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.

Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma.

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

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.

Levothyroxine prescribing and laboratory test use after a minor change in reference range for thyroid-stimulating hormone.

BACKGROUND: Prescribing of levothyroxine and rates of thyroid function testing may be sensitive to minor changes in the upper limit of the reference range for thyroid-stimulating hormone (TSH) that increase the proportion of abnormal results. We evaluated the population-level change in levothyroxine prescribing and TSH testing after a minor planned decrease in the upper limit of the reference range for TSH in a large urban centre with a single medical laboratory. METHODS: Using provincial administrative data, we compared predicted volumes of TSH tests with actual TSH test volumes before and after a planned change in the TSH reference range. We also determined the number of new levothyroxine prescriptions for previously untreated patients and the rate of changes to the prescribed dose for those on previously stable, long-term levothyroxine therapy before and after the change in the TSH reference range. RESULTS: Before the change in the TSH reference range, actual and predicted monthly volumes of TSH testing followed an identical course. After the change, actual test volumes exceeded predicted test volumes by 7.3% (95% confidence interval [CI] 5.3%-9.3%) or about 3000 to 5000 extra tests per month. The proportion of patients with newly "abnormal" TSH results almost tripled, from 3.3% (95% CI 3.2%-3.4%) to 9.1% (95% CI 9.0%-9.2%). The rate of new levothyroxine prescriptions increased from 3.24 (95% CI 3.15-3.33) per 1000 population in 2013 to 4.06 (95% CI 3.96-4.15) per 1000 population in 2014. Among patients with preexisting stable levothyroxine therapy, there was a significant increase in the number of dose escalations (p < 0.001) and a total increase of 500 new prescriptions per month. INTERPRETATION: Our findings suggest that clinicians may have responded to mildly elevated TSH results with new or increased levothyroxine prescriptions and more TSH testing. Knowledge translation efforts may be useful to accompany minor changes in reference ranges.

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.

Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia.

Low bone density is a growing concern in aging men with hemophilia and may result in high-morbidity fragility fractures. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we demonstrate low trabecular and cortical bone density contributing to lower volumetric bone mineral density (BMD) at both distal radius and tibia in patients with hemophilia compared with age- and sex-matched controls. The low trabecular bone density found in hemophilia is attributed to significantly decreased trabecular number and increased separation; the lower cortical bone density results from thinner cortices, whereas cortical porosity is maintained. Microfinite element analysis from three-dimensional HR-pQCT images demonstrates that these microarchitectural deficits seen in patients with hemophilia translate into significantly lower estimated failure load (biomechanical bone strength) at the distal tibia and radius when compared with controls. In addition, an inverse association of joint score with BMD and failure load suggests the negative role of hemophilic arthropathy in bone density loss.

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.

How Good is Our Best Guess? Clinical Application of the WHO FRAX Tool in Osteoporotic Fracture Risk Determination and Treatment Decisions.

Historically, treatment decisions for osteoporosis were based on bone mineral density. However, many fractures occur in patients with T-scores outside the osteoporotic range, emphasizing the importance of multi-factorial risk assessments. The World Health Organization Fracture Risk Assessment Tool (FRAX) predicts 10-year risk of osteoporotic fracture. We hypothesized that physicians' clinical estimates of osteoporotic fracture risk would differ significantly from that calculated by FRAX. Thus, treatment decisions would differ depending whether or not physicians used FRAX. A survey consisting of five clinical scenarios was administered to 76 endocrinologists, family physicians, internists, and internal medicine residents. They were asked to estimate the osteoporotic fracture risk and decide whether they would offer preventative treatment. Their estimates were compared to the risk predicted by FRAX and national treatment threshold guidelines. The primary outcome was the difference between the participant's estimate and the FRAX-based estimate of the 10-year risk of osteoporotic fracture for each scenario. In each scenario, physicians statistically significantly over-estimated fracture risk compared to that predicted by FRAX. Estimates for hip fracture risk were 2-4 times higher than FRAX estimates. The major osteoporotic fracture risk at which participants would offer treatment varied with physician group, with endocrinologists, family physicians, and residents requiring a 10-20 % 10-year risk, while internal medicine physician thresholds ranged from 2 to 20 %. Physicians greatly over-estimated the risk of hip fracture based on clinical information. FRAX is necessary to accurately quantify risk, but because physicians varied in the level of risk required before they would offer treatment, uniform approaches to risk estimation may still not result in uniform clinical treatment decisions.