A recent update on childhood obesity: aetiology, treatment and complications

Endocrine

A complex pathway of neuro-hormonal regulators forms the gut–brain axis, which plays a significant role in hunger and satiety. Sensory stimulation and gastrointestinal peptides contribute to food intake. The role of gut microbiome dysbiosis and release of short chain fatty acids take part in calorie metabolism causing increased weight [11]. Apart from direct effects causing obesity, they are also involved in the pathogenesis of obesity-related comorbidities through the gut–liver axis [12]. Only 2–3 % of obesity is due to endocrinopathies, and this is commonly associated with short stature [13]. Untreated hypothyroidism, Cushing syndrome and growth hormone deficiency are associated with obesity. Hypothalamic obesity may arise after trauma, surgery, radiation, inflammation and infiltration of the hypothalamic–pituitary area or due to a genetically determined congenital malformation of the hypothalamus [14].

Genetic factors

Genetic causes of obesity can either be monogenic or polygenic, including those relating to structural disorders of the hypothalamus. Monogenic obesity is due to genetic variants in genes within the leptin/melanocortin pathway that is essential for the regulation of food intake/satiety, body weight and energy metabolism [15], such as melanocortin-4 receptor (MC4R), pