Case series: Primary aldosteronism diagnosed despite normal screening investigations: A report of three cases.

RATIONALE: Since the introduction of the aldosterone-to-renin ratio (ARR) as a screening tool for primary aldosteronism (PA), there has been a marked increase in the reported prevalence of this condition among hypertensive, even normotensive, subjects. PATIENT CONCERNS: But ARR as a spot blood draw for estimating a patient's aldosterone secretory status is influenced by many factors. DIAGNOSES: Here, we describe a series of patients with biochemically confirmed PA, whose diagnosis was delayed by the initial ARR assessment with non-suppressed renin. INTERVENTIONS: Patient 1 had a history of resistant hypertension for many years and had a negative initial screening for secondary hypertension (including ARR). At the reevaluation, ARR was close to cutoff still with normal renin after strict and extended drug washout, and the further workup for PA demonstrated a unilateral aldosterone producing adenoma that was surgically removed, with subsequent complete biochemical remission and partial clinical success. Patient 2 was diagnosed with idiopathic hyperaldosteronism combined with obstructive sleep apnea syndrome, which could increase renin resulting in a negative ARR, and finally got a better treatment effect with PA-specific spironolactone, as well as continuous positive airway pressure. Patient 3 with hypokalemia as the main presentation was finally diagnosed with PA after excluding other diseases, and proceeded to laparoscopic adrenalectomy and histologically confirmed an aldosterone producing adenoma. Postoperatively, patient 3 achieved complete biochemical success without any medicine. OUTCOMES: The clinical status of all three patients was effectively managed, resulting in either complete resolution or notable improvement of their respective conditions. LESSONS: After rigorous standardized diagnostic evaluation, there are still many reasons for ARR negative in PA, but they all basically occur in the background of normal or normal-high renin without suppression. A negative screening test result should be repeated and analyzed carefully if this is not consistent with the clinical picture. If, despite a repeatedly negative ARR, clinical suspicion remains high, we recommend consideration of further evaluation, including confirmatory tests and adrenal venous blood sampling (AVS) or even 68Ga-pentixafor PET/CT to better confirm the diagnosis and improve patient outcomes.

Reproducibility of ultrasound-guided attenuation parameter (UGAP) to the noninvasive evaluation of hepatic steatosis.

The aim of this study was to identify the applicability of an ultrasound-guided attenuation parameter (UGAP) for the noninvasive assessment of hepatic steatosis in clinical practice and to compare its correlation with B-mode ultrasound (US). From May to July 2021, 63 subjects with different body mass index (BMI) grades were included in the prospective study. All of them performed UGAP measurements, under different breathing manipulations, positions, diet statuses, and operators. After that, the UGAP values were compared with the visual grades of hepatic steatosis on B-mode US using a 4-point scale method. The intraclass correlation (ICC) of the UGAP values between the two radiologists was 0.862 (p < 0.001), and the ICCs of the UGAP values on the same day and different days by radiologist A were 0.899 (p < 0.001) and 0.910 (p < 0.001), respectively. There were no significant differences in UGAP values under different breathing manipulations (p > 0.05), positions (p > 0.05), or diet statuses (p = 0.300). The UGAP values in the fasting (supine position, segment V, 1) condition among the lean (BMI < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 28 kg/m2) and obese groups (BMI ≥ 28 kg/m2) were 0.60 ± 0.12, 0.66 ± 0.14, and 0.71 ± 0.11 dB/cm/MHz, respectively, with a significant difference (p = 0.006). The correlation coefficients (Rho) between the UGAP values and the visual grades of hepatic steatosis by the two reviewers were 0.845 (p < 0.001) and 0.850 (p < 0.001), corresponding to a strong relationship. Steatosis grades by reviewer 1 (p = 0.036) and reviewer 2 (p = 0.003) were significant factors determining the UGAP values according to the multivariate linear regression analysis. UGAP demonstrated excellent intraobserver and interobserver reproducibility in the assessment of hepatic steatosis. UGAP may be a promising tool in clinical practice to predict hepatic steatosis.

Successful treatment of dupilumab in Kimura disease independent of IgE: A case report with literature review.

