Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

BACKGROUND: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. METHODS: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. RESULTS: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. CONCLUSIONS: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Time-dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia.

PURPOSE: The aim of this study was to explore the time-course of hospitalization due to hyponatremia associated with omeprazole and esomeprazole. METHODS: In this register-based case-control study, we compared patients hospitalized with a main diagnosis of hyponatremia (n = 11,213) to matched controls (n = 44,801). We used multiple regression to investigate time-related associations between omeprazole and esomeprazole and hospitalization because of hyponatremia. RESULTS: The overall adjusted OR (aOR) between proton pump inhibitor (PPI) exposure, regardless of treatment duration and hospitalization with a main diagnosis of hyponatremia, was 1.23 (95% confidence interval CI 1.15-1.32). Exposure to PPIs was associated with a prompt increase in risk of hospitalization for hyponatremia from the first week (aOR 6.87; 95% CI 4.83-9.86). The risk then gradually declined, reaching an aOR of 1.64 (0.96-2.75) the fifth week. The aOR of ongoing PPI treatment was 1.10 (1.03-1.18). CONCLUSION: The present study shows a marked association between omeprazole and esomeprazole and hyponatremia related to recently initiated treatment. Consequently, newly initiated PPIs should be considered a potential culprit in any patient suffering from hyponatremia. However, if the patient has had this treatment for a longer time, the PPI should be considered a less likely cause.

Cardiovascular risk in Cuban adolescents and young adults with congenital adrenal hyperplasia.

BACKGROUND: Hyperandrogenism and supraphysiologic glucocorticoid replacement may lead to subclinical atherosclerosis in people with congenital adrenal hyperplasia (CAH) and predispose the development of cardiovascular diseases from an early age. OBJECTIVES: To determine if cardiometabolic risk factors and subclinical atherosclerosis are more frequent in patients with CAH due to 21-hydroxylase deficiency (21OHD) and if there is an association with clinical, hormonal and treatment of 21OHD. MATERIAL AND METHODS: A descriptive prospective cross-sectional study exploring clinical variables, biochemical, hormonal variables, endothelial dysfunction (flow-mediated dilation < 5%) and carotid intima media thickness (≥ 95 percentile in adolescents and ≥ 75 percentile in adults) and epicardial fat. Adolescents and young patients with 21OHD were compared with controls matched by age, sex, body mass index and Tanner stage. RESULTS: Forty four subjects (22 with CAH), 36 (82%) females, with a mean age of 17.1 ± 5.5 years (range 10-30 years) were included. Family history revealed diabetes, hypertension, and hypercholesterolemia with high frequencies in both groups. The blood pressure was similar in both groups. Blood glucose levels were lower and triglycerides higher in patient (both p < 0.01). Epicardial fat was similar between groups and in patients with CAH it was related to cholesterol levels ​​(r = 0.679, p < 0.01), time since CAH diagnosis (r = 0.462, p = 0.03) and glucocorticoid dose (r = 0.499, p = 0.04). Carotid intima media thickness (CIMT) had a tendency to be increased in patients (p = 0.07) and was directly related to 17-hydroxyprogesterone (r = 0.510, p = 0.018), diastolic blood pressure (r = 0.444, p = 0.04) and the homeostatic model assessment (HOMA) index (r = 0.507, p = 0.01). Endothelial dysfunction was not different between groups. CONCLUSIONS: Some cardiometabolic risk factors were increased in patients with CAH and were associated with clinical, hormonal and treatment parameters of CAH. Cardiometabolic risk should be evaluated regularly in patients with CAH.

