Potential for Optimization of Growth Hormone Treatment in Children with Growth Hormone Deficiency (GHD), Small for Gestational Age (SGA), and Turner Syndrome (TS) in Germany - Data from the PATRO® Children Study.

INTRODUCTION: Growth hormone (GH) treatment in children with growth hormone deficiency (GHD), short children born small for gestational age (SGA), and Turner syndrome (TS) is well established. However, a variety of parameters are still under discussion to achieve optimal growth results and efficiency of GH use in real world treatment. METHODS: German GH-treatment naïve patients of the PATRO Children database were grouped according to their start of treatment into groups of 3 years from 2007 to 2018. Time trends in age, gender, GH dose, height standard deviation score (SDS), first year growth response, and Index of Responsiveness (IoR) were investigated in children with GHD, short children born SGA, and TS starting GH treatment in the German patient population of the PATRO Children database from 2007 - 2018 to determine specific parameters for GH treatment optimization. RESULTS: All patient groups started GH treatment at a relatively high chronological age (2007 - 2009: GHD 8.33 ± 3.19, SGA 7.32 ± 2.52, TS 8.65 ± 4.39) with a slight but not significant trend towards younger therapy start up to 2016 to 2018 (GHD 8.04 ± 3.36, SGA 6.67 ± 2.65, TS 7.85 ± 3.38). In the GHD and SGA groups female patients were underrepresented compared to male patients (GHD 32.3 %, SGA 43.6 %) with no significant change over the 4 time periods. Patients with GHD started GH treatment at a low dose (0.026 mg/kg/day). In SGA and TS patients GH therapy was started below the registered dose recommendation (0.030 mg/kg/day and 0.0337 mg/kg/day, respectively). In the first year of treatment the mean GH dose was increased moderately (GHD: 0.0307, SGA: 0.0357, TS: 0.0408 mg/kg/day). There was no significant change of GH dosing over time from 2007 - 2018. The IoR was comparable between time-groups for all three diagnoses. DISCUSSION: This study shows potential for improvement of GH treatment results in GHD, SGA, and TS patients in terms of early dose adjustment and younger age at start of treatment. This is in accordance with important parameters used in prediction models.

Safety and Effectiveness of a Biosimilar Recombinant Human Growth Hormone in Children Requiring Growth Hormone Treatment: Analysis of Final Data from PATRO Children, an International, Post-Marketing Surveillance Study.

Purpose: Omnitrope® (somatropin) was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. Here, we report final data from the PAtients TReated with Omnitrope® (PATRO) Children study, a post-marketing surveillance study designed to monitor the long-term safety and effectiveness of this treatment in pediatric patients. Methods: The study population included all pediatric patients treated with Omnitrope® (biosimilar rhGH), administered via daily injection, in routine clinical practice. The primary objective was to assess long-term safety, with effectiveness assessed as a secondary objective. Results: In total, 7359 patients were enrolled and treated in the PATRO Children study; 86.0% were treatment-naïve at baseline. Growth hormone deficiency was the most frequent indication (57.9%), followed by patients born small for gestational age (SGA; 26.6%). The mean (SD) duration of exposure to biosimilar rhGH was 3.66 years (2.39). A total of 16,628 adverse events (AEs) were reported in 3981 (54.1%) patients, most of which were mild/moderate. AEs suspected to be treatment related occurred in 8.3% of patients, most frequently headache (1.6%), injection-site pain (1.1%), or injection-site hematoma (1.1%). The incidence rate (IR) of type 2 diabetes mellitus was 0.11 per 1000 person-years (PY) across all patients, and 0.13 per 1000 PY in patients born SGA. The IR of newly diagnosed primary malignancies was 0.22 per 1000 PY across all patients. In the 6589 patients included in the effectiveness population, a sustained catch-up growth was observed across all indications. After 5 years of treatment, height SDS increased from baseline by a median (range) of +1.79 (-3.7 to 6.2) in treatment-naïve patients and +0.73 (-1.4 to 3.7) in pretreated patients. Conclusion: This final analysis of the PATRO Children study indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice. These data are consistent with the well-characterized safety profile of rhGH treatment in pediatric patients.

