Norlela Sukor

Impact of Different Diagnostic Criteria During Adrenal Vein Sampling on Reproducibility of Subtype Diagnosis in Patients With Primary Aldosteronism

In patients with primary aldosteronism, adrenal vein sampling (AVS) is considered the only reliable technique to distinguish between unilateral and bilateral autonomous production of aldosterone, but agreement is lacking on the best criteria indicating successful cannulation and lateralization. The objective of this study was to assess the impact of differing criteria for the successful cannulation and lateralization on the reproducibility of subtype diagnosis. Sixty-two patients with confirmed primary aldosteronism underwent AVS on 2 separate occasions, because the first was unsatisfactory. We compared the different diagnoses of primary aldosteronism subtype reached using AVS data assessed by permissive (type 1), intermediate (type 2), and strict (type 3) criteria. Although 91.1% of all of the (both first and second) AVSs were “successful” by type 1 criteria (50.8% by type 2 and 33.9% by type 3), in only 35.3% of patients was the diagnosis concordant between the first and second AVS. Type 1 criteria also led to a higher rate of diagnosis of unilateral primary aldosteronism (67.3% of successful procedures) than type 2 (36.5%) or type 3 (26.2%). There was considerable disparity in the diagnosis reached using the 3 different criteria, with concordance in only 32.2%. Using either type 1 or 2 criteria, the minimal adrenal/peripheral vein cortisol ratio necessary to obtain the same diagnosis in the first and second AVS procedures was ≥2.75. In conclusion, permissive criteria for successful cannulation and lateralization on AVS achieve poor diagnostic reproducibility and should be avoided.

Role of unilateral adrenalectomy in bilateral primary aldosteronism: a 22-year single center experience.

OBJECTIVE The aim of the study was to examine blood pressure and biochemical responses to unilateral adrenalectomy in patients with bilateral primary aldosteronism (PA) and identify predictive parameters. CONTEXT PA considered due to bilateral autonomous production of aldosterone is usually treated medically. Unilateral adrenalectomy has been considered ineffective. Because quality outcome data are lacking and medical treatment may cause adverse effects or fail to control hypertension, defining the role for unilateral adrenalectomy in bilateral PA is an important clinical issue. DESIGN AND SETTING Between 1984 and 2004, 51 of 684 patients diagnosed with bilateral PA underwent unilateral adrenalectomy. This report is based on the records of the 40 considered suitable for inclusion, who were followed for at least 12 (median, 56.4) months. RESULTS Hypertension was cured in 15% of patients and improved in 20%, usually within 1 yr of unilateral adrenalectomy. The proportion with controlled hypertension was significantly (P < 0.001) higher after adrenalectomy (65%) than before (25%). Mean systolic (P < 0.001) and diastolic (P < 0.001) blood pressure, left ventricular mass index (P < 0.05), plasma upright aldosterone (P < 0.05), and aldosterone/renin ratio (P < 0.001) fell. Serum creatinine independently predicted hypertension cure. CONCLUSION Although this retrospective analysis of patients from a single center does not permit prediction of response rates among patients diagnosed elsewhere, it suggests that unilateral adrenalectomy can be beneficial in some patients with apparent bilateral PA and should not be dismissed as a treatment option.

Improved Quality of Life, Blood Pressure, and Biochemical Status Following Laparoscopic Adrenalectomy for Unilateral Primary Aldosteronism

CONTEXT In 22 patients with unilateral primary aldosteronism (UPA), unilateral laparoscopic adrenalectomy (ADX) not only corrected hypokalemia and led to cure or improvement of hypertension, but also significantly improved quality of life (QOL). SETTING AND DESIGN In this pilot study, QOL was evaluated prospectively using SF-36 questionnaire before and 3 and 6 months after ADX in 22 patients [14 males] with UPA who underwent ADX within the Endocrine Hypertension Research Center, Greenslopes and Princess Alexandra Hospitals, between June 2007 and June 2008. RESULTS Eighty-six percent of patients were cured of hypertension, and the remainder improved. Plasma potassium normalized and, whereas renin concentration increased, plasma aldosterone, aldosterone/renin ratio, and number of antihypertensive agents decreased. Preoperatively, SF-36 scores for each QOL domain were lower for UPA patients than reported for the Australian general population, especially for physical functioning, role physical, vitality, and general health. Significant improvements were seen at 3 months in physical functioning, role physical, social functioning, role emotional, general health, mental health, and vitality and at 6 months in physical functioning, role physical, general health, role emotional, mental health, and vitality. CONCLUSION Unilateral adrenalectomy had positive impacts not only on blood pressure and biochemical parameters, but also on QOL, which was impaired preoperatively but significantly improved by 3 months postoperatively.

Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families.

Background Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. Objective To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). Methods Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. Results All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (&thetas; = 0) for markers D7S462 and D7S517. Conclusion Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.

Quality of Life in Patients with Bilateral Primary Aldosteronism before and during Treatment with Spironolactone and/or Amiloride, Including a Comparison with Our Previously Published Results in Those with Unilateral Disease Treated Surgically

BACKGROUND Measurement of quality of life (QOL) allows assessment of the impact of a disease or treatment from the patients perspective, including need for social, emotional, or physical support. We are not aware of any published QOL assessment in patients with bilateral primary aldosteronism (BPA), before or after commencing medical treatment (MT) with spironolactone and/or amiloride. METHODS Using the internationally validated Medical Outcomes Study Short Form 36 General Health Survey (SF-36), QOL was assessed in 21 patients with BPA at baseline (time of diagnosis), and at 3 and 6 months after commencing MT. QOL scores at baseline were compared with published normative values for the Australian population. The results of the current study were compared with those from our previous study showing reduced QOL in patients with unilateral primary aldosteronism (UPA) with normalization by 3 months after unilateral laparoscopic adrenalectomy. RESULTS Compared with the general population, patients with BPA showed significant reduction (P < 0.01) in four QOL domains--physical functioning, role limitations due to physical health problems, general health perceptions, and vitality. After 6 months (but not 3 months) of MT, statistically significant (P < 0.05) improvements were detected in all these domains of QOL. When compared with patients with UPA treated surgically, scores were significantly (P < 0.05) lower at 3 months for five domains (role limitations due to physical health, general health, role limitations due to emotional health, mental health, and vitality) but at 6 months for only one domain (role limitations due to emotional problems). CONCLUSION Subnormal QOL scores were improved after 6 months of MT in 21 patients with BPA, but more slowly and to a lesser degree than surgical treatment had previously been shown to improve QOL scores in 22 patients with UPA.

EXAMINATION OF CHROMOSOME 7p22 CANDIDATE GENES RBaK, PMS2 AND GNA12 IN FAMILIAL HYPERALDOSTERONISM TYPE II

1 There are two types of familial hyperaldosteronism (FH): FH‐I and FH‐II. FH‐I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH‐II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We previously reported linkage of FH‐II to a ~5 Mb region on chromosome 7p22. We subsequently reported finding no causative mutations in the retinoblastoma‐associated Kruppel‐associated box gene (RBaK), a candidate at 7p22 involved in tumorigenesis and cell cycle control. 2 In the current study we investigated RBaK regulatory regions and two other candidate genes: postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide‐binding protein alpha‐12 (GNA12, a transforming oncogene). 3 The GNA12 and PMS2 genes were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from a large 7p22‐linked FH‐II family (family 1). No mutations were found. 4 The RBaK and PMS2 distal promoters were sequenced to –2150 bp from the transcription start site for RBaK and–2800 bp for PMS2. Five unreported single nucleotide polymorphisms (SNPs) were found in subjects A1, A2 but not in U1 or U2; A(–2031 bp)T, T(–2030 bp)G, G(–834 bp)C, C(–821 bp)G in RBaK and A(–876 bp)G in PMS2. Additional affected and unaffected subjects from family 1 and from two other 7p22‐linked FH‐II families and 58 unrelated normotensive control subjects were genotyped for these SNPs. 5 The five novel SNPs were found to be present in a significant proportion of normotensive controls. The four RBaK promoter SNPs were found to be in linkage disequilibrium in the normal population. The RBaK promoter (–)2031T/2030G/834C/821T allele was found to be in linkage disequilibrium with the causative mutation in FH‐II family 1, but not in families 2 and 3. The PMS2 promoter (–)876G allele was also found to be linked to affected phenotypes in family 1. 6 The RBaK and PMS2 promoter SNPs alter the binding sites for several transcription factors. Although present in the normal population, it is possible that the RBaK (–)2031T/2030G/834C/821T and PMS2 (–)876G alleles may have functional roles contributing to the FH‐II phenotype in family 1.