Transition Readiness in Adolescents and Young Adults Living With Congenital Adrenal Hyperplasia.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect cortisol biosynthesis and the need for glucocorticoid treatment is lifelong. The complexities of CAH can greatly affect teenage life and the transition from pediatric to adult care. The aim was to assess transition readiness and the impact on quality of life (QoL) as well as medication adherence rates in adolescents and young adults with CAH. METHODS: Prospective assessment of transition readiness was conducted through standardized questionnaires for adolescents and young adults (aged 16-35 years). Four open-ended questions on self-care were summarized in adolescents (aged 18-19 years) and their parents. Transition readiness was assessed using a modified CAH specific questionnaire: "Transition preparation and readiness to transfer from pediatric to adult care" with a cutoff level of >25 defined as good transition readiness. Measurement of QoL was performed using Rand 36. Medication adherence rate was measured using the self-reported questionnaire Adherence Starts with Knowledge. RESULTS: Thirty-eight adolescents and young adults with CAH were included in the study. Transition readiness was classified as good in 26 (68%) of the participants. Good transition readiness was more frequent in participants with good medication adherence rates. A general linear model analysis showed a good transition readiness affected QoL by increasing QoL scores. CONCLUSION: Self-reported transition readiness was found in the majority of adolescents and young adults with CAH. A good medication adherence rate was associated with a better transition readiness and a good transition readiness was associated with increased QoL scores.

Hypermagnesemia in Clinical Practice.

Hypermagnesemia is a relatively uncommon but potentially life-threatening electrolyte disturbance characterized by elevated magnesium concentrations in the blood. Magnesium is a crucial mineral involved in various physiological functions, such as neuromuscular conduction, cardiac excitability, vasomotor tone, insulin metabolism, and muscular contraction. Hypomagnesemia is a prevalent electrolyte disturbance that can lead to several neuromuscular, cardiac, or nervous system disorders. Hypermagnesemia has been associated with adverse clinical outcomes, particularly in hospitalized patients. Prompt identification and management of hypermagnesemia are crucial to prevent complications, such as respiratory and cardiovascular negative outcomes, neuromuscular dysfunction, and coma. Preventing hypermagnesemia is crucial, particularly in high-risk populations, such as patients with impaired renal function or those receiving magnesium-containing medications or supplements. Clinical management of hypermagnesemia involves discontinuing magnesium-containing therapies, intravenous fluid therapy, or dialysis in severe cases. Furthermore, healthcare providers should monitor serum magnesium concentration in patients at risk of hypermagnesemia and promptly intervene if the concentration exceeds the normal range.

Adrenal trauma experience at a major tertiary centre in Sweden: Clinical and radiological findings.

BACKGROUND AND OBJECTIVE: Information on the incidence of adrenal trauma and its association with other injuries is limited. Our objective was to study the incidence of adrenal haemorrhage, its association with other injuries, clinical parameters, and long-term outcomes. PATIENTS AND MEASUREMENTS: All patients treated for severe abdominal trauma (Level 1) at Karolinska University Hospital, Solna, between January 1, 2013 and December 31, 2018 were included. Patients with a radiological picture of adrenal haematoma were selected. The injury severity score (ISS) was analysed in the entire cohort. Data were collected from the electronic medical files. RESULTS: In total, 1.7% (n = 29/1743) was affected by adrenal trauma. Right adrenal trauma (n = 20/29;69%) was more common than left (n = 6/29;21%, p < 0.01), and 10% were bilateral (n = 3/29). There was no difference in volume in right versus left adrenal trauma [(median 13 (interquartile range (IQR) (7-15) versus 8 (5-13)] ml, p = 0.30). ISS was 23.4 (17-43) in adrenal haematoma patients, higher compared with other trauma patients 16 (8-27) (n = 1714)(p < 0.001). Rib fractures, pneumothorax, and liver lacerations were the three most common findings in association with adrenal trauma. The underlying cause in 48% of the cases was falling from height (≥3 m). Biochemical data demonstrated normal sodium and potassium levels while the lowest haemoglobin level was 72 g/l. At follow-up, 4 (2-6) years after the trauma, except for three patients who died as in-patients, all other persons were still living. None seemed to have adrenal insufficiency. CONCLUSIONS: Adrenal trauma is rare and does not seem to be associated with clinical features of adrenal insufficiency, even if the bleeding is bilateral.

Ambulatory fludrocortisone suppression test in the diagnosis of primary aldosteronism: Safety, accuracy and cost-effectiveness.