Outpatient screening for anxiety and depression symptoms in adolescents with type 1 diabetes - a cross-sectional survey.

BACKGROUND: The daily demands of type 1 diabetes management may jeopardize adolescents' mental health. We aimed to assess anxiety and depression symptoms by broad-scale, tablet-based outpatient screening in adolescents with type 1 diabetes in Germany. METHODS: Adolescent patients with type 1 diabetes mellitus (n = 2,394; mean age 15.4 y [SD 2.0]; 50.7% male) were screened for anxiety (GAD-7) and depression symptoms (PHQ-9) by self-report questionnaires and linked to clinical data from the DPV patient registry. Logistic regression was used to estimate the contribution of clinical parameters to positive screening results. RESULTS: Altogether, 30.2% showed a positive screening (score ≥ 7 in either test), and 11.3% reported suicidal ideations or self-harm. Patients with anxiety and depression symptoms were older (15.7 y [CI 15.5-15.8] vs. 15.3 y [CI 15.2-15.4]; p < 0.0001), had higher HbA1c levels (7.9% [CI 7.8-8.0] (63 mmol/mol) vs. 7.5% [CI 7.4-7.5] (58 mmol/mol); p < 0.0001), and had higher hospitalization rates. Females (adjusted odds ratio (aOR) 2.66 [CI 2.21-3.19]; p < 0.0001), patients > 15 years (aOR 1.40 [1.16-1.68]; p < 0.001), who were overweight (aOR 1.40 [CI 1.14-1.71]; p = 0.001), with HbA1c > 9% (> 75 mmol/mol; aOR 2.58 [1.83-3.64]; each p < 0.0001), with a migration background (aOR 1.46 [CI 1.17-1.81]; p < 0.001), or smoking (aOR 2.72 [CI 1.41-5.23]; p = 0.003) had a higher risk. Regular exercise was a significant protective factor (aOR 0.65 [CI 0.51-0.82]; p < 0.001). Advanced diabetes technologies did not influence screening outcomes. CONCLUSIONS: Electronic mental health screening was implemented in 42 centers in parallel, and outcomes showed an association with clinical parameters from sociodemographic, lifestyle, and diabetes-related data. It should be integrated into holistic patient counseling, enabling early recognition of mild mental health symptoms for preventive measures. Females were disproportionally adversely affected. The use of advanced diabetes technologies did not yet reduce the odds of anxiety and depression symptoms in this cross-sectional assessment.

Changes in cardiovascular risk factors among children and young adults with type 1 diabetes during the COVID-19 pandemic compared to previous years-Results from the German DPV registry.

BACKGROUND: The diverse stages of the COVID-19 pandemic led to several social circumstances that influenced daily life and health behavior. PURPOSE: To evaluate changes in cardiovascular risk factors and physical activity among children and young adults with type 1 diabetes (T1D) during the COVID-19 pandemic in Germany compared to previous years. METHODS: A total of 32 785 individuals aged 6-21 years at baseline with T1D from the German diabetes patient follow-up (DPV) registry contributed data on 101 484 person-years between 2016 and 2021. The first treatment year of each individual within this period was considered as baseline. Based on trends from 2016 to 2019, we estimated differences in body mass index-SD score (BMI-SDS), blood pressure (BP-SDS), and lipid levels (non-high-density lipoprotein [non-HDL]) between observed and predicted estimates for the years 2020 and 2021 using linear regression analysis standardized for age, diabetes duration, sex, and migratory background. The proportion doing organized sports and smoking cigarettes was analyzed using multivariable logistic regression models. RESULTS: BMI-SDS increased constantly from 2016 to 2021 without a significant increase above expected values for 2020/2021. Systolic BP-SDS (difference observed vs. expected with 95% confidence interval, 2020: 0.10 [0.07-0.14], 2021: 0.17 [0.14-0.20]) and non-HDL (2020: 2.7 [1.3-4.1] mg/dl, 2021: 4.1 [2.7-5.5] mg/dl) were significantly increased (all p < .001) in both pandemic years. The proportion of subjects participating in organized sports was reduced from over 70% in prepandemic years to 35%-65% in diverse stages/waves of the COVID-19 pandemic. The percentage smoking cigarettes did not change. CONCLUSIONS: We describe an increase in BP and atherogenic lipid levels coinciding with a reduction in physical activity but no acceleration of the prepandemic increases in BMI-SDS among young people with T1D during the COVID-19 pandemic.

