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BACKGROUND In patients with congenital adrenal hyperplasia (CAH) type and doses of glucocorticoids used as well as sex hormone secretion during puberty have important actions on bone mineral density (BMD) in adulthood. AIM To evaluate BMD in adult CAH patients depending on current glucocorticoid therapy and on androgen levels in adulthood and at age 16 years. METHODS We included 244 CAH patients from the dsd-LIFE cohort (women n = 147, men n = 97; salt-wasting n = 148, simple-virilizing n = 71, nonclassical n = 25) in which BMD and bloods were available. Clinical and hormonal data at age 16years were retrieved from patients' files. RESULTS Simple-virilizing women showed lower BMD compared to salt-wasting women at trochanter (0.65 ± 0.12 vs 0.75 ± 0.15 g/cm2 ; P

ObjectiveTo assess cost-effectiveness of stroke care for Aboriginal compared with non-Aboriginal patients in the Northern Territory (NT), Australia.DesignCost-effectiveness analysis using data from a cohort-based follow-up study of stroke incidents.SettingPublic hospitals in the NT from 1992 to 2013.ParticipantsIndividual patient data were extracted and linked from the hospital inpatient and primary care information systems.Outcome measuresIncremental cost-effectiveness ratios were calculated and assessed graphically. Survival time was used to measure effectiveness of stroke care, in comparison with the net costs per life-year gained, from a healthcare perspective, by applying multivariable models to account for time-dependent confounding.Results2158 patients with incident stroke were included (1171 males, 1178 aged ConclusionsStroke care for the NT Aboriginal population is at least as cost-effective as the non-Aboriginal population. Stroke care presents worthwhile and equitable survival benefits for Aboriginal patients in remote communities, notwithstanding their higher level burden of disease. These findings are relevant for healthcare planning and policy development regarding equal access to stroke care for Aboriginal patients.

Representatives for congenital adrenal hyperplasia (CAH) continue to desire early feminizing surgery in girls with 46,XX-CAH. The aim of this analysis, which included 174 46,XX- individuals with salt-wasting (SW) or simple-virilizing (SV) CAH, a female gender identity, and an age > 16 years participating in a multicenter cross-sectional clinical evaluation study (dsd-LIFE), was to evaluate the long-term results of surgery and patient-reported outcomes (PRO). The gynecological examination (n = 84) revealed some shortcomings concerning surgical feminization. A clitoris was absent in 9.5% of cases, while a clitoral hood was missing in 36.7% of cases. Though all women had large labia, they didn’t look normal in 22.6% of cases. Small labia were absent in 23.8% of cases. There was no introitus vaginae, and the urethra and vagina had no separate opening in 5.1% of cases. A mucosal lining was missing in 15.4% of cases. Furthermore, 86.2% of the women had scars at the region of their external genitalia. A vaginal stenosis was described in 16.5% of cases, and a meatal stenosis was described in 2.6% of cases. Additionally, PRO data showed a very-/high satisfaction rate of 21.3%/40.2% with cosmesis and 23.8%/38.1% with functionality, while 3.3%/10.7% showed a very-/low satisfaction with cosmesis as well as 5.6%/10.3% with functionality. The remaining women—24.6% and 23.8%—were indifferent. Satisfaction concerning sex life was very-/high in 9.6%/27.7%. In 12.0%/16.9% it was very-/low. Furthermore, 33.7% had no opinion. Furthermore, 27.0%/31.6% of the women reported that clitoriplasty, but not clitoridectomy, had a very-/positive influence on their lives, while 1.3%/8.9% felt it to be very-/negative, and 28.4% were indifferent. Vaginoplasty had a very-/positive influence in 25.7%/33.8% and a very-/negative effect in 3.6%/6.8%. 29.7% had no opinion. Additionally, 75.7% of the women preferred feminizing surgery during infancy/childhood, especially concerning clitoreduction. In conclusion, though the majority of the participants (76%) preferred early feminizing surgery and 60% described a positive effect on their lives, about 10% felt it to have been negative. About 15% of the women suffered from insufficient cosmesis and functionality after surgery. Sex life was even described as poor in nearly 30%. Therefore, the decision about early genital surgery in 46,XX-CAH girls should be considered carefully. Parents should get detailed information about possible complications of surgery and should receive support to understand that postponing surgery does not inevitably cause harm for their child. Importantly, genital surgery when performed in children should only be performed in expert centers with a specialized team including surgeons who are trained in feminizing surgery.

Contains fulltext : 244176.pdf (Publisher’s version ) (Closed access) Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

ContextP450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases.ObjectiveTo determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency, and disorders of sexual development (DSD).Data SourcesPubMed and Web of Science from January 2004 to February 2018.Study SelectionPublished case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations, and their clinical features were reported.Data ExtractionPatient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient.Data SynthesisOf the 211 patients published in the literature, 90 were eligible for inclusion. More than 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modeling, as having significantly different skeletal malformation scores. Maternal virilization in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%), but were less common for males (46XY) with homozygous R457H mutations.ConclusionsPORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analyzing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.

