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Objective Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. Design In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. Results We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. Conclusions Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin-angiotensin-aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin-angiotensin-aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04-0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05-60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11-7.27], p 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42-10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86-5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57-6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin-angiotensin-aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.

Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping. Peripheral neuropathy in particular is often misdiagnosed or underdiagnosed because of a lack of awareness amongst both patients and physicians. Furthermore, crude screening tools, such as the 10‐g monofilament, only detect advanced neuropathy and a normal test will lead to false reassurance of those with small fiber mediated painful neuropathy. The underestimation of peripheral neuropathy is highly prevalent in the South‐East Asia region due to a lack of consensus guidance on routine screening and diagnostic pathways. Although neuropathy as a result of diabetes is the most common cause in the region, other causes due to infections (human immunodeficiency virus, hepatitis B or C virus), chronic inflammatory demyelinating polyneuropathy, drug‐induced neuropathy (cancer chemotherapy, antiretrovirals and antituberculous drugs) and vitamin deficiencies (vitamin B1, B6, B12, D) should be actively excluded., Diabetic neuropathy has a major impact on morbidity and mortality. However, the diagnosis and management of diabetic neuropathy is South‐East Asia is limited. Clear guidance is required to diagnose and manage patients with diabetic and other neuropathies.

Introduction Aldosterone regulates sodium homeostasis thereby affecting blood volume and blood pressure. Physiologically, aldosterone is synthesized in the zona glomerulosa (ZG) by aldosterone synthase (CYP11B2) when there is a lack of salt. However, in the adult human adrenal ZG is sparse and confined to discrete islets (1). We hypothesize that the high salt in modern diets change ZG cell function from synthesis to apoptosis/migration mode when aldosterone is not required. This hypothesis is based on: [i] CYP11B2−/− mice, where ZG cells migrate and apoptose (2); [ii] the disappearance from most of human ZG of CYP11B2, which became apparent with selective antisera (3); [iii] apoptosis in monkeys following aldosterone synthase inhibition (4). Herein we aim to test our hypothesis by silencing CYP11B2 in human adrenal cells. Methods The HAC15, a subclone of the H295R human adrenocortical cancer cell line, was transfected with scrambled siRNA (siScrambled) or siRNA targeting CYP11B2 (siCYP11B2) using the Neon™ Transfection System (Thermofisher Scientific, USA). An apoptosis assay 48-h post-transfection was performed using the Pacific Blue™ Annexin V/SYTOX™ AADvanced™ apoptosis kit on the BD FACSVerseTM system (BD Biosciences, USA). The supernatants and cells were harvested for aldosterone and cortisol, and RNA isolation. Experiments were repeated 3 times independently in triplicates. RNA-Sequencing (RNAseq) of siCYP11B2 and siScrambled was performed on a representative sample from each independent experiment (BGI Genomics, China). Results Transfected HAC15 cells with siCYP11B2 showed reduction of aldosterone production by 69.8% (p=0.001) and suppression of CYP11B2 mRNA by 8 folds (p=0.001) compared to control, with no significant change on cortisol production and CYP11B1 mRNA expression. This confirmed that the silencing was specific to CYP11B2 despite the gene being highly homologous to CYP11B1. In all 3 independent experiments, 3 genes were significantly downregulated; CYP11B2, HNRNPA1, and UHMK1 expression in siCYP11B2 cells were 32%, 65% and 67% of matched control siScramble cells. Result of KEGG pathway from each independent experiment showed the most enriched pathways among the differentially expressed genes (DEG) were mitophagy and autophagy. However, analysis of flow cytometric apoptosis assay showed silencing of CYP11B2 did not induce cell apoptosis. Conclusion Our finding showed that silencing of CYP11B2 can affect mitophagy and autophagy but does not affect cell apoptosis in the HAC15 human adrenocortical cancer cell line. Further investigation on cell proliferation and in non-cancerous adrenal cells may be needed to identify the effect of modulating aldosterone synthesis on ZG cell fate. Reference (1) Vinson G., Front Neurosci 2016; 10: 238. (2) Lee G, et al., Endocrinology 2005; 146: 2650–2656. (3) Gomez-Sanchez CE, et al., Mol Cell Endocrinol 2014; 383: 111–117. (4) Bogman K, et al., Hypertension. 2017; 69(1): 189–196. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Introduction Primary aldosteronism (PA) contributed to the cardiovascular disease and metabolic alterations independent of the blood pressure level. Evidence exists that aldosterone excess also affects calcium and mineral homeostasis. PA subjects have been shown to have greater prevalence of vitamin D deficiency. However, the impact of vitamin D treatment in this population has never been assessed. Objective This study aimed to evaluate the effect of vitamin D treatment on clinical and biochemical outcomes of PA patients. Methods Two hundred forty hypertensive subjects were screened, 31 had positive ARR, and 17 patients with newly confirmed PA following positive confirmatory test that has not been subjected for definitive treatment were enrolled. Clinical parameter (blood pressure) and biochemical parameters (renal profile, plasma aldosterone concentration, plasma renin activity, serum calcium, vitamin D, intact parathyroid hormone, 24-hour urinary calcium) were measured at baseline and 3 months of treatment with Bio-D3 capsule. Primary outcomes were the changes in the blood pressure and biochemical parameters. Results About 70% of our PA subjects have low vitamin D levels at baseline. Three months following treatment, there were significant: (a) improvement in 25(OH)D levels; (b) reduction in systolic blood pressure and plasma aldosterone concentration; and (c) improvement in the eGFR. The vitamin D deficient subgroup has the greatest magnitude of the systolic blood pressure reduction following treatment. Conclusions This study demonstrated significant proportion of PA patients has vitamin D insufficiency. Vitamin D treatment improves these interrelated parameters possibly suggesting interplay between vitamin D, aldosterone, renal function and the blood pressure.