Safety and effectiveness of Omnitrope® (somatropin) in PATRO Children: a multi-center, post-marketing surveillance study comparison of US and international cohort data.

There are known geographical differences in growth hormone deficiency (GHD) patient populations and treatment practices. Here, we present a comparison of safety and effectiveness data from patients treated with recombinant human growth hormone (rhGH) in the USA versus other countries. PAtients TReated with Omnitrope® (PATRO) Children is an international, non-interventional study with Omnitrope® (somatropin, Sandoz Inc.). All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. By September 2018, 294 patients had been enrolled in the USA (53% rhGH-naïve) and 6206 patients had been enrolled across 13 other countries (international group; 86% rhGH-naïve). The most common indication in both groups was GHD. Overall, 194 US patients (66%) and 2977 international patients (48%) experienced adverse events (AEs; 886 and 11,716 events, respectively), most of which were of mild or moderate intensity. The AEs were suspected to be treatment-related in five US patients (1.7%) and 452 international patients (7.3%). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No cases of diabetes mellitus or hyperglycemia were reported. In rhGH-naïve GHD patients, after 3 years of rhGH therapy, the improvement in mean height SD score from baseline was + 1.25 and + 1.35 in US and international patients, respectively. CONCLUSION: Omnitrope® treatment appears to be well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, there was no evidence of an increased risk of developing uncommon or unexpected AEs with rhGH. TRIAL REGISTRATION: NA. WHAT IS KNOWN: • Continued monitoring of patients treated with recombinant human growth hormone (rhGH) is important, particularly in terms of diabetogenic potential and the risk of malignancies. • The PAtients TReated with Omnitrope® (PATRO) Children study is a long-term, post-marketing surveillance program for the rhGH Omnitrope®. WHAT IS NEW: • Omnitrope® is well tolerated and effective in US patients, and those from other countries. • Across all indications included, there were no unexpected adverse events and there was no evidence of an increased risk of developing malignancies or diabetes.

Screening for hypophosphatasia: does biochemistry lead the way?

OBJECTIVES: Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population. METHODS: We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5'-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP. RESULTS: We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease. CONCLUSIONS: A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study.

INTRODUCTION: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). METHODS: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. RESULTS: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7-18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was -2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of -2.02 (0.9). CONCLUSION: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Choice of basal insulin therapy is associated with weight and height development in type 1 diabetes: A multicenter analysis from the German/Austrian DPV registry in 10 338 children and adolescents.

BACKGROUND: Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height-SDS and BMI-SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. METHODS: Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow-up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population-based German reference data were used to calculate height-SDS and BMI-SDS. Multiple linear regression was conducted. RESULTS: BMI-SDS increased significantly in all regimes (NPH P = .0365; IDet P = .0003; IGla P < .0001; and CSII P < .0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI-SDS was observed for all insulins in females, but only for IGla in males. BMI-SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height-SDS declined during the observation period, except for CSII. Apart from the 5.0- to 7.9-year-old subgroup, long-acting insulin analogues were associated with a significant loss of height-SDS. CONCLUSIONS: Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI-SDS, most evident in females.

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE "HypoDok").

Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry "HypoDok" for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of L-thyroxine (L-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and L-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily L-T4 dosage at 1 year was 3.1 µg/kg (90% sensitivity, 63% specificity; 36 µg/day) and at 2 years of age 2.95 µg/kg (91% sensitivity, 59% specificity; 40 µg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together.Conclusion: The decision to continue or cease L-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual L-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured. What is Known: • The course of congenital primary hypothyroidism may be transient, causing potential overtreatment. • The dose of l-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism. What is New: • TSH screening concentration and l-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.

Frequency of thyroid dysfunction in pediatric patients with congenital heart disease exposed to iodinated contrast media - a long-term observational study.

Background The thyroid gland of patients with congenital heart disease may be exposed to large doses of iodine from various sources. We assessed the thyroid response after iodine exposure during conventional angiography in cardiac catheterization and angiographic computer tomography in childhood. Methods Retrospective mid- to long-term follow-up of 104 individuals (24% neonates, 51% infants, 25% children) with a median age and body weight of 104 days [0-8 years] and 5.3 kg [1.6-20]. Serum levels of thyroid-stimulating hormone, free triiodthyronine and free thyroxine were evaluated at baseline and after excess iodine. We also assessed risk factors that may affect thyroid dysfunction. Results Baseline thyroidal levels were within normal range in all patients. The mean cumulative iodinate contrast load was 6.6 ± 1.6 mL/kg. In fact, 75% had experienced more than one event involving iodine exposure, whose median frequency was three times per patient [1-12]. During the median three years follow-up period [0.5-10], the incidence of thyroid dysfunction was 15.4% (n=16). Those patients developed acquired hypothyroidism (transient n=14, long-lasting n=2 [both died]) with 10 of them requiring temporary replacement therapy for transient thyroid dysfunction, while four patients recovered spontaneously. 88 individuals (84.6%) remained euthyroid. Repeated cardiac interventions, use of drugs that interfere with the thyroid and treatment in the intensive care unit at the index date were strong predictors for acquired thyroid dysfunction. Conclusions The incidence of acquired hypothyroidism after iodine excess was 15.4%. However, most patients developed only transient hypothyroidism. Systemic iodine exposure seems to be clinically and metabolically well tolerated during long-term follow-up.

Safety and Effectiveness of Omnitrope®, a Biosimilar Recombinant Human Growth Hormone: More Than 10 Years' Experience from the PATRO Children Study.

INTRODUCTION: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. OBJECTIVE: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children - an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. METHODS: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. RESULTS: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0-133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). CONCLUSIONS: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. AIMS: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7). CONCLUSION: Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.

Elevated Plasma Vitamin B12 in Patients with Hepatic Glycogen Storage Diseases.

Background: Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism affecting the synthesis or breakdown of glycogen in the liver. This study, for the first time, systematically assessed vitamin B12 status in a large cohort of hepatic GSD patients. Methods: Plasma vitamin B12, total plasma homocysteine (tHcy) and methylmalonic acid concentrations were measured in 44 patients with hepatic GSDs and compared to 42 healthy age- and gender-matched controls. Correlations of vitamin B12 status with different disease markers of GSDs (including liver transaminase activities and triglycerides) as well as the vitamin B12 intake were studied. Results: GSD patients had significantly higher plasma vitamin B12 concentrations than healthy controls (p = 0.0002). Plasma vitamin B12 concentration remained elevated in GSD patients irrespective of vitamin B12 intake. Plasma vitamin B12 concentrations correlated negatively with triglyceride levels, whereas no correlations were detected with liver transaminase activities (GOT and GPT) in GSD patients. Merging biomarker data of healthy controls and GSD patients showed a positive correlation between vitamin B12 status and liver function, which suggests complex biomarker associations. A combined analysis of biomarkers permitted a reliable clustering of healthy controls versus GSD patients. Conclusions: Elevated plasma concentration of vitamin B12 (irrespective of B12 intake) is a common finding in patients with hepatic GSD. The negative correlation of plasma vitamin B12 with triglyceride levels suggests an influence of metabolic control on the vitamin B12 status of GSD patients. Elevated vitamin B12 was not correlated with GOT and GPT in our cohort of GSD patients. Merging of data from healthy controls and GSD patients yielded positive correlations between these biomarkers. This apparent dichotomy highlights the intrinsic complexity of biomarker associations and argues against generalizations of liver disease and elevated vitamin B12 in blood. Further studies are needed to determine whether the identified associations are causal or coincidental, and the possible impact of chronically elevated vitamin B12 on GSD.

