Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Tackling access and payer barriers for growth hormone therapy in Saudi Arabia: a consensus statement for the Saudi Working Group for Pediatric Endocrinology.

Prompt diagnosis and early treatment are key goals to optimize the outcomes of children with growth hormone deficiency (GHD) and attain the genetically expected adult height. Nonetheless, several barriers can hinder prompt diagnosis and treatment of GHD, including payer-related issues. In Saudi Arabia, moderate-to-severe short stature was reported in 13.1 and 11.7 % of healthy boys and girls, respectively. Several access and payer barriers can face pediatric endocrinologists during the diagnosis and treatment of GHD in Saudi Arabia. Insurance coverage policies can restrict access to diagnostic tests for GHD and recombinant human growth hormone (rhGH) due to their high costs and lack of gold-standard criteria. Some insurance policies may limit the duration of treatment with rhGH or the amount of medication covered per month. This consensus article gathered the insights of pediatric endocrinologists from Saudi Arabia to reflect the access and payer barriers to the diagnostic tests and treatment options of children with short stature. We also discussed the current payer-related challenges endocrinologists face during the investigations of children with short stature. The consensus identified potential strategies to overcome these challenges and optimize patient management.

The Risks and Challenges of Artificial Intelligence in Endocrinology.

Artificial intelligence (AI) holds the promise of addressing many of the numerous challenges healthcare faces, which include a growing burden of illness, an increase in chronic health conditions and disabilities due to aging and epidemiological changes, higher demand for health services, overworked and burned-out clinicians, greater societal expectations, and rising health expenditures. While technological advancements in processing power, memory, storage, and the abundance of data have empowered computers to handle increasingly complex tasks with remarkable success, AI introduces a variety of meaningful risks and challenges. Among these are issues related to accuracy and reliability, bias and equity, errors and accountability, transparency, misuse, and privacy of data. As AI systems continue to rapidly integrate into healthcare settings, it is crucial to recognize the inherent risks they bring. These risks demand careful consideration to ensure the responsible and safe deployment of AI in healthcare.

Influence of endocrine multidisciplinary tumor board on patient management and treatment decision making.

BACKGROUND: Multidisciplinary Tumor Boards (MDT) are used to obtain input regarding cancer management. This study assessed the impact of our institutional Endocrine MDT. METHODS: MDT notes on patients with thyroid cancer treated during 2012-2018 were abstracted retrospectively from the electronic medical record. Management change (MC) was prospectively collected by the MDT coordinator. Biannual evaluations reviewed the impact of the MDT as observed by attendees. RESULTS: MC was recommended in 47 (15%) of 286 presentations, with additional imaging being the most frequent (43%). Presentation of recurrences were more likely to result in MC (24% vs. 13% initial, p = 0.03). Overall, 98% of attendees found the conference exceeded educational expectations. About 24% reported intending to use a more evidence/guideline-based approach after attending and this trend increased over time (p = 0.002). CONCLUSION: MDT presentations led to a higher rate of MC particularly in recurrent TC patients and increased evidenced-based practice for attendees.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c < 6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

ENDOCRINOLOGY IN THE TIME OF COVID-19-2021 UPDATES: The management of diabetes insipidus and hyponatraemia.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20-30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3-5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Synacthen Stimulation Test Following Unilateral Adrenalectomy Needs to Be Interpreted With Caution.