OBJECTIVE: The aims of this study were to explore if the ambulatory fludrocortisone suppression test (FST) was safe, accurate and cost-effective. CONTEXT: The diagnosis of primary aldosteronism (PA) remains time-consuming and complex. The FST is used to confirm PA, but it is an in-patient test due to potentially serious complications such as hypokalemia. In Stockholm, FST has been performed since 2005 as an ambulatory procedure. DESIGN: This is a retrospective study including all patients investigated with FST in four hospitals in Stockholm, Sweden, during 2005-2019. PATIENTS/MEASUREMENTS: In total, 156 cases of ambulatory FST (FSTamb) and 15 cases of in-patient FST (FSTin) were included. FSTamb and FSTin were compared regarding health costs, clinical characteristics and laboratory results. RESULTS: No difference was found in the outcomes of FSTamb and FSTin. No severe complications were reported in FSTamb patients. No difference was found in the median value for plasma potassium on Day 5 between the two groups. Only three patients (1.9%) in the FSTamb had to repeat the test due to incomplete intake of medications. FSTamb and FSTin were equally accurate. The cost of performing FSTamb was at least 50% lower compared with FSTin ($2400 vs. $5200 per patient). The time needed for FSTamb was 60 min of physician's time and 150 min of nurse's time which were lower than the 5 days in FSTin. CONCLUSIONS: Ambulatory FST is safe and accurate and can be performed with significantly less healthcare costs compared to FSTin.

The impact of adherence and therapy regimens on quality of life in patients with congenital adrenal hyperplasia.

OBJECTIVE: Varying outcomes regarding the quality of life (QoL) have been reported in patients with congenital adrenal hyperplasia (CAH). To assess the impact of adherence rate to medical therapy regimens on QoL in patients with CAH. PATIENTS: Adolescents and adults aged 15-72 years with CAH due to 21-hydroxylase deficiency at Karolinska University Hospital, Stockholm, Sweden. MEASUREMENTS: QoL was assessed using the Addison QoL (n = 72) and RAND 36 questionnaires (n = 75). Adherence to therapy regimens was measured using the Adherence Starts with Knowledge questionnaire (ASK-12). Associations between QoL, type of glucocorticoid therapy prescribed and ASK-12 results were examined. Results were compared to reference RAND 36 data obtained from a representative sample from the general Swedish population. RESULTS: A good adherence rate to therapy regimens and a younger age were key factors for a better QoL in study participants with CAH. Younger patients on hydrocortisone and with good adherence had higher RAND 36 scores than older patients on prednisolone independently adherence. Participants with classic CAH (both the salt-wasting and simple virilizing form) reported higher QoL than those with nonclassic CAH. Patients with CAH, especially nonclassic, more frequently reported an impaired QoL than the general population, especially regarding limitations related to body pain, vitality and mental health. CONCLUSION: A poor adherence rate to therapy regimens, rather than type of glucocorticoid was associated with impaired QoL in adolescents and adults with CAH.

Characteristics and health outcomes of patients hospitalised with hypomagnesaemia: a retrospective study from a single centre in the Northern Territory of Australia.

BACKGROUND: Magnesium is an essential cation in the human body involved in many processes in the human body. Hypomagnesium has been linked to many poor health outcomes. AIMS: To study the clinical and biochemical characteristics and health outcomes of patients admitted and found to have hypomagnesaemia in an Australian hospital with a high proportion of Indigenous Australians. METHODS: A retrospective cohort study was conducted of all patients with hypomagnesaemia hospitalised between 1 August 2008 and 31 December 2014 at Royal Darwin Hospital. All relevant demographic, clinical and biochemical data were collected from patients' medical records. The hospital database was reviewed in January 2018 for mortality of all included patients. RESULTS: A total of 876 patients had been admitted with a confirmed diagnosis of hypomagnesaemia during the study period, with mean follow-up period of 4.0 ± 2.7 years. The mean age at admission was 52.4 ± 19.1 years, 52.2% were females and 56.5% were Indigenous Australians. Chronic kidney disease (99.7%), excessive alcohol consumption (45.7%), hypertension (43.9%) and respiratory diseases (15.0%) were the most common conditions in these patients. Hypomagnesaemia was associated with prolonged length of hospital stay. Most patients did not receive treatment for hypomagnesaemia during admission. During the follow-up period, 38.6% of patients died, and the most common causes of death were malignancies (29.9%). CONCLUSION: Hypomagnesaemia was a common and undertreated condition in hospitalised patients and was associated with poor health outcomes. Therefore, hospitals should develop guidelines for replacing and monitoring magnesium levels during hospitalisation, achieving better outcomes.

