Gisella Pitter

Adrenal vein sampling for primary aldosteronism: the assessment of selectivity and lateralization of aldosterone excess baseline and after adrenocorticotropic hormone (ACTH) stimulation.

Background Adrenal vein sampling is crucial for identifying the primary aldosteronism subtypes, but the cutoff values for ascertaining selectivity of catheterization and lateralization of aldosterone secretion remain controversial. Objectives To investigate the safety of adrenal vein sampling, the cutoff values for the selectivity and lateralization indexes, and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index performance. Design We assessed the proportion of selective adrenal vein sampling at different selectivity index cutoff values in 151 consecutive patients with primary aldosteronism undergoing bilaterally simultaneous adrenal vein sampling. Aldosterone-producing adenoma was diagnosed on the basis of the evidence of primary aldosteronism and lateralized aldosterone secretion, adenoma at pathological examination, and normokalemia, and correction of primary aldosteronism and cure or improvement of hypertension at follow-up. In 44 patients with bilaterally selective adrenal vein sampling and unequivocal diagnosis of aldosterone-producing adenoma on the basis of all these criteria, we examined the cutoff values of the lateralization index for assessing the lateralization of aldosterone excess and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index. Results Adrenal vein rupture occurred in one case (0.7%). Bilaterally selective adrenal vein sampling decreased steadily (from 79.9 to 40.2%) with increase in the selectivity index cutoffs from 1.1 to 5.0. Likewise, the proportion of correctly identified aldosterone-producing adenomas decreased (from 95.5 to 43.2%) with increase in lateralization index cutoffs from 1.125 to 5.0. Adrenocorticotropic hormone improved the assessment of selectivity but exerted a confounding effect on lateralization index. Conclusion Adrenal vein sampling is safe; increasing the selectivity index cutoffs lowers the number of usable adrenal vein samplings; higher lateralization index cutoff values lead to missing a proportion of aldosterone-producing adenomas. The improved selectivity rate provided by adrenocorticotropic hormone stimulation should be weighed against the loss of correct lateralization.

Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling for Identifying Surgically Curable Subtypes of Primary Aldosteronism. Comparison of 3 Different Protocols

Adrenocorticotropic hormone administration was proposed to overcome the biases associated with pulsatile aldosterone secretion during adrenal venous sampling, but the usefulness of different protocols of stimulation was never systematically assessed. We, therefore, compared the effects of a high dose (HD; 250 &mgr;g IV as a bolus), a very low dose (VLD; 250 pg IV), and an intermediate dose (ID; 50 &mgr;g/h) of adrenocorticotropic hormone on the selectivity index (SI) and the lateralization index in primary aldosteronism patients, using the diagnosis of aldosterone-producing adenoma, based on pathology and follow-up data, as a reference. The HD (n=47) significantly increased plasma cortisol concentration in infrarenal inferior vena cava (+79%) blood and the SI on both sides (SIRIGHT +113% and SILEFT +131%), as compared with baseline values. The ID (n=14) also markedly increased both plasma cortisol concentration inferior vena cava (+93%) and the SI (SIRIGHT +690% and SILEFT +410%); the very low dose (n=6) had no effect on either the plasma cortisol concentration or SI. In the patients with unilateral aldosterone-producing adenoma, the increase of selectivity with the HD and ID was counterbalanced by a confounding effect on the correct identification of the aldosterone-producing adenoma side, which was attributed to the wrong side in 3.0% and 12.5% with HD and ID, respectively. In conclusion, the HD and the ID, but not the very low dose, adrenocorticotropic hormone stimulation protocol facilitated the ascertainment of selectivity of adrenal vein catheterization. However, this favorable effect was overridden by a confounding effect on the identification of lateralized aldosterone excess to the aldosterone-producing adenoma side. Hence, we do not recommend adrenocorticotropic hormone stimulation.

Impact of Accessory Hepatic Veins on Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism

Adrenal vein sampling is the gold standard for identification of surgically curable primary aldosteronism, but its accuracy might be hindered by blood dilution from accessory vein blood. We prospectively investigated the presence of accessory veins draining into adrenal veins and their effect on the selectivity index (SI) in 74 consecutive patients undergoing adrenal vein sampling. On the right side, the venous anatomic pattern could be conclusively determined in 91.8% of the cases: we detected hepatic accessory veins in 12.1%, no accessory veins in 42.4%, and renal capsular veins in 45.5%. On the left side there was a phrenico-adrenal trunk in 89.4% and renal capsular accessory veins in 10.6% of the cases. On both sides, renal capsular and phrenic accessory veins did not affect the SI. At variance, on the right side, hepatic accessory veins were associated with SI values ≈3-fold lower than that found when such accessory veins were absent (median: 3.10 [range: 0.80 to 84.2] versus median: 1.10 [range: 0.70 to 2.20]; P=0.01). However, superselective adrenal catheterization resulted into higher SI values (median: 23.88; range: 4.80 to 84.20) in these cases. Thus, hepatic accessory veins sharing egress into the inferior vena cava with the right adrenal vein occurred in ≈12% of the patients and imply a low SI, likely because of adrenal blood dilution by hepatic blood carrying a low cortisol concentration. In the presence of this anatomic variation, superselective catheterization of the right adrenal vein should be undertaken to determine the lateralization of aldosterone secretion.

Association of Maternal Education, Early Infections, and Antibiotic Use With Celiac Disease: A Population-Based Birth Cohort Study in Northeastern Italy

We conducted a population-based birth cohort study of approximately 203,000 babies born in northeastern Italy (1989-2012) to investigate perinatal variables, early infections leading to hospital admission, and antibiotic use in the first 12 months of life as possible risk factors for celiac disease (CD). Incident CD cases were identified from pathology reports, hospital discharge records, and exemptions from prescription charges for clinical tests. Multivariate Poisson regression models were fitted to estimate incidence rate ratios (IRRs). A total of 1,227 children had CD; CD was histopathologically confirmed in 866 (71%). Female sex, maternal age, and high maternal educational level were found to be significantly associated with CD. Gastrointestinal infections were strongly associated with a subsequent diagnosis of CD (IRR = 2.04, 95% confidence interval (CI): 1.30, 3.22). Antibiotic use was significantly associated with CD onset (IRR = 1.24, 95% CI: 1.07, 1.43), with a dose-response relationship for number of courses (P-trend < 0.01). Cephalosporin use strongly increased the risk of CD (IRR = 1.42, 95% CI: 1.18, 1.73). Use of antibiotics (supported by the dose-response relationship) and gastrointestinal infections in the first year of life may facilitate the early onset of CD by altering intestinal microflora and the gut mucosal barrier. Perinatal factors, including cesarean section, had little influence on the risk of childhood CD.

Genetic Variation in the Endothelin System

Abstract:  Endothelin‐1 (ET‐1) exerts multiple biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET‐1 is synthesized by ET‐converting enzymes (ECE), chymases (CMAs), and non‐ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET‐1 acts through the activation of Giprotein–coupled receptors. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET‐1, and the inhibition of ECE‐1. ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET‐1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of preproET‐1, ECE‐1, CMA, ETA and ETB receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. Thus, even though ET antagonists are being used for the treatment of pulmonary hypertension, there is no convincing evidence for a role of SNPs in affecting the therapeutic strategies.

Coeliac disease and asthma association in children: the role of antibiotic consumption

