Cardiovascular abnormalities and impaired exercise performance in adolescents with congenital adrenal hyperplasia

Context: Patients with classic Congenital Adrenal Hyperplasia (CAH) are treated with lifelong glucocorticoids (GCS). Cardiovascular (CV) and metabolic effects of such therapy in adolescents have never been quantified. Objective: To investigate left ventricular (LV) morphology, function and exercise performance in adolescents with CAH. Design and Setting: cross-sectional and controlled study conducted at a tertiary referral centre. Patients: Twenty patients with classic CAH (10 females) aged 13.6±2.5 years and 20 healthy controls comparable for sex and pubertal status were enrolled in the study and compared to a group of 18 patients without CAH receiving a similar dose of GCS for Juvenile Idiopathic Arthritis (JIA). Main Outcomes Measures: Echocardiographic assessment and symptom-limited exercise testing were performed. Anthropometric, hormonal and biochemical parameters were also measured. Results: Compared to healthy controls, patients with CAH exhibited an increased BMI (p<0.001), waist-to-height ratio (p<0.001), percentage of body fat (p<0.001) as well as higher insulin concentrations and HOMA index even after adjustment for BMI (p=0.03 and p=0.05, respectively). Moreover, CAH patients exhibited an impaired exercise capacity as shown by reduced peak workload (99±27 vs 126±27 W, p<0.01) and higher systolic blood pressure response at peak (156±18 vs 132±11 mmHg, p<0.01; Δ=45±24 vs 22±10 mmHg, p=0.05) with respect to healthy controls. CAH males displayed mild LV diastolic dysfunction as documented by significant prolongation of both isovolumic relaxation time (IRT) (118±18 vs 98±11ms, p<0.05) and mitral deceleration time (MDT) (138±25 vs 111±15 ms, p<0.01). No significant differences in CV function were found between CAH and JIA patients. Conclusion: Adolescents with CAH exhibit impaired exercise performance and enhanced systolic blood pressure response during exercise. In our population, such abnormalities appear related to GCS therapy rather than CAH per se. CAH males, but no females, present mild LV diastolic dysfunction that correlates with testosterone concentrations suggesting a sex hormone related difference

Attitudes of Healthcare Workers toward Influenza Vaccination in the COVID-19 Era

none8Sani, Tommaso; Morelli, Ilaria; Sarti, Donatella; Tassinari, Giovanni; Capalbo, Maria; Espinosa, Emma; Gasperini, Beatrice; Prospero, EmiliaSani, Tommaso; Morelli, Ilaria; Sarti, Donatella; Tassinari, Giovanni; Capalbo, Maria; Espinosa, Emma; Gasperini, Beatrice; Prospero, Emili

Cardiovascular Health in Children and Adolescents With Congenital Adrenal Hyperplasia Due to 21-Hydroxilase Deficiency

Increasing evidence indicates that adults with Congenital Adrenal Hyperplasia (CAH) may have a cluster of cardiovascular (CV) risk factors. In addition, ongoing research has highlighted that children and adolescents with CAH are also prone to developing unfavorable metabolic changes, such as obesity, hypertension, insulin resistance, and increased intima-media thickness, which places them at a higher risk of developing CV disease in adulthood. Moreover, CAH adolescents may exhibit subclinical left ventricular diastolic dysfunction and impaired exercise performance, with possible negative consequences on their quality of life. The therapeutic management of patients with CAH remains a challenge and current treatment regimens do not always allow optimal biochemical control. Indeed, overexposure to glucocorticoids and mineralocorticoids, as well as to androgen excess, may contribute to the development of unfavorable metabolic and CV abnormalities. Long-term prospective studies on large cohorts of patients will help to clarify the pathophysiology of metabolic alterations associated with CAH. Meanwhile, further efforts should be made to optimize treatment and identify new therapeutic approaches to prevent metabolic derangement and improve long-term health outcomes of CAH patients

Novel Findings into AIRE Genetics and Functioning: Clinical Implications

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), formerly known as autoimmune polyendocrine syndrome type 1, is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE's function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications

IGF-I responses in young adults

BACKGROUND/AIMS: Physiological growth hormone (GH) secretion and insulin-like growth factor-I (IGF-I) levels are greater in young compared to older adults. We evaluated IGF-I levels and predictors of IGF-I responses in young adults on GH replacement. DESIGN: From the KIMS database, 310 young adults (age 15-26 years) with severe GH deficiency related to childhood-onset disease and commenced on 'adult GH replacement' were identified. 'IGF-I responses' were estimated from first-year increments in IGF-I standard deviation scores (SDS) and adjusted for GH dose. Body composition was assessed by bioimpedance in 143 patients. RESULTS: IGF-I levels increased markedly from baseline to 1 year of replacement (-3.75 ± 1.94 vs. -1.36 ± 1.86 SDS, p < 0.0001), but remained low compared to normative data despite dose titration. In multivariate models, IGF-I responses were positively associated with age [B (SE) SDS/(mg/m2); 0.52 (0.15), p = 0.0007] and BMI SDS [1.06 (0.25), p < 0.0001] and inversely associated with female gender [-4.45 (0.79), p < 0.0001] and baseline IGF-I SDS [-1.44 (0.20), p < 0.0001]. IGF-I responses were positively associated with first-year increases in lean body mass (r = 0.19, p = 0.003) and haemoglobin A1c (r = 0.15, p = 0.031). CONCLUSIONS: Low IGF-I levels in young adults on treatment may reflect suboptimal GH replacement. Identification of predictors for IGF-I responses could lead to a more appropriate replacement strategy. Association between IGF-I responses and lean body mass suggests that maintaining age-appropriate IGF-I levels is important during therapy.The study was funded by an investigator-initiated research (IIR) grant from Pfizer Inc. Pfizer provided statistical support as well as advice as to logistical aspects of interrogating the KIMS database. D Capalbo and H Simpson have nothing to declare. A Thankamony received salary support from the IIR grant and speaker honoraria from Pfizer Inc. D.B Dunger was a member of the KIGS steering committee and received consultant and speaker honoraria from Pfizer Inc. P.J Jonsson is an employee of Pfizer Inc., Sweden and provided statistical support for the study.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Karger Publishers

Unbalanced Immune System: Immunodeficiencies and Autoimmunity

Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained

Effect of initial levothyroxine dose on neurodevelopmental and growth outcomes in children with congenital hypothyroidism

We designed a multicentre open prospective randomized trial to evaluate the risk-benefit profile of two different initial treatment schemes with levothyroxine (L-T4), 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, on growth and neurodevelopmental outcomes in children with congenital hypothyroidism (CH) detected by neonatal screening to identify the best range dose to achieve optimal neurocognitive development

Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome

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CROSS-TALK BETWEEN ENDOCRINE SYSTEM AND OTHER BIOLOGICAL PATHWAYS: PHYSIOLOGICAL AND PATHOLOGICAL IMPLICATIONS IN PAEDIATRIC ENDOCRINOPATHIES

Endocrine system exerts relevant effects on multiple organs and tissues. Pleiotropic and redundant functions of circulating hormones are due to the various receptors expressed on multiple target cells. Moreover, receptors of circulating hormones share common transducing elements with receptors of many other molecules. Consequently, endocrine system participate to an integrated network of mediators that communicate and coordinate responsive cells to achive effective functions in an appropriate fashion. The presence of such a complex interplay contribute to unravel previously unappreciated functions of circulating hormones and the mechanisms of coordination and integration of several pathways. An example of this interplay is the complex interaction between endocrine and immune system. Cytokines and growth factors, in fact, after their binding to cell-surface receptos, activate common intracytoplasmatic signaling molecules. In the recent years the description of complex phenotypes, in which immunodeficiency and growth failure were associated at a different extent, greatly contributed to define how several signaling molecules play a role in both systems. As well as immunodeficiency, autoimmune diseases represent a unique model to study interactions between endocrine and immune systems. Cardiovascular system also represents a biological system higly sensitive to the effects of circulating hormones as suggested by the presence of several cardiovascular and metabolic alterations found in many endocrine diseases. In fact, patient with growth hormone deficiency as well as thyroid dysfunction, may present an increased morbidity due to cardiovascular events and an increased incidence of atherosclerosis. Aim of this project was to evaluate physiological and pathological implications of these complex molecular interactions on paediatric endocrinopathies starting from complex phenotype involving endocrine and other biological systems. To this aim, we started from the study of 3 model of complex diseases: • The model of autoimmune diseases • The model of Growth Hormone (GH) Deficiency (GHD) • The model of Congenital Hypothyroidism (CH) Moreover, during the study of patients affected with Growth Hormone and thyroid disorders we also identified new genetic causes of GH deficiency and hyperthyroidism, highlithing new insights in the genetics of endocrine diseases, as described in the last chapter of the thesis

MANAGEMENT OF ENDOCRINE DISEASE Subclinical hypothyroidism in children

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors