Panagiota Pervanidou

Metabolic consequences of stress during childhood and adolescence

Stress, that is, the state of threatened or perceived as threatened homeostasis, is associated with activation of the stress system, mainly comprised by the hypothalamic-pituitary-adrenal axis and the arousal/sympathetic nervous systems. The stress system normally functions in a circadian manner and interacts with other systems to regulate a variety of behavioral, endocrine, metabolic, immune, and cardiovascular functions. However, the experience of acute intense physical or emotional stress, as well as of chronic stress, may lead to the development of or may exacerbate several psychologic and somatic conditions, including anxiety disorders, depression, obesity, and the metabolic syndrome. In chronically stressed individuals, both behavioral and neuroendocrine mechanisms promote obesity and metabolic abnormalities: unhealthy lifestyles in conjunction with dysregulation of the stress system and increased secretion of cortisol, catecholamines, and interleukin-6, with concurrently elevated insulin concentrations, lead to development of central obesity, insulin resistance, and the metabolic syndrome. Fetal life, childhood, and adolescence are particularly vulnerable periods of life to the effects of intense acute or chronic stress. Similarly, these life stages are crucial for the later development of behavioral, metabolic, and immune abnormalities. Developing brain structures and functions related to stress regulation, such as the amygdala, the hippocampus, and the mesocorticolimbic system, are more vulnerable to the effects of stress compared with mature structures in adults. Moreover, chronic alterations in cortisol secretion in children may affect the timing of puberty, final stature, and body composition, as well as cause early-onset obesity, metabolic syndrome, and type 2 diabetes mellitus. The understanding of stress mechanisms leading to metabolic abnormalities in early life may lead to more effective prevention and intervention strategies of obesity-related health problems.

Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident.

BACKGROUND This study examined prospectively the activity of the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system and inflammatory factors in children shortly after a motor vehicle accident (MVA) in relation to later posttraumatic stress disorder (PTSD) development. PATIENTS AND METHODS Fifty six children, aged 7-18, were studied after an MVA and 1 and 6 months later; 40 subjects served as controls. Morning serum cortisol and interleukin (IL)-6 and plasma catecholamine concentrations were measured within 24h after the event. Salivary cortisol was measured 5 times at defined time points during the same day. PTSD diagnoses 1 and 6 months later were based on K-SADS interview. RESULTS Morning serum IL-6 concentrations, measured within the first 24h after the accident, were higher in children that developed PTSD 6 months later than those who did not and those of the control group. Longitudinal IL-6 measurements revealed normalization of IL-6 in the PTSD group, while no differences between the three groups were detected 1 and 6 months later. Evening salivary cortisol and morning serum IL-6 after the accident were positively inter-related (r=0.54, p<0.001) and in separate regression analyses both predicted PTSD development 6 months later. In contrast, morning serum IL-6 did nor correlate with morning serum or salivary cortisol concentrations. CONCLUSIONS Immediate posttraumatic alterations in neuroendocrine or inflammatory factors-increased evening salivary cortisol and/or increased morning serum IL-6 concentrations-are involved in subsequent PTSD development in children and adolescents.

Neuroendocrinology of post-traumatic stress disorder.

Dysregulation of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-sympathetic nervous system (SNS), is involved in the pathophysiology of post-traumatic stress disorder (PTSD), an anxiety disorder that develops after exposure to traumatic life events. Neuroendocrine studies in individuals with PTSD have demonstrated elevated basal cerebrospinal fluid corticotropin-releasing hormone concentrations and contradictory results from peripheral measurements, exhibiting low 24 hours excretion of urinary free cortisol, low or normal circulating cortisol levels or even high plasma cortisol levels. The direction of HPA axis activity (hyper-/or hypo-activation), as evidenced by peripheral cortisol measures, may depend on variables such as genetic vulnerability and epigenetic changes, age and developmental stage of the individual, type and chronicity of trauma, co-morbid depression or other psychopathology, alcohol or other drug abuse and time since the traumatic experience. On the other hand, peripheral biomarkers of the SNS activity are more consistent, showing increased 24h urinary or plasma catecholamines in PTSD patients compared to control individuals. Chronically disturbed hormones in PTSD may contribute to brain changes and further emotional and behavior symptoms and disorders, as well as to an increased cardiometabolic risk.

The natural history of neuroendocrine changes in pediatric posttraumatic stress disorder (PTSD) after motor vehicle accidents: progressive divergence of noradrenaline and cortisol concentrations over time.