Context Glucose-lowering medications have occasionally been reported to cause hyponatremia, but the evidence is scarce. Objectives To explore the association between glucose-lowering medications and severe hyponatremia. Design, setting, and participants Subjects hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Data were derived by linkage of national population-based registers. Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations, and socioeconomic factors was used to explore the association between hospitalization for hyponatremia and the use of different glucose-lowering medications. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately. Main outcome measures Hospitalization due to hyponatremia. Results The unadjusted ORs (95% CI) for hospitalization due to hyponatremia were 1.41 (1.29–1.54) for insulins, 1.38 (1.27–1.50) for metformin, and 1.22 (1.07–1.38) for sulfonylureas. However, after adjustment for confounding factors the association was consistently reversed. Thus, for any glucose-lowering medication the adjusted OR was 0.63 (0.58–0.68). For insulins, metformin and sulfonylureas, adjusted ORs (95% CI) were 0.58 (0.52–0.65), 0.81 (0.72–0.90) and 0.81 (0.69–0.94), respectively. Odds ratios for newly initated medications were overall higher while those for ongoing treatment were further decreased. Thus, adjusted ORs (95% CI) for ongoing treatment with insulins, metformin, and sulfonylureas were 0.54 (0.48–0.61), 0.82 (0.73–0.91) and 0.78 (0.66–0.92). Conclusions Glucose-lowering medications did not increase the risk for hospitalization due to severe hyponatremia. In fact, the association was inverse across all investigated drugs. The association may be mediated by pharmacologic mechanisms, but the uniform effects across drug-classes suggest properties of the diabetic disease are of importance.

Context A seasonal variation in hyponatremia, with higher incidence rates during hot summer days, has been demonstrated. Whether this applies to cool temperate regions is currently unknown. Objective The aim of this study was to investigate the influence of ambient temperature on hyponatremia in the Swedish population under current and future climate scenarios. Methods This nationwide cohort study identified all patients hospitalized with a first-ever principal diagnosis of hyponatremia between October 2005 and December 2014. Incidence rates for hyponatremia were calculated as number of hospitalizations divided by person-days at risk in the adult Swedish population at a given temperature, in increments of 1 °C. Results The incidence of hyponatremia was stable at 0.3 per million person-days from −10 to 10 °C, but increased rapidly at 24-hour mean temperatures above 15 °C, with 2.26 hospitalizations per million days at the highest recorded temperature of 25 °C. Women and elderly carried the greatest risk, with an incidence of 35 hospitalizations per million days in individuals ≥ 80 years of age on the hottest days, corresponding to a 15-fold increase in incidence compared with cool days. A future 1 or 2 °C increase in mean temperature is expected to increase the incidence of hyponatremia by 6.3% and 13.9%, respectively. Conclusion The risk of hospitalization due to hyponatremia increases rapidly at temperatures above 15 °C, indicating a threshold effect. Over the next decades, rising global temperatures are expected to increase the inpatient burden of hyponatremia by approximately 10%. Strategies for protecting vulnerable groups are necessary to reduce this risk.

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30-50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team.

Offloading intervention is an important component in the management of diabetes-related foot ulcer (DFU). The NT population is unique with certain distinctive challenges. Potential advantages of and barriers to optimal offloading methods in our setting were investigated.Consecutive patients with DFU treated with offloading devices between 2003 and 2015 at the Multidisciplinary Foot Clinic (MDFC), Royal Darwin Hospital were included. The outcome measures were healing, amputation and discontinuation. Risk factors for offloading failure were studied.Total contact cast (TCC) was the most common offloading used (n = 175). The other removable non-TCC devices used were therapeutic footwear (n = 74), CamWalker (n = 35), and orthotic devices (n = 43). The overall healing rate was 88.7%. Healing rates were higher (93.2% versus 83.5%, P 0.05) and amputation rates were lower (4.0% versus 7.3%, P = 0.026) in the TCC group than in the removable non-TCC group. The mean duration of offloading was longer in the TCC group (3.6 ± 1.5 versus. 3.2 ± 1.5 months, P = 0.008). Wagner grade ≥ 2 and removable non-TCC devices were significant risk factors for offloading failure.Patients treated with TCC had higher healing rates than those treated with removable non-TCC devices. The duration of offloading was longer than reported in other studies. Higher Wagner grade and removable non-TCC devices were risk factors for offloading failure. Non-removable offloading devices are the first choice in diabetes-related neuropathic ulcers.

Background: The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH. Summary: This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed. Key Messages: The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages.

There have been increased reports of orthostatic intolerance post-bariatric surgery. However, the prevalence, pathophysiology and long-term outcomes have not been well described. Therefore, we sought to summarize evidence of orthostatic intolerance after bariatric surgery. We conducted a systematic review using PubMed, Scopus, CINAHL, Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify relevant articles from the date of inception until 1st April 2020. Study selection, data extraction and quality assessment of the included studies were performed independently by two reviewers. The findings of the included studies were narratively reported. When feasible, a meta-analysis was done to summarize the relevant results. We included 20 studies (n = 19 843 participants) reporting findings of 12 prospective cohort studies, 5 retrospective cohort studies, 2 cross-sectional studies and one randomized controlled trial. The 5-year cumulative incidence of orthostatic intolerance was 4.2% (one study). Common clinical presentations of orthostatic intolerance were lightheadedness, dizziness, syncope and palpitation. The pooled data suggested improvement in overall cardiac autonomic function (sympathetic and parasympathetic) post-bariatric surgery. In addition, a significant systolic blood pressure drop may reflect a reset of the balance between the sympathetic and parasympathetic nervous systems after weight loss in the pooled analysis. Existing literature on orthostatic intolerance post-bariatric surgeries was limited or of low quality, and larger studies are needed to know the true incidence of orthostatic intolerance post-bariatric surgeries and the pathophysiology. We found one study reporting the 5-years cumulative incidence of orthostatic intolerance post-bariatric surgeries as only 4.2%. This could challenge the idea of increased orthostatic intolerance prevalence post-bariatric surgeries. Registration The review protocol was registered at the International Prospective Register of Systemic Reviews PROSPERO (CRD42020170877).

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.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.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.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%).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.

Magnesium is the fourth most abundant mineral in the human body, which facilitates more than 300 enzymatic reactions. Magnesium is essential for nucleic material and protein synthesis, neuromuscular conduction, cardiac contractility, energy metabolism, and immune system function. Gastrointestinal system and kidneys closely regulate magnesium absorption and elimination to maintain adequate storage of magnesium. Magnesium deficiency has been linked to many diseases and poor health outcomes. Magnesium has also been proven to be an effective therapeutic agent in many diseases, such as bronchial asthma, cardiac arrhythmia, and pre-eclampsia.

Purpose Recently published papers have demonstrated that particularly in untreated individuals, clinical parameters more often associate with thyroid hormone, particularly free thyroxine (FT4), levels than with thyrotropin (TSH) levels. Clinical and research assessments of the thyroid state of peripheral tissues would therefore be more precise if they were based on FT4 levels rather than on TSH levels. In this paper we describe implications of, and opportunities provided by, this discovery. Conclusions The FT4 level may be the best single test of thyroid function. The addition of free triiodothyronine (FT3) and TSH levels would further enhance test sensitivity and distinguish primary from secondary thyroid dysfunction respectively. There are opportunities to reconsider testing algorithms. Additional potential thyroidology research subjects include the peripheral differences between circulating FT4 and FT3 action, and outcomes in patients on thyroid replacement therapy in terms of thyroid hormone levels. Previously performed negative studies of therapy for subclinical thyroid dysfunction could be repeated using thyroid hormone levels rather than TSH levels for subject selection and the monitoring of treatment. Studies of outcomes in older individuals with treatment of high normal FT4 levels, and pregnant women with borderline high or low FT4 levels would appear to be the most likely to show positive results. There are fresh indications to critically re-analyse the physiological rationale for the current preference for TSH levels in the assessment of the thyroid state of the peripheral tissues. There may be opportunities to apply these research principles to analogous parameters in other endocrine systems.

Purpose Several studies have reported an association between hyponatremia and lethality. However, it remains elusive whether hyponatremia independently contributes to lethality. The aim of the study was to investigate associations between hyponatremia and lethality and differences in lethality between men and women hospitalized due to hyponatremia. Methods Four registries were utilized in this population-based retrospective study: The National Patient Registry, the Cause of Death Register, the Swedish Prescribed Drug Register and the Total Population Register (NPR) from which the controls were sampled. All hospitalized patients with a first-ever principal ICD10 diagnosis of hyponatremia or syndrome of inappropriate ADH secretion in the NPR between 1 October 2005 and 31 December 2014 were defined as cases. Cox regression with adjustment for potential confounders was used. Results 14,359 individuals with a principal diagnosis of hyponatremia, and 57,382 matched controls were identified. Median age was 76 years and the majority were women (72%). Median age for women and men was 79 and 68 years, respectively. Adjusted hazard ratios (and 95% CI) for lethality in those with hyponatremia compared with controls were for the entire population 5.5 (4.4–7.0) and in the subgroup free from previously known underlying disease 6.7 (3.3–13.3). Lethality in women with hyponatremia was lower compared with men: HR: 0.56 (0.49–0.64). In the healthier group the lethality remained lower for women: HR: 0.49 (0.34–0.71). Conclusions Patients hospitalized due to hyponatremia faced an increased subsequent lethality that was independent of concomitant disease. This increase was nearly twice as large among men compared with women.