Background: Cortisol levels in response to stress are highly variable. Baseline and stimulated cortisol levels are commonly used to determine adrenal function following unilateral adrenalectomy. We report the results of synacthen stimulation testing following unilateral adrenalectomy in a tertiary referral center. Methods: Data were collected retrospectively for 36 patients who underwent synacthen stimulation testing one day post unilateral adrenalectomy. None of the patients had clinical signs of hypercortisolism preoperatively. No patient received pre- or intraoperative steroids. Patients with overt Cushing's syndrome were excluded. Results: The median age was 58 (31-79) years. Preoperatively, 16 (44%) patients had a diagnosis of pheochromocytoma, 12 (33%) patients had primary aldosteronism and 8 (22%) patients had non-functioning adenomas with indeterminate/atypical imaging characteristics necessitating surgery. Preoperative overnight dexamethasone suppression test results revealed that 6 of 29 patients failed to suppress cortisol to <50 nmol/L. Twenty (56%) patients achieved a stimulated cortisol ≥450 nmol/L at 30 minutes and 28 (78%) at 60 minutes. None of the patients developed clinical adrenal insufficiency necessitating steroid replacement. Conclusions: Synacthen stimulation testing following unilateral adrenalectomy using standard stimulated cortisol cut-off values would wrongly label many patients adrenally insufficient and may lead to inappropriate prescriptions of steroids to patients who do not need them.

Determinants of treatment modification before and after implementation of the updated 2015 NICE guideline on type 2 diabetes: A retrospective cohort study.

AIMS: To identify patient-specific factors associated with early metformin treatment modification among type 2 diabetes patients before and after implementation of the updated 2015 NICE (National Institute for Health and Care Excellence) guideline. METHODS: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink GOLD database (2009-2016). Patients ≥ 18 years, newly treated with metformin only, during the period of valid data collection were included. The first prescription defined start of follow-up. Determinants of treatment modification in two cohorts (before and after implementation of the updated guideline) were studied by time-dependent Cox proportional hazards regression. RESULTS: After implementation of the updated guideline, patients were less likely to receive sulphonylureas (62.3% vs 41.3%) or thiazolidediones (4.7% vs 2.2%) and more likely to receive dipeptidyl peptidase-4 inhibitors (15.8% vs 27.1%) or sodium-glucose cotransporter-2 inhibitors (0.8% vs 9.9%). Some determinants influenced general practitioners' prescribing differently after implementation of the updated guideline compared to before, including a high body mass index and heart failure. CONCLUSIONS: Our results indicate that a first step towards tailored prescribing has been made. However, not all determinants that are important to consider when prescribing second-line glucose-lowering agents were of influence on general practitioners' prescribing.

A Predictive Nomogram for Red Blood Cell Transfusion in Pheochromocytoma Surgery: A Study on Improving the Preoperative Management of Pheochromocytoma.

Purpose: Surgery is the major treatment option for pheochromocytoma but carries potential risks, including hemorrhage and hemodynamic instability. Even with laparoscopic adrenalectomy, intraoperative blood transfusion happens from time to time, but few studies have investigated risk factors. For the first time we develop and validate a nomogram for prediction of red blood cell transfusion in pheochromocytoma surgery. Methods: There were 246 patients in our center and 56 patients in Peking Union Medical College Hospital, who underwent pheochromocytoma surgery, enrolled in the study. We incorporated clinical and radiological risk factors, and presented this with a nomogram. Lasso regression model was used for feature selection. Logistic regression analysis was performed to identify the odd ratios. The performance of the nomogram was assessed with respect to its discrimination, calibration and clinical usefulness. Results: Thirty-two features were reduced to five, which were phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction heart rate, tumor diameter and surgical procedure. The model showed good discrimination (C-index, 0.857; 95% CI, 0.781-0.836) and application in the validation sets also gave good discrimination (internal validation: C-index, 0.831; 95% CI, 0.750-0.822; external validation: C-index, 0.924; 95% CI, 0.766-1.000). Calibration tested with the Hosmer-Lemeshow test yielded a good agreement between prediction and observation (training P=0.358; internal validation P=0.205; external validation P=0.395). Odd ratios of phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction HR, tumor diameter and open surgery were 13.32 (95% CI, 1.48-197.38; P = 0.034), 1.04 (95% CI, 0.99-1.08; P = 0.092), 1.04 (95% CI, 1.01-1.08; P=0.006), 1.03 (95% CI, 1.02-1.06; P<0.001), 17.13 (95% CI, 5.18-78.79; P<0.001), respectively. Decision curve analysis demonstrated the clinical usefulness of the nomogram. Conclusions: This study presents a nomogram that may be used to facilitate the prediction of red blood cell transfusion in pheochromocytoma surgery and help to do the preoperative management more efficiently.

