Band 33, Heft 5

Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver injury closely correlated with insulin resistance. Currently, the methods for clinical management of NAFLD patients mainly include removing causes, changing lifestyle and dietary structure, drug therapy and weight-loss surgery. This paper summarizes the occurrence and clinical management of NAFLD in patients with obesity, with the aim of formulating scientific clinical interventions for these patients and thus preventing the occurrence of NAFLD.

This review summarizes current data on influences of childhood obesity on the 12-lead electrocardiogram (ECG). Studies on obese adults showed a higher risk of cardiovascular complications and also, partly pathological, ECG alterations. Data on ECG alterations in obese children is rare. In current studies, no pathological findings were found. All alterations, which mimic the later pathological phenomena in obese adults, were within normal ranges. Studies reported significantly longer P-wave time and P-wave dispersion (Pd) in obese children [Üner A, Doğan M, Epcacan Z, Epçaçan S. The effect of childhood obesity on cardiac functions. J Pediatr Endocr Met 2014;27:261–71.], no correlation of heart rate, P-wave, or QT dispersions (QTd) [Akyüz A, Alpsoy S, Akkoyun DC, Nalbantoǧlu B, Tülübaș F, et al. Effect of overweight on P-wave and QT dispersions in childhood. Turk Kardiyol Dern Ars 2013;41:515–21.], significantly higher QTd in obese children [Yildirim S, Binnetoglu FK, Battal F, Aylanc H, Nazan Kaymaz N, et al. Relation between QT variables and left ventricular geometry in athletes and obese children. Acta Med Port 2016;29:95–100.], no significant association between obesity and QTc interval (QTc), but longer PR intervals, wider QRS duration and left axis shifting of frontal P-wave, QRS and T-wave axes [Sun G, Li Y, Zho X, Guuo X, Zhang X, et al. Association between obesity and ECG variables in children and adolescents: a cross-sectional study. Exp Ther Med 2013;6:1455–62.], significant prolongation of QTc, T peak-to-end, and QTd in the obese children [Paech C, Liebold A, Gebauer RA, Wagner F, Vogel M, et al. Relative QT interval prolongation and electrical inhomogeneity of cardiac repolarization in childhood obesity. Prog Pediatr Cardiol 2017;47:64–7.], slight shift to the left in the QRS axis (with no changes in the P axis), increased amplitudes of the left-sided leads in obese children, and no correlation of the heart rate with the weight [Paech C, Anhalt M, Gebauer RA, Wagner F, Vogel M, et al. New normal limits for pediatric ECG in childhood obesity? Influence of childhood obesity on the ECG. Prog Pediatr Cardiol 2018;48:119–23.]. Altogether, the study results are inconsistent. Clearly, pathological phenomena in the ECG of obese children were not reported: only preliminary stages like QTc prolongation within the norm were found. The pathological alterations seen in adult obese patients are not (yet) seen in childhood. The slight changes reported in childhood obesity are likely to manifest later and to develop into pathological phenomena in obese adults and, therefore, might increase the risk of cardiovascular events like arrhythmia and sudden cardiac death in adulthood.

Background Oxidative stress is implicated in both, the onset and the progression of type 1 diabetes mellitus (T1DM). There is accumulated evidence of increased biomarkers of oxidative stress in newly diagnosed, T1DM patients without complications, and in those with advanced disease. In this cross-sectional study, we investigated factors affecting oxidative stress status in pediatric patients with T1DM. Methods Advanced oxidation protein products (AOPP), prooxidant-antioxidant balance (PAB), total sulfhydryl (SH) groups, and superoxide dismutase (SOD) activity were determined in 170 children and adolescents with T1DM. Principal component analysis was used to investigate clustering of clinical and laboratory variables associated with elevated oxidative stress and reduced antioxidative defense biomarkers. Results Factor analysis extracted five factors, interpreted as (1) “weight status factor” including age, BMI, waist and hip circumferences; (2) “proatherogenic factor” that included LDL-cholesterol, non-HDL-cholesterol, and triglycerides; (3) “metabolic control factor” including glucose and HbA 1c ; (4) “renal marker factor” with positive loading of urinary albumin excretion rate and negative loading of GFR; and (5) “antiatherogenic factor” that included HDL-cholesterol. High AOPP levels were independently predicted by “proatherogenic” (OR: 2.32; 95% CI: 1.44–3.71; p < 0.001), “metabolic control” (OR: 2.24; 95% CI: 1.35–3.73; p < 0.01), and “renal marker” (OR: 1.65; 95% CI: 1.03–2.65; p < 0.05) factors. “Renal marker factor” was a significant predictor of PAB (OR: 0.52; 95% CI: 0.34–0.81; p < 0.01). Regarding antioxidative defense markers, reduced SH groups were predicted by “proatherogenic factor” (OR: 0.56; 95% CI: 0.34–0.94; p < 0.05), while “weight status factor” predicted lower SOD activity (OR: 1.66; 95% CI: 1.03–2.67; p < 0.05). Conclusions Cardiometabolic risk factors and renal function are associated with oxidative stress in pediatric T1DM patients.

Background Given the importance of anxiety and quality of life for the mental health of children with type 1 diabetes (T1D), exercise prescription can be of crucial significance. The present study aims to explore the effect of concurrent resistance-aerobic training on serum cortisol level, anxiety, and quality of life among pediatric T1D. Methods Forty children (aged 8–14 years) were randomly assigned to experimental (n = 20) and control groups (n = 20) for 16 weeks. The exercise training program was composed of 16 weeks of interval concurrent resistance-aerobic training with a duration of 60 min performed three times a week. The subjects first performed the resistance training (20 min of Pilates exercises and 20 min of body weight-bearing exercises). Then, the aerobic exercises were performed with an intensity of 50–75% of maximum heart rate. Before and after the training, blood tests including cortisol were carried out on the subjects by RIA kit. Anxiety and quality of life were measured by the Revised Children’s Manifest Anxiety Scale (RCMAS) and Pediatric Quality of Life (PedsQL), respectively. Body composition was measured by InBody. Data were analyzed by paired and independent t-test at p < 0.05 significance level. Results Sixteen weeks of concurrent resistance-aerobic exercise significantly reduced the anxiety index (p = 0.001) and increased the quality of life (p = 0.003). Although the cortisol index was increased, it did not reveal any significant differences between the experimental and control groups (p = 0.781). No significant differences were observed in the indices of quality of life, anxiety, and cortisol in the control group. Conclusions A 16-week program of concurrent resistance-aerobic training can improve the quality of life and anxiety among children suffering from T1D, but it may not influence the cortisol level (p > 0.05).

Background Psychiatric consultation is important in the follow-up of disorders of sex development (DSD) patients. In this study, we aimed to present the 12-year psychiatric follow-up data of the patients who were referred by Ege University Medical Faculty DSD Multidisciplinary Team and followed up in Child and Adolescent Psychiatry. Methods Psychiatric data of 118 patients, who were followed by the DSD multidisciplinary team between 2007 and 2019, were reviewed retrospectively. The psychiatric diagnoses of the patients were evaluated according to semi-structured interview form Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Turkish Version. Results The mean age of the 118 cases was 13.21 years (±7.18). Endocrine diagnoses of the cases were 46 XX DSD in 35 (29.6%), 46 XY DSD in 81 (68.7%), and chromosome disorders in 2 (1.7%). There was at least psychiatric diagnosis in 36 (30.5%) cases. The most common psychiatric diagnosis was attention deficit and hyperactivity disorder (ADHD) (n = 18, 15.3%). ADHD was most common in congenital adrenal hyperplasia (n = 4, 22.4%) and androgen synthesis defects (ASD) (n = 4, 22.4%); depression was most common in complete gonadal dysgenesis and ASD (n = 3, 23.1%); and mental retardation was most common in ASD (n = 3, 37.5%). Conclusions In order to provide a healthy perspective for cases with DSD, it is important to make a psychiatric evaluation and to share observations and clinical findings in regular team meetings.

