10(8) M(-1)) and high binding capacity (b(1): 51.8 x 10(-8) M) of IA in the patient detected by the Scatchard analysis were not compatible with those of IA associated with exogenous insulin injections in the diabetic patients, but compatible with those of the insulin autoantibodies found in patients with insulin autoimmune syndrome (IAS), although he had DRB1*0405, which may have protection against IAS development. The glucose infusion rate during hyperinsulinemic euglycemic clamp was 2.84 mg/kg/min, suggesting a high level of insulin resistance. Steroid pulse therapy (1000 mg for 3 days) aimed at reducing the possible effect of the IA on his insulin resistance and glycemic instability successfully decreased IA titer (from 89.8 to 58.3%), lowered its binding capacity (51.8-9.8 x 10(-8) M), increased glucose infusion rate (from 2.84 to 5.55 mg/kg/min) and improved glycemic control (HbA(1c): from 10.0 to 7.4%) with reduced blood glucose excursion. In conclusion, the alteration in insulin pharmacokinetics induced by IA seemed to be the cause of the brittle diabetes of the present case. Steroid treatment might be useful for the improvement of glycamic control in such patients with high IA levels and unstable blood glucose.

A case of hyperinsulinemia of undetermined origin, successfully treated with long-acting octreotide.

Major causes of fasting hypoglycemia in adults are insulinoma, factitious hypoglycemia and nesidioblastosis. The primary treatment for insulinoma is surgical removal of the tumor, but there are cases with hyperinsulinemia that cannot undergo surgery. Somatostatin analogue is one of the treatments used in such cases of insulinoma or persistent hyperinsulinemic hypoglycemia. We report here a patient who had undetermined hyperinsulinemia and was successfully treated with a long-acting somatostatin analogue, which had recently become available. The patient, a 72-year-old female, who had previously been diagnosed as insulinoma and undergone partial pancreatectomy, was admitted complaining of the recurrence of hypoglycemic attacks after an interval of ten years. On admission, hypoglycemia (42 mg/dl), hyperinsulinemia (IRI: 79.3 microU/m) and low HbA1c (3.6%) were present. In 75 g-OGTT at 30 min after load, IRI reached 6623 microU/ml, while plasma glucose level was 88 mg/dl. The anti-insulin antibody was not present. Since attempts at tumor localization by imaging techniques failed and the patient refused further examinations or surgical treatment, we recommended her to take a medication with a somatostatin analogue. Insulin suppression test using 50 microg of octreotide improved plasma glucose and IRI levels, suggesting the usefulness of the treatment, and a monthly administration of 20 mg of long-acting octreotide has successfully controlled her symptoms of hypoglycemia for 10 months. Our case demonstrated the utility of the long-acting somatostatin analogue for long-term treatment of undetermined hyperinsulinemia. A preliminary loading test using short-acting octreotide may be useful to determine appropriate medication, especially in cases who cannot receive surgical treatment.

[Clinical courses of two male siblings on hemodialysis for Fabry disease ].

Fabry disease is an X-linked recessive disease resulting from a deficiency of the lysosomal hydrolase alpha-galactosidase A. In male patients with the classic hemizygous form, acroparesthesias, hypohidrosis, corneal opacities, and dysfunction of the heart, brain, and kidney are observed. Recently, it was reported that 0.5-1.2% of male chronic hemodialysis (HD) patients were diagnosed as having Fabry disease based on the measurement of alpha-galactosidase A activity. Fabry disease is thought to be an important cause of end-stage renal disease. There are a few reports of patients with Fabry disease on long-term HD. Here we report two male siblings with classical type Fabry disease on HD. They had acroparesthesias, and hypohidrosis. Their mother had severe heart failure due to a heterozygous form of Fabry disease. Case 1 is a 44-year-old male. He had mid-cerebral apoplexy at 30 years of age. He started maintenance HD in 2000. Remarkable left ventricular hypertophy and conduction disorders of the heart were found. In 2004, he collapsed and ventricular-tachycardia and severe hypoxic brain damage were found. Now his consciousness level has been in the range of 100 to 300 on the Japan Coma Scale. Case 2 is a 40-year-old male. He started maintenance HD in 1993. Malnutrition due to chronic diarrhea and severe ischemic change in the brain were found. In 1998, he had severe joint pain of shoulders and fingers with ectopic calcifications detected by X ray. The ectopic calcifications were extended to the whole body. In 2004, his dementia by ischemic change in the brain has rapidly progressed. In conclusion, cardiovascular complications, cerebrovascular manifestations, painful ectopic carcifications, and chronic diarrheas in our patients were considered to be specific symptoms of Fabry disease. Young HD patients with these symptoms will need to be examined for Fabry disease.

AICAR, an activator of AMP-activated protein kinase, down-regulates the insulin receptor expression in HepG2 cells.

The liver is one of the major target organs of insulin in which the expression of insulin receptor is abundant. We analyzed the effect of AICAR, an AMPK activator, on the expression of insulin receptor in a human hepatoma cell line, HepG2 cells. AICAR treatment for 48 h significantly decreased the expression of the insulin receptor protein in a dose-dependent manner, however, this same effect of AICAR was not observed in either 3T3-L1 adipocytes or CHO cells. The expression of insulin receptor mRNA also decreased after AICAR treatment. In addition, the transcriptional activity of the insulin receptor gene promoter investigated with a luciferase assay was down-regulated by AICAR treatment. Dipyridamole, an adenosine transporter inhibitor, and 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, blocked the effect of AICAR on the down-regulation of the insulin receptor protein, mRNA, and promoter activity. Our findings suggest, for the first time, that AMPK activation could reduce the expression of insulin receptor, at least in part, by a down-regulation of the transcriptional level, and this effect may be liver specific.