Takotsubo syndrome (TS), also known as neurogenic stunned myocardium or broken heart syndrome, is a recognized acute cardiac syndrome. In about 70% of cases, the syndrome is preceded by an emotional or a physical stressor. Among the innumerable physical trigger factors that may induce TS are pheochromocytomas and paragangliomas (PPGLs). PPGL-associated cardiovascular complications as "myocarditis", "myocardial infarction", "reversible cardiomyopathies", and "transient repolarization electrocardiographic changes" have been described since more than 70 years. During the last two decades, dozens of cases of PPGL-induced TS have been reported. PPGLs display increased catecholamine levels, sometimes massively elevated, which may trigger TS, most likely through hyperactivation of sympathetic nervous system including the cardiac sympathetic nerve terminal disruption with norepinephrine seethe and spillover. PPGL-induced TS is characterized by a dramatic clinical presentation with hemodynamic compromise and high complication rates. The prevalence of global and apical sparing pattern of TS in PPGL-induced TS is significantly higher than in other TS populations. In this report, the associations of PPGL-induced cardiovascular complications are analyzed, and clinical features, complications, outcome and treatment of PPGL-induced TS are reviewed.

Background Lower extremity amputations (LEAs) in diabetic patients are common in the indigenous population. There is no published data from the Northern Territory. Methods All patients with diabetic foot ulcer, presenting for the first time to the multi-disciplinary foot clinic at Royal Darwin Hospital, between January 2003 and June 2015, were included. These patients were followed until 2017, or death. LEA rates over the follow-up period and the risk factors were studied. Results Of the 513 included patients, 62.8% were males and 48.2% were indigenous. The majority (93.6%) had type 2 diabetes with median diabetes duration of 7.0 years (interquartile range 3-12). During the follow-up period of 5.8 years (interquartile range 3.1-9.8), a total of 435 LEAs (16.6% major; 34.7% minor) occurred in 263 patients (mean age 57.0 ± 11.8 years). In multivariate analysis, the following variables were associated with LEAs (adjusted odds ratio (95% confidence interval)): prior LEA (4.49 (1.69-11.9)); peripheral vascular disease (2.67 (1.27-5.59)); forefoot ulcer (7.72 (2.61-22.7)); Wagner grade 2 (3.71 (1.87-7.36)); and Wagner grade 3 (17.02 (3.77-76.72)). Indigenous patients were 1.8 times more likely to have LEAs than non-indigenous patients. Indigenous amputees were approximately 9 years younger than their non-indigenous counterparts. Conclusion Half of patients presenting with diabetic foot ulcer had LEA during follow-up. Prior LEAs, peripheral vascular disease, forefoot ulcers and higher Wagner grades were independent risk factors for LEA. Indigenous patients were at higher risk for LEAs and were younger at the time of amputation.

Context Information about adrenal medullary hyperplasia (AMH) is scarce. Objective To study a large cohort of AMHs. Design, Setting, and Participants Nineteen AMH cases were compared with 95 pheochromocytomas (PCCs) without AMH. AMH without (n = 7) and with PCC (n = 12) were analyzed separately. Results Of 936 adrenalectomies, 2.1% had AMH. Mean age was 47.2 ± 15.1 years. Only two (11%) AMHs had no concurrent PCC or adrenocortical adenoma. In AMHs, a genetic syndrome was present in 58% vs 4% in PCCs (P < 0.001). The noradrenaline/metanephrine levels were lower in AMHs, whereas suppression of dexamethasone was less than in PCCs. Cushing syndrome was found in 11% of AMHs. More AMHs were found during screening and less as incidentalomas. PCC symptoms were less prevalent in AMHs. Surgical management was similar; however, fewer of the AMHs were pretreated with alpha-blockers. Adrenalectomy improved blood pressure slightly less in AMHs. The disappearance of glycemic disturbances was similar to the PPCs. During a period of 11.2 ± 9.4 years, a new PCC developed in 32% of patients with AMH, 11% died, but no PCC metastasis occurred (PCCs: 4%, P < 0.001; 14% and 5%). AMHs without PCC had milder symptoms but more often Cushing disease than patients with PCC, whereas AMH with PCC more often displayed a familiar syndrome with more PCC recurrences. Conclusion A total of 2.1% of all adrenalectomies displayed AMH. AMH seemed to be a PCC precursor. The symptoms and signs were milder than PCCs. AMHs were mainly found due to screening. Outcomes seemed favorable, but new PCCs developed in many during follow-up.

Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.

Context The prevalence of autoimmune disorders in individuals with 21-hydroxylase deficiency (21OHD) is unclear. The gene responsible, CYP21A2, is located in a highly immunologically active region. Objective To study the prevalence of autoimmune disorders in individuals with 21OHD. Design, Setting, and Participants Patients with 21OHD (n = 714) were compared with controls matched for sex, year, and place of birth (n = 71,400). Data were derived by linking National Population-Based Registers. Subgroup analyses were performed regarding phenotype and CYP21A2 genotype. Main Outcome Measures Number and type of autoimmune disorders. Results Mean age (± SD) was 29.8 ± 18.4 years. Individuals with 21OHD had more autoimmune disorders than did controls [7.4% vs 5.1%, P < 0.01; relative risk (RR) 1.47 (95% CI, 1.13 to 1.91)], especially male patients [6.8% vs 4.1%, P < 0.05; RR, 1.64 (95% CI, 1.08 to 2.49)], whereas it did not reach significance for female patients [7.9% vs 5.8%, P = 0.068; RR, 1.37 (95% CI, 0.98 to 1.92)]. Among the specific autoimmune groups and disorders, autoimmune endocrine disorders and autoimmune thyroid disorders, including Graves disease, were significantly increased in the entire cohort of patients and for male and female patients separately. Inflammatory bowel disease (IBD) and systemic connective tissue disorders did not reach significant levels for the entire cohort (P = 0.075 and 0.05, respectively), but male patients were more affected by IBD (P = 0.022). The groups with milder phenotypes and genotypes seemed to be more affected by autoimmune disorders. Conclusions 21OHD was associated with an increased prevalence of autoimmune disorders. The relatively young age of the patient cohort and possible protective effects by glucocorticoid treatment may have underestimated the risk.

Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.

Background Antipsychotics have been claimed to cause hyponatremia. The risk associated with individual antipsychotics, or groups (first-generation [FGAs] or second-generation [SGAs] antipsychotics), is not well-documented. The objective of this study was to investigate the association between antipsychotics and hospitalization due to hyponatremia. Methods The general Swedish population was the base of this register–based case–control study. Comparisons were made between patients hospitalized with a principal diagnosis of hyponatremia (n = 14,359) and matched controls (n = 57,383). Multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors was performed to investigate the association between hyponatremia and antipsychotic use. In addition newly initiated (≤90 days) or ongoing use was analysed separately. Results Compared to controls, the adjusted OR (95%CI) for hospitalization due to hyponatremia was for any antipsychotic 1.67(1.5–1.86). Individuals on FGA were more likely to experience severe hyponatremia (2.12[1.83–2.46]) than those on any SGA (1.32[1.15–1.51]). No increased risks, neither as newly initiated nor ongoing therapy, were found for risperidone (0.86[0.56–1.31] and 0.83[0.67–1.02]) and aripiprazole (1.16[0.30–4.46] and 0.62[0.27–1.34]), respectively. Conclusions There was an association between antipsychotic therapy and hospitalization due to hyponatremia. The association was stronger for FGAs than SGAs. Risperidone was not associated with an increased risk.

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.

Contains fulltext : 232500.pdf (Publisher’s version ) (Open Access) Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p

Magnesium is the fourth most abundant mineral in the human body, which facilitates more than 300 enzymatic reactions. Magnesium is essential for nucleic material and protein synthesis, neuromuscular conduction, cardiac contractility, energy metabolism, and immune system function. Gastrointestinal system and kidneys closely regulate magnesium absorption and elimination to maintain adequate storage of magnesium. Magnesium deficiency has been linked to many diseases and poor health outcomes. Magnesium has also been proven to be an effective therapeutic agent in many diseases, such as bronchial asthma, cardiac arrhythmia, and pre-eclampsia.

Introduction Secondary neoplasms in the thyroid are rare. The study aim was to provide an overview of non-thyroid tumours that metastasize to the thyroid through our institutional experience. Materials and methods This study entailed a review of the pathology database searching for patients with metastasis to the thyroid at the Karolinska University Hospital between 1992 and 2019 and review of their medical files. Results Out of 1939 surgical procedures with a histopathological diagnosis of a thyroid malignancy, 31 cases (1.6%, 65% females) with a diagnosis of metastatic epithelial neoplasms to the thyroid gland were identified. The median age at discovery of the thyroid metastasis was 68 years (range 48–85). The most common primary tumours were clear cell renal cell carcinoma (ccRCC) (36%), followed by non-small cell lung cancer (19%), oesophageal cancer (16%), head and neck malignancies (16%), malignant melanoma (10%) and unknown primary tumour (3%). The median time from the diagnosis of the primary tumour to diagnosis of the thyroid metastasis was 20 months (0–232) and was longest for patients with ccRCC (median 107 months). At 12 months after the non-thyroid metastasis diagnosis 48% had died. The longest survival was observed in ccRCC and the shortest in lung cancer. Surgical management of the metastasis was associated with improved survival (25 vs 3.8 months, p = 0.001). Conclusions Non-thyroid metastases to the thyroid were rare but should be suspected in patients with previous history of non-thyroid malignancy and a thyroid nodule. Prognosis was poor, but surgical management was beneficial in selected patients.

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.

Parathyroid lesions exhibiting a water clear cell morphology are exceedingly rare manifestations in primary hyperparathyroidism (PHPT), and the phenomenon has been reported both for uniglandular (water clear cell adenoma; WCCA) and multiglandular disease (water clear cell hyperplasia; WCCH). In all, only 24 previous descriptions of WCCA exist in the literature. Herein, we present seven cases with water clear cell morphology (6 WCCAs and 1 case of WCCH) in an institutional series of approximately 4000 parathyroid lesions spanning 29 years in a tertiary centre setting. Major histological attributes and clinical parameters associated with this morphological subtype were reviewed, and a literature search was conducted. WCCA and WCHH exhibited an institutional prevalence of 0.15% and 0.025%, respectively. All cases displayed histological hallmarks of water clear cell morphology, with cells exhibiting abundant cytoplasm filled with vacuoles. Atypical findings or unequivocal evidence of invasive behaviour were not observed. The gender distribution was 6:1 (F:M), patients were generally symptomatic with mild hypercalcaemia, and the median age at surgery was 53 years (range 38-78). The preoperative localisation was inconclusive in four of seven, and neck exploration of all four glands was undertaken in five cases. The excised WCCAs exhibited an average weight of 1215 mg, markedly higher than conventional adenomas, and all patients were cured of PHPT following parathyroidectomy. Interestingly, previous reports mirror our observations that these lesions often are large, in relation to their sizes biochemically fairly indolent, and indecisively localised using scintigraphy, providing correlations of possible clinical value when pre-operatively assessing these rare lesions.

