Primary ovarian insufficiency in women with Addison's disease

Context Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison’s disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. Objective To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics. Methods An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation. Results The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). Conclusion One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC.publishedVersio

Preclinical cardiac disease in women and men with primary aldosteronism

Purpose We tested the sex-specific associations between primary aldosteronism (PA), left ventricular (LV) hypertrophy and LV systolic myocardial function. Material and methods Conventional and speckle tracking echocardiography was performed in 109 patients with PA and 89 controls with essential hypertension (EH). LV hypertrophy was identified if LV mass index exceeded 47.0 g/m2.7 in women and 50.0 g/m2.7 in men. LV systolic myocardial function was assessed by global longitudinal strain (GLS) and midwall shortening. Results PA patients had higher prevalence of LV hypertrophy (52 vs. 21%, p < 0.001) than EH patients in both sexes, while GLS did not differ by sex or hypertension aetiology. In multivariable analyses, presence of LV hypertrophy was associated with PA and obesity in both sexes, while lower systolic myocardial function, whether measured by GLS or midwall shortening, was not associated with PA, but primarily with higher body mass index and LV mass index, respectively, in both sexes (all p < 0.05). Conclusion Having PA was associated with higher prevalence of LV hypertrophy both in women and men, compared to EH. PA was not associated with LV systolic myocardial function in either sex.publishedVersio

Efficacy of adrenal venous sampling is increased by point of care cortisol analysis

Primary aldosteronism (PA) is a common cause of secondary hypertension and is caused by unilateral or bilateral adrenal disease. Treatment options depend on whether the disease is lateralized or not, which is preferably evaluated with selective adrenal venous sampling (AVS). This procedure is technically challenging, and obtaining representative samples from the adrenal veins can prove difficult. Unsuccessful AVS procedures often require reexamination. Analysis of cortisol during the procedure may enhance the success rate. We invited 21 consecutive patients to participate in a study with intra-procedural point of care cortisol analysis. When this assay showed nonrepresentative sampling, new samples were drawn after redirection of the catheter. The study patients were compared using the 21 previous procedures. The intra-procedural cortisol assay increased the success rate from 10/21 patients in the historical cohort to 17/21 patients in the study group. In four of the 17 successful procedures, repeated samples needed to be drawn. Successful sampling at first attempt improved from the first seven to the last seven study patients. Point of care cortisol analysis during AVS improves success rate and reduces the need for reexaminations, in accordance with previous studies. Successful AVS is crucial when deciding which patients with PA will benefit from surgical treatment.publishedVersio

Primary aldosteronism in Western Norway. Studies of diagnostic approach and treatment outcome

Primary aldosteronism (PA) is the most common cause of secondary hypertension (HT), accounting for 5 to 12% of all hypertensive individuals. Patients with PA experience increased cardiovascular, renal and metabolic complications and have impaired quality of life compared with essential HT. We aimed to determine the clinical and biochemical characteristics of the PA population in Western Norway, to identify the optimal diagnostic procedures, and to evaluate long-term treatment outcome after medical and surgical treatment. Three clinical studies were conducted. We retrospectively identified all PA patients admitted to Haukeland University Hospital from 1998 to 2012, a total of 108 cases. The majority had unilateral PA and hypokalaemia, indicating that mostly patients with florid PA were detected. Cure rate of HT after adrenalectomy was low. Female sex, presence of somatic KCNJ5 mutations and a histopathological adenoma were associated with cure of HT. We also conducted an adrenal vein sampling (AVS) study, where we found that the use of intraprocedural point-of-care cortisol assay increased the AVS success rate substantially compared with historical controls. In our cardiac magnetic resonance imaging (CMR) study, we found that left ventricular (LV) mass decreased rapidly after PA treatment, most pronounced in adrenalectomised patients. Dynamic contrast enhancement and T1 mapping did not reveal increase in myocardial fibrosis in PA compared with healthy subjects. In conclusion, PA is probably grossly underdiagnosed in Norway, in particular bilateral PA, which often exhibits a mild phenotype. HT cure rate after adrenalectomy was low. Intraprocedural cortisol assay increased the success rate of AVS, and is now in routine clinical use at our centre. Specific PA treatment rapidly reduced LV mass, underlining the importance of correct diagnosis allowing for efficient treatment. Although cardiovascular risk is increased in PA, myocardial fibrosis may not represent a common clinical problem

The natural history of 21-hydroxylase autoantibodies in autoimmune Addison’s disease

Background: The most common cause of primary adrenal failure (Addison’s disease) in the Western world is autoimmunity characterized by autoantibodies against the steroidogenic enzyme 21-hydroxylase (CYP21A2, 21OH). Detection of 21OH-autoantibodies is currently used for aetiological diagnosis, but how levels of 21OH-autoantibodies vary over time is not known. Setting: Samples from the national Norwegian Addison’s Registry and Biobank established in 1996 (n = 711). Multi-parameter modelling of the course of 21OH-autoantibody indices over time. Results: 21OH-autoantibody positivity is remarkably stable, and >90% of the patients are still positive 30 years after diagnosis. Even though the antibody levels decline with disease duration, it is only rarely that this downturn reaches negativity. 21OH-autoantibody indices are affected by age at diagnosis, sex, type of Addison’s disease (isolated vs autoimmune polyendocrine syndrome type I or II) and HLA genotype. Conclusion: 21OH-autoantibodies are reliable and robust markers for autoimmune Addison’s disease, linked to HLA risk genotype. However, a negative test in patients with long disease duration does not exclude autoimmune aetiology.publishedVersio

