Adult-onset reversible idiopathic hypogonadotropic hypogonadism in male adult carrying a WDR11 missense mutation.

Idiopathic hypogonadotropic hypogonadism (IHH) occurs mostly in childhood or adolescence and very rarely in adulthood. It is characterised by delayed onset of secondary sexual characteristics. Many genetic abnormalities have been reported in congenital IHH cases, but rarely in adult-onset IHH cases. IHH requires lifelong hormone replacement therapy; however, a few reports suggest the reversibility of this condition.In this case, after having his first child, a man in his 20s was diagnosed with gynecomastia followed by IHH. He improved with gonadotropin-releasing hormone replacement therapy and had two more children. The treatment was discontinued after 4 years, but the improvement was sustained. He had a heterozygous missense variant in WDR11 (c.2390G>A; p.Arg797His), which may play a role in adult-onset IHH reversal. Accumulation of such cases can contribute to our understanding of the pathogenesis and genetic component of IHH.

Association of Papillary Thyroid Carcinoma with Primary Aldosteronism.

Objective The association of primary aldosteronism (PA) with thyroid disease has already been suggested. The aim of this study was to examine the presence of PA in patients with papillary thyroid carcinoma (PC) and to characterize such PC patients with PA. Methods We examined the presence of PA in 81 consecutive patients with PC, whose random sitting blood pressure (BP) was ≥140/90 mmHg in the office (n= 68), who had an incidental adrenal tumor or adrenal enlargement (n=9), or who showed hypokalemia (n=4). Thirty-one of these 81 patients had been treated with anti-hypertensive drugs. The plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were first measured before operation in 16 patients and after operation in 65 patients. PA was diagnosed according to the guidelines of the Japan Endocrine Society. Results Forty patients with PC with a random PAC/PRA ratio of over 200 were subjected to a further study (12 of these patients had been treated with anti-hypertensive drugs). Ultimately, 15 patients with PC were diagnosed with PA. Adrenal venous sampling was done in 9 out of 15 patients with PC associated with PA. No patients were diagnosed as having unilateral lesions. Among the 15 patients, white-coat hypertension was observed in 5 patients, and normotension was observed in 1 patient. Conclusion These findings suggest that the prevalence of PA may be high among patients with PC. An active examination is needed to detect PA, as its signs and symptoms may be mild in patients with PC associated with hypertension.

Acidosis-Induced Hypochloremic Alkalosis in Diabetic Ketoacidosis Confirmed by The Modified Base Excess Method.

CONTEXT AND OBJECTIVE: Diabetic ketoacidosis (DKA) is associated with a metabolic alkalosis, which is thought to be due to vomiting. However, alkalosis can occur in DKA without vomiting. We retrospectively reviewed the acid-base disturbances in DKA admissions without vomiting. PARTICIPANTS AND METHODS: We included admissions of the patients with blood glucose and beta-hydroxybutyrate (ßOHB) levels > 250 mg/dL and > 1.0 mmol/L, respectively. Admissions without vomiting were classified into a group with a ßOHB > 3.0 mmol/L (DKA group) and a group with ßOHB of 1.0-3.0 mmol/L (pre-DKA group). The acid-base status was analyzed by the modified base excess (BE) method. BE effects were calculated by changes in sodium (BE free water, [BEFW]), and chloride (BECl). Positive and negative values for each parameter suggested alkalosis and acidosis, respectively. RESULTS: Forty-five included admissions were divided into DKA (n = 34) and pre-DKA (n =11) groups. Sodium-corrected chloride level and the chloride/sodium ratio were significantly lower in the DKA group than in the pre-DKA group. In both groups, BEFW values were modestly negative. The mean BECl values were positive in both groups, but significantly higher in the DKA group. The alkalinizing effects by hypochloremia diminished the base deficit in the DKA group by approximately 25%. The BECl value significantly correlated with serum total ketone levels (r = 0.66; P < .0001). CONCLUSION: The modified BE method successfully proved the presence of hypochloremic alkalosis in DKA without vomiting. This suggests the direct participation of serum ketoacids in the pathogenesis of hypochloremic alkalosis.

Serum albumin-adjusted glycated albumin is a better predictor of mortality in diabetic patients with end-stage renal disease on hemodialysis.

AIMS: Glycated albumin (GA) is a marker for monitoring glycemic control in diabetic patients with end-stage renal disease (ESRD). We evaluated whether serum albumin-adjusted GA (adjusted GA) could predict mortality in diabetic patients with ESRD on hemodialysis. METHODS: Seventy-eight patients with type 2 diabetes treated with regular hemodialysis were enrolled and followed up for 5-years. The adjusted GA was calculated from the regression formula and mean GA. The cut-off values for GA and adjusted GA that predicted mortality risk were determined using receiver operating characteristic curve analysis. RESULTS: During the follow-up period (median: 36months), 15 patients died. In the Kaplan-Meier analysis, there were no significant differences in the 5-year cumulative survival rate (58.3% [GA ≥19.8%] vs. 88.6% [GA <19.8%], P=0.075). Conversely, this rate was significantly higher in patients with adjusted GA <21.2% than adjusted GA ≥21.2% (86.4 vs. 49.5%, P=0.0068). After adjustment for other confounders, adjusted GA ≥21.2% was an independent predictor for mortality (hazard ratio 3.76, 95% confidence interval 1.12-17.44, P=0.031), but GA ≥19.8% was not (hazard ratio 2.63, 95% confidence interval 0.65-17.69, P=0.19). CONCLUSIONS: Adjusted GA is a better predictor of mortality than GA in diabetic patients with ESRD on hemodialysis.