A Genetic Risk Score Improves the Prediction of Type 2 Diabetes Mellitus in Mexican Youths but Has Lower Predictive Utility Compared With Non-Genetic Factors.

Background: Type 2 diabetes (T2D) is a multifactorial disease caused by a complex interplay between environmental risk factors and genetic predisposition. To date, a total of 10 single nucleotide polymorphism (SNPs) have been associated with pediatric-onset T2D in Mexicans, with a small individual effect size. A genetic risk score (GRS) that combines these SNPs could serve as a predictor of the risk for pediatric-onset T2D. Objective: To assess the clinical utility of a GRS that combines 10 SNPs to improve risk prediction of pediatric-onset T2D in Mexicans. Methods: This case-control study included 97 individuals with pediatric-onset T2D and 84 controls below 18 years old without T2D. Information regarding family history of T2D, demographics, perinatal risk factors, anthropometric measurements, biochemical variables, lifestyle, and fitness scores were then obtained. Moreover, 10 single nucleotide polymorphisms (SNPs) previously associated with pediatric-onset T2D in Mexicans were genotyped. The GRS was calculated by summing the 10 risk alleles. Pediatric-onset T2D risk variance was assessed using multivariable logistic regression models and the area under the receiver operating characteristic curve (AUC). Results: The body mass index Z-score (Z-BMI) [odds ratio (OR) = 1.7; p = 0.009] and maternal history of T2D (OR = 7.1; p < 0.001) were found to be independently associated with pediatric-onset T2D. No association with other clinical risk factors was observed. The GRS also showed a significant association with pediatric-onset T2D (OR = 1.3 per risk allele; p = 0.006). The GRS, clinical risk factors, and GRS plus clinical risk factors had an AUC of 0.66 (95% CI 0.56-0.75), 0.72 (95% CI 0.62-0.81), and 0.78 (95% CI 0.70-0.87), respectively (p < 0.01). Conclusion: The GRS based on 10 SNPs was associated with pediatric-onset T2D in Mexicans and improved its prediction with modest significance. However, clinical factors, such the Z-BMI and family history of T2D, continue to have the highest predictive utility in this population.

Distance from the endocrinology clinic and diabetes control in a rural pediatric population.

OBJECTIVE: We analyzed the impact of geographic distance from the clinic on adherence to recommended clinic visits and diabetes control among patients with type 1 diabetes (T1D) seen in a pediatric endocrinology clinic serving a rural region in eastern North Carolina. METHODS: We retrospectively included patients with T1D age ≤20 years seen in our clinic during 2017. Outcomes were tracked until June 2018. Distance from the clinic was determined according to the zone improvement plan (ZIP) code of patient address. Visit adherence was defined based on the number of attended visits during the study period, aiming for 1 every 3 months. Glycated hemoglobin (HbA1c) was measured at the first and last visits during the review period. RESULTS: The analysis included 368 patients, of whom 218 (59%) completed at least 1 visit every 3 months. The median HbA1c was 9.1 (interquartile range [IQR]: 8.0, 10.3) at the initial visit, and 9.3 (IQR: 8.0, 11.1) at the final visit. Median distance from the clinic was 56 km (IQR: 35, 86). On multivariable logistic regression, greater distance from the clinic was associated with lower odds of visit adherence (odds ratio per 10 km: 0.93; 95% confidence interval: 0.87, 0.99; p=0.030). Neither distance to the clinic nor clinic visit adherence were associated with HbA1c. CONCLUSIONS: Patients living further away from the clinic were less likely to adhere to the recommended visit schedule, but distance was not correlated with HbA1c levels. Further work is needed to assist families living far from the clinic with adhering to recommended visits.