The relationship between coeliac disease and asthma has been scarcely investigated. Infant antibiotic exposure has been linked to both diseases. We evaluated the association between childhood coeliac disease and asthma and the role of antibiotics in the first year of life. We followed a cohort of children born in 1995–2011 in the Friuli-Venezia Giulia region (Italy). Prescriptions for antibiotics in the first year of life and subsequent treated asthma were retrieved from drug prescription records; coeliac disease incident cases were identified from pathology reports, hospital discharges and exemption from prescription charges for clinical tests. We estimated incidence rate ratios (IRRs) using multivariate Poisson regression models. Among the 143 144 children, we identified 717 coeliac children and 34 969 asthmatics. Children with asthma were at increased risk of coeliac disease (IRR 1.46, 95% CI 1.25–1.67). Restricting the analysis to asthma that occurred before the diagnosis of coeliac disease, the excess risk disappeared, except for coeliac disease diagnosed after 5 years of age (IRR 1.37, 95% CI 1.09–1.71). Antibiotics were not a confounding factor in these associations. Childhood treated asthma and coeliac disease are significantly associated. This association is not confounded by antibiotic exposure in the first year of life and may be explained by other shared risk factors. Coeliac disease associated with asthma in children is not explained by antibiotic exposure during the first year of life http://ow.ly/IJZ3Y

Risk of Fractures in Youths with Celiac Disease—A Population-Based Study

Objective To assess the risk of any fracture requiring hospital care in a cohort of individuals with celiac disease diagnosed in childhood/adolescence compared with reference individuals matched by age and sex. Study design Our study cohort consisted of 213 635 people born and residing in Friuli‐Venezia Giulia Region, Italy, in 1989‐2011. We selected, through pathology reports, hospital discharge records, or co‐payment exemptions, 1233 individuals with celiac disease (aged 0‐17 years at diagnosis) and compared them with 6167 reference individuals matched by sex and year of birth. Fractures were identified through hospital discharge records. We calculated hazard ratios (HRs) for any fracture after celiac disease diagnosis (or index date for reference individuals) with Cox regression and ORs for any fracture before celiac disease diagnosis with conditional logistic regression. Results During the follow‐up period (maximum 23 years), 22 individuals with celiac disease (9394 person‐years) and 128 reference individuals (47 308 person‐years) experienced a fracture, giving an overall HR of 0.87 (95% CI 0.55‐1.37). The risk was not modified by sex, age at diagnosis, or calendar period of diagnosis. We obtained similar HRs when excluding fractures occurring after the age of 18 years and adjusting for maternal education or vitamin D supplementation. The odds of previous fracture also did not differ between subjects with celiac disease and reference individuals (22 and 96 cases, respectively: OR 1.15; 95% CI 0.72‐1.84). Conclusions We did not find any evidence of an increased risk of fractures during childhood and youth among patients with celiac disease.

Reply to Bianchi et al.: In Italy anti-asthmatic drug prescription is not always a reliable proxy of asthma.

As suggested by Bianchi et al. [1], we have conducted a sensitivity analysis of our previously published data [2], identifying treated asthmatics as those individuals with at least one prescription after the first year of life of any nonnebulised formulation of inhalatory anti-asthmatic drugs [3]. With this new criteria, 12,948 cases of asthma (8.5 % in our population) were detected. Antibiotic consumption in the first year of life significantly increased the risk of new-onset asthma at any age [IRR 1.32, 95 % CI 1.28–1.37]. Compared with our previous analysis [2], the risk of asthma occurrence at C72 months was unaffected [IRR 1.16 (95 % CI 1.09–1.23)], whereas the remaining risks were weakened [IRR 1.80 (95 % CI 1.68–1.94) at 13–35 months, IRR 1.23 (95 % CI 1.16–1.30) at 36–71 months]. Early antibiotic use was also associated with an increased risk of current asthma at age C6 years (IRR 1.21, 95 % CI 1.15–1.27). Since nebulised formulations of anti-asthmatic drugs are frequently prescribed for respiratory infections [1], our previous definition may have misclassified as asthmatics a proportion of non-asthmatic subjects particularly in the 13–71 months groups and might have biased our results: children treated with antibiotics in the first year of life may be more predisposed to respiratory infections in early childhood; alternatively, antibiotic use may be a marker of parental tendency to seek medications for children. The definition proposed by Bianchi et al. [3] has been validated in a limited setting and the variability of its accuracy across different pediatricians was high. Therefore, it should be tested in different settings before being considered the gold standard for pediatric asthma detection using healthcare databases in Italy or elsewhere. Anyhow, our previous [2] and present results consistently show an association between early antibiotic use and later pediatric treated asthma across a wide range of asthma definitions.