Effects of weight reduction in overweight and obese children and adolescents

In the last decades, in many countries worldwide childhood and adolescent levels of overweight and obesity have reached epidemic status. According to “WHO European Childhood Obesity Surveillance Initiative” [1] the prevalence of overweight (including obesity) ranged from 18% to 57% among boys and from 18% to 50% among girls aged 6 to 9 years. The highest overweight prevalence was found in Southern European countries [1]. In Greece for example, the prevalence of abdominal obesity in 7-year-old children was about 25% in 2010 [2]. A lower, but still very high prevalence was found in Germany: Here, in the period from 2014 up to 2017, the prevalence of overweight/obesity was 15.4%/5.9% in children and adolescents aged 3 to 17 years [3], yet no increase in the period from 2003 to 2006 was found. Similar figures were reported by Ogden, et al. [4]: In their cohort the prevalence of overweight and obesity among U.S. children/adolescents was 16.9%, but there was no further increase from 2003/2004 to 2011/2012 [4]. Interestingly, in most of the countries analyzed overweight and obesity were more prevalent in lower social classes [5-7].


Introduction
In the last decades, in many countries worldwide childhood and adolescent levels of overweight and obesity have reached epidemic status. According to "WHO European Childhood Obesity Surveillance Initiative" [1] the prevalence of overweight (including obesity) ranged from 18% to 57% among boys and from 18% to 50% among girls aged 6 to 9 years. The highest overweight prevalence was found in Southern European countries [1]. In Greece for example, the prevalence of abdominal obesity in 7-year-old children was about 25% in 2010 [2]. A lower, but still very high prevalence was found in Germany: Here, in the period from 2014 up to 2017, the prevalence of overweight/obesity was 15.4%/5.9% in children and adolescents aged 3 to 17 years [3], yet no increase in the period from 2003 to 2006 was found. Similar figures were reported by Ogden, et al. [4]: In their cohort the prevalence of overweight and obesity among U.S. children/adolescents was 16.9%, but there was no further increase from 2003/2004 to 2011/2012 [4]. Interestingly, in most of the countries analyzed overweight and obesity were more prevalent in lower social classes [5][6][7].
These relatively high prevalences of overweight and obesity have also led to significant numbers of overweight-and obesity-related comorbidities at early ages. These comorbidities include metabolic disorders such as dyslipidaemia, type 2 diabetes mellitus, arterial hypertension, liver alterations and increased inflammatory activity as well as a reduced quality of life and well-being [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In a cohort of Japanese school children there was a clear association between obesity, higher levels of lipids (triglycerides LDL-cholesterol, HDL-cholesterol) and hs-CRP as marker of inflammatory disorders [22]. In a paper published in 2018, Yu, et al. found among a cohort of 408 adolescents (mean age of 13.2 years) with a body-mass index percentile of 98.0, a prevalence of non-alcoholic fatty liver disease (NAFLD) of 26.0% [23]. Yue S, et al. also revealed that "obese children with NAFLD are more susceptible to osteoporosis than children with only obesity" [24]. In a recently published review Coakley [20], using post-mortem studies of obese children, reported on coronary atheroma and other signs of premature cardiovascular diseases ("fatty streaks were found in the coronary arteries of 50% of 2-15-year-old children, while actual coronary atheroma were found in 8% of this age group. In the 16-20-yearold group, coronary atheroma was present in 33%", [20]). Additionally insulin resistance and a pre-diabetic state seem to be strongly associated to premature type 2 diabetes mellitus and its increasing incidence [21,[25][26]. Van der Aa, et al. [27] found, in a meta-analysis of children and adolescents, prevalence rates of insulin resistance between 3.1 and 44%. Although there were significant differences between the studies all results demonstrated a notably elevated prevalence rate in overweight and obese children [27].
These consequential data highlight the importance and challenge of developing improved intervention and evaluation methods for effective and long-term weight reduction programs. The risk factors must also be assessed and analyzed at a very early age. Thus it was the aim of the present trial to analyze the effectiveness of an in-house 6-week weight reduction program for overweight and obese children and adolescents in a specialized hospital. In addition to weight reduction and changes in body composition, risk factors for obesity associated co-morbidities such as blood pressure, lipids, insulin resistance and parameters of liver function were studied.

