Adrenal Insufficiency In Children Research Articles

N14 The IBD nurse's role in screening for iatrogenic adrenal insufficiency in children with inflammatory bowel disease on discontinuing glucocorticoid therapy

Abstract Background With a wide range of medical treatment on offer, ensuring patient safety by monitoring and or preventing side effects is a key part of holistic care. Glucocorticoids are widely used in inflammatory bowel disease (IBD) treatment to induce remission or treat flares. Iatrogenic adrenal insufficiency (AI), due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an established side effect of exogenous glucocorticoids. Symptoms of AI can range from life-threatening adrenal crisis to more subtle chronic symptoms including fatigue, abdominal pain and diarrhoea. The rate of AI in this population is unknown. There is no standard guidance or recommendations to suggest routine screening of paediatric IBD (pIBD) patients. This study aimed to report our experience on set up a monitoring pathway to manage pIBD patients coming off glucocorticoid therapy(GT). Methods A database was created to capture all IBD patients under the age of 18 who had received GT for IBD between March 2022 and July 2023. At the time of starting treatment, predicted last day on GT was identified and patients were booked in for testing serum early morning cortisol (Vitros Ortho Clinical Diagnostics immunoassay) and ACTH. After tapering, patients remained on the lowest dose of GT until results review. Evaluation of the adrenal-axis response was then assessed by a protocol piloted by this study – see figure 1. The patients needing treatment for AI were seen in the Nurse led clinic for prescribing, education and training. The training included IM injection training, sick day training and safety netting. To ensure safe evidence based training, the IBD nurse had received training form the endocrine nurse before the pilot. Results Following the initial screening, 9 patients were seen in the clinic with AI ( 8 prednisolone and 1 Budesonide). Of these 9,8 (88%) were followed up by the IBD nurse and 1(11%) was followed up by a local paediatrician with an endocrine interest. Treatment with hydrocortisone was commenced and follow up 3 months blood tests organised. The school was notified of the risk of Adrenal suppression and emergency kits provided. Repeat adrenal axis testing was offered at 3 months (5 of 9) and 6 months (3 of 9). AI was noted in 3 patients and 2 patients at 3 and 6-month respectively. At the 6 month mark, patients were discharged from the clinic if they had returned to a normal adrenal axis or referred to the endocrine team for further follow up. Patients were discussed in a multi-displinary meeting at every point on the pathway and no child suffered an adrenal crisis during the study period. Conclusion AI following GT is common in this small pIBD cohort. The IBD nurse can play a critical role in providing safe care for these patients.

Peak Serum Cortisol Cutoffs to Diagnose Adrenal Insufficiency Across Different Cortisol Assays in Children

Current peak serum cortisol cutoffs for the diagnosis of adrenal insufficiency (AI) after Cosyntropin stimulation have been established using polyclonal antibody (pAb) immunoassays. However, new and highly specific cortisol monoclonal antibody (mAb) immunoassays are being used more widely, which can potentially yield higher false positive rates. Thus, this study aimed to redefine the biochemical diagnostic cutoff points for AI in children when using a highly specific cortisol mAb immunoassay and liquid chromatography tandem mass spectrometry (LC/MS) to avoid unnecessary steroid use. Cortisol levels from 36 children undergoing 1 mcg Cosyntropin stimulation tests to rule out AI were measured using pAb immunoassay (Roche Elecsys Cortisol I), mAB immunoassay (Roche Elecsys Cortisol II), and LC/MS. Logistic regression was used to predict AI using the pAB as the reference standard. A receiver operator characteristic curve, area under the curve (AUC), sensitivity, specificity, and kappa agreement were also calculated. Using a peak serum cortisol cutoff value of 12.5 μg/dL for the mAb immunoassay provided 99% sensitivity and 94% specificity for diagnosing AI, when compared to the historical pAb immunoassay cutoff of 18 μg/dL (AUC=0.997). Likewise, a cutoff of value of 14 μg/dL using the LC/MS, provided 99% sensitivity and 88% specificity when compared to the pAb immunoassay (AUC=0.995). To prevent overdiagnosis of AI in children undergoing 1 mcg Cosyntropin stimulation test, our data support using a new peak serum cortisol cutoff of 12.5 μg/dL and 14 μg/dL to diagnose AI when using mAb immunoassays and LC/MS in children, respectively.