Obstructive sleep apnoea and adherence to continuous positive airway therapy among Australian women.

BACKGROUND: Clinical characteristics of women with different obstructive sleep apnoea (OSA) severity and adherence to continuous positive airway pressure (CPAP) therapy have not been previously explored. AIMS: To assess OSA prevalence, predictors, clinical and polysomnographic (PSG) characteristics and adherence to CPAP therapy among adult Australian women in a retrospective study. METHODS: All female patients who underwent a diagnostic PSG between 2014 and 2015 were included. CPAP adherence was assessed during the study period between 2018 and 2019 using multiple regression models. RESULTS: Among a total of 591 women included in this study (Aboriginal, n = 86), OSA was diagnosed in 458/591 (78%) patients; mild, moderate and severe OSA was present in 44%, 27% and 29% respectively. Older age, higher BMI and hypertension predicted the presence and severity of OSA. The Epworth Sleepiness Scale (ESS) score was not significantly different with (8 (5, 12)) or without (10 (5, 13)) OSA. PSG showed the rapid eye movement (REM) sleep-associated apnoea-hypopnea index (AHI) was higher with all severity of OSA. Adherence to CPAP therapy was noted in 171 (57%) patients; 47% mild, 57% moderate and 63% with severe OSA respectively. Three multiple regression models (clinical, PSG parameters, OSA severity, combined (clinical and PSG)) showed the combined model had the strongest predictive value and demonstrated that higher ESS and more severe oxygen desaturation were associated with CPAP adherence irrespective of OSA severity. CONCLUSIONS: Older age, higher BMI and the presence of hypertension predicted the presence of OSA. The REM sleep-related AHI was higher. Adherence to CPAP was associated with symptomatic OSA and severe oxygen desaturation.

Comparison and outcomes of emergency department presentations with respiratory disorders among Australian indigenous and non-indigenous patients.

BACKGROUND: There is sparse evidence in the literature assessing emergency department presentation with respiratory disorders among Indigenous patients. The objective of this study was to evaluate the clinical characteristics and outcomes for Indigenous Australians in comparison to non-Indigenous patients presenting to Emergency Department (ED) with respiratory disorders. METHODS: In this study, two non-contiguous one-month study periods during wet (January) and dry (August) season were reported on, and differences in demographics, respiratory diagnosis, hospital admission, length of hospital stay, re-presentation to hospital after discharge and mortality between Australian Indigenous and non-Indigenous patients was assessed. RESULTS: There were a total of 528 respiratory ED presentations, 258 (49%) during wet and 270 (51%) in dry season, from 477 patients (52% female and 40% Indigenous). The majority of ED presentations (84%) were self-initiated, with a difference between Indigenous (80%) and non-Indigenous (88%) presentations. Indigenous presentations recorded a greater proportion of transfers from another healthcare facility compared to non-Indigenous presentations (11% vs. 1%). Less than half of presentations (42%) resulted in admission to the ward with no difference by Indigenous status. Lower respiratory tract infections were the most common cause of presentation (41%), followed by airway exacerbation (31%) which was more commonly seen among Indigenous (34%) than non-Indigenous (28%) presentations. Almost 20% of Indigenous patients reported multiple presentations to ED compared to 1% of non-Indigenous patients, though mortality on follow up did not differ (22% for both). CONCLUSIONS: The results of this study may be an avenue to explore possibilities of implementing programs that may be helpful to reduce preventable ED presentation and recurrent hospitalisations among Indigenous population.