Endocrine hypertension--current understanding and comprehensive management review.

Hypertension is a very common disease, leading to significant morbidity with reduction in quality of life. In addition to being a major cause of morbidity and mortality, hypertension places a heavy burden on health care systems, families, and society as a whole. In patients with hypertension, the ability to identify a contributing or secondary cause that is potentially curable or amenable to specific forms of management is of great importance. Endocrine hypertension has emerged as one of the common forms of secondary hypertension. Primary aldosteronism, pheochromocytoma and Cushings syndrome are among the common causes of endocrine hypertension. The application of new clinical, biochemical, and radiologic approaches has significantly advanced our understanding of the pathophysiology and clinical spectrum of these diseases and improved the management strategies of these challenging conditions.

Primary aldosteronism: from bench to bedside

Primary aldosteronism is now thought to be the commonest potentially curable and specifically treatable form of hypertension. The detection of primary aldosteronism is of utmost importance not only because it provides an opportunity for a targeted treatment, but also because it has been demonstrated that patients with primary aldosteronism are more prone to cardiovascular events and target organ damage than essential hypertensives. Normalization of blood pressure and hypokalemia should not be the only goal of treatment. Normalization of circulating aldosterone or mineralocorticoid blockade is necessary to prevent aldosterone-induced tissue damage that occurs independent of blood pressure. This review will focus on the current understanding and comprehensive management review of primary aldosteronism, highlighting the new evidence that has become recently available.

Aldosterone-Producing Adenomas: Histopathology–Genotype Correlation and Identification of a Novel CACNA1D Mutation

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.

Switching from sulphonylurea to a sodium-glucose cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia.

The aim of the present study was to assess the hypoglycaemia risk and safety of dapagliflozin compared with sulphonylurea during the fasting month of Ramadan. In this 12‐week, randomized, open‐label, two‐arm parallel group study, 110 patients with type 2 diabetes who were receiving sulphonylurea and metformin were randomized either to receive 10 mg (n = 58) of dapagliflozin daily or to continue receiving sulphonylurea (n = 52). The primary outcome was to compare the effects of dapagliflozin and sulphonylurea on the proportions of patients with at least one episode of hypoglycaemia during Ramadan, as well as to assess the safety of dapagliflozin when used to treat patients observing Ramadan. A lower proportion of patients had reported or documented hypoglycaemia in the dapagliflozin group than in the sulphonylurea group: 4 (6.9%) versus 15 (28.8%); p = 0.002. The relative risk of any reported or documented hypoglycaemia in the 4th week of Ramadan was significantly lower in the dapagliflozin group: RR=0.24, 95%CI: 0.09, 0.68; p=0.002. No significance differences were observed between the two groups regarding postural hypotension (13.8 vs 3.8%; p = 0.210) or urinary tract infections (10.3 vs 3.8%; p = 0.277). In conclusion, fewer patients exhibited hypoglycaemia in the dapagliflozin group than in the sulphonylurea group.