Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study.

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.

Apparent failed and discordant adrenal vein sampling: A potential confounding role of cortisol cosecretion?

OBJECTIVE: Adrenal vein sampling (AVS) and computed tomography (CT) often show confusingly discordant lateralisation results in primary aldosteronism (PA). We tested a biochemical algorithm using AVS data to detect cortisol cosecretion as a potential explanation for discordant cases. DESIGN: Retrospective analysis from a large PA + AVS database. PATIENTS: All patients with PA and AVS, 2005-2020. MEASUREMENTS: An algorithm using biochemical data from paired AVS + CT images was devised from physiological first principles and informed by data from unilateral, AVS-CT concordant patients. The algorithm involved calculations based upon the expectation that low cortisol levels exist in adrenal vein effluent opposite an aldosterone-and-cortisol-producing adrenal mass and may reverse lateralisation due to inflated aldosterone/cortisol ratios. MAIN OUTCOMES: The algorithm was applied to cases with discordant CT-AVS lateralisation to determine whether this might be a common or explanatory finding. Clinical and biochemical characteristics of identified cases were collected via chart review and compared to CT-AVS concordant cases to detect evidence of biological plausibility for cortisol cosecretion. RESULTS: From a total of 588 AVS cases, 141 AVS + CT pairs were clear unilateral PA cases, used to develop the three-step algorithm for AVS interpretation. Applied to 88 AVS + CT discordant pairs, the algorithm suggested possible cortisol cosecretion in 40%. Case review showed that the proposed cortisol cosecretors, as identified by the algorithm, had low/suppressed adrenocorticotropic hormone levels, larger average nodule size and lower plasma aldosterone. CONCLUSIONS: Pending external validation and outcome verification by surgery and tissue immunohistochemistry, cortisol cosecretion from aldosteronomas may be a common explanation for discordant CT-AVS results in PA.

A retrospective review of the community medicine needs from osteoporosis services in Canada.

BACKGROUND: Comprehensive, real-world osteoporosis care has many facets not explicitly addressed in practice guidelines. We sought to determine the areas of knowledge and practice needs in osteoporosis medicine for the purpose of developing an osteoporosis curriculum for specialist trainees and knowledge translation tools for primary care. METHODS: This was a retrospective review of referral questions received from primary care and specialists to an academic, multi-disciplinary tertiary osteoporosis and metabolic bone clinic. There were 400 referrals in each of 5 years (2015-2019) selected randomly for review. The primary referral question was elucidated and assigned to one of 16 pre-determined referral topics reflecting questions in the care of osteoporosis and metabolic bone patients. The top 7 referral topics by frequency were determined while recording the referral source. RESULTS: The majority of referrals (71%) came from urban primary care. The most common specialists to request care included rheumatology, oncology, gastroenterology and orthopedic surgery (fracture liaison services). Primary care referrals predominantly requested assistance with routine osteoporosis assessments, bisphosphonate holidays, bisphosphonate adverse effects/alternatives, fractures occurring despite therapy and adverse changes on bone densitometry despite treatment. Specialists most often referred patients with complex secondary bone diseases or cancer. The main study limitation was that knowledge needs of referring physicians were inferred from the referral question rather than tested directly. CONCLUSION: By assessing actual community demand for services, this study identified several such topics that may be useful targets to develop high quality knowledge translation tools and curriculum design in programs training specialists in osteoporosis care.

How common is primary aldosteronism?

PURPOSE OF REVIEW: Primary aldosteronism, characterized by renin-independent aldosterone secretion from one or both adrenal glands, is the most common and modifiable form of secondary hypertension. The prevalence of primary aldosteronism is increasingly recognized to be much higher than previously thought with many cases still undetected. RECENT FINDINGS: Prior prevalence studies on primary aldosteronism have reported a wide range of estimates due to heterogeneity of both disease definitions and study populations such that it is difficult to claim a single point estimate. More recent evidence demonstrates that primary aldosteronism, as defined by conventional biochemical diagnostic criteria, is highly prevalent within populations where it is not typically considered such as mild-to-moderate hypertension, prehypertension, and even normotension. Yet, our current screening approach fails to capture many cases. Furthermore, there is mounting evidence that renin-independent aldosteronism exists as a continuum of disease that extends below the current biochemical diagnostic thresholds used to define primary aldosteronsim and has clinically relevant treatment and outcome implications for a much broader patient population. Indeed, much of what we current label as 'essential hypertension' is, in fact, renin-independent aldosterone-mediated hypertension. SUMMARY: Primary aldosteronism and milder forms of renin-independent aldosteronism are highly prevalent, yet vastly under-recognized, in the general population.

