Arterial hypertension is associated with an increased risk of metabolic complications in pediatric patient with obesity

Introduction

Childhood obesity is an epidemic worldwide. Its prevalence is a growing global trend, with the number of children with obesity rising from 0.7 and 0.9% in 1976 to 5.6 and 7.8% in 2016 for girls and boys, respectively [1, 2]. In 2016 more than 124 millions of children and adolescents were obese [1]. It is estimated, that currently across 23 European countries, 14% of boys and 10% of girls aged 7–8 years old present with excessive body weight [3]. In the US, 19.3% of children and adolescents aged 2–19 years suffer from obesity, including 6.1% with severe obesity [4]. Obesity is not only a chronic disease itself but also a major risk factor for the world’s leading causes of poor health and early death including arterial hypertension (AH) and cardiovascular disease [5]. Elevated blood pressure affects about 3% of children with the body mass index (BMI) below the 90th percentile, and up to 11% with BMI≥95th percentile[6]. Compared to children with normal weight, the odds ratio for the risk of hypertension is 1.7 in overweight, 2.6 in those with obesity, 3.7 in children with severe obesity, and 4.8 in extremely obese [7]. It has been found, that each increase by 10 of BMI units was associated with an increase in systolic blood pressure of 10 mmHg and diastolic blood pressure of 3 mmHg [8]. Recently attention is drawn to the fact that AH, along with other metabolic complications of childhood obesity, may constitute a very dangerous cluster of risk factors contributing to health deterioration and shortening of life [8]. Children with AH have been shown to have increased carotid intima-media thickness, increased left ventricular mass, and eccentric left ventricular geometry. That subsequently is associated with excess mortality in adults. Other risk factors including dyslipidemia and abnormal glucose tolerance are frequently present in adolescents with obesity-associated AH [9]. In a 25-year follow-up, the presence of the metabolic syndrome risk-factor cluster in childhood predicted clinical cardiovascular disease in adult subjects at 30–48 years of age [10]. To understand this relationship, it is necessary to realize that AH is not only the co-morbidity or isolated complication of obesity but a part of a cluster of metabolic disorders with a common origin. The abnormal biochemical activity of excessive fat-tissue, local production of cytokines, hormones leading to insulin resistance, and hyperinsulinemia are the most important factors in the development of hypertension and other elements belonging to that cluster of metabolic complications of obesity [11]. Therefore, it seems justified to consider those children who, apart from excessive body weight, suffer from arterial hypertension as a group of particular risk of developing more serious complications. Elevated blood pressure could be a simple tool to stratify metabolic risk in children and adolescents with obesity, what could allow for more personalized approach to this group of patients [5, 12]. However, the literature data on this subject is limited.

Therefore, the present study aimed to compare metabolic profiles in children with obesity, and with and without AH.

Materials and methods

The retrospective analysis included consecutive children and adolescents with the BMI Z-score ≥2, aged 10–18, who were treated in the Department of Pediatrics and Adolescent Endocrinology, Children’s University Hospital between 2001 to 2019. The exclusion criteria were: known history of AH, antihypertensive treatment, obesity secondary to other diseases or medication. Initially, 598 patients’ records were included in the study. After elimination of incomplete medical data, the final analysis included 534 patients [295 (55.2%) girls, 239 (44.8%) boys], aged 13 ± 3. Systolic and diastolic arterial pressure was measured at least twice with the use of an aneroid sphygmomanometer in all patients. The diagnosis of AH was based on the European Society of Hypertension (2016) criteria adjusted for age, gender, and height. To determine the metabolic profile, in every patient standard oral glucose load test (1.75 g/kg of body weight; max. 75 g) was performed with the assessment of glucose and insulin levels before and 120 min after the load. Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were estimated in the fasting blood sample using the dry chemistry method with a Vitros 5.1.FF machine (Ortho-Clinical Diagnostics, Rochester, NY, USA). Insulin concentrations were measured using an ADVIA Centaur^® XP.

As retrospective data were used for the analysis, therefore the ethics committee approval and patient consent for inclusion in the study were not required.

Results

The mean BMI Z-Score was 4.39 ± 1.9. Detailed characteristics of the study group are presented in Table 1. The AH was found in 179 (33.5%) of children [102 (34.6%) girls, and 77 (19.7%) boys]. Both groups did not differ regarding age (12.8 in AH vs. 13.2 in non-AH, p=0.13) (Table.2). The mean BMI of Z-SCORE was significantly higher in patients with AH (4.9 vs. 4.1 p=0.000028). The mean fasting insulin level was significantly higher in AH than in non-AH patients (22 vs. 19.7 mIU/L respectively, p=0.04). There was no significant difference regarding insulin level 120’ after oral glucose challenge (113 vs. 100 mIU/L in AH and non-AH respectively, p=0.056). Mean fasting glucose level was not significantly different in both groups (4.5 vs. 4.5 mmol/L, p=0.5), but the difference was noticed regarding post-load glucose level (6.3 in AH vs. 5.7 in non-AH, p=0.000041). The mean insulin resistance expressed by the HOMA-IR index was significantly higher in AH patients (4.5 vs. 4.0, p=0.029). Details regarding lipid profiles of AH and non-AH patients are outlined in Table 2. Sixty three (35%) children from the AH group had a family history of AH.