Structure of the STTP
In respect of weight reduction and long-term goal achievement multicomponent interventions have been highlighted as essential for lifestyle modification (Arbeitsgemeinschaft Adipositas im Kindesund Jugendalter [15,28]. The STTP should empower patients to make behavioral changes. Strategies should include and combine aspects of diet, physical activity and weight maintenance techniques (Arbeitsgemeinschaft Adipositas im Kindes-und Jugendalter [15,28]. The STTP (Arbeitsgemeinschaft Adipositas im Kindes-und Jugendalter [15,28]  As support of the STTP teaching materials were developed [15]. During the therapeutic sessions the children and adolescents used these materials. They used them also in homework for repetition. The details of the program and its evaluation were published by Schiel, et al. in 2008 [30].

Schedule of the trial
At the beginning of the trial and at the end of in-house rehabilitation during inpatient treatment the following examinations were performed: 1. In all patients physical examinations were performed.
4. Blood pressure in the sitting position was measured after the patients had rested for 10 min by using a standard sphygmomanometer according to the World Health Organization (WHO) recommendations [31]. In all patients a 24-hour-monitoring was performed (Premo Trend, Zimmer Elektromedizin, Neu-Ulm, Germany).

5.
Ultrasound examination (Siemens Acuson X300PE, München, Germany): On ultrasound images the diagnosis steatosis hepatis (fatty liver) was given, if the liver looks brighter than normal (but not lumpy or shrunken like cirrhotic livers).
Measurements of carotid intima-media thickness (IMT) were done by one physician performing 5 measurements on each side and calculating the mean. Definition of normal values was according to the German standard [32].
6. Blood-glucose (glucose-oxidase-method, Speedy, Müller Gerätebau GmbH, Saalfeld, Germany) and HbA1c-measurements (DCA2000®method, Bayer Diagnostics, Leverkusen, Germany, following DCCTstandard [HbA1c/mean normal] x mean according to the DCCTstandard [33]) were done directly in the laboratory of the Medigreif Inselklinik Heringsdorf GmbH using blood samples derived from finger pricking. Additionally venous blood samples taken in the morning of the first day after hospital admission (at onset/beginning of the trial) and at the last day of patients' in-hospital stay (at the end of the trial) following an overnight fasting period were analyzed (Laborgemeinschaft IMD, Prof. Dr. med. G. Menzel, Pappelallee 1, 17489 Greifswald, Germany) from all patients. The parameters analyzed and the methods of measurement are shown in (Table 1).
The HOMA calculation is an iterative structural model to estimate the ß-cell function together with insulin sensitivity. HOMA was calculated according to the formula: HOMA=(fasting plasma insulin x fasting plasma glucose)/22.5 (http://www.dtu.ox.ac.uk/homacalculator/ index.php, 27.06.2019).

Statistical analysis
Statistical analysis was performed using SPSS®22.0 (Statistical Package for Social Science, SPSS, Chicago, IL, USA). Values showing normal distribution were registered as mean (MW) ± standard deviation (SD), non-normal distributed values were given as median and range. Comparisons were evaluated with chi-square-tests or Fisher's exact test in case of frequencies less than 5. Paired Student's t-test and Wilcoxon-tests were used to compare the mean values. Correlations were calculated according to Pearson and for multivariate analyses

Baseline characteristics
The baseline characteristics of the patients in respect of age, sex, height, weight, BMI, BMI-SDS and duration of in-house rehabilitation are given in (Table 2). (Table 3) shows the educational levels of the 124 children and adolescents.

Laboratory parameters Lipids
During the in-house rehabilitation there was a significant reduction in all lipid sub-groups. Moreover, the percentage of children and adolescents with concentrations of total cholesterol, LDL-cholesterol and triglycerides above the recommended level [21] decreased significantly. However, in contrast to international recommendations [21], following participation in the structured treatment and teaching program (Arbeitsgemeinschaft Adipositas im Kindes-und Jugendalter [15,28] for patients with overweight and obesity, there was no increase, but a decrease of HDL-cholesterol in the present cohort (Table 6).

Parameters of liver function
The parameters of liver function are shown in (Table 7).