Preclinical Cushing's syndrome resulting from black adrenal adenoma. A case report.

A 59-year-old Japanese woman, admitted for the treatment of diabetes mellitus and hypertension, was incidentally discovered to have a solid mass of 1.4 cm in diameter by CT scan with the attenuation value of 38 Hounsfield units, relatively higher for ordinary adrenal adenomas. Magnetic resonance imaging revealed no reduction of signal intensity on opposite-phase image on T1-weighted sequence. Adrenal scintigraphy imaging with 131I-adosterol did not show any uptake of the isotope in the area corresponding to both adrenals. Although she had no characteristic feature of overt Cushing's syndrome, her serum cortisol level was not suppressed after an overnight dexamethasone administration. She was diagnosed as having preclinical Cushing's syndrome. Left adrenalectomy was performed, revealing the well-circumscribed black tumor, mainly consisted of compact cell, in which cytoplasm was filled with numerous granules pigmented with dark to golden brown colors on hematoxylin-eosin staining. These findings suggested that her incidentaloma was a black adrenal adenoma. Production of steroid hormones was confirmed by immunohistochemical analysis of steroidogenic enzymes and by measurement of the tissue contents of hormones, whose levels were comparable with those in adenomas of overt Cushing's syndrome. This is the first case report of preclinical Cushing's syndrome resulting from black adrenal adenoma.

A case of ACTH-independent macronodular adrenal hyperplasia: simultaneous expression of several aberrant hormone receptors in the adrenal gland.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing's syndrome. Recently, aberrant expression of adrenal receptors for various hormones and/or cytokines has been identified in several cases with AIMAH, which may act as a pathogenetic factor for the disorder. We report here an AIMAH patient with a Rathke's cleft cyst. Endocrinological examinations revealed that the pituitary cyst had no hormonal secretion. Administrations of either AVP or isoproterenol provoked cortisol production in the patient, whereas DDAVP, mosapride or endogenous LH induced by GnRH did not. Reverse transcriptional-PCR analysis of total RNA obtained from the patient's adrenal tissue revealed the expression of mRNA of receptors for V1a, V1b, V2, and LH/hCG. Three of these receptors except for V1a receptor were not expressed in normal adrenal tissue. Hyperosmolar saline infusion promoted the patient's cortisol secretion through the increase in endogenous AVP (peak plasma AVP level reached 90.4 pg/ml during the test). These results suggest that endogenous AVP and catecholamines are involved in the pathophysiology of the patient. Further study will be necessary to clarify the molecular mechanisms that regulate tissue-specific expression of these receptors and their role in the overgrowth of adrenal in AIMAH.

Evaluation of urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in type 2 diabetes.

OBJECTIVE: To evaluate urinary 8-hydroxydeoxyguanosine (8-OHdG) as a marker for the progression of diabetic macroangiopathic complications. RESEARCH DESIGN AND METHODS: The content of urinary 8-OHdG, common carotid intima-media thickness (IMT), the coronary heart disease (CHD) risk score, the severity of diabetic retinopathy, and urinary albumin excretion were examined in 96 patients with type 2 diabetes, including 32 patients who had been nominated for the Kumamoto Study [Shichiri M, et al. Diabetes Care 23 (Suppl 2):B21-B29, 2000]. In addition, the patients from the Kumamoto Study were further evaluated regarding the effect of intensive insulin therapy on urinary 8-OHdG excretion. RESULTS: The urinary 8-OHdG:creatinine ratio (U8-OHdG) was 2.5-fold higher in patients with increased HbA(1c) than in those with normal HbA(1c) (P < 0.05). In addition, U8-OHdG was 2.3-fold higher in patients with increased IMT (P < 0.005). A similar result was observed between U8-OHdG and CHD risk score (P < 0.01). U8-OHdG was significantly higher in patients with simple retinopathy (P < 0.05) and those with advanced retinopathy (P < 0.01) than in patients without retinopathy. Similarly, U8-OHdG was significantly higher in patients with albuminuria (P < 0.01). Furthermore, in the Kumamoto Study, U8-OHdG was significantly lower in the multiple insulin injection therapy group compared with the conventional insulin injection therapy group (P < 0.01). CONCLUSIONS: Hyperglycemia independently increases 8-OHdG in patients with type 2 diabetes. 8-OHdG is a useful biomarker of not only microvascular but also macrovascular complications in patients with type 2 diabetes.

Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta-subunit for ClC-Ka and ClC-Kb chloride channels, barttin.

Bartter syndrome comprises several related renal tubular disorders including classic Bartter, infantile Bartter (IBS), and Gitelman syndrome. A new distinct group in Bartter syndrome accompanied by sensorineural deafness (BSND) has been identified among the IBS patients. Recently a gene encoding an essential beta-subunit for ClC chloride channels, named barttin, with several mutations of the gene as the cause of BSND, has been described. We have observed a male who had not been diagnosed as Bartter syndrome until 28 yr because of a mild clinical manifestation. The patient was affected with congenital deafness, which urged us to analyze his gene for barttin, and a mutation G47R, which was previously reported, has been identified. However, the clinical feature in the patient lacking the characteristic symptoms of IBS such as polyhydramnios, premature labor, or severe salt loss in neonatal period contrasts with that of the typical BSND patients described so far in the literature. This might be due to a less severe loss of function of barttin induced by G47R mutation, compared with others, and our observation seems to suggest a possibility of the prevalence of mild form BSND with various levels of barttin dysfunction among patients with congenital deafness of unknown origin.