Incidence, patterns, risk factors and clinical outcomes of intravenous acyclovir induced nephrotoxicity.

Objectives: Acyclovir is approved to treat herpes simplex virus (HSV) type 1, type 2 and varicella-zoster virus. It is mainly eliminated via the kidneys, for which drug crystals accumulation might lead to nephrotoxicity. This study aimed to determine the incidence, risk factors, preventive measures, and clinical outcomes of acyclovir induced-nephrotoxicity. Methods: This is a retrospective cohort study of patients >12 years of age at Sultan Qaboos University Hospital (SQUH) receiving IV acyclovir therapy between January 2016 and December 2020. Results: Out of 191 included patients, 40 (20.1%) developed acyclovir induced-nephrotoxicity. Age (per year older: OR 1.04, 95 %CI 1.01-1.07), total duration of treatment (per day OR1.19, 95 %CI 1.06-1.33), and concomitant use of vancomycin (OR 5.96, 95 %CI 1.87-19.01) were significant independent risk factors for acyclovir induced-nephrotoxicity development. Nine patients (4.5%) died during the same hospitalization, including those three patients who required renal replacement therapy (1.5%). Conclusion: Frequent monitoring of kidney function for older patients with concurrent use of vancomycin and IV hydration is essential to prevent IV acyclovir induced-nephrotoxicity. Antimicrobial stewardship is a crucial method to reduce the duration of treatment with IV acyclovir as appropriate.

First insights into the genetics of 21-hydroxylase deficiency in the Roma population.

BACKGROUND: 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with an incidence of 1:10,000-1:20,000 and is the result of various mutations in the CYP21A2 gene. 21OHD has been described in many different populations, but it has not been studied in Roma individuals so far. The aim of the study was to analyse the genotype in Roma patients with 21OHD and the prevalence of the disease in the Roma population of North Macedonia. METHODS: Molecular analysis of the nine most frequent CYP21A2 mutations in all known Roma patients with CAH in North Macedonia, relatives and healthy individuals of Roma ancestry, using the PCR/ACRS method. RESULTS: Ten Roma patients with 21OHD were identified, of which nine had the salt-wasting and one had the simple virilizing form. Calculated incidence of 21OHD in the North Macedonian Roma population was 1:3375. Interestingly, 9/10 patients (90%) were homozygous for the In2G splicing mutation (293-13A/C > G). Standard therapy with hydrocortisone and fludrocortisone had been introduced according to the guidelines. In 16 healthy relatives investigated for CYP21A2 mutations, heterozygosity for the In2G mutation was detected in 13/32 (40.6%) alleles. In 100 healthy Roma individuals, none related to the analysed families, no CYP21A2 mutations were detected. CONCLUSION: The Roma population in North Macedonia had a very high incidence of classic 21OHD. Almost all patients had the severe salt-wasting form and the In2G/In2G genotype.

Non-thiazide diuretics and hospitalization due to hyponatraemia: A population-based case-control study.

OBJECTIVE: Diuretics are often implicated in hyponatraemia. While thiazides constitute one of the most common causes of hyponatraemia, data on loop diuretics and potassium-sparing agents are limited and partly conflicting. The objective of this investigation was to study the association between use of different types of non-thiazide diuretics and hospitalization due to hyponatraemia. DESIGN, PATIENTS AND MEASUREMENTS: This was a register-based case-control study on the adult Swedish population. By linking national registers, patients hospitalized with a principal diagnosis of hyponatraemia (n = 11,213) from 1 October 2005 through 31 December 2014 were compared with matched controls (n = 44,801). Multivariable logistic regression, adjusted for multiple confounders, was used to analyse the association between use of diuretics and hyponatraemia. In addition, newly initiated use (≤90 days) and ongoing use were examined separately. RESULTS: Adjusted odds ratios (aORs) (95% CI) were 0.61 (0.57-0.66) for the use of furosemide, 1.69 (1.54-1.86) for the use of amiloride and 1.96 (1.78-2.18) for the use of spironolactone and hospitalization due to hyponatraemia. For newly initiated therapy, aORs ranged from 1.23 (1.04-1.47) for furosemide to 3.55 (2.75-4.61) for spironolactone. The aORs for ongoing use were 0.52 (0.47-0.57) for furosemide, 1.62 (1.47-1.79) for amiloride and 1.75 (1.56-1.98) for spironolactone. CONCLUSIONS: Ongoing use of furosemide was inversely correlated with hospitalization due to hyponatraemia, suggesting a protective effect. Consequently, if treatment with furosemide precedes the development of hyponatraemia by some time, other causes of hyponatraemia should be sought. Spironolactone and amiloride may both contribute to hyponatraemia; this effect is most prominent early in treatment.