Correlation analyses
In the total cohort of 124 children and adolescents with overweight and obesity there were significant correlations between BMI-SDS and body fat mass (r=0.74, p<0.001), percentage of body fat (r=0.70, p<0.001), concentration of uric acid (r=0. 19

Discussion
The prevalence of overweight and obesity in childhood and adolescence is strikingly high, and has continued to increase over the last decades in most countries [1]. In addition to this epidemiological phenomenon is the significantly increased incidence of risk profiles in children and adolescents (dyslipidaemia, type 2 diabetes mellitus, arterial hypertension, liver alterations, high inflammatory activity, reduced quality of life and well-being) [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Following these findings the American Heart Association (AHA) updated their scientific statement "Cardiovascular Risk Reduction in High-Risk Pediatric Patients" in 2019. In this new statement the authors clearly state that "the evidence base has grown sufficiently to justify the need for an updated scientific statement to guide the provider, researcher, and policy maker concerned with youth at increased risk for premature CVD" [21]. Moreover the American Heart Association strongly suggested: "Early identification and treatment are important for all youth but particularly for the high-risk patients…" [21]. In view of these recommendations, it was the goal of the present trial to analyze and identify the risk profile of overweight and obese children admitted to an in-house rehabilitation.
The results of the study were impressive: More than two thirds of all the children and adolescents who were treated during the rehabilitation had at least one risk factor at beginning of the procedure. These were either non-normal laboratory parameters or higher blood pressure values and/or increased thickness of A. carotis intima media or steatosis hepatis. In particular, increased levels of insulin resistancy (in 48% of the patients), elevated LDL-cholesterol (in 70% of the patients), fatty liver (in 53% of the patients) and increased thickness of A. carotis intima media (in 32% of the patients) were striking. Multivariate analysis showed that the most important factors associated with thickness of A. carotis intima media were patients' body weight, HbA1c and fasting blood glucose. Similar results were found with regard to the HOMA index (as parameter indicating the risk for premature type 2 diabetes mellitus) and blood pressure. In both models body weight or BMI were identified as the most important factors associated. These results agree well with the literature: For at least 20 years obesity has been known to be a correlating factor with vascular fatty streaks and atherosclerotic lesions [21,35,36]. Also more recently published studies confirm this association [37][38][39]. Furthermore higher BMI is often accompanied by dyslipidemia, hyperglycemia and insulin resistance, inflammation and oxidative stress [21,40,41].
During the in-house rehabilitation grogram overweight and obese children and adolescents reached a mean weight reduction of about 4 kg, accompanied by a reduction in BMI, BMI-SDS and body fat mass. These changes were associated with an improvement in laboratory parameters (total cholesterol, LDL-cholesterol, glucose metabolism, liver enzymes). However, the follow-up period was too short to demonstrate improvements in sonographical density of the liver, in blood pressure or in carotid-intima media thickness. In children and adolescents with overweight and obesity rehabilitation has proven to be an effective therapeutic approach for weight reduction. The effectiveness of this therapy was evaluated by Schiel, et al. [15,30], but also in a German multicenter-trial by van Egmond-Fröhlich [29]. In general the weight and BMI-reduction in these studies were comparable to the effects of the present trial, but they lacked data on the improvement of risk parameters. In 2019 Ferranti, et al. conclude: "The magnitude of weight loss necessary to elicit meaningful improvement in CVD risk factors among youth with obesity has not been fully determined; a BMI reduction of 5% to 10% or 0.25 to 0.5 in BMI standard deviation score could be required". In view of this lack of evidence the American Heart Association cites the CHARON study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label) which was able to demonstrate in children that treatment with rosuvastatin let to regression of carotid intima-media thickness [21,42]. Similar results in regarding risk reduction for type 2 diabetes mellitus were found in the TODAY 2 study (Treatment Options for Type 2 Diabetes in Adolescents and Youth Phase II Study) [43] or for children and adolescents with elevated blood pressure values [21].
In conclusion, the present trial demonstrates that in-house rehabilitation leads to an effective weight reduction in children and adolescents with overweight and obesity. Moreover, overweight and obese children and adolescents already show a magnitude of metabolic  Table 7. Parameters of liver function in 124 children and adolescents and cardiovascular risk factors. Along with weight reduction there is also an improvement regarding these risk factors. However, up today there remains a lack of data about long-term benefits. Further controlled trials are mandatory to elucidate the long-term effect in regarding body weight, BMI and BMI-SDS, but also with respect to risk factors and the development of metabolic and cardiovascular disorders.