Background Although vitamin D deficiency is associated with several inflammatory conditions, there have been few studies on the effects of vitamin D supplementation on markers of oxidative stress (OS) and inflammation. The aim of the current study was to evaluate the effects of high-dose vitamin D supplementation on heat shock protein 27 antibody (anti-Hsp27) titers in adolescent girls. Methods Five hundred and fifty adolescent girls received vitamin D3 at a dose of 50,000 IU/week for 9 weeks. Demographic, clinical and biochemical markers including serum fasting blood glucose (FBG), lipid profile and anti-Hsp27 titers as well as hematological parameters including white blood cell (WBC) count and red blood cell (RBC) distribution width (RDW) were determined in all the subjects at baseline and at the end of the study. Results Serum vitamin D significantly increased from 6.4 (4.2–9.6) ng/mL to 35.6 (25.8–47.5) ng/mL (p < 0.001) following the intervention. Furthermore, serum anti-Hsp27 titers were significantly lower after the 9-week vitamin D administration period (0.22 [0.12–0.33] optical density [OD] vs. 0.19 [0.11–0.31] OD; p = 0.002). A significant correlation was found between serum anti-Hsp27 and RDW (r = 0.13, p = 0.037). The reduction in RDW values after intervention was particularly evident in subjects with the greatest increase in serum vitamin D levels. Conclusions High-dose vitamin D supplementation was found to reduce antibody titers to Hsp27. Further randomized placebo-controlled trials are warranted to determine the long-term effect of vitamin D administration on the inflammatory process especially that associated with chronic disease.

Background Whole-body vibration training has recently been proposed as a complementary training modality to improve the bone health of adolescent swimmers. However, there is no longitudinal study regarding the effects of this training combination on bone metabolism. Therefore, the main goal was to analyze the effects of swimming and vibration training on bone turnover markers during adolescence. Methods The present study included 68 adolescent swimmers and 41 normoactive controls (CON). Swimmers were randomly selected to either continue with their regular swimming training (SWI) or participate in an additional vibration protocol (VIB). Anthropometric measurements and serum level determinations of osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide crosslaps (CTX) were performed before and after the 6-month intervention. Results Statistically significant group by time interactions were found for both bone formation markers. VIB showed a decrease over time in OC (baseline: 101.4 μg/mL, follow-up: 82.8 μg/mL, p < 0.05) and P1NP (baseline: 528.4 μg/mL, follow-up: 389.0 μg/mL, p < 0.05) and SWI had analogous reductions in P1NP (baseline: 685.8 μg/mL, follow-up: 542.0 μg/mL, p < 0.05), whereas CON experienced an increase in OC levels (baseline: 94.4 μg/mL, follow-up: 103.4 μg/mL, p < 0.05). After stratifying the sample according to the pubertal status, similar interactions were observed. Conclusions The combination of swimming training and this particular vibration protocol led to a decrease in bone formation markers, especially during early puberty. Whole-body vibration might not induce an osteogenic stimulus in adolescent swimmers.

Background In genital anomalies, measurement of total testosterone is required but is expensive and technically difficult to assay. Therefore, the measurement of anogenital distance, which is non-invasive and cheap, could be used to estimate total serum testosterone in neonates. The objective if this study is to determine the relationship between total serum testosterone and anogenital distance and estimate total serum testosterone levels in term neonates using measurements of anogenital distance. Methods This was a prospective cross-sectional study. Consecutive healthy term neonates were recruited in the first 72 h of postnatal life. Anogenital distance was measured with a digital vernier calliper. Total serum testosterone was determined using enzyme linked immunoassay. Results A total of 240 term neonates comprising 124 (51.7%) males and 116 (48.3%) females were studied. The overall mean anogenital distance was 19.7 (7.7) mm and 26.5 (3.7) mm for males which was more than twice 12.4 (2.3) mm for females (t = 35.3, p < 0.001, 95% confidence interval [CI], 13–14). The overall mean total serum testosterone level was 267.1 (204.8) ng/dL; and 357.4 (241.7) ng/dL in males which was more than twice of 170.6 (80.7) ng/dL for females (t = 7.9, p < 0.001, 95% CI, 144–221). There was positive correlation between total serum testosterone and anogenital distance (r = 0.425, p < 0.001). The correlation was stronger in males than in females. The linear regression equation was as follows: total serum testosterone (ng/dL) = 44.3 + 11.3*AGD (mm) with 95% CI, 8–14. Conclusions The known value of anogenital distance could be used to estimate total serum testosterone levels in term neonates.