Background Given the rarity of 11β-hydroxylase deficiency (11βOHD), there is a paucity of data about the differences in clinical and biochemical characteristics of classic (C-11βOHD) and nonclassic 11βOHD (NC-11βOHD). Objective To characterize a multicenter pediatric cohort with 11βOHD. Method The clinical and biochemical characteristics were retrospectively retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Results 102 patients (C-11βOHD, n = 92; NC-11βOHD, n = 10) from 76 families (46,XX; n = 53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female adult height was 152 cm [−1.85 SD score (SDS)] and male 160.4 cm (−2.56 SDS).None of the NC-11βOHD girls had ambiguous genitalia (C-11βOHD 100%), and none of the NC-11βOHD patients were hypertensive (C-11βOHD 50%). Compared to NC-11βOHD, C-11βOHD patients were diagnosed earlier (1.33 vs 6.9 years; P 2.2, Conclusion NC-11βOHD can escape from clinical attention due to relatively mild clinical presentation. However, steroid profiles enable the diagnosis, differential diagnosis, and subtyping of 11βOHD.

Context Congenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH. Objective We investigated whether the mortality was lower, and determined the cause of death in carriers and population controls. Design A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age. Results The overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls. Conclusion Obligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.

IntroductionThe 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.MethodsPatients 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. PH was defined as a tricuspid regurgitation velocity ≥2.75 m/s measured by Doppler echocardiography. The etiology of PH, as categorized by published guidelines, was determined by reviewing electronic health records.Results1764 patients were identified comprising 49% males and 45% Indigenous people. The prevalence of PH was 955 per 100,000 population (with corresponding prevalence of 1587 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, ePASP and Indigenous ethnicity.ConclusionPH is prevalent in Northern Australia, with a high frequency of modifiable risk factors and other treatable conditions. Whether earlier diagnosis, interpretation and intervention improves outcomes merits further assessment.

Background Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. Case presentation At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient’s medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. Conclusions For the first time, we report the detection of HPV45 in a case of ANEC. To our belief, PIK3CA mutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or the PIK3CA mutation may have contributed to the favorable outcome.

Patients with adrenal insufficiency (AI) are at risk of life-threatening illness. Medical jewellery is recommended for emergencies, but its uptake is unknown. This study assessed the use of medical jewellery among Australian AI patients aged 25 years and under.Data on the age, sex, region, and diagnosis of subscribers to the largest medical jewellery provider in Australia were analysed. Subscription rates were calculated using 2017 Australian population data.There were 666 patients aged 25 years and under in the database but only 358 (53.8%) had an active (up to date) subscription, corresponding to a subscription rate of 43.67/million or approximately 14.6% of the estimated patient population. The majority (n = 238, 66.5%) had primary AI; followed by secondary AI (n = 82, 22.9%); and the remaining patients (n = 38, 10.6%) could not be classified. Congenital adrenal hyperplasia (CAH) was the most frequent diagnosis (n = 153, 42.7%), corresponding to a subscription rate of 18.67/ million or 28.9% of the estimated number of patients with CAH. The mean age of subscribers was 15.9 (SD = 5.8) years. Only 18 (5%) patients were aged under 5 years. More females (n = 199, 55.9%) than males were active subscribers and subscription rates differed significantly by geographic area. Inactive (lapsed) subscriptions increased with age and were highest in the 20-25 year age group.Subscription rates were lower than recommended; increased with age; and were more common in females. Older age was associated with higher levels of lapsed subscriptions. Factors leading to low use and discontinuation in young adults should be addressed.

Congenital adrenal hyperplasia (CAH) was the fourth disorder added to the national Swedish neonatal screening program in 1986, and approximately 115,000 newborns are screened annually. Dried blood spot (DBS) screening with measurement of 17-hydroxyprogesterone (17OHP) is also offered to older children moving to Sweden from countries lacking a national DBS screening program. Here, we report an update on the CAH screening from January 2011 until December 2019. Results: During the study period, 1,030,409 newborns and 34,713 older children were screened. In total, 87 newborns were verified to have CAH, which gives an overall positive predictive value (PPV) of 11% and 21% for term infants. Including the five missed CAH cases identified during this period, this gives an incidence of 1:11,200 of CAH in Sweden. Among the older children, 12 of 14 recalled cases were found to be true positive for CAH. All patients were genotyped as part of the clinical follow-up and 70% of the newborns had salt wasting (SW) CAH and 92% had classic CAH (i.e., SW and simple virilizing (SV) CAH). In the group of 12 older children, none had SW CAH and two had SV CAH. Conclusion: The incidence of classic CAH is relatively high in Sweden. Early genetic confirmation with CYP21A2 genotyping has been a valuable complement to the analysis of 17OHP to predict disease severity, make treatment decisions and for the follow-up and evaluation of the screening program.