Successful Treatment with Cyclosporin A in Tocilizumab-resistant TAFRO Syndrome.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is a unique clinicopathologic variant of multicentric Castleman's disease that has recently been identified in Japan. Previous reports have shown that affected patients typically respond to immunosuppressive therapy, such as prednisolone and tocilizumab. However, the optimal treatment for refractory TAFRO syndrome, which can be fatal, remains unclear. We herein report a case of tocilizumab-resistant TAFRO syndrome successfully treated with cyclosporin A, indicating that cyclosporine A may be an alternative therapy for refractory TAFRO syndrome.

Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes.

Type 2 11ß-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids. We investigated the association of HSD11B2 variant with glucose homeostasis. Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2. Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4 degree of freedom) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction. In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-ß. Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion.

Giant cell phlebitis: a potentially lethal clinical entity.

An 83-year-old woman presented to us with a 4-week history of general malaise, subjective fever and lower abdominal pain. Despite the intravenous infusion of antibiotics, her blood results and physical condition worsened, resulting in her sudden death. Autopsy study revealed that the medium-sized veins of the mesentery were infiltrated by eosinophil granulocytes, lymphocytes, macrophages and multinucleated giant cells; however, the arteries were not involved. Microscopically, venous giant cell infiltration was observed in the gastrointestinal tract, bladder, retroperitoneal tissues and myocardium. The final diagnosis was giant cell phlebitis, a rare disease of unknown aetiology. This case demonstrates for the first time that giant cell phlebitis involving extra-abdominal organs, including hearts, can cause serious morbidity.

Hyperglycemic chorea-ballism or acute exacerbation of Huntington's chorea? Huntington's disease unmasked by diabetic ketoacidosis in type 1 diabetes mellitus.

CONTENT: Hyperglycemic chorea-ballism is predominantly observed in older type 2 diabetic patients, and it is rare in type 1 diabetes and diabetic ketoacidosis (DKA). Huntington's disease (HD) is one of several genetic syndromes associated with diabetes, although the reported prevalence of the association varies. There are few opportunities for most physicians to diagnose early-stage HD. OBJECTIVE: We describe bilateral hyperglycemic chorea-ballism in a 40-yr-old female type 1 diabetes patient with DKA and HD. SETTING: The study was conducted in a tertiary care referral hospital. RESULTS: On admission, the patient exhibited severe involuntary movement of bilateral extremities with DKA, and hyperglycemic chorea-ballism was diagnosed. She recovered from chorea-ballism with admission of fluids and insulin, but mild choreatic movement persisted in the upper extremities. Brain magnetic resonance imaging and DNA analysis revealed HD. Although it has been considered that depletion of striatal γ-aminobutyric acid (GABA) content is rare in DKA, it is largely decreased in HD. Therefore, it is probable that hyperglycemic chorea-ballism or exacerbation of Huntington's chorea resulted from transient depletion of GABA. CONCLUSION: The present case provides important insights on the role of GABA in hyperglycemic chorea-ballism and on the clinical issues associated with HD diagnosis.

Muscle hematoma: a critically important complication of alcoholic liver cirrhosis.

An iliopsoas hematoma can occur either spontaneously or secondary to trauma or bleeding tendency due to hemophilia and anticoagulant therapy. Although liver cirrhosis is commonly associated with coagulopathy, iliopsoas hematoma is very rare. We herein, present a case of bilateral iliopsoas hematoma in a patient with alcoholic cirrhosis, and review the literature on muscle hematoma associated with cirrhosis. A 56-year-old man with alcoholic cirrhosis was admitted in a state of shock with anemia. The cause of anemia could not be detected, and the patient was treated conservatively. The site of bleeding was not detected with either gastroduodenal endoscopy or upper abdominal computed tomography, the latter of which did not include the iliopsoas muscle. He died on the 10th day of admission and bilateral iliopsoas hematomas were found on autopsy. An iron stain was positive in the iliopsoas muscle. Eight cases of muscle hematoma associated with cirrhosis, including the present case, were found in a review of the literature. Four of these cases involved the rectus abdominis muscle, 3 involved the iliopsoas muscle and 1 involved combined muscles. Alcoholic cirrhosis accounted for 75% of the cases. One case (12.5%) was associated with virus-related cirrhosis, and another with combined virus- and alcohol-related cirrhosis. The mortality rate was 75% despite early diagnosis and low risk scores for cirrhosis. Muscle hematoma in patients with cirrhosis is closely related to alcoholism, and the mortality rate of the condition is extremely high. In conclusion, muscle hematoma should be recognized as an important complication of cirrhosis.