Background Individual inborn errors of metabolism (IEMs) are rare disorders. Expanded newborn screening for IEMs by tandem mass spectrometry (TMS) is an efficient approach for early diagnosis. Here we provide the newborn screening program for the application of this approach (between July 2014 and March 2019) to the identification of newborns in Beijing at risk of developing a potentially fatal disease. Methods The amino acids and acylcarnitines in dried blood spots were analyzed by TMS. Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis. Results Among the healthy newborns, 16 metabolic disorder cases were confirmed, giving a total birth prevalence of 1:3666 live births. Organic acidemia (OA) was the most common (9/16 patients; 56%), and methylmalonic acidemia was the most frequently observed OA (7/9 patients; 89%). Five infants were diagnosed with methylmalonic acidemia with homocystinuria type CblC, two with isolated methylmalonic acidemia, one with propionic acidemia, and one with isovaleric acidemia. Four patients (4/16, 25%) were diagnosed with hyperphenylalaninemia. One suffered with medium-chain acyl CoA dehydrogenase deficiency, one with carnitine uptake deficiency, and one with citrin deficiency. Eleven cases underwent genetic analysis. Seventeen mutations in eight IEM-associated genes were identified in 11 confirmed cases. Symptoms were already present within 2 days after birth in 44% (7/16) cases. The infant with propionic acidemia died at 7 days after birth. The other cases received timely diagnosis and treatment, and most of them grew well. Conclusions The results illustrate challenges encountered in disease management highlighting the importance of newborn screening for inherited metabolic disorders, which is not yet nationally available in our country. Regional newborn screening programs will provide a better estimation of the incidence of IEM.

Background Mucolipidosis II is a rare inherited metabolic disorder characterized by multiple pathologies including coarse facial features, thickened skin, dysostosis multiplex, and skeletal abnormalities. The disorder results due to variants in GNPTAB leading to reduced activity of the enzyme GlcNAc-1-phosphotransferase (GlcNAc-PT). Methods In the present study, a consanguineous Pakistani family was diagnosed with MLII based on clinical and biochemical examination. Peripheral blood samples were collected and subjected to DNA sequencing of all coding exons along with exon-intron boundaries of GNPTAB . Results Molecular investigation of the family identified two novel variants c.25C > T: p.Gln9* (maternal allele) in exon 1 and c.1160C > T: p.Ala387Val (paternal allele) in exon 10 segregating in compound heterozygous form in the affected individuals. Conclusions The GNPTAB variant c.25C > T variant is highly plausible to undergo nonsense-mediated mRNA decay, while the GNPTAB variant c.1160C > T is located in a highly conserved domain, thus both the variants predict to lead to affect the enzyme activity. Two novel variants have been identified in GNPTAB as the underlying cause of ML-II in a Pakistani family. The study thus expands the available GNPTAB mutation spectrum.