Background:Many drugs used in psychiatry have been reported to cause hyponatraemia. However, lithium may be an exception due to its potential for causing nephrogenic diabetes insipidus, but clinical data are largely absent. The objective of this investigation was to study the association between lithium therapy and hospitalization due to hyponatraemia.Methods:This study was a register-based case–control investigation of the general Swedish population. Patients hospitalized with a principal diagnosis of hyponatraemia ( n=11,213) were compared with matched controls ( n=44,801). Analyses using multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors were deployed to calculate the association between severe hyponatraemia and the use of lithium. Additionally, newly initiated (⩽90 days) and ongoing lithium therapy was studied separately.Results:Compared with controls, the unadjusted odds ratio (OR) (95% confidence interval (CI)) for hospitalization due to hyponatraemia was 1.07 (0.70–1.59) for lithium. However, after adjustment for confounding factors the risk was reduced (adjusted OR: 0.53 (0.31–0.87)). Newly initiated lithium therapy was not significantly associated with hyponatraemia (adjusted OR 0.73 (0.35–5.38)). In contrast, for ongoing therapy the corresponding adjusted OR was significantly reduced (adjusted OR: 0.52 (0.30–0.87)).Conclusions:A marked inverse association was found between ongoing lithium therapy and hospitalization due to hyponatraemia.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuro-endocrine tumors. The catecholamine surge causes paroxysmal or chronic secondary hypertension. PPGLs may present as hypertensive- or PPGL-crisis with severe life-threatening cardiac and cerebrovascular complications. PPGLs-induced cardiac manifestations have been reported with diagnoses as PPGLs-induced electrocardiogram (ECG) changes “mimicking acute myocardial infarction”, arrhythmias, myocarditis, acute coronary syndrome, dilated cardiomyopathy, and lately as takotsubo syndrome. Critical analysis of these reports reveals that most of these cardiac manifestations have certain features in common. They have a dramatic clinical presentation and are reversible if the disease is treated with appropriate medical therapy and surgical resection of the PPGL tumor. They may have the same repolarization ECG changes irrespective of the clinical cardiac diagnosis, usually associated with mild to moderate elevations of myocardial biomarkers as troponins and normal coronary arteries. The histopathological findings are usually focal or multifocal in the form hypercontracted sarcomeres and contraction band necrosis (myofibrillar degeneration) with subsequent secondary mononuclear cell infiltration. Evidences argue the PPGL caused surge of catecholamines triggers hyperactivation of the sympathetic nervous system with cardiac sympathetic nerve terminal disruption with norepinephrine spillover causing the cardiac complications. A comprehensive review of various reported cardiovascular manifestations and complications of PPGLs are presented.

Background. There are several studies that show a good genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). However, there is well-documented evidence of inconsistency in some cases. Objectives. To determine if there is a correlation between the identified mutations and the clinical manifestations of 21OHD in the Cuban population. Methods. A cross-sectional descriptive study of all patients referred for a molecular diagnosis of 21OHD in Cuba from January 2000 to December 2018. The clinical manifestations of each patient were identified and classified according to the phenotype. The CYP21A2 gene was analyzed for the presence of 5 point mutations involved in the pathogenesis of 21OHD (intron 2, deletion of 8bp, I172N, P30L, and Q318X); correlation was sought between the phenotypic characteristics and the frequencies of point mutations in the patients using the Spearman test. Results. A total of 55 patients underwent direct analysis of the CYP21A2 gene in order to determine the presence of the 5 point mutations. Point mutations were identified in 31 patients, which corresponded to 56%. A statistically significant genotype-phenotype correlation was found. Conclusions. The correlation between the detected molecular defect and the clinical expression of 21OHD was reasonable in the Cuban population, which could allow phenotypic predictions to be made from the genotype.

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.

Background: Diabetes mellitus causes a large majority of non-traumatic major and minor amputations globally. Patients with diabetes are clinically complex with a multifactorial association between diabetic foot ulcers (DFU) and subsequent lower extremity amputations (LEA). Few studies show the long-term outcomes within the cohort of DFU-associated LEA. Aim: To highlight the long-term outcomes of LEA as a result of DFU. Methods: PubMed/MEDLINE and Google Scholar were searched for key terms, "diabetes", "foot ulcers", "amputations" and "outcomes". Outcomes such as mortality, re-amputation, re-ulceration and functional impact were recorded. Peer-reviewed studies with adult patients who had DFU, subsequent amputation and follow up of at least 1 year were included. Non-English language articles or studies involving children were excluded. Results: A total of 22 publications with a total of 2334 patients were selected against the inclusion criteria for review. The weighted mean of re-amputation was 20.14%, 29.63% and 45.72% at 1, 3 and 5 years respectively. The weighted mean of mortality at 1, 3 and 5 years were 13.62%, 30.25% and 50.55% respectively with significantly higher rates associated with major amputation, re-amputation and ischemic cardiomyopathy. Conclusion: Previous LEA, level of the LEA and patient comorbidities were significant risk factors contributing to re-ulceration, re-amputation, mortality and depreciated functional status.

Objective. Several smaller studies on adrenal incidentalomas (AI) suggested an association between autonomous cortisol secretion (ACS) and mortality (Di Dalmazi Lancet Diabetes Endocrinol 2014, Debono J Clin Endocrinol Metab 2014, Patrova Endocrine 2017). However, a recent meta-analysis (9 studies, 1356 patients) could not confirm these findings (Elhassan Ann Intern Med 2019). Aim. To investigate the effects of ACS on mortality, prevalence of cardiovascular (CV) risk factors, and (CV) morbidity, in a representative cohort of AI. Design. Retrospective observational study conducted at 27 ENS@T centers from 15 countries. Methods. Inclusion criteria: AI diagnosed 1996-2015, 1 mg dexamethasone suppression test, follow-up (FU) of ≥36 months, known survival status. Exclusion criteria: clinically relevant adrenal hormone excess (i.e. Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism), known malignancy. Patient stratification: serum cortisol after dexamethasone (>5 µg/dl, ACS; 1.9-5 µg/dl, possible ACS (PACS); ≤1.8 µg/dl, non-functioning adenoma (NFA)). Definition of CV events (CVE): hospitalization due to myocardial infarction and related interventions (PTCA, surgical bypass), stroke, deep vein thrombosis, pulmonary embolism. Results. 3640 patients (57% NFA, 36% PACS, 7% ACS) were considered eligible: 64% females; median age 61 years (range 18-91); median FU 84 months (36-277) (distribution between subgroups n.s.). 352 patients died during FU. Age- and sex adjusted overall survival was significantly reduced in patients with PACS (HR 1.55; 95%CI 1.24-1.94) and ACS (1.84; 1.29-2.61). Prevalence of CV risk factors were significantly higher in PACS and ACS than in NFA (hypertension: 72, 73, 57%, p

KEY POINTS A 40-year-old Indigenous Australian woman was airlifted to hospital from a remote community. She had central chest pain, dyspnea, pedal edema and diabetic ketoacidosis, which she had developed after she stopped taking insulin because of her chest pain. Anxious to remain in her community

Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive disorder that results in little or no cortisol biosynthesis, increased production of precursor steroids, and excess production of adrenal androgens. Glucocorticoid (GC) treatment, the current standard of care for CAH, is used to correct cortisol deficiency and reduce excessive androgens. Elevated 17-hydroxyprogesterone (17OHP) is used for diagnosis and management. GC titration to achieve 17OHP Methods: TriNetX, a research network that includes electronic medical records from >37 million U.S. patients, was searched on 30Aug2019 for patients who met the following criteria: diagnosis code of E25.0 (ICD-10) or 255.2 (ICD-9); history of GC use; available 17OHP laboratory result; and ≥15 years of age (“grown”) at the most recent 17OHP assessment. Patients were categorized as “adequately controlled” (17OHP Results: Of 511 grown CAH patients, 352 were adequately controlled and 159 were poorly controlled. Mean concentrations for 17OHP were 244 and 5939 ng/dL in the adequately and poorly controlled cohorts, respectively (p Conclusions: In this retrospective analysis, patients with adequately controlled CAH (17OHP

Congenital adrenal hyperplasia (CAH) is a genetic condition of the steroidogenic enzymes in the adrenal cortex normally leading to variable degrees of cortisol and aldosterone deficiency as well as androgen excess. Exposure to androgens prenatally might lead to ambiguous genitalia. The fetal brain develops in traditional male direction through a direct action of androgens on the developing nerve cells, or in the traditional female direction in the absence of androgens. This may indicate that sexual development, including sexual orientation, are programmed into our brain structures prenatally. The objective of this study was to perform a systematic review of the literature, investigating sexual orientation in individuals with CAH. The study also aimed at identifying which measures are used to define sexual orientation across studies. The review is based on articles identified through a comprehensive search of the OVIDMedline, PsycINFO, CINAHL, and Web of Science databases published up to May 2019. All peer-reviewed articles investigating sexual orientation in people with CAH were included. Quantitative, qualitative, and mixed methods were considered, as well as self-, parent-, and third-party reports, and no age or language restrictions were enforced on publications. The present review included 30 studies investigating sexual orientation in patients with CAH assigned female at birth (46, XX) (n = 927) or assigned male at birth (46, XY and 46, XX) (n = 274). Results indicate that assigned females at birth (46, XX) with CAH had a greater likelihood to not have an exclusively heterosexual orientation than females from the general population, whereas no assigned males at birth (46, XY or 46, XX) with CAH identified themselves as non-heterosexual. There was a wide diversity in measures used and a preference for unvalidated and self-constructed interviews. Hence, the results need to be interpreted with caution. Methodological weaknesses might have led to non-heterosexual orientation being overestimated or underestimated. The methodological challenges identified by this review should be further investigated in future studies.