Primary aldosteronism and obstructive sleep apnea: A single-center cross-sectional study of the Japanese population.

ABSTRACT: A recent report demonstrated that the prevalence of obstructive sleep apnea (OSA) is 67.6% among Caucasian and Chinese patients with primary aldosteronism (PA). Moreover, the report showed a significant association between plasma aldosterone concentration (PAC) and the severity of OSA in Caucasian patients. However, no studies have examined the prevalence of OSA with PA or the association of its severity with PAC in the Japanese population. We retrospectively evaluated the prevalence and severity of OSA in 71 newly diagnosed Japanese patients with PA. Thirty-nine (55%) of the 71 patients were diagnosed with OSA, and 69% of PA patients with OSA reported snoring. No correlation was found between the respiratory event index (REI), snoring index, and PAC and plasma renin activity (PRA). In contrast, REI correlated significantly with body mass index (BMI), which was significantly correlated with PRA. In conclusion, although the severity of OSA did not correlate with PAC and PRA, there was a high prevalence of OSA among Japanese patients with PA. Moreover, the severity of OSA was strongly affected by BMI. Thus, the examination of OSA in patients with PA and the proper management of OSA might be important for the Japanese population.

Association between plasma aldosterone and markers of tubular and glomerular damage in primary aldosteronism.

OBJECTIVE: Although renal impairments are observed in patients with primary aldosteronism (PA), the association between plasma aldosterone concentration (PAC) and specific structural kidney damage remains unknown. Thus, we analysed the association between PAC, and markers of glomerular and tubular damage. DESIGN: This was a retrospective cross-sectional study of 96 PA patients, in which we analysed the association between PAC and markers of kidney damage, including urinary albumin-creatinine ratio (ACR) for glomerular damage, and urinary liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG) for tubular damage. In addition, we evaluated the association between PAC and N-terminal pro-brain natriuretic peptide (NT-proBNP) as a marker for body fluid volume. RESULTS: Urinary ACR, L-FABP, NAG, ß2-MG and NT-proBNP significantly correlated with PAC. PAC (<415 pmol/L, 415-550, 550-740, 740 <)-based quartile analysis revealed that both elevated markers of kidney damage and NT-proBNP could be observed in PA patients with a PAC over 550 pmol/L. Logistic regression analysis showed that PAC was significantly associated with a risk of both microalbuminuria and lowered eGFR (<60 mL/min/1.73 m2 ), with its optimal cut-offs for predicting each, 558 and 594 pmol/L, respectively. CONCLUSIONS: Increased PAC, especially over 550 pmol/L, is associated with excessive damage to the tubule and glomerulus.

Prevalence of Carnitine Deficiency and Decreased Carnitine Levels in Patients on Hemodialysis.

BACKGROUND: Patients on hemodialysis (HD) are known to be at risk of carnitine deficiency. The aims of this study were to investigate the prevalence of carnitine deficiency in patients on dialysis and to compare the likelihood of a reduction in the serum carnitine level on HD with that on hemodiafiltration (HDF). METHODS: The prevalence of carnitine deficiency, defined as a serum free carnitine level < 20 µmol/L, and that of carnitine insufficiency, defined as an acyl/free carnitine ratio > 0.4, was investigated in 150 patients on dialysis. The reduction rate of serum carnitine was then compared between HD and HDF. RESULTS: The prevalence of carnitine deficiency and that of carnitine insufficiency was 25.3 and 86.7%, respectively. Patients at high risk of carnitine deficiency accounted for 64.7%. Multivariate regression identified an association of duration of dialysis with the free serum carnitine level. The reduction rates of serum free carnitine in HD and HDF were 64 ± 4 and 75 ± 7%, respectively (p < 0.0001). CONCLUSION: The prevalence rates of carnitine deficiency and carnitine insufficiency were high in patients on dialysis. The serum carnitine reduction rate was greater with HDF than with HD.

Retention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy.

Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing's signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing's syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli.

Lipoprotein Lipase Deficiency Arising in Type V Dyslipidemia.

A 40-year-old Japanese man presented with child-onset hypertriglyceridemia recently complicated by diabetes mellitus. The patient's diabetes mellitus was maintained, but he had persistent insulin resistance. The patient also had persistent severe hypertriglyceridemia (1,224-4,104 mg/dL), despite the administration of bezafibrate and ezetimibe. Type V dyslipidemia was revealed by agarose gel electrophoresis and the refrigerator test, and a significantly reduced post-heparin lipoprotein lipase mass of 26 ng/mL was confirmed. Genetic testing confirmed two heterozygous LPL variants, p.Tyr88X and p.Gly215Glu in trans; thus, the patient was diagnosed with lipoprotein lipase deficiency. Lipoprotein lipase deficiency typically arises in type I dyslipidemia, but is latent in type V dyslipidemia.