BACKGROUND The hypothalamic-pituitary-adrenal axis and the catecholaminergic system are involved in the pathophysiology of post-traumatic stress disorder (PTSD). This was a prospective and longitudinal study of neuroendocrine physiology in children with PTSD following a motor vehicle accident (MVA). METHODS Sixty children aged 7-18 were studied immediately after an MVA and 1 and 6 months later. Fasting morning plasma catecholamine and serum cortisol concentrations were measured. Salivary cortisol concentrations were measured serially five times daily to examine circadian variation in all three assessments. Values were compared between those who did (PTSD) or did not develop PTSD (non-PTSD) after the trauma and a control group at months 1 and 6. RESULTS Twenty-three of the children had PTSD at the 1-month and 9 children at the 6-month evaluations. 1) Plasma noradrenaline concentrations were higher in the PTSD group than in the other two groups at both months 1 and 6 (p = .001 and p = .001, respectively). Additionally, the PTSD patients presented with significantly higher salivary cortisol concentrations at 18.00 (p = .03) and 21.00 (p = .04) at month 1.2) Eight children suffering from PTSD at both months 1 and 6 had significantly elevated plasma noradrenaline concentrations at month 6 compared with those at month 1 and at baseline and to the other two groups (within subjects: p < .001; between subjects: p = .005). The initially elevated evening salivary cortisol concentrations in this group normalized at month 6. CONCLUSIONS This progressive divergence of noradrenaline and cortisol concentrations over time might underlie the natural history and pathophysiology of PTSD.

Retinol-Binding Protein 4 and Lipocalin-2 in Childhood and Adolescent Obesity: When Children Are Not Just “Small Adults”

BACKGROUND although there is much evidence regarding the physiologic and pathogenic roles of the newly described adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 as potential promoters of insulin resistance in obese adults, relatively little information exists regarding their roles in obese children. METHODS we investigated the circulating concentrations of RBP4 and lipocalin-2 in 80 obese girls (ages 9- 15 years) and their relationships with high-sensitivity C-reactive protein (hs-CRP) and the adipokines leptin and adiponectin. We divided participants by their body mass index standard deviation scores (BMI SDSs) into 4 groups of 20 girls each: overweight [mean BMI SDS (SD), 1.8 (0.4)], obese [2.2 (0.4)], morbidly obese [3.6 (0.4)], and lean controls [-0.11 (0.4)]. We measured plasma-soluble RBP4, the RBP4-binding protein transthyretin, lipocalin-2, hs-CRP, leptin, and adiponectin and calculated the homeostatic assessment model (HOMA) index from fasting glucose and insulin concentrations. RESULTS unexpectedly, plasma RBP4 and lipocalin-2 concentrations were correlated negatively with BMI SDS values (P = 0.005, and P < 0.03, respectively). These results were different from those of adults and were not correlated with the HOMA index. In contrast, hs-CRP and leptin concentrations were positively correlated with BMI SDS values (P < 0.0001, and P < 0.00001, respectively), as expected, whereas the adiponectin concentration was negatively correlated (P = 0.008). CONCLUSIONS although the correlations of leptin, adiponectin, and hs-CRP concentrations with BMI in children are similar to those of adults, the correlations of RBP4 and lipocalin-2 with BMI in children are the inverse of those observed in adults. Thus, although systemic inflammation and mild insulin resistance are present in childhood obesity, RBP4 and lipocalin-2 concentrations are not increased in children as they are in obese adults with long-standing severe insulin resistance and type 2 diabetes.

Circadian cortisol profiles, anxiety and depressive symptomatology, and body mass index in a clinical population of obese children

Obesity is highly co-morbid with anxiety and/or depression in children, conditions that may further worsen the metabolic and cardiovascular risks for obese individuals. Dysregulation of the hypothalamic–pituitary–adrenal axis is involved in the pathophysiology of anxiety disorders, depression, and obesity, and diverse cortisol concentrations may be found in obese children, depending on their degree of psychological distress. The aim of this study was to examine cortisol profiles among obese children with or without symptoms of anxiety and depression. A group of 128 children (53% females; mean age ± SD: 11.2 ± 2.2 years) derived from a pediatric obesity clinic were studied. Anxiety and depressive symptomatology were assessed with appropriate instruments. Morning serum and five diurnal salivary cortisol concentrations were measured. Obese children were 3.1/2.3 times more likely to report state and trait anxiety, respectively, and 3.6 times more likely to report depressive symptoms than children of the same age group, from a contemporary Greek sample. Trait anxiety and noon salivary cortisol concentrations were significantly positively correlated (p = 0.002). Overall, salivary cortisol concentrations were increased in children with anxiety or depression symptomatology compared to obese children without any affective morbidity (p = 0.02) and to those with anxiety and depression co-morbidity (p = 0.02). In conclusion, in obese children, emotional distress expressed by symptoms of anxiety and/or depression is associated with circadian cortisol profiles reflecting a potential pathway for further morbidity. Longitudinal studies may reveal a role of cortisol in linking obesity, anxiety, and depression to the development of further psychological and physical morbidity.