Home waking salivary cortisone to screen for adrenal insufficiency in children

Home waking salivary cortisone to screen for adrenal insufficiency in children

The Reliability of Salivary Cortisol Compared to Serum Cortisol for Diagnosing Adrenal Insufficiency with the Gold Standard ACTH Stimulation Test in Children.

The ACTH (adrenocorticotropic hormone) stimulation test is the gold standard for the diagnosis of adrenal insufficiency (AI), performed with ACTH high dose (HDT) or low dose (LDT). As salivary cortisol has been proposed as an alternative to serum cortisol, our aim was to evaluate the reliability of salivary cortisol compared to serum cortisol for diagnosing AI in children. Data were collected retrospectively. Salivary and serum cortisol values derived by 80 ACTH stimulation tests were obtained (39 F, 36 M; median age 11.5 years, IQR 6.9). Sampling was performed at baseline and after 30 and 60 min from ACTH administration during the HDT, and at baseline and 10, 20, 30, 40 and 60 min after the stimulation for the LDT. A serum cortisol level > 420 nmol/L ruled out AI. The correlation coefficients between serum and salivary cortisol for the HDT (n = 24) were 0.80 at t0, 0.48 at t30 and 0.75 at t60. All patients were adrenal sufficient. In 41% of the LDT, peak serum cortisol indicated insufficient adrenal function. The correlation coefficients between serum and salivary cortisol were 0.59 at t0 and 0.33 at the peak. For a cut-off of salivary cortisol < 15 nmol/L, sensitivity was 73.9% and specificity 69.6%. Our data do not support salivary cortisol as a valid alternative to serum cortisol during LDT. Regarding the HDT, results are more encouraging, however, further studies are needed.

Genetic and phenotypic spectrum of non-21-hydroxylase-deficiency primary adrenal insufficiency in childhood: data from 111 Chinese patients

BackgroundPrimary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition.MethodsTo describe the genetic composition and presentations...

Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy.

Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. We conducted a retrospective medical chart review of pediatric patients with ALD. All patients were seen in a leukodystrophy clinic in an academic medical center. We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Epidemiology and Causes of Primary Adrenal Insufficiency in Children: A Population-Based Study.

Incidence and causes of primary adrenal insufficiency (PAI) have not been comprehensively studied in children. Our objective was to describe the epidemiology and to assess causes of PAI in Finnish children. A population-based descriptive study of PAI in Finnish patients aged 0-20 years.Diagnoses referring to adrenal insufficiency in children born in 1996-2016 were collected from the Finnish National Care Register for Health Care. Patients with PAI were identified by studying patient records. Incidence rates were calculated in relation to person-years in the Finnish population of same age. Of the 97 patients with PAI, 36% were female. The incidence of PAI was highest during the first year of life (in females 2.7 and in males 4.0/100 000 person-years). At 1-15 years of age, the incidence of PAI in females was 0.3/100 000 and in males 0.6/100 000 person-years. Cumulative incidence was 10/100 000 persons at age of 15 years and 13/100 000 at 20 years. Congenital adrenal hyperplasia was the cause in 57% of all patients and in 88% of patients diagnosed before age of 1 year. Other causes among the 97 patients included autoimmune disease (29%), adrenoleukodystrophy (6%), and other genetic causes (6%). From the age of 5 years, most of the new cases of PAI were due to autoimmune disease. After the first-year peak, the incidence of PAI is relatively constant through ages 1-15 years, and 1 out of 10 000 children are diagnosed with PAI before the age of 15 years.

Current Screening Strategies for the Diagnosis of Adrenal Insufficiency in Children.

Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of hypothalamic-pituitary-adrenal axis due to exogenous glucocorticoids. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often subtle and nonspecific. Clinician awareness and recognition is crucial for timely diagnosis to avoid adrenal crisis. Current screening strategies for the diagnosis of adrenal insufficiency in children in various clinical situations are discussed in this review.

Familial Glucocorticoid Deficiency Presenting with Tonic-Clonic Seizure: A Case Report

Familial glucocorticoid deficiency (FGD) is a rare cause of adrenal insufficiency in children. The condition can present with features of low cortisol and high adrenocorticotropic hormone (ACTH). Late diagnosis can be associated with high morbidity and high mortality rates. The presented case was a three-year-old Saudi girl who presented with dehydration and seizures as a complication of hypoglycemia. The initial examination and investigations revealed hyperpigmentation and normal arterial blood pressure. The lab investigation and genetic study revealed hypoglycemia, metabolic acidosis, low serum cortisol: 53 nmol/L (N: 140-690 nmol/L), normal androgens: 0.65 nmol/L (N: 0.5-2.4 nmol/L) and aldosterone: 50 pgmL (N: 2-200 pg/mol), and normal serum electrolytes. The ACTH level was more than 2000 pg/mL. A genetic study indicated a homozygous likely variant in the nicotinamide nucleotide transhydrogenase (NNT) gene, consistent with a genetic diagnosis of autosomal recessive glucocorticoid deficiency type 4. No mutations were found regarding MC2R, MRAP, and TXNRD2. The child was started on hydrocortisone, initially at 100 mg/m2/dose IV and then 100 mg/m2/day divided to q 6 hr. The dose was gradually decreased to 15 mg/m2/day PO BID, with clinical improvement and normalization of the serum ACTH level. The autosomal recessive glucocorticoid deficiency, a variant of FGD type 4, is a very rare condition that may lead to high rates of mortality when the diagnosis and treatment occur late. Therefore, early diagnosis and treatment is essential for good outcomes.

Overdiagnosis of adrenal insufficiency in children with biliary atresia.

Serum cortisol mainly binds to the cortisol-binding globulin (CBG). Children with biliary atresia (BA) may have low serum CBG levels; thus, low serum total cortisol (TC) levels and adrenal insufficiency (AI) may be overdiagnosed. This study aimed to assess adrenal function in children with BA. All the patients underwent adrenocorticotropic hormone (ACTH) stimulation tests. Plasma ACTH, serum TC, and CBG levels were measured at baseline, with additional TC measurements at 30 and 60 min during testing. Free cortisol (FC) index (FCI) and calculated FC (cFC) were also calculated. AI was defined as peak TC <500 nmol/L (<18 μg/dL), peak FCI <12 nmol/mg, or peak cFC <33 nmol/L (<1.2 μg/dL). This study enrolled 71 children with BA. The Median (IQR) age of the patients was 5.5 (1.7-11.4) years. Twenty-five (35%) patients were diagnosed with AI based on the peak TC. In the AI group, the median serum CBG level was significantly lower than that in the non-AI group (481 vs. 533 nmol/L, p = 0.03). Only eight patients (11%) met all three AI criteria (six secondary AI and two primary AI). In conclusion, low serum CBG levels contribute to reduced peak TC and, consequently, overdiagnosing AI. Peak FCI and cFC could help reduce the overdiagnosis of AI.

Diagnosis of adrenal insufficiency in children: a survey among pediatric endocrinologists in North America.

Adrenal insufficiency (AI) is a life-threatening condition where an accurate diagnosis is critical. While the ACTH stimulation test is the diagnostic test of choice, there remains uncertainty around its protocols and interpretation of results. In this context, the objective of this study was to understand practices of North American pediatric endocrinology providers on the diagnosis of AI in children. An anonymous electronic survey was sent to members of the Pediatric Endocrine Society. A total of 221 participants were included. The majority practiced in academic centers (78%). All respondents ordered ACTH stimulation tests. While 85% used high-dose ACTH stimulation tests (HDST) to diagnose primary AI, there was less consistency in the choice of tests (HDST vs. low-dose ACTH stimulation test; LDST) when diagnosing secondary AI. When interpreting results, 95% used peak cortisol levels, 70% considered the clinical picture, and 49% used relative increase in cortisol levels. Median (IQR) cortisol cutoff level after ACTH stimulation test that was considered sufficient was 18 (15.5-18) μg/L [496 (428-496) nmol/L]; 17% used different cutoffs for LDST, and 18% used different cutoffs for newborns. Finally, 47% were unaware of the assay that was used in their institution for cortisol measurements. Pediatric endocrinology providers use ACTH stimulation tests variably, including in the choice between HDST vs. LDST, test protocols, and interpretation of results.