Involvement of complement 3 in the salt-sensitive hypertension by activation of renal renin-angiotensin system in spontaneously hypertensive rats.

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.

Marked alteration of glycemic profile surrounding lanreotide administration in acromegaly: A case report.

Whether somatostatin analogs for acromegaly improve or worsen a patient's glycemic profile is controversial. A risk of hypoglycemia should be presumed, especially when patients receive insulin therapy, as the package inserts caution. However, a detailed clinical course of such a case has never been reported in research articles. An 80-year-old Japanese female diabetes patient treated with insulin therapy was diagnosed with acromegaly, and the somatostatin analog, lanreotide, was given. On day 4 of lanreotide treatment, repeated hypoglycemia as a result of exogenous insulin arose and the patient required inpatient care. After lanreotide treatment, the total daily insulin dose could be reduced, but her fasting C-peptide level decreased from 1.6 to 0.4 ng/mL, implying improved insulin resistance and impaired endogenous insulin secretion. In the present case, marked alteration surrounding lanreotide administration was observed; careful co-administration with insulin therapy is required, as the package insert cautions.

Plasma adrenocorticotropic hormone but not aldosterone is correlated with blood pressure in patients with aldosterone-producing adenomas.

Although plasma aldosterone concentration (PAC) varies depending on primary aldosteronism (PA) subtypes, patients with different subtypes may have similar blood pressure (BP). The authors hypothesized that hormones other than aldosterone might influence BP in PA patients. A total of 73 PA cases, including 30 cases of aldosterone-producing adenomas (APAs), 29 cases of bilateral hyperaldosteronism, and 24 control cases of essential hypertension were enrolled retrospectively. The authors examined the levels of aldosterone, cortisol, renin, and adrenocorticotropic hormone (ACTH) measured at 12 am, 6 am, 12 pm, and 6 pm and BP in the early morning (6 am to 7 am), late morning (9 am to 11 am), and early evening (5 pm to 7 pm). Results showed no statistically significant correlation between PAC and BP in the patients with PA; however, early and late morning systolic BP strongly correlated with ACTH at 6 am in patients with APA. These results suggest that hormones other than aldosterone, such as ACTH, may affect BP in patients with APA.

Scoring system for the diagnosis of bilateral primary aldosteronism in the outpatient setting before adrenal venous sampling.

OBJECTIVE: The only reliable method for subtyping primary aldosteronism (PA) is adrenal venous sampling (AVS), which is costly and time-consuming. Considering the limited availability of AVS, it would be helpful to obtain information on the diagnosis of bilateral hyperaldosteronism (BHA) from routine tests. We aimed to establish new, simple criteria for outpatients to diagnose BHA from PA before AVS. DESIGN: We retrospectively analysed 82 patients who were diagnosed with PA and underwent AVS. Thirty-seven patients were diagnosed with unilateral hyperaldosteronism (UHA), and 36 with BHA and nine were undetermined. Among the variables that were significantly different between UHA and BHA in the univariate analysis, we chose three variables to be included in multivariate logistic regression models and constructed a subtype prediction score. RESULTS: The subtype prediction score was calculated as follows: 3 points for no adrenal nodules on computed tomography imaging, 2 for serum potassium of ≥3·5 mmol/l and 2 for aldosterone-to-renin ratio of <490 after a captopril challenge test. Receiver operating characteristic curve analysis for the ability to discriminate BHA from UHA showed that a score of 7 points had 50% sensitivity and 100% specificity and a score of 5 points had 67% sensitivity and 94% specificity (area under the curve: 0·922; 95% CI: 0·863-0·980). CONCLUSIONS: Our new, simple criteria specifically distinguished BHA from UHA in the outpatient setting before AVS. Furthermore, not only endocrinologists but also general internists can use this convenient, safe scoring system.

Subtype prediction in primary aldosteronism: measurement of circadian variation of adrenocortical hormones and 24-h urinary aldosterone.