Kimura disease (KD) is a rare and benign chronic inflammatory disease of unknown cause. It is characterized by subcutaneous granuloma of soft tissues in the head and neck region, increased eosinophil count, and elevated serum IgE. Currently, no definitive treatments are recommended. A 57-year-old Chinese man was diagnosed with KD after 7 years of slow subcutaneous masses growth. The patient underwent treatment of oral glucocorticoids for 1 year, but the masses recurred as the dosage was tapered down. Subsequent anti-IgE therapy of omalizumab administered subcutaneously at 450 mg/day at a 4-week interval did not show improvement. The size of masses and serum IgE and circulating eosinophils did not decrease significantly after 19 cycles of continuous treatment. Ultimately, switched strategy of dupilumab was applied at an initial dose of 600 mg, followed by 300 mg every 2 weeks for 4 months. This treatment demonstrated dramatical effects with reduced masses in each area and fast dropdown of eosinophil counts, while the high level of serum IgE remained without changes. Recently, different biologics including anti-IgE, anti-IL-5, and anti-IL-4/IL-13 have been applied to treat KD with satisfied results and help to explore the pathogenesis of this rare disease. To our knowledge, this is the first report that demonstrates the effects of two different biologics in the same patient and reveals the impressive clinical efficacy of dupilumab to treat KD independent of IgE. Therefore, further investigation of the underlying mechanism and the development of diagnosis and treatment of KD is valuable.

Normotensive presentation in primary aldosteronism: A report of two cases.

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC-1α/SIRT1 signaling pathway.

The objective of the research was to investigate the function of endothelial progenitor cells (EPCs) in the conditions of high glucose and lipids, which has been widely used to mimic the metabolic disorder that occurs in type 2 diabetic mellitus, and further to verify the role of PGC-1α and SIRT1, cellular energy metabolism regulators, in the process of senescence of EPCs with these combined stimuli. Circulating EPCs were incubated in absence or presence of high glucose (25 mM), FFA (200 µM) or both. EPCs senescence was assessed by ß-galactosidase staining, EPCs telomerase activity was measured by telomeric repeat ampli-fication protocol assay, in vitro angiogenesis assay and MTT assays were performed to assess angiogenesis and proliferation ability of EPCs. The results showed that combined stimuli inhibited EPCs reendothelialization ability in vitro, accelerated EPCs senescence and decreased the telomerase activity. Meanwhile, with combined stimuli, the expression of PGC-1α increased whereas SIRT1 expression decreased in EPCs accompanied by activation of P53/P21 signaling pathway. Conversely, transfection of EPCs with PGC-1α-siRNA rescued EPCs premature senescence and up-regulated SIRT1 and decreased P53/P21 expression, correlating closely with the down-regulation of PGC-1α itself. In addition, the combined stimuli induced up-regulation of PGC-1α expression was partly mediated by ROS and P38 signaling pathway. Overall, the data presented here identify PGC-1α as a potent negative regulator of EPCs' senescence under combined stimuli, which is partly mediated by SIRT1/P53/P21 signaling pathway.

[Progress on genetic basis of primary aldosteronism].

It has been proven that familial aldosteronism type I is related to 11-beta hydroxylase (CYP11B1)/aldosterone synthase (CYP11B2) chimeric genes. In recent years, accumulated evidences indicate that the genetic basis of primary aldosteronism may involve chromosome 7p22 candidate genes, polymorphisms of CYP11B1 and CYP11B2 genes, mutations of ion channel- related KCNJ5, ATP1A1, CACNA1D genes. The article reviews the progress on genetic basis of primary aldosteronism.

Computational analysis of functional single nucleotide polymorphisms associated with the CYP11B2 gene.

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans and play a major role in the genetics of human phenotype variation and the genetic basis of human complex diseases. Recently, there is considerable interest in understanding the possible role of the CYP11B2 gene with corticosterone methyl oxidase deficiency, primary aldosteronism, and cardio-cerebro-vascular diseases. Hence, the elucidation of the function and molecular dynamic behavior of CYP11B2 mutations is crucial in current genomics. In this study, we investigated the pathogenic effect of 51 nsSNPs and 26 UTR SNPs in the CYP11B2 gene through computational platforms. Using a combination of SIFT, PolyPhen, I-Mutant Suite, and ConSurf server, four nsSNPs (F487V, V129M, T498A, and V403E) were identified to potentially affect the structure, function, and activity of the CYP11B2 protein. Furthermore, molecular dynamics simulation and structure analyses also confirmed the impact of these nsSNPs on the stability and secondary properties of the CYP11B2 protein. Additionally, utilizing the UTRscan, MirSNP, PolymiRTS and miRNASNP, three SNPs in the 3'UTR region were predicted to exhibit a pattern change in the upstream open reading frames (uORF), and eight microRNA binding sites were found to be highly affected due to 3'UTR SNPs. This cataloguing of deleterious SNPs is essential for narrowing down the number of CYP11B2 mutations to be screened in genetic association studies and for a better understanding of the functional and structural aspects of the CYP11B2 protein.