Assessment of medication adherence in children and adults with congenital adrenal hyperplasia and the impact of knowledge and self-management.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is caused by a deficiency of one of the enzymes required for cortisol biosynthesis. The disease is classified as either classic (severe phenotype), subdivided into simple virilizing (SV) and salt-wasting (SW), or non-classic (NC) CAH. The treatment regime involves life-long glucocorticoid replacement, especially in classic phenotype. OBJECTIVES: We aimed to assess medication adherence, endocrine knowledge and self-management in patients with CAH and to compare patients' and physicians' assessments of medication adherence. METHODS: A prospective cross-sectional study of 108 patients with CAH (52 children and 56 adults) and 45 parents/caregivers. Two adherence measures were used, a self-reported questionnaire named Adherence Starts with Knowledge (ASK-12) with a cut-off level > 22 defined as poor adherence rate, and an assessment by a physician based on growth rate, 17-hydroxyprogesterone profile, and medical history, ranked using a five-point Likert scale. Measurements of the patients'/parents' knowledge and self-management were performed using Endocrine Society Clinical Practice Guidelines. RESULTS: Self-reported medication adherence was good with 74% of the participants reported good adherence with higher adherence in patients with the SW form. The highest endocrine knowledge and self-management were found in parents compared with children and adults with classic CAH. There was 30% discordance between the assessments by a physician and the self-reported ASK-12 scores independent of the severity of CAH. CONCLUSION: Patients and endocrinologists reported high medication adherence, however, discordance was found in 30% of the studied patients. Patients with the more severe form of CAH had higher adherence rates and demonstrated good endocrine knowledge/self-management.

Association between lipid-lowering agents and severe hyponatremia: a population-based case-control study.

PURPOSE: Drug-induced hyponatremia is common, with medications from many drug-classes implicated. Lipid-lowering agents are among the most prescribed drugs. Limited evidence suggests an inverse association between statins and hyponatremia, while data on other lipid-lowering agents is absent. The objective of this investigation was to study the association between lipid-lowering drugs and hospitalization due to hyponatremia. METHODS: This was a register-based case-control study of the general Swedish population. Those hospitalized with a main diagnosis of hyponatremia (n = 11,213) were compared with matched controls (n = 44,801). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between severe hyponatremia and the use of lipid-lowering drugs. RESULTS: Unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.28 (1.22-1.35) for statins, 1.09 (0.79-1.47) for ezetimibe, 1.38 (0.88-2.12) for fibrates, and 2.12 (1.31-3.35) for resins. After adjustment for confounding factors the adjusted odds ratios (95% CI) compared with controls were 0.69 (0.64-0.74) for statins, 0.60 (0.41-0.86) for ezetimibe, 0.87 (0.51-1.42) for fibrates, and 1.21 (0.69-2.06) for resins. CONCLUSIONS: Use of statins and ezetimibe was inversely correlated with severe hyponatremia. Consequently, these drugs are unlikely culprits in patients with hyponatremia, and they appear safe to initiate in hyponatremic patients. A potential protective effect warrants further studies on how statins and other lipid-lowering drugs are linked to dysnatremias.

Association between newly initiated thiazide diuretics and hospitalization due to hyponatremia.