OBJECTIVE: Currently, adrenal venous sampling (AVS) is the only reliable method to distinguish unilateral from bilateral hyperaldosteronism in primary aldosteronism (PA). However, AVS is costly and time-consuming compared with simple blood tests. In this study, we conducted a retrospective study to determine whether circadian variation in plasma adrenocortical hormone levels (i.e. aldosterone, cortisol and ACTH) and a 24-h urinary aldosterone could contribute to the clinical differentiation between unilateral hyperaldosteronism (UHA) and bilateral hyperaldosteronism (BHA). DESIGN: In 64 patients who were diagnosed with PA and underwent AVS, 32 and 22 patients were diagnosed with UHA and BHA, respectively. Plasma adrenocortical hormone levels at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone under a condition of 6 g daily dietary sodium chloride intake were measured. RESULTS: Baseline plasma aldosterone concentration (PAC) and 24-h urinary aldosterone level in patients with UHA were significantly higher than in patients with BHA, particularly at 6:00. The area under the ROC curve for PAC at 0:00, 6:00, 12:00 and 18:00 and 24-h urinary aldosterone to discriminate UHA and BHA was 0·839 [95% confidence interval (CI); 0·73-0·95], 0·922 (95% CI; 0·85-1·00), 0·875 (95% CI; 0·78-0·97), 0·811 (95% CI; 0·69-0·93), 0·898 (95% CI; 0·81-0·99), respectively. CONCLUSIONS: PAC at different blood sampling times and 24-h urinary aldosterone level may be diagnostically helpful in discriminating between UHA and BHA. We believe that these tests could reduce the number of unnecessary AVS procedures.

Unusual Manifestation of Graves' Disease: Ventricular Fibrillation.

BACKGROUND: It is well known that thyrotoxicosis causes rhythm disorders including sinus tachycardia, atrial fibrillation, and atrial flutter. Atrial fibrillation is the most common arrhythmia in thyrotoxicosis, occurring in 5-15% of patients over 60 years of age, whereas ventricular arrhythmia is an unusual manifestation. CASE REPORT: An 18-year-old Japanese woman was admitted to our emergency department because of loss of consciousness caused by ventricular fibrillation. She had been diagnosed with Graves' disease only 5 days earlier and had no other past medical history. Blood examination showed no obvious abnormality except thyrotoxicosis, and coronary angiography revealed patent coronary arteries. She was diagnosed with thyroid storm due to Graves' disease and is currently healthy during outpatient follow-up. CONCLUSION: This case highlights that thyrotoxicosis can, albeit extremely rarely, cause ventricular fibrillation even in the absence of hypokalemia or underlying cardiovascular disease.

A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration.

UNLABELLED: Pyrrole-imidazole (PI) polyamides are nuclease-resistant novel compounds that inhibit transcription factors by binding to the minor groove of DNA. A PI polyamide that targets mouse ABCA1 and increases ABCA1 gene expression was designed and evaluated as an agent to increase plasma HDL concentration. A PI polyamide was designed to bind the activator protein-2 binding site of the mouse ABCA1 promoter. The effect of this PI polyamide on ABCA1 expression was evaluated by real-time RT-PCR and Western blotting using RAW264 cells. In vivo effects of this polyamide on ABCA1 gene expression and plasma HDL level were examined in C57B6 mice. One milligram per kilogram of body weight of PI polyamide was injected via the tail veins every 2 days for 1 week, and plasma lipid profiles were evaluated. PI polyamide showed a specific binding to the target DNA in gel mobility shift assay. Treatment of RAW264 cells with 1.0 µM PI polyamide significantly increased ABCA1 mRNA expression. PI polyamide also significantly increased apolipoprotein AI-mediated HDL biogenesis in RAW264 cells. Cellular cholesterol efflux mediated by apolipoprotein AI was significantly increased by the PI polyamide treatment. PI polyamide significantly increased expression of ABCA1 mRNA in the liver of C57B6 mice. Plasma HDL concentration was increased by PI polyamide administration. All of the HDL sub-fractions showed a tendency to increase after PI polyamide administration. The designed PI polyamide that targeted ABCA1 successfully increased ABCA1 expression and HDL biogenesis. This novel gene-regulating agent is promising as a useful compound to increase plasma HDL concentration. KEY MESSAGES: A novel pyrrole-imidazole (PI) polyamide binds to ABCA1. PI polyamide interfered with binding of AP-2ɑ protein to the ABCA1 gene promoter. PI polyamide inhibited the AP-2ɑ-mediated reduction of ABCA1 gene and protein expression. PI polyamide increased ABCA1 protein and apolipoprotein AI mediated HDL biogenesis. PI polyamide is a new gene regulator for the prevention of atherosclerotic diseases.