Primary aldosteronism (PA), the most common cause of secondary hypertension, is a well-recognized condition that can lead to cardiovascular and renal complications. PA is frequently left undiagnosed and untreated, leading to aldosterone-specific morbidity and mortality. In this review we highlight the evidence linking PA with other conditions such as (i) diabetes mellitus, (ii) obstructive sleep apnea, and (iii) bone health, along with clinical implications and proposed underlying mechanisms.

Currently, the gold standard for identifying a unilateral Primary Aldosteronism (PA) is adrenal vein sampling (AVS), an invasive and technically challenging procedure. In this study, we aim to identify the clinical-laboratory characteristics associated with successful AVS, and clinical parameters associated with PA patients that had successful AVS (on 1st, 2nd, or 3rd attempt), or had rejected further attempts after a failed AVS attempt.100 records of AVS from eighty-three AVS patients conducted between 2015 and 2020 at the National University of Malaysia (UKM) Medical Centre, Kuala Lumpur, Malaysia were analysed retrospectively. Of the 83 PA patients studied, 47 were performed on men and 36 were on women. Variables significantly associated with patients who booked for a further attempt of AVS was having a serum aldosterone of Presentation: No date and time listed

The Asian Pacific Society of Cardiology convened a consensus statement panel for optimising cardiovascular (CV) outcomes in type 2 diabetes, and reviewed the current literature. Relevant articles were appraised using the Grading of Recommendations, Assessment, Development and Evaluation system, and consensus statements were developed in two meetings and were confirmed through online voting. The consensus statements indicated that lifestyle interventions must be emphasised for patients with prediabetes, and optimal glucose control should be encouraged when possible. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are recommended for patients with chronic kidney disease with adequate renal function, and for patients with heart failure with reduced ejection fraction. In addition to SGLT2i, glucagon-like peptide-1 receptor agonists are recommended for patients at high risk of CV events. A blood pressure target below 140/90 mmHg is generally recommended for patients with type 2 diabetes. Antiplatelet therapy is recommended for secondary prevention in patients with atherosclerotic CV disease.

BackgroundHistory of severe hypoglycemia (SH) has been associated with cardiovascular (CV) events among patients with type II diabetes mellitus (T2DM). In this study, we screened patients with SH for atherosclerotic coronary artery disease (ACAD) .MethodsWe conducted a matched case-control study involving 28 T2DM patients with SH within the last 5 years with no documented ACAD and matched them with 28 T2DM patients with no SH. All subjects underwent coronary artery calcium scoring (CACS) followed by CT coronary angiography (CCTA) if indicated.ResultsHistory of SH in T2DM was associated with 78% (22 out of 28) incidence of significant ACAD compared to 46% (13 out of 28) in those without SH, based on either CACS≥400, or at least one coronary artery with ≥50% stenosis from CCTA, ( P =0.026).ConclusionThis study supported that SH in T2DM is associated with ACAD compared to T2DM without SH.

AbstractEstrogen (17β-estradiol or E2) is a crucial regulator of the synthesis and secretion of pituitary reproductive hormones luteinizing hormone, follicle-stimulating hormone, and prolactin. In this review, we summarize the role of estrogen receptors in nonfunctioning pituitary neuroendocrine tumors (NF-Pitnets), focusing on immunoexpression and gonadotroph cell proliferation and apoptosis. Gonadotroph tumors are the most common subtype of NF-Pitnets. Two major estrogen receptor (ER) isoforms expressed in the pituitary are estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Overall, estrogen actions are mostly exerted through the ERα isoform on the pituitary. The G protein–coupled estrogen receptor (GPER) located at the plasma membrane may contribute to nongenomic effects of estrogen. Nuclear immunoreactivity for ERα and ERβ was highest among gonadotroph and null cell tumors. Silent corticotroph tumors are the least immunoreactive for both receptors. A significantly elevated ERα expression was observed in macroadenomas compared with microadenomas. ERα and ERβ may act in opposite directions to regulate the Slug-E-cadherin pathway and to affect invasiveness of NF-Pitnets. In the cellular pathway, ERs regulate estrogen-induced proliferation and differentiation and impact several signaling pathways including the MAPK and PI3K/Akt pathway. Estrogen was the first-discovered inducer of pituitary tumor transforming gene 1 that was abundantly expressed in NF-Pitnets. ERα can be a potential biomarker for predicting tumor size and invasiveness as well as therapeutic target for NF-Pitnets. Selective estrogen receptor modulators or antiestrogen may represent as an alternative choice for the treatment of NF-Pitnets.

Studies on excised aldosterone-producing lesions have found somatic mutations in five genes (KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1) commonly causes the excess aldosterone production. Interestingly, Oriental cohorts had the highest frequency of KCNJ5 mutations whereas CACNA1D mutations were most common in Black African Caribbean patients, suggesting that genetic background affects the prevalence and distribution of aldosterone-driving somatic mutation. We therefore aimed to identify the common germline variants that associates with excess aldosterone production through performing a pilot genome wide association study (GWAS) on primary aldosteronism (PA) patients. GWAS was performed using the Human Infinium OmniExpressExome-8 v1.4 BeadChip containing 960,919 markers to compare gDNA of 154 PA patients with 78 healthy controls. Samples were checked for sex discordance, heterozygosity rate, missing rate and the degree of recent shared ancestry for each pair of individuals using the PLINK program and Genome Studio (Illumina). In total, 150 patients and 75 controls (112 males and 113 females) were included in the downstream analysis. 630,749 markers that passed quality control steps (missing call rate 1%) were used to perform association analysis using the Chi-square Test which was then subjected to multiple testing corrections (Bonferroni correction). As expected with a pilot sample size, no variants passed the suggestive significant threshold of Bonferroni corrected P-value < 5 x 10-6 (-log10 P = 5.3). However, 27 SNPs had the uncorrected P-value2, and differences of frequencies in cases compared to control >0.1 or References aChu et al., Int J Clin Exp Pathol 2017;10(9):10009-10018. bTanaka et al., Hypertens Res 2019;42(2):165-173. cNogueira et al., Mol Cell Endocrinol 2009; 302(2): 230–236. dGTEx Analysis Release V7 (dbGaP Accession phs000424.v7.p2) Acknowledgements This research was supported by the Malaysian Ministry of Higher Education Grant (FRGS/1/2015/SKK08/UKM/02/3), The National University of Malaysia (UKM) University Grant (GUP-2016-083), and The UKM Medical Center Fundamental Grant (FF-2016-302).