LBSMON194 Diagnosing Adrenal Insufficiency In Children: A Survey Among Pediatric Endocrinologists In North America

Abstract Accurately diagnosing adrenal insufficiency (AI) is of vital importance, but it can be challenging, particularly in children. While the ACTH stimulation test remains the gold standard test for diagnosing AI, its protocols and interpretation of results remain controversial. There are no international recommendations specific for the pediatric age group. Objective to understand current practices of North American pediatric endocrinologists, regarding the diagnosis of AI in children, with focus in interpreting results of ACTH stimulation tests. Methods an anonymous, electronic survey was sent to members of the Pediatric Endocrine Society in February of 2022. Email reminders were sent over the following month, and the survey was closed after 6 weeks. RedCap was used to administer the survey and store data. Results 221 survey responses were included. 52% of participants had more than 10 years of clinical experience, and 78% practiced in academic centers. All respondents ordered ACTH stimulation tests for the diagnosis of AI; 82% also used morning cortisol levels, 77% used cortisol levels during stress, and 14% used random cortisol. For the diagnosis of primary AI, 85% chose high-dose ACTH stimulation tests (HDST). For secondary AI, 62% ordered low-dose ACTH stimulation tests (LDST), 22% HDST, and the remainder used both. The most frequently used time points for the HDST were 0 and 60 minutes, and for the LDST, 0, 30 and 60 minutes. For interpretation of ACTH stimulation test results, 95% considered peak cortisol levels, 70% also took into context the clinical picture, and 48% considered the relative increase in cortisol levels from baseline. 17% of respondents used different cutoff values for LDST vs. HDST; 18% used specific cutoffs for newborns. Median (IQR) cortisol levels after ACTH stimulation tests for diagnosing AI was 18 (15.5-18) ug/L; 54% of participants used 18 ug/dL, 40% considered levels between 10 and 18 ug/L, and 7% used cutoffs between 18 and 20 ug/L. Finally, 43% of providers did not know what type of cortisol assay was used in their laboratory. Discussion In North America, pediatric endocrinology providers use ACTH stimulation protocols variably, including decisions about HDST vs. LDST, time points for cortisol measurement, and interpretation of results. Notably, there was a wide distribution of responses concerning cortisol cutoffs. Also, a significant proportion of providers who ordered and interpreted results of ACTH stimulation tests did not know which biochemical assay was employed. These exploratory results highlight the need for pediatric-specific recommendations on ACTH stimulation protocols, based on the best available evidence. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

BSPED consensus guidelines: emergency and peri-operative management of adrenal insufficiency in children and young people

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Performance of glucagon stimulation test in diagnosing central adrenal insufficiency in children when utilising the Roche Elecsys® cortisol II assay: a pilot study.