Maintained Bone Density in Young Hypoestrogenized Women with a High BMI: Case Series.

Estrogen deficiency and obesity are factors that affect bone mass in a manner that is independent and in opposing directions. Obesity favours higher bone mass and increased bone formation whereas estrogen deficiency leads to significant bone loss in leaner individuals. To report the impact of the competing effects of a hypoestrogenized state and obesity on long-term bone health, we present two cases of young chronically hypoestrogenized females whose bone parameters were assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT) and revealed a bone mineral density and microstructure that did not change despite the long history of a low estrogen state. As evidenced by the outcomes for these patients, the obesity-related effect on bone mass may be dominant when obesity is marked and appears to be highly protective even in the setting of sub-physiologic circulating estrogen. Recognition of this interaction should be considered in decisions around estrogen replacement therapy in such cases.

Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward. In sum, we provide here our conference deliberations on potassium homeostasis in health and disease, guidance for evaluation and management of dyskalemias in the context of kidney diseases, and research priorities in each of the above areas.

Moderate renal impairment does not preclude the accuracy of 24-hour urine normetanephrine measurements for suspected pheochromoctyoma.

OBJECTIVE: A 24-hour urine nor/metanephrine (urine NM-MN) measurements are a recommended first step in pheochromocytoma diagnosis. We hypothesized the presence of renal impairment (CKD) significantly confounds the results obtained in a urine NM-MN collection, giving artificially lower measurements. DESIGN: Retrospective review of a comprehensive laboratory database with all urine NM-MN results from Southern Alberta from 2010 to 2018 (n = 15 505). After excluding high probability pheochromocytoma cases, results from patients with three levels of CKD (n = 796) were compared to those without CKD to determine the potential CKD effect. PATIENTS: All patients having urine NM-MN collection during the time period, irrespective of ordering physician or test indication. MEASUREMENTS: Urine NM-MN was measured by liquid chromatography-tandem mass spectrometry and glomerular filtration rate determined within a median of 1.9 days, as estimated by CKD-EPI equation. RESULTS: In subjects with mild-to-moderate renal impairment, there was no continuous gradient between subnormal renal function and urine NM-MN measures. When the estimated GFR was < 15 mL/min/m2 , the hypothesized effect on lowered urine NM-MN became apparent. CONCLUSIONS: A 24-hour urine NM-MN measurement is unlikely to be affected by mild-to-moderate renal impairment and may be used as a reliable diagnostic test. With more advanced renal impairment, CKD-specific reference ranges or an alternative test may be needed.

Adrenal vein sampling: External validation of multinomial regression modelling and left adrenal vein-to-peripheral vein ratio to predict lateralization index without right adrenal vein sampling.