Primary aldosteronism (PA), also known as Conn’s syndrome, is a common curable cause of hypertension. Family studies of essential hypertensive patients suggest that heritable genetic factors play a role in blood pressure regulation1. Interestingly, single nucleotide polymorphisms (SNP) in genes encoding enzymes involved with adrenal steroidogenesis, CYP11B2, CYP11B1 and CYP17A1, associate with increased risk of hypertension2. Therefore, we analysed whether selected SNPs in these genes are associated with PA. We performed an association study using genotype imputation for selected SNPs of the steroidogenic enzyme genes CYP11B2 (rs4546, rs1799998, rs13268025), CYP11B1 (rs6410, rs149845727), and CYP17A1 (rs1004467, rs138009835, rs2150927) from a pilot genome wide association study of Malaysian PA patients and healthy controls which was merged with the Singapore Genome Variation Project (SGVP) population dataset3. Genotype imputation for minor and major alleles was validated using PCR sequencing (n>10 for each genotype). Further, one SNP from each steroidogenic enzyme (CYP11B2:rs1799998, CYP11B1:rs6410 and CYP17A1:rs1004467) was validated using commercial TaqMan genotyping assays on the ABI 7000 Sequence Detection System which was performed on 149 PA patients and 78 non-hypertensive healthy individuals. Case-control genetic association analysis was performed at http://www.oege.org/software/orcalc.html and the association between genotypes and phenotypes was done using the independent-samples Kruskal-Wallis test on SPSS (version 25). The Minor Allele Frequencies (MAFs) for rs1004467, rs6410 and rs1799998 were similar to East Asian populations but differed significantly different from European, African, American and South Asian populations (rs1004467 MAF: C=0.258/298, rs6410 MAF: A=0.265/298, rs1799998 MAF: C=0.225/298). In Chinese patients matched by gender, heterozygotes for rs6410 had significantly increased risk of PA compared to common homozygotes (OR: 3.15, 95% CI: 1.01–9.8, p=0.04). Across patients of different ethnicity, the distribution of aldosterone levels was significantly different (p=0.039). In summary, only SNP rs6410 in Chinese patients matched by gender showed association with PA in our South East Asian cohort. More functional experiments need to be done to find out whether this is causal for PA or whether the SNP is in linkage disequilibrium with the actual functional causative SNPs. Once the functional SNP is known, identification of these germline variants in asymptomatic family members would allow early screening of PA to be offered and potentially provide novel drug targets to treat the disease. References: 1Timberlake et al., Curr Opin Nephrol Hypertens. 2001 Jan;10(1):71-9. 2MacKenzie et al., Int J Mol Sci. 2017 Mar 7;18(3). pii: E579. 3Teo et al., Genome Res. 2009 Nov;19(11):2154-62.

Many modifiable factors contribute to the high prevalence rates of hypertension, among them is the consumption of too much salt (sodium). Another curable cause of hypertension is the excess of the hormone aldosterone. Aldosterone is normally produced by the zona glomerulosa (ZG) of the adrenal glands in response to a lack of salt and conversely suppressed by salt excess. We hypothesize that [i] suppression of aldosterone production induces apoptosis of ZG cells, as occurs following genetic deletion1; [ii] this sets up a maladaptive response to chronic salt overload by conferring a survival advantage to cells in which mutations drive autonomous aldosterone production. To address [i], we measured apoptosis of cells in which aldosterone synthesis was inhibited; to address [ii] we undertook a cross-sectional clinical study of aldosterone and sodium excretion, hypothesising that aldosterone excretion will be highest in the outside quartiles of sodium excretion. Aldosterone was inhibited by modification, in human adrenocortical H295R cells, of either CADM1 expression (mutated in aldosterone-producing adenomas2) or intracellular calcium concentration3. Apoptosis was measured by flow cytometric analysis of annexin V conjugates. 24-hour urinary aldosterone excretion (24h-Ualdo) was correlated with 24-hour urinary sodium (24h-Usodium) in 24h-urine samples collected for a Malaysian population-based salt intake study (MyCoSS). The prevalence of autonomous aldosterone production was estimated from the proportion of subjects with serum measurement whose “SUSSPUP” ratio (= serum sodium to urinary sodium)/(serum potassium2 to urinary potassium) was >5.34. Modification of CADM1 in human adrenocortical H295R cells decreased aldosterone production by half compared to vector control, and this was associated with a 3 to 5-fold increase of apoptotic cells (p3). Pilot investigation of a Cav1.3 inhibitor decreased aldosterone production by 70%, and increased apoptosis by 7-fold (p150mmol/d) had higher urinary aldosterone (4+0.18 ug/d) than other quartiles (p=0.00001). Overall, the estimated prevalence of autonomous aldossterone production using SUSSPUP ratio was 4.5% (8 of 179 subjects). In 63 subjects with 24h-Usodium>200 mmol/day, autonomous aldosterone secretion (conventionally >10µg/d) was found in 9.5%. Our results support the hypothesis that initial suppression of aldosterone production by salt excess may create a selective advantage for cells which autonomously produce aldosterone, and hence an inappropriate long-term increase in aldosterone production. 1Lee et al., Endocrinology. 2005;146:2650-6. 2Wu et al., 21st European Congress of Endocrinology. Vol. 63. BioScientifica, 2019. 3Xie et al., Sci Rep. 2016;6:24697. 4Willenberg et al., Eur J Clin Invest. 2009;39:43-50.