The glucagon stimulation test (GST) is used for the simultaneous assessment of central adrenal insufficiency (CAI) and growth hormone deficiency. The new Roche cortisol II (C II) assay was recently introduced, confounding interpretation of the GST. The performance of the GST in diagnosing central adrenal insufficiency (CAI), utilising the C II assay, was therefore compared with that of the overnight metyrapone test (ONMTPT). A diagnostic accuracy study was performed by retrospectively analysing folders and laboratory records of 25 children and adolescents investigated for hypopituitarism with the GST and the ONMTPT between September 2016 and December 2019. The peak serum cortisol (C)of the GST, the post-metyrapone serum 11-deoxycortisol and adrenocorticotropin levels of the ONMTPT were recorded. Diagnostic performance of the GST at a previously suggested cut-off of 374nmol/L was evaluated. Seventeen boys and 8 girls, aged 1.7-16.3years (median 7.3years) were identified. The sensitivity of the post-GST C-level at 374nmol/L was 0.40 (95% confidence interval [CI] 0.17-0.69), specificity 0.64 (95% CI 0.39-0.84), positive predictive value 0.44 (95% CI 0.19-0.73), negative predictive value 0.60 (95% CI 0.36-0.80), accuracy 0.54 (95% CI 0.35-0.72), positive likelihood ratio (+LR) 0.93 (95% CI 0.49-1.77) and negative LR 1.12 (95% CI 0.40-3.15). The area under the receiver of operating characteristics(ROC) curve was 0.379 (95% CI 0.142-0.615). This study suggests that the GST at any C II cut-off cannot replace the ONMTPT as a diagnostic test for CAI in children. Findings should be confirmed in a larger study.

Autoimmune Primary Adrenal Insufficiency in Children

Objective:Primary adrenal insufficiency (PAI) is a rare condition in children, and is potentially life-threatening. The most common cause is congenital adrenal hyperplasia, and autoimmune etiology is the most frequent acquired cause in this age group. Symptoms are usually non-specific and, when suspected, investigation should include adrenocorticotropin hormone (ACTH) and morning serum cortisol measurement and, in some cases, a cosyntropin test to confirm the diagnosis. Prompt treatment is essential to prevent an adverse outcome.Methods:We retrospectively collected clinical and laboratory data from adrenal insufficiency due to autoimmune adrenalitis, observed from 2015 to 2020 in a pediatric endocrinology department of a tertiary care hospital.Results:Eight patients were identified, seven males and one female, with age at diagnosis between 14 and 17 years. The symptoms at presentation ranged from non-specific symptoms, such as chronic fatigue and weight loss, to a severe presentation, with altered mental status and seizures. The median duration of symptoms was 4.5 months. The diagnosis was confirmed by serum cortisol and plasma ACTH measurement and all were confirmed to have autoimmune etiology (positive anti-adrenal antibodies). At diagnosis, the most common laboratory abnormality was hyponatremia. All patients were treated with hydrocortisone and fludrocortisone. One patient presented with evidence of type 2 autoimmune polyglandular syndrome.Conclusion:PAI is a rare condition in the pediatric age group. Due to non-specific symptoms, a high index of suspicion is necessary to establish a prompt diagnosis. Once an autoimmune etiology is confirmed, it is important to initiate the appropriate treatment and search for signs and symptoms of other autoimmune diseases during follow-up.

The etiology and clinical features of non-CAH primary adrenal insufficiency in children.

BackgroundThe most common cause of primary adrenal insufficiency (PAI) in children is congenital adrenal hyperplasia; however, other genetic causes occur. There is limited epidemiological and clinical information regarding non-CAH PAI.MethodsData for patients diagnosed from January 2015 to December 2021 at a tertiary hospital in northern China were retrospectively analyzed. We excluded those with CAH, which is the most common pathogenic disease among PAI patients. Next-generation sequencing was used for genetic analysis.ResultsThis retrospective study included 16 children (14 males and 2 females) with PAI. A genetic diagnosis was obtained for 14/16 (87.5%) individuals. Pathogenic variants occurred in 6 genes, including ABCD1 (6/16, 37.5%), NR0B1 (4/16, 25.0%), NR5A1/steroidogenic factor-1 (2/16; 12.5%), AAAS (1/16, 6.25%), and NNT (1/16, 6.25%). No genetic cause of PAI diagnosis was found in 2 girls (2/16, 12.5%).ConclusionsCauses of PAI in children are diverse and predominantly affect males. Most PAI in children is congenital, and ABCD1 gene defects account for the largest proportion of PAI cases. Whole-exome sequencing is a tool for diagnosis. However, diagnoses are unclear in some cases.