Short-Term Effects of Growth Hormone on Lipolysis, Glucose and Amino Acid Metabolism Assessed in Serum and Microdialysate of Healthy Young Men.

OBJECTIVE: We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS: This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS: Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION: As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.

Age, maturation and serum lipid parameters: findings from the German Health Survey for Children and Adolescents.

BACKGROUND: Recommendations on preventive lipid screening among children and adolescents remain controversial. The aim of the study was to assess age and puberty-related changes in serum lipids, including total cholesterol (TC), and high-density (HDL-C) and non-high-density lipoprotein cholesterol (Non-HDL-C). METHODS: Using cross-sectional data from the National Health Interview and Examination Survey for Children and Adolescents in Germany (KiGGS 2003-2006; N = 13,676; 1-17 years), changes in distributions of serum lipids were visualized according to sex, age and maturation. Youth aged 10-17 years were classified as prepubescent, early/mid-puberty, and mature/advanced puberty. Multiple linear regressions were used to quantify the impact of pubertal stage on serum lipid levels, adjusted for potential confounding factors. RESULTS: Among children 1-9 years mean serum lipid measures increased with age, with higher mean TC and Non-HDL-C among girls than boys. Among children 10-17 years, advanced pubertal stage was independently related to lower lipid measures. Adjusted mean TC, HDL-C and Non-HDL-C was 19.4, 5.9 and 13.6 mg/dL lower among mature/advanced puberty compared to prepubescent boys and 11.0, 4.0 and 7.0 mg/dL lower in mature/advanced puberty compared to prepubescent girls. CONCLUSIONS: Lipid concentrations undergo considerable and sex-specific changes during physical growth and sexual maturation and significantly differ between pubertal stages. Screening recommendations need to consider the fluctuations of serum lipids during growth and sexual maturation.

Start low, go slowly - mental abnormalities in young prolactinoma patients under cabergoline therapy.

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5-17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients - seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25-2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.

Hemoglobin A1c and retinal arteriolar narrowing in children with type 1 diabetes: the diagnostics of early atherosclerosis risk in kids study.

BACKGROUND/OBJECTIVE: Microvascular alterations play a key role in the development of diabetes complications. Retinal vessel analysis is a unique method to examine microvascular changes in brain-derived vessels. METHODS: Sixty-seven pediatric and adolescent type 1 diabetes patients and 58 healthy control persons (mean age 12.4 ± 2.9 years) underwent non-mydriatic retinal photography of both eyes. Central retinal arteriolar and central retinal venular (CRVE) diameter equivalents as well as the arteriolar-to-venular ratio were calculated using a semiautomated software. All anthropometric and laboratory parameters were measured according to standardized procedures for children. RESULTS: Retinal vessel diameter did not differ between type 1 diabetic children and healthy controls. However, there was an independent association of higher hemoglobin A1c (HbA1c) levels with arteriolar narrowing. Arteriolar narrowing of 5.4 µm was observed with each percent increase in HbA1c. Longer duration of diabetes was associated with wider retinal arterioles. CRVE was not associated with diabetes duration or HbA1c. CONCLUSIONS: Microvascular arteriolar alterations are already present in childhood and may indicate subclinical atherosclerosis and increased risk of diabetes complications later in life. Future research will have to investigate the potential use of retinal vessel diameters for treatment monitoring and guidance of therapy in children.