Background Thyroid hormone plays an important role in the adaptation of metabolic function to critically ill. The relationship between thyroid hormone levels and the outcomes of septic shock is still unclear. The aim of this study was to assess the predictive value of thyroid hormone for prognosis in pediatric septic shock. Methods We performed a prospective observational study in a pediatric intensive care unit (PICU). Patients with septic shock were enrolled from August 2017 to July 2019. Clinical and laboratory indexes were collected, and thyroid hormone levels were measured on PICU admission. Results Ninety-three patients who fulfilled the inclusion criteria were enrolled in this study. The incidence of nonthyroidal illness syndrome (NTIS) was 87.09% (81/93) in patients with septic shock. Multivariate logistic regression analysis showed that T4 level was independently associated with in-hospital mortality in patients with septic shock (OR: 0.965, 95% CI: 0.937–0.993, p = 0.017). The area under receiver operating characteristic (ROC) curve (AUC) for T4 was 0.762 (95% CI: 0.655–0.869). The cutoff threshold value of 58.71 nmol/L for T4 offered a sensitivity of 61.54% and a specificity of 85.07%, and patients with T4 < 58.71 nmol/L showed high mortality (60.0%). Moreover, T4 levels were negatively associated with the pediatric risk of mortality III scores (PRISM III), lactate (Lac) level in septic shock children. Conclusions Nonthyroidal illness syndrome is common in pediatric septic shock. T4 is an independent predictor for in-hospital mortality, and patients with T4 < 58.71 nmol/L on PICU admission could be with a risk of hospital mortality.

Background Type 1 tyrosinemia is a hereditary metabolic disease in which tyrosine metabolites damage the liver and kidneys. Nitisinone medication revolutionized the treatment, but the effects of the drug during human pregnancy are unknown. Case presentation A 17-year-old tyrosinemia patient became pregnant. Nitisinone was continued throughout pregnancy with a varying serum concentration and dose ranging from 0.8 to 1.4 mg/kg/day. Blood tyrosine remained stable until it increased in late pregnancy. α-fetoprotein increased to 284 μg/L without new changes in liver. Urine succinylacetone remained undetectable, but there were signs of possibly reoccurring kidney tubulopathy. Fetal ultrasound monitoring was normal throughout the pregnancy and the newborn healthy. After the delivery, α-fetoprotein normalized, but tyrosine continued to rise for up to 1 year. The child is developing normally. Conclusions Pregnancy during nitisinone was successful, but tailoring of the drug dose and possibly reappearing complications, as also increasing serum tyrosine concentration after delivery warranted intensified surveillance.

Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

Background Congenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI. Case presentation A term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide. Conclusions Biallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

Background The hyperinsulinism/hyperammonaemia (HI/HA) syndrome is the second most common cause of hyperinsulinaemic hypoglycaemia, caused by activating mutations in GLUD1. In this article, we report a series of three unrelated patients with HI/HA syndrome who demonstrated variable phenotypes, ranging from delayed presentation to spontaneous resolution of hypoglycaemia, thereby expanding the current knowledge and understanding of GLUD1 mutations. Case presentation This paper is a retrospective analysis of patients with HI/HA syndrome who demonstrated a variable disease course. Patient 1 presented with hypoglycaemic seizures at the age of 7 months and was diagnosed with HI/HA syndrome. Patient 2, a 5-year-old boy, on anti-convulsants since 8 months of age, was diagnosed with HI/HA at the age of 4 years. Patient 3, an 11-year-old girl with a history of transient neonatal hypoglycaemia, was diagnosed with HI/HA at the age of 12 months following evaluation for absence seizures. Patients 1 and 2 had raised ammonia levels, whilst patient 3 had normal ammonia level. The genetic analysis in all three patients confirmed GLUD1 mutation. Good glycaemic control was observed in all following diazoxide treatment. All patients have learning difficulties. Patient 1 demonstrated spontaneous resolution of hypoglycaemia at the age of 8 years, enabling discontinuation of diazoxide. Conclusions The cases highlight the diagnostic challenges in HI/HA syndrome due to a highly variable presentation. Knowledge of variable phenotypes would enable early diagnosis, thereby decreasing the risk of long-term neurological damage. Spontaneous resolution of hyperinsulinism could occur, and it is important to consider a trial off diazoxide therapy especially if the patients are on a small dose of diazoxide.