PURPOSE: Thiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden. METHODS: Population-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides. RESULTS: Individuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28-89). The associations gradually declined reaching an aOR of 2.9 (2.7-3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia. CONCLUSIONS: Thiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.

The epidemiology of primary and secondary adrenal malignancies and associated adrenal insufficiency in hospitalised patients: an analysis of hospital admission data, NSW, Australia.

BACKGROUND: Adrenal insufficiency (AI) causes considerable morbidity but may remain undiagnosed in patients with adrenal malignancy (AM). The epidemiology of AI and adrenal crises (AC) in AM is uncertain. METHODS: This was a retrospective study examining hospital admission data from 2006 to 2017. All admissions to all hospitals in NSW, Australia over this period with a principal or comorbid diagnosis of an adrenal malignancy were selected. Data were examined for trends in admissions for AM and associated AI/AC using population data from the corresponding years. RESULTS: There were 15,376 hospital admissions with a diagnosis of AM in NSW over the study period, corresponding to 1281 admissions/year. The AM admission rate increased significantly over the study period from 129.9/million to 215.7/million (p < 0.01). An AI diagnosis was recorded in 182 (1.2%) admissions, corresponding to an average of 2.1/million/year. This rate increased significantly over the years of the study from 1.2/million in 2006 to 3.4/million in 2017 (p < 0.01). An AC was identified in 24 (13.2%) admissions with an AI diagnosis. Four patients (16.7%) with an AC died during the hospitalisation. CONCLUSION: Admission with a diagnosis of AM has increased over recent years and has been accompanied by an increase in AI diagnoses. While AI is diagnosed in a small proportion of patients with AM, ACs do occur in affected patients.

Prevalence of Nelson's syndrome after bilateral adrenalectomy in patients with cushing's disease: a systematic review and meta-analysis.

PURPOSE: Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. DATA SOURCES: Systematic literature search in four databases. STUDY SELECTION: Observational studies reporting the prevalence of NS after BA in adult patients with CD. DATA EXTRACTION: Data extraction and risk of bias assessment were performed by three independent investigators. DATA SYNTHESIS: Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22-31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27-50%). The prevalence of treatment for NS was 21% (95% CI 18-26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5-1.6)] or pituitary surgery [0.6 (95% CI 0.4-1.0)]. CONCLUSIONS: Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Top End Pulmonary Hypertension Study: Understanding Epidemiology, Therapeutic Gaps and Prognosis in Remote Australian Setting.

INTRODUCTION: The Top End of Australia has a high proportion of Indigenous people with a high burden of chronic cardiac and pulmonary diseases likely to contribute to pulmonary hypertension (PH). The epidemiology of PH has not been previously studied in this region. METHODS: Patients with PH were identified from the Northern Territory echocardiography database from January 2010 to December 2015 and followed to the end of 2019 or death. Pulmonary hypertension was defined as a tricuspid regurgitation velocity ≥2.75 m/s measured by Doppler echocardiography. The aetiology of PH, as categorised by published guidelines, was determined by reviewing electronic health records. RESULTS: 1,764 patients were identified comprising 49% males and 45% Indigenous people. The prevalence of PH was 955 per 100,000 population (with corresponding prevalence of 1,587 for Indigenous people). Hypertension, atrial fibrillation, diabetes and respiratory disease were present in 85%, 45%, 41% and 39%, respectively. Left heart disease was the leading cause for PH (58%), the majority suffering from valvular disease (predominantly rheumatic). Pulmonary arterial hypertension (PAH), respiratory disease related PH, chronic thromboembolic PH (CTEPH) and unclear multifactorial PH represented 4%, 16%, 2% and 3%, respectively. Underlying causes were not identifiable in 17% of the patients. Only 31% of potentially eligible patients were on PAH-specific therapy. At census, there was 40% mortality, with major predictors being age, estimated pulmonary artery systolic pressure (ePASP) and Indigenous ethnicity. CONCLUSION: Pulmonary hypertension is prevalent in Northern Australia, with a high frequency of modifiable risk factors and other treatable conditions. Whether earlier diagnosis, interpretation and intervention improve outcomes merits further assessment.