BACKGROUND: Adrenal vein sampling (AVS) failure is mainly due to right adrenal vein unavailability. Multinomial regression modelling (MRM) and left adrenal vein-to-peripheral vein ratio (LAV/PV) were proposed to predict the lateralization index without the right AVS. OBJECTIVE: To assess external validity of MRM and LAV/PV to predict lateralization index when right adrenal vein sampling is missing. DESIGN: Diagnostic retrospective study. PATIENTS: Development and validation cohorts included AVS of 174 and 122 patients, respectively, from 2 different centres. MEASUREMENTS: Development and validation cohort data were used, respectively, for calibration and for validation of MRM and LAV/PV to predict the lateralization index without the right adrenal vein sampling. Sensitivity and specificity of MRM and LAV/PV were compared between both centres at different pre-established specificity thresholds based on receiver operating characteristic curves generated from the development cohort data. RESULTS: At a specificity threshold of 95% set in the development cohort, specificity values exceeded 90% (range, 90.6%-98.8%) for all verified MRM and LAV/PV models in the validation cohort. Corresponding sensitivities for MRM and LAV/PV, respectively, range from 54.1% to 83.7% and 32.8% to 88.4% for the development cohort compared to 33.3%-87.5% and 2.8%-79.2% for the validation cohort. Overall, diagnostic accuracy of both methods was higher to detect right (82.8%-93.5%) than left (70.2%-80.6%) lateralization index status in both centres. CONCLUSIONS: Minimal changes in specificity from development to validation cohorts validate the use of MRM and LAV/PV to predict the lateralization index when the right AVS is missing. Both methods had better accuracy for right than left lateralization detection.

At Odds About the Odds: Women's Choices to Accept Osteoporosis Medications Do Not Closely Agree with Physician-Set Treatment Thresholds.

BACKGROUND: Osteoporosis guidelines recommend pharmacologic therapy based on 10-year risk of major osteoporotic fracture (MOF) and hip fracture, which may fail to account for patient-specific experiences and values. OBJECTIVE: We aimed to determine whether patient decisions to initiate osteoporosis medication agree with guideline-recommended intervention thresholds. DESIGN AND PARTICIPANTS: This prospective cohort study included women aged ≥ 45 with age-associated osteoporosis who attended a group osteoporosis self-management consultation at a tertiary osteoporosis center. INTERVENTION: A group osteoporosis self-management consultation, during which participants received osteoporosis education and then calculated1 their 10-year MOF and hip fracture risk using FRAX and2 their predicted absolute fracture risk with therapy (assuming 40% relative reduction). Participants then made autonomous decisions regarding treatment initiation. MAIN MEASURES: We evaluated agreement between treatment decisions and physician-set intervention thresholds (10-year MOF risk ≥ 20%, hip fracture risk ≥ 3%). KEY RESULTS: Among 85 women (median [IQR] age 62 [58-67]), 27% accepted treatment (median [IQR] MOF risk, 15.1% [9.9-22.0]; hip fracture risk, 3.3% [1.3-5.3]), 46% declined (MOF risk, 9.5% [6.5-11.6]; hip fracture risk, 1.8% [0.6-2.3]), and 27% remained undecided (MOF risk, 14.0% [9.8-20.2]; hip fracture risk, 4.4% [1.7-4.9]). There was wide overlap in fracture risk between treatment acceptors and non-acceptors. Odds of accepting treatment were higher in women with prior fragility fracture (50% accepted; OR, 5.3; 95% CI, 1.9-15.2; p = 0.0015) and with hip fracture risk ≥ 3% (32% accepted; OR, 3.6; 95% CI, 1.4-9.2; p = 0.012), but not MOF risk ≥ 20% (47% accepted; OR, 3.0; 95% CI, 1.0-8.5; p = 0.105). CONCLUSIONS: Informed decisions to start osteoporosis treatment are highly personal and not easily predicted using fracture risk. Guideline-recommended intervention thresholds may not permit sufficient consideration of patient preferences.

Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion.

BACKGROUND: Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. METHODS: We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT. RESULTS: Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 µg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. CONCLUSION: Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve.

Neuroendocrine Dysfunction in a Young Athlete With Concussion: A Case Report.

An 18-year-old female ringette and basketball player presented to our sport concussion clinic 27 months after concussion with fatigue, headache, exercise intolerance, polyuria, nocturia, and difficulties concentrating. Her history was remarkable for 4 previous concussions. Her neurologic examination was normal. Neuroendocrine screen including thyroid function, morning cortisol, glucose, and insulin-like growth factor-1 (screening test for growth hormone deficiency) were normal. Further testing for growth hormone deficiency with an insulin hypoglycemia test revealed severe growth hormone deficiency. Urine and serum electrolytes were borderline normal, suggesting partial diabetes insipidus. Treatments with growth hormone replacement lead to complete recovery. This case highlights the importance of maintaining a high index of suspicion for neuroendocrine abnormalities in athletes with persistent symptoms after sport concussion. Symptoms can be nonspecific and go undiagnosed for years, but appropriate recognition and treatment can restore function.