Premixed insulins are an important tool for glycemic control in persons with diabetes. Equally important in diabetes care is the selection of the most appropriate insulin regimen for a particular individual at a specific time. Currently, the choice of insulin regimens for initiation or intensification of therapy is a subjective decision. In this article, we share insights, which will help in rational and objective selection of premixed formulations for initiation and intensification of insulin therapy. The glycemic status and its variations in a person help to identify the most appropriate insulin regimen and formulation for him or her. The evolution of objective glucometric indices has enabled better glycemic monitoring of individuals with diabetes. Management of diabetes has evolved from a ‘glucocentric’ approach to a ‘patient-centered’ approach; patient characteristics, needs, and preferences should be evaluated when considering premixed insulin for treatment of diabetes. Funding: Novo Nordisk, India.

Background: Relatively little is known on the aspects of research that matter most to patients with thyroid dysfunction (TD). We aimed to explore the patients’ experience when they were diagnosed and treated for TD, as well as what they needed to improve their care: Methods: Qualitative data were obtained online using the Malay language version of the semi-structured qualitative survey in Malaysia, part of the larger research: A CORE OUTCOME SET FOR THYROID DYSFUNCTION. The questionnaires were developed from interactive discussions with patients who have thyroid dysfunction. The responses were analyzed using Braun and Clark’s thematic analysis framework guided by the question: What are the perceptions and experiences of thyroid care that matter most to patients with TD? Results: Responses from 38 participants, in the 18-60 age range, with TD, were analyzed. Most patients across the spectrum of thyroid dysfunctions experienced emotional disturbances. These negative emotions were related to the whole spectrum of disease state, the associated treatments, pre-treatment, post-treatment care, and personal aspects of daily life. Uncertainties in medical outcomes were associated with the personal need for further information. Functional psychosocial impairments and socioeconomic disruptions have a strong ability to arouse the anxiety of outcome uncertainties further. Getting treatment and independence in routine daily activities were prioritized while acknowledging treatments may differ in modality and risk of complications. Physician-patient interactions were valued in alleviating concerns and fear. Four salient themes emerged suggesting emotional security, functional ability, self-care (including psychosocial and socioeconomic well-being), and quality of physician-patient relationships were what matters to these participants. Conclusion: This insight into the problems of patients with TD underlined the need for quality patient-centered thyroid care and may be enhanced, personalized, and improved through outcomes that mattered most to patients in clinical research/trials, routine clinical practice, and the health system.

Mutations in KCNJ5 , ATP1A1 , ATP2B3 , CACNA1D , and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata–like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel’s inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1 / CACNA1D mutant adenomas had a predominantly negative expression ( P value =1.20×10 −4 ). ATP1A1 / CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%–1.9%] versus 0.4% [0.3%–0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.

Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in KCNJ5 frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). KCNJ5 mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of KCNJ5 mutations was estimated through targeted DNA sequencing of KCNJ5 in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a KCNJ5 mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males (p = 0.009; Mann-Whitney U test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA (p = 0.01; Spearman's rho) but not with the KCNJ5 genotype. KCNJ5 mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of KCNJ5 mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.

Background: Cushing’s syndrome (CS) in a patient with VHL has been attributed to a number of possible causes; pancreatic NET and renal cell carcinoma. The precise location of ectopic ACTH aid enormously in the management of VHL. Clinical case: A 31-year-old woman with Type 2 diabetes and family history of VHL presented with florid features of CS in her second trimester of pregnancy. A diagnosis of ACTH dependent CS was made based on elevated 24h urinary cortisol (1122 and 2448nmol/24hr, n

Background: Type 2 diabetes mellitus (T2DM) is a chronic disease that consumes a large amount of health-care resources. It is essential to estimate the cost of managing T2DM to the society, especially in developing countries. Economic studies of T2DM as a primary diagnosis would assist efficient health-care resource allocation for disease management. Objective: This study aims to measure the economic burden of T2DM as the primary diagnosis for hospitalization from provider's perspective. Methods: A retrospective prevalence-based costing study was conducted in a teaching hospital. Financial administrative data and inpatient medical records of patients with primary diagnosis (International Classification Disease-10 coding) E11 in the year 2013 were included in costing analysis. Average cost per episode of care and average cost per outpatient visit were calculated using gross direct costing allocation approach. Results: Total admissions for T2DM as primary diagnosis in 2013 were 217 with total outpatient visits of 3214. Average cost per episode of care was RM 901.51 (US$ 286.20) and the average cost per outpatient visit was RM 641.02 (US$ 203.50) from provider's perspective. The annual economic burden of T2DM for hospitalized patients was RM 195,627.67 (US$ 62,104) and RM 2,061,520.32 (US$ 654,450) for those being treated in the outpatient setting.Conclusions: Economic burden to provide T2DM care was higher in the outpatient setting due to the higher utilization of the health-care service in this setting. Thus, more focus toward improving T2DM outpatient service could mitigate further increase in health-care cost from this chronic disease.

Aim To systematically review the literature to compare the use of DPP4 inhibitors vs sulphonylurea in type 2 diabetic Muslim patients who fast in Ramadan, with regards to its safety, tolerability, glycemic control, and body weight changes. Methods All English-language medical literature published from inception till October 2014 which met the inclusion criteria were reviewed and analyzed. Results A total of nine papers were included, reviewed and analyzed. The total sample size was 4276 patients. All studies used either of the two DPP4 inhibitors – Vildagliptin or Sitagliptin, vs sulphonylurea or meglitinides. Patients receiving DPP4 inhibitors were less likely to develop symptomatic hypoglycemia (risk ratio 0.46; 95% CI, 0.30–0.70), confirmed hypoglycemia (risk ratio 0.36; 95% CI, 0.21–0.64) and severe hypoglycemia (risk ratio 0.22; 95% CI, 0.10–0.53) compared with patients on sulphonylureas. There was no statistically significant difference in HbA1C changes comparing Vildagliptin and sulphonylurea. Conclusion DPP4 inhibitor is a safer alternative to sulphonylurea in Muslim patients with type 2 diabetes mellitus who fast during the month of Ramadan as it is associated with lower risk of symptomatic, confirmed and severe hypoglycemia, with efficacy comparable to sulphonylurea.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Ketoconazole has long been the first-line medical therapy for controlling hypercortisolism secondary to either pituitary or adrenal pathology. However, it is largely unavailable in most countries. As a result, we have turned to fluconazole as a viable alternative in view of its favourable safety profile. Case Presentation: A 50-year-old lady developed recurrent Cushing’s disease after being in remission following transsphenoidal surgery (TSS) for a left pituitary microadenoma 16 years ago. The repeat MRI showed a right pituitary microadenoma (1.7 mm � 1.3 mm) for which she underwent a second TSS. However, she continued to have persistent hypercortisolism despite repeated MRIs showing absence of tumour recurrence. She refused bilateral adrenalectomy and external radiotherapy. Ketoconazole was commenced at 200 mg twice daily for disease control but this was hindered by intolerable side effects including pruritus and skin exfoliation. In the meantime, she suffered a right hypertensive basal ganglia hemorrhage. Treatment was subsequently switched to cabergoline and the dose titrated to 0.5 mg daily. Fluconazole 400 mg daily was later added to control the persistent disease. Her clinical and biochemical parameters improved markedly three months after the addition of fluconazole. No adverse event was reported. Her disease has remained stable for the last 15 months up until the time of the recent clinic review. Conclusions: This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing’s disease.