Pseudohypoparathyroidism with Hashimoto's thyroiditis and Turner syndrome: a case report.

OBJECTIVE: To report the case of an individual with PHP, Turner syndrome and Hashimoto's thyroiditis. CASE: A 16-year-old girl was referred to our hospital with chief complaint of short stature. She presented with round chubby facies, short neck, obesity and short stature. Radiography indicated short metatarsals and metacarpals, which mainly affected the second, third and fourth digits. Biochemistry revealed hyperphosphatemia, increased serum concentrations of parathyroid hormone and thyroid stimulating hormone, elevated levels of follicular-stimulating hormone and prolactin, and increased thyroid peroxidase antibody and thyroglobulin antibody. Radiographic examination revealed delayed bone age and pelvic ultrasonography demonstrated an immature uterus. Karyotype analysis showed 46,X,i(Xq10), while molecular analysis revealed a same sense mutation in exon 5 of GNAS (ATC → ATT, Ile).The specific diagnosis was made of Turner syndrome in the presence of Hashimoto's thyroiditis and PHP. She was treated with calcium supplementation, calcitriol and thyroxine. CONCLUSIONS: This is the first case report to describe a combination of Turner syndrome with these other clinical entities, and their co-existence should be considered and further investigated.

Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis.

BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive. METHODOLOGY: Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value. PRINCIPAL FINDINGS: A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63-3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13-3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95-1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45-2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21-0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32-0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22-0.91, Z = 3.43, P = 0.001), respectively. CONCLUSIONS: This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.

ß-catenin overexpression in the nucleus predicts progress disease and unfavourable survival in colorectal cancer: a meta-analysis.

BACKGROUND: ß-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial. METHODOLOGY: Identical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between ß-catenin expression and clinicopathological features and prognosis was analyzed. PRINCIPAL FINDINGS: A total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that ß-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28-2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12-2.14; Z = 2.62; P = 0.009). However, there was no significant association between ß-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88-1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of ß-catenin in the nucleus indicated that ß-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53-0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25-0.96, Z = 2.06, P = 0.039). ß-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41-2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76-2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46-1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4-1.68, Z = 0.53, P = 0.594). CONCLUSIONS: This study showed that ß-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.

Association of CYP11B2 polymorphisms with susceptibility to primary aldosteronism: a meta-analysis.

The association of CYP11B2 gene polymorphisms with the risk of primary aldosteronism (PA) was controversial in previous studies. Here we selected two commonly studied CYP11B2 alleles: T-344C, A2718G to explore their associations with PA risk by meta-analyses of published case-control studies. Six electronic databases were searched for relevant studies up to November 2012. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random or fixed effects model. Seven studies (621 cases and 1027 controls) on T-344C polymorphism, three studies (327 cases and 336 controls) on A2718G polymorphism were finally included. Then significant association was observed between T-344C polymorphism and idiopathic hyperaldosteronism (IHA) under three genetic models (CC vs. TT, OR=0.544, 95% CI=0.324~0.914; CT vs. TT, OR=0.554, 95% CI=0.406~0.757; CC+CT vs. TT, OR=0.542, 95% CI=0.402~0.731). But patients with aldosterone-producing adenoma had no significant association with T-344C polymorphism under all genetic models except CT vs. TT model. Concerning A2718G polymorphism, a decreased PA risk was observed only under GG+GA vs AA model. But this association disappeared after removing the studies not in Hardy-Weinberg equilibrium. The evidence accumulated suggested that -344C allele may be associated with decreased risk of IHA and there was still no enough evidence to indicate the association of A2718G polymorphism with PA risk.