A clinical prediction score for diagnosing unilateral primary aldosteronism may not be generalizable.

BACKGROUND: A published clinical prediction score indicated that a unilateral adrenal adenoma and either hypokalemia or an estimated glomerular filtration rate of 100 ml/min/1.73 m2 was 100% specific for unilateral primary aldosteronism. This study aimed to validate this score in a separate cohort of patients with primary aldosteronism. METHODS: A review of patients with primary aldosteronism from June 2005 to July 2013 at a single center's hypertension clinic. One hundred twelve patients with primary aldosteronism underwent successful adrenal vein sampling and the 110 patients with full data available were included in the final analysis. Adrenal vein sampling was performed all patients desiring surgery by the simultaneous collection of sample prior to and 15 minutes after a cosyntropin infusion with a 3:1 aldosterone/cortisol ratio diagnosing unilateral primary aldosteronism. The derived score was applied to the cohort. Sensitivity and specificity were calculated for clinical prediction score of ≥5 points. RESULTS: There were 64 patients found to have unilateral primary aldosteronism and 48 had bilateral disease. A score ≥5 points had 64% sensitivity (95% confidence interval, 51-76) and 85% specificity (95% confidence interval, 71-94) for unilateral disease. Four patients had lateralization of primary aldosteronism to the side contralateral to the adenoma. CONCLUSIONS: The 100% specificity of the score for the unilateral origin of primary aldosteronism was not validated in this cohort with a score of ≥5 points. At best, a high score in this prediction rule may be an additional tool for helping to confirm a decision to offer patients adrenal vein sampling.

Addison's Disease in Evolution: An Illustrative Case and Literature Review.

OBJECTIVE: To present a case of symptomatic autoimmune adrenal insufficiency with initially normal serum cortisol and to caution about limitations of the current diagnostic algorithm for adrenal insufficiency, which does not reflect the pathophysiology of early disease. METHODS: We describe the clinical presentation and relevant investigations of a patient ultimately found to have Addison's disease, which is followed by a focused review of the literature. RESULTS: A 41-year-old Caucasian woman with autoimmune hypothyroidism, premature ovarian failure, and microscopic colitis presented with nausea, salt craving, increased skin pigmentation, and postural hypotension. Initial bloodwork revealed a normal morning cortisol of level of 19.2 µg/dL (normal, 7.2 to 25 µg/dL) but an adrenocorticotropic hormone (ACTH) level 10 times normal, at 513.6 pg/mL (normal, <52.5 pg/mL). Her potassium was normal, but her aldosterone level was 4.12 ng/dL (normal, 12.3 to 62.5 ng/dL) and her renin activity was increased (23.0 mg/dL/hour; normal, <6.0 mg/dL/hour). Six weeks after initial presentation, she was found to have anti-adrenal antibodies. It was not until 10 weeks after her initial symptomatic presentation that her morning cortisol level was found to be subnormal and a formal diagnosis of adrenal insufficiency was made. CONCLUSION: The present case and literature review reveal that common diagnostic approaches will miss patients with (possibly symptomatic) early adrenal insufficiency. We suggest that serum ACTH level testing or tests of mineralocorticoid function be included in the initial step of investigation for suspected primary adrenal insufficiency.

Biomarkers to Guide Medical Therapy in Primary Aldosteronism.

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin-biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed.

Cushing syndrome from an ACTH-producing pheochromocytoma or paraganglioma: structured review of 94 cases.

Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are rare neuroendocrine tumors that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome (CS). This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case series describing adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an adrenocorticotropin (ACTH)-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years, and females accounted for 72% of cases. A cushingoid appearance was reported in 82% of patients, and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least three-fold above normal in 74% of cases. ACTH levels were high in 88% of patients and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients, with 88% achieving a cure for both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic CS. Surgical cure is achieved in most patients, and infections are the leading cause of peri-operative mortality.