Preclinical cardiac disease in women and men with primary aldosteronism

Purpose We tested the sex-specific associations between primary aldosteronism (PA), left ventricular (LV) hypertrophy and LV systolic myocardial function. Material and methods Conventional and speckle tracking echocardiography was performed in 109 patients with PA and 89 controls with essential hypertension (EH). LV hypertrophy was identified if LV mass index exceeded 47.0 g/m2.7 in women and 50.0 g/m2.7 in men. LV systolic myocardial function was assessed by global longitudinal strain (GLS) and midwall shortening. Results PA patients had higher prevalence of LV hypertrophy (52 vs. 21%, p < 0.001) than EH patients in both sexes, while GLS did not differ by sex or hypertension aetiology. In multivariable analyses, presence of LV hypertrophy was associated with PA and obesity in both sexes, while lower systolic myocardial function, whether measured by GLS or midwall shortening, was not associated with PA, but primarily with higher body mass index and LV mass index, respectively, in both sexes (all p < 0.05). Conclusion Having PA was associated with higher prevalence of LV hypertrophy both in women and men, compared to EH. PA was not associated with LV systolic myocardial function in either sex

Primary ovarian insufficiency in women with Addison's disease

Context Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison’s disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. Objective To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics. Methods An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation. Results The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). Conclusion One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC

Cardiac magnetic resonance imaging of myocardial mass and fibrosis in primary aldosteronism

Background Primary aldosteronism (PA) is associated with increased cardiovascular morbidity, presumably due to left ventricular (LV) hypertrophy and fibrosis. However, the degree of fibrosis has not been extensively studied. Cardiac magnetic resonance imaging (CMR) contrast enhancement and novel sensitive T1 mapping to estimate increased extracellular volume (ECV) are available to measure the extent of fibrosis. Objectives To assess LV mass and fibrosis before and after treatment of PA using CMR with contrast enhancement and T1 mapping. Methods Fifteen patients with newly diagnosed PA (PA1) and 24 age- and sex-matched healthy subjects (HS) were studied by CMR with contrast enhancement. Repeated imaging with a new scanner with T1 mapping was performed in 14 of the PA1 and 20 of the HS median 18 months after specific PA treatment and in additional 16 newly diagnosed PA patients (PA2). Results PA1 had higher baseline LV mass index than HS (69 (53–91) vs 51 (40–72) g/m2; P < 0.001), which decreased significantly after treatment (58 (40–86) g/m2; P < 0.001 vs baseline), more with adrenalectomy (n = 8; −9 g/m2; P = 0.003) than with medical treatment (n = 6; −5 g/m2; P = 0.075). No baseline difference was found in contrast enhancement between PA1 and HS. T1 mapping showed no increase in ECV as a myocardial fibrosis marker in PA. Moreover, ECV was lower in the untreated PA2 than HS 10 min post-contrast, and in both PA groups compared with HS 20 min post-contrast. Conclusion Specific treatment rapidly reduced LV mass in PA. Increased myocardial fibrosis was not found and may not represent a common clinical problem

Persistent cardiac organ damage in surgically and medically treated primary aldosteronism

Objective: We compared persistent cardiac organ damage in patients treated surgically or medically for primary aldosteronism. Methods: Eighty-four patients (age 57 ± 11 years, 27% women) with primary aldosteronism underwent echocardiography at time of diagnosis and after one year of treatment (49% adrenalectomy, 51% medical treatment). Persistent cardiac organ damage was defined as presence of left ventricle (LV) hypertrophy, low LV midwall shortening, global longitudinal strain and/or enlarged left atrium both at baseline and at follow-up. Results: At one year, a significant regression of LV hypertrophy was observed in surgically (44 vs. 22%, P= 0.039), but not in medically treated patients (60 vs. 51%, P = 0.206). The prevalence of enlarged left atrium was reduced in both groups (both P < 0.001), whereas systolic myocardial function remained unchanged. In multivariable logistic regression analysis, medical treatment [odds ratio (OR) 4.88 (95% confidence interval (CI) 1.26–18.88)] was a strong predictor of persistent LV hypertrophy independent of higher BMI [OR 1.20 (95% CI 1.04–1.38)] and presence of diabetes [OR 6.48 (95% CI 1.20–34.83), all P < 0.05]. Persistently low midwall shortening was associated with suppressed plasma renin after one year [OR 6.11 (95% CI 1.39–26.7)] and lower renal function [OR 0.96 (95% CI 0.94–0.99), both P < 0.05]. The strongest predictor of persistently low global longitudinal strain was higher HbA1c [OR 2.37 (95% CI 1.12–5.02), P = 0.024]. Conclusion: Persistent cardiac organ damage was more common in the medical treatment group and associated with incomplete aldosterone blockade, impaired renal function and presence of metabolic comorbidities.publishedVersio