GNAS mutation is an unusual cause of primary adrenal insufficiency: a case report

BackgroundPrimary adrenal insufficiency in children has non-specific and extensive clinical features, so the diagnosis of its etiology is complex and challenging. Although congenital adrenal hyperplasia is the most common cause, more and more other genetic causes have been identified. GNAS mutation is easily overlooked as a rare cause of primary adrenal insufficiency. Here we firstly report a neonatal case of primary adrenal insufficiency caused by GNAS mutation.Case presentationA boy was diagnosed with congenital hypothyroidism 10 days post-partum and treated immediately. He also had persistent hyperkalaemia and hyponatraemia with elevated adrenocorticotropic hormone. At 70 days after birth, he was transferred to our hospital on suspicion of congenital adrenal hyperplasia. Physical examination found no other abnormalities except for growth retardation. Laboratory examination revealed increased aldosterone and normal cortisol, 17-hydroxyprogesterone, and androstenedione levels. Abnormally elevated parathyroid hormone was accompanied by normal blood calcium. Genetic assessment found a de novo, heterozygous c.432 + 1G > A variant in GNAS.ConclusionsWe report this case to highlight that GNAS mutation is an unusual cause of primary adrenal insufficiency. The combination of primary hypothyroidism and /or pseudohypoparathyroidism will provide diagnostic clues to this condition.

Congenital Adrenal Hyperplasia and Brain Health: A Systematic Review of Structural, Functional, and Diffusion Magnetic Resonance Imaging (MRI) Investigations.

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affects the adrenal glands and is the most common cause of primary adrenal insufficiency in children. In the past few decades, magnetic resonance imaging (MRI) has been implemented to investigate how the brain may be affected by CAH. A systematic review was conducted to evaluate and synthesize the reported evidence of brain findings related to CAH using structural, functional, and diffusion-weighted MRI. We searched bibliographical databases through July 2021 for brain MRI studies in individuals with CAH. Twenty-eight studies were identified, including 13 case reports or series, 10 studies that recruited and studied CAH patients vs unaffected controls, and 5 studies without a matched control group. Eleven studies used structural MRI to identify structural abnormalities or quantify brain volumes, whereas 3 studies implemented functional MRI to investigate brain activity, and 3 reported diffusion MRI findings to assess white matter microstructure. Some commonly reported findings across studies included cortical atrophy and differences in gray matter volumes, as well as white matter hyperintensities, altered white matter microstructure, and distinct patterns of emotion and reward-related brain activity. These findings suggest differences in brain structure and function in patients with CAH. Limitations of these studies highlight the need for CAH neuroimaging studies to incorporate larger sample sizes and follow best study design and MRI analytic practices, as well as clarify potential neurologic effects seen across the lifespan and in relation to clinical and behavioral CAH phenotypes.

Components of Metabolic Syndrome in Youth With Classical Congenital Adrenal Hyperplasia.

Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common primary adrenal insufficiency in children, involving cortisol deficiency, hyperandrogenism, and cardiometabolic risk. Prior studies have reported that youth with classical CAH have a higher prevalence of the components of metabolic syndrome: obesity, hypertension, elevated fasting blood glucose, and dyslipidemia. Yet, the incidence of the complete metabolic syndrome itself in children and adolescents with CAH is relatively rare. Traditional cardiometabolic risk factors can surface early in children with classical CAH, and continue to present and evolve over the lifetime, although it is only recently that reports of Type 2 diabetes and adverse cardiac events have begun to surface in adults affected by this condition. The pathophysiology underlying the increased prevalence of cardiometabolic risk factors in patients with CAH is not well-understood, with disease treatments and androgen excess having been studied to date. The aim of this review is to evaluate the recent literature on traditional cardiometabolic risk factors in youth with classical CAH, and to consider non-traditional risk factors/biomarkers for subclinical atherosclerosis, inflammation, and insulin resistance. A better understanding of these traditional and non-traditional risk factors in youth with CAH could help guide treatment options and prevent the onset of metabolic syndrome in adulthood, reducing overall patient morbidity.

Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis.

Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.