Association Between Polymorphisms in MTHFR and APOA5 and Metabolic Syndrome in the Greek Population

Impaired energy homeostasis and low-grade inflammation have been related to components of the metabolic syndrome (MetS) such as dyslipidemia, obesity, and insulin resistance. Single-nucleotide polymorphisms in the genes encoding for IL-6 (g.-634G>C; c.174G>C), TNFα (g.-308G>A), methylenetetrahydrofolate reductase (MTHFR) (c.677C>T), APOC3 (c.3175C>G), and APOA5 (g.-1131T>C) have been implicated in the processes of inflammation and energy intake that take place in the development of MetS manifestations. The aim of this study was to investigate the association between these polymorphisms and MetS, as defined by the National Cholesterol Education Program-Adult treatment Panel III criteria, in the Greek population. Overall, 30 unrelated subjects who met the criteria of MetS and 60 matched control subjects from central Greece were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. There was a significant association between both MTHFR c.677C>T (odds ratio: 4.02; confidence interval: 1.496-10.777; p=0.003) and APOA5 g.-1131T>C (odds ratio: 3.514; confidence interval: 1.065-11.585; p=0.035) and MetS. Analysis of constructed haplotypes showed a highly significant association between 677C-1131T-3175C haplotype and MetS (p<0.0001). Carriers of both MTHFR c.677T and APOA5 g.-1131C were associated with increased triglyceride levels (p=0.001 and p=0.003, respectively), compared with noncarriers. These results support a role for MTHFR and APOA5 as risk factors for MetS and suggest their further validation in larger independent populations.

Gender Dimorphic Associations between N-Terminal Pro-Brain Natriuretic Peptide, Body Mass Index and Blood Pressure in Children and Adolescents

Background: Obesity and hypertension are often comorbid, but the pathophysiologic mechanisms that link them are not fully understood. Natriuretic peptides might play a role in this association. The majority of studies show lower brain natriuretic peptide (BNP) concentrations as well as lower concentrations of the N-terminal of the prohormone (NT-proBNP) in obese than normal body mass index (BMI) adults and higher BNP concentrations in hypertensive than in normotensive individuals. In children, there are no studies examining the relations between NT-proBNP, BMI and blood pressure. Materials and Methods: Ninety-six children, 24 obese/25 normal BMI boys, and 23 obese/24 normal BMI girls, aged 10–16 years, were studied. Plasma NT-proBNP was measured using electrochemiluminescence. Results: In males, NT-proBNP concentrations were lower in the obese than the normal BMI group but higher in the obese hypertensive than the obese normotensive group (p = 0.04). In addition, a significant positive correlation was noted between plasma NT-proBNP and blood pressure (p = 0.03) only in obese males. In females, no correlations were detected between NT-proBNP, BMI and systolic or diastolic blood pressure. Conclusions: Longitudinal studies are needed to define the role of NT-proBNP as a screening biomarker in obese children, particularly males, to determine their risk for developing arterial hypertension.

Assessment of metabolic profile in a clinical setting.

Purpose of reviewThe metabolic syndrome, a clustering of abnormalities such as hyperglycemia, insulin resistance, hypertension, dyslipidemia, and central obesity, is a principal risk factor for cardiovascular disease, the leading cause of morbidity and mortality in the Western world. There are several definitions of the metabolic syndrome, all aiming at including as many persons at risk as possible. The assessment and, hence, the identification of such persons in a clinical setting is of utmost importance. Recent findingsClinicians should document the presence of central obesity, assessed by waist circumference measurement or determination of body composition using dual X-ray absorptiometry or measurement of visceral fat using computed tomography or magnetic resonance imaging. The presence of dyslipidemia, insulin resistance, and arterial hypertension constitutes the full profile of the metabolic syndrome. Nevertheless, elevated uric acid levels or presence of nonalcoholic fatty liver, or the diagnosis of the polycystic ovary syndrome in women of reproductive age, all are reflected in high risk of later occurrence of the full metabolic syndrome and atherosclerotic cardiovascular disease. SummaryAlthough no unified definition for the metabolic syndrome exists, it is important to identify persons at risk, in order to reduce the resultant high morbidity and mortality rates.

Circulating leptin and adiponectin and their relation to glucose metabolism in children with Crohn’s disease and ulcerative colitis

Background:Crohn’s disease (CD) and ulcerative colitis (UC) result in metabolic consequences. We assessed circulating leptin and adiponectin concentrations and examined their relations to glucose metabolism in children with CD and UC.Methods:Circulating morning fasting concentrations of leptin, adiponectin, glucose, and insulin were measured in 32 children with CD and 18 children with UC. Insulin resistance (IR) and β-cell function were evaluated by the updated homeostatic model assessments (HOMA2-IR and HOMA2-B).Results:Leptin was positively related to BMI z-scores overall and in the CD and the UC subgroups (P < 0.001). A negative correlation between leptin and disease activity was observed in the entire population (P = 0.034) and in the UC (P = 0.03) group. None of the assessed parameters was related to adiponectin. Fourteen percent of the participants were insulin resistant (15.6% in the CD group and 11.1% in the UC group), significantly more than expected (P < 0.001). Leptin was associated with HOMA2-IR (overall: r = 0.29, P = 0.045). Pathway analysis suggested that, overall, disease activity and BMI significantly affect leptin, which in turn is the only correlate of HOMA2-IR.Conclusion:Disease activity was significantly and inversely related to leptin in children with inflammatory bowel disease (IBD). A significant proportion of the patients had increased IR, which is positively related to circulating leptin.