Discussion

In the study group, AH was found in 33.5% of the patients, similarly as in the studies previously published by other authors [6, 13]. The presence of excessive weight appears to be one of the most important factors related to AH in children and adolescents worldwide and that this relation seems to be linear [14, 15]. Common elements in the pathogenesis of the development of AH and other metabolic complications of obesity, cause that in people with excess body weight and AH, hyperinsulinemia, glucose metabolic disorders, and dyslipidemia should be more frequent than in normotensive ones. The results of the present study indicate a significantly higher concentration of fasting insulin level (22 vs. 19.7 mIU/L, respectively, p=0.04) and HOMA-IR (4.5 vs. 4.0, p=0.029) in children with obesity and AH compared to those with normal blood pressure. Also post-load glucose level was significantly higher in the AH group (6.3 in AH vs. 5.7 in non-HA, p=0.000041). That observation seems to be particularly important, as hyperglycemia and hyperinsulinemia induce inflammation, oxidative stress, vascular dysfunction, sodium retention, sympathetic excitation, renin–angiotensin–aldosterone system activation, and kidney damage, all of which elevate systemic blood pressure and lead to AH development [16, 17]. Insulin resistance and hyperinsulinemia, both of which are present in obesity, are independent activators of the sympathetic nervous system. This, in turn, causes vasoconstriction and reduced renal blood flow, which is a trigger for renin release, and subsequent renin–angiotensin–aldosterone system leading to sodium and water retention, which raises blood pressure [17]. On the other side, the direct relation between hyperglycemia and hypertension has not been well explained. Despite epidemiological studies do not confirm the simple relationship between fasting glucose and blood pressure in healthy children and adolescents, several adult studies point to the existence of the association of hyperglycemia and with AH in obese individuals [18], [19], [20], [21], [22]. To date, no similar analyzes concerning children and adolescents have been published. Interestingly, there were no significant differences in lipid parameters or fasting glucose levels between patients with and without AH. Contrary to adult patients, in which such co-existence occurs at a prevalence of 15–31% [23, 24]. Moreover, the coexistence of dyslipidemia and hypertension seems to carry a higher risk for the development of cardiovascular diseases than elevated systolic blood pressure, or dyslipidemia alone [23, 25]. The presence of lipid disorders is thought to be an additional risk factor for the development of AH in adults with obesity [25]. In obesity, adipose tissue releases excessive amounts of several substances, such as non-esterified fatty acids, glycerol, hormones (e.g. leptin and adiponectin), and proinflammatory cytokines, which modulate metabolism, inducing insulin resistance and diminishing insulin sensitivity [26]. This leads to progressive dysfunction of the pancreatic beta-cells. As a result, insulin becomes inadequately secreted and the liver and muscle glucose uptake decrease. Insulin resistance plays an important role in the pathophysiology of this atherogenic triad, by increasing fatty-acid flux from adipose tissue, lipogenesis, and uptake of remnant lipoproteins, being the three main sources of TG for very-low-density lipoproteins (VLDL) synthesis. Overproduction of the VLDLs and LDLs, and together with a change in lipase activity the metabolism of lipoproteins becomes modulated, further promoting atherogenesis. Hyperinsulinemia additionally, leads to excessive production of intestinal chylomicrons, causing an increase in postprandial lipemia [27]. Therefore, insulin resistance often co-exists with dyslipidemia. A typical lipid pattern, known as combined dyslipidemia, includes elevation of TG, LDL, and total cholesterol with a decrease of HDL cholesterol and is strongly associated with the risk of atherosclerosis and heart disease in adults [14, 28, 29] Lipid disorders are common in children with obesity. In a recently published Polish study, at least one type of lipid disorder occurred in more than 39% of the study group, while in the current German and Danish studies these values were 24, 7, and 28%, respectively [30], [31], [32]. However, in the present study, no differences were found between patients with and without AH. Similar to the results of the present study, the results obtained by Boyd et al. showed, that the rates of abnormal plasma lipid levels were high among overweight children with and without arterial hypertension [33]. Therefore, it seems that disturbances of lipid metabolism in children and adolescents are not as strongly associated with the occurrence of arterial hypertension as in adults.

Conclusions

Children with obesity and AH characterize by higher insulin resistance and hyperinsulinemia, as compared to normotensive patients. The relationship between hypertension and the occurrence of lipid disorders is not so obvious. Measurement of arterial blood pressure can be an easy screening test, especially in children with obesity give us information about the risk of glucose metabolism disturbances, especially insulin resistance. The mechanisms of obesity-induced hypertension have not been fully understandable, but considerable progress has been made towards unravelling the complex interactions between fat tissue, renal, hormonal, and nervous system factors.