Longitudinal study of patients with idiopathic isolated TSH deficiency: possible progression of pituitary dysfunction in lymphocytic adenohypophysitis.

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.

Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas.

CONTEXT: CYP11B2, the gene encoding aldosterone synthase, has several frequent polymorphisms. In particular, the Lys173Arg (K173R) polymorphism is in complete genetic linkage disequilibrium with the -344T/C polymorphism in the promoter of CYP11B2 that involves a binding site for the steroidogenic factor-1 transcription factor. These polymorphisms have been associated with cardiovascular parameters, including hypertension, but not directly with gene expression. OBJECTIVE: The objective of this study was to correlate CYP11B2 genotype with gene expression in adrenal tissue. DESIGN: We measured mRNA levels of CYP11B2 [presented as a ratio against glyceraldehyde-3-phosphate dehydrogenase (B2/G)] and CYP11B1 in relation to the K173R polymorphism. SUBJECTS: We studied 28 subjects with aldosterone-producing adenomas (APA) and 18 subjects with normal adrenals. MAIN OUTCOME MEASURE: The main outcome measure was CYP11B2 expression levels. RESULTS: Preoperative treatment with spironolactone or beta-blocker in five APA patients was associated with higher B2/G. The B2/G and B2/B1 ratios were much higher even in the remaining 23 APA patients than in subjects with normal adrenals. The B2/G and B2/B1 ratios in normal adrenals and APA were higher in the KK genotype than in the RR genotype. In patients with APA, urinary aldosterone excretion was higher in those with the KK genotype than in those with the KR genotype. Measurement of cDNA band intensities from normal and APA samples of the KR genotype revealed that the R173 allele was transcribed at levels 46.6 +/- 12.2% (mean +/- sd; n = 7) and 49.1 +/- 20.8% (n = 6), respectively, those of the K173 allele. CONCLUSIONS: A CYP11B2 haplotype including -344T and K173 is associated with higher gene expression than the -344C/R173 haplotype, supporting reported associations of -344T with higher aldosterone production and blood pressure.

Circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 are associated with early carotid atherosclerosis.

OBJECTIVE: Growth hormone (GH)-insulin-like growth factor (IGF)-1 axis regulates growth and survival of vascular cells and cardiomyocytes. The role of GH-IGF-1 axis in cardiovascular disease is controversial. METHODS AND RESULTS: We assessed the association of circulating levels of IGF-1 and IGF binding protein-3 (IGFBP-3) with early carotid atherosclerosis and atherosclerotic risk factors in 330 Japanese men (age 51.6+/-8.6 years, range 29 to 77, body mass index [BMI] 23.6+/-2.9 kg/m2). Intima-media thickness (IMT) of the common carotid artery was measured by ultrasound. Abdominal visceral adipose and subcutaneous adipose tissue area by computer-assisted tomographic scan were determined. Correlation coefficients were calculated by partial correlation analysis. BMI and plasma insulin showed positive associations with circulating IGF-1 and IGFBP-3. Subcutaneous adipose tissue was correlated with IGF-1. High-density lipoprotein cholesterol was inversely associated with IGF-1. Blood pressure, total cholesterol, triglyceride, and visceral adipose tissue were positively associated with IGFBP-3. IGF-1 and IGFBP-3 were associated with carotid IMT independent of age, BMI, blood pressure, and insulin. Insulin was associated with carotid IMT in univariate analysis. However, it was not correlated with carotid IMT in the multivariate analyses which included IGF-1 or IGFBP-3 as a covariate. CONCLUSIONS: Increased circulating IGF-1 and IGFBP-3 may be stimulators of atherosclerosis.

Hypopituitarism and diabetes insipidus with localized hypertrophic pachymeningitis (Tolosa-Hunt syndrome) associated with Hashimoto thyroiditis.

We report a 69-year-old woman with intracranial pachymeningitis showing hypopituitarism, diabetes insipidus, and Tolosa-Hunt syndrome associated with Hashimoto thyroiditis confirmed by autopsy. A large tumorous lesion of the hypothalamo-pituitary gland was revealed on magnetic resonance imaging, after the patient complained of gait and visual field disturbance. These symptoms subsided after thyroid hormone supplementation. Hypopituitarism and diabetes insipidus were diagnosed after cessation of the treatment by the patient herself. Multiple cranial nerve palsies and orbito-frontalgia appeared. Methylprednisolone pulse therapy improved the symptoms, but they recurred when the dose of glucocorticoid was decreased. The patient died of brain thrombosis. Autopsy revealed typical findings of Hashimoto thyroiditis and intracranial pachymeningitis involving the cranial base and pituitary gland. The high titer of rheumatoid factor and Hashimoto thyroiditis in this patient suggest an immunological role in the pathogenesis of pachymeningitis.