15 research outputs found
Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia
OBJECTIVE: Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. DESIGN: We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. METHODS: Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. RESULTS: The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5â
nmolâ
L-1 (IQR 8.3) versus 10.5â
nmolâ
L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83â
ngâ
L-1â
s-1 (IQR 1.0) to 0.48â
ngâ
L-1â
s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53â
ngâ
L-1â
s-1 (IQR 0.66) to 0.52â
ngâ
L-1â
s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9â
mmolâ
L-1 to 139.3 ± 1.8â
mmolâ
L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6â
mmolâ
L-1 to 139.3 ± 1.9â
mmolâ
L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. CONCLUSION: 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP
Perspectives in weight control in diabetes â SGLT2 inhibitors and GLP-1âglucagon dual agonism
Treatment of people with type 2 diabetes mellitus (T2D) and obesity should include glycemic control and sustained weight loss. However, organ protection and/or risk reduction for co-morbidities have also emerged as important goals. Here, we define this combined treatment approach as âweight loss plusâ and describe it as a metabolic concept where increased energy expenditure is central to outcomes. We suggest there are currently two drug classes â sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1)âglucagon dual agonists â that can facilitate this âweight loss plusâ approach. We describe evidence supporting that both classes address the underlying pathophysiology of T2D and facilitate normalization of metabolism through increased periods of energy expenditure, which effect other organ systems and may facilitate long-term cardio-renal benefits. These benefits have been demonstrated in trials of SGLT2is, and appear, to some degree, to be independent of glycemia and substantial weight loss. The combined effect of caloric restriction and metabolic correction facilitated by SGLT2i and GLP-1âglucagon dual agonists can be conceptualized as mimicking dietary restriction and physical activity, a phenomenon not previously observed with drugs whose benefits predominantly arise from absolute weight loss, and which may be key to achieving a âweight loss plusâ approach to treatment
Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia
Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises.
We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education.
Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations.
A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P †0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03).
Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children
Management Challenges in a Child with Chronic Hyponatremia: Use of V2 Receptor Antagonist
Chronic hyponatremia is very rare in children and is often seen in the setting of congestive heart failure or liver failure in adults. Here, we report an 8-year-old child with hypothalamic glioma who presented with severe hyponatremia. Initial management consisted of fluid restriction. This was very difficult for the child to follow and the child developed bizarre drinking habits requiring intervention from child psychiatry. So therapy was initiated with low dose V2 receptor antagonist under close inpatient monitoring. While initial response was reassuring, her sodium levels tended to drift down with longer duration of treatment requiring us to increase the dose frequently. Her response to therapy and her stable clinical situation off therapy suggest that she may have reset osmostat
A TNXB
Abstract Background Congenital adrenal hyperplasia (CAH) due to 21âhydroxylase deficiency is an autosomal recessive disease of steroidogenesis that affects 1 in 15,000. Approximately, 10% of the CAH population also suffer from CAHâX, a connective tissue dysplasia consistent with hypermobility type EhlersâDanlos syndrome (EDS). Most patients with CAHâX carry a contiguous gene deletion involving CYP21A2 encoding 21âhydroxylase and TNXB encoding tenascinâX (TNX), but some are of unknown etiology. Methods We conducted clinical evaluation and medical history review of EDSârelated manifestations in subjects from two unrelated CAH families who carry a heterozygous TNXB c.12463+2T>C variant that alters the splice donor site of intron 42. A next generation sequencing (NGS) based EDS panel composed of 45 genes was performed for index patients from each family. TNX expression in patient skin biopsy tissues and dermal fibroblasts was assessed by qRTâPCR and Sanger sequencing. Results All three evaluated CAH patients carrying the TNXB splice site variant had moderate EDS manifestations. An NGS panel excluded involvement of other known EDSârelated variants. RNA assay on skin biopsies and dermal fibroblasts did not detect splicing errors in TNX mRNA; however, the removal of intron 42 was less efficient in the allele harboring the splice site variant as evidenced by the existence of a premature TNX RNA form, leading to an allele specific decrease in TNX mRNA. Conclusions Carrying a TNXB c.12463+2T>C variant at the intron 42 splice donor site causes an allele specific decrease in TNX expression, which can be associated with moderate EDS in CAH patients
An Evidence-Based Model of Multidisciplinary Care for Patients and Families Affected by Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
In 2002 a consensus statement pertaining to the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency was jointly produced by the Lawson Wilkins Pediatric Endocrine Society and the European Society of Pediatric Endocrinology. One of the recommendations of this consensus was that centers should maintain multidisciplinary teams for providing care and support to these patients and their families. However, the specifics for how this should be accomplished were not addressed in the original consensus statement. Here we interpret and translate the 2002 consensus statement recommendations into medical, surgical and mental health protocols. Additionally, we provide preliminary evidence that such protocols result in improved care and support for patients and families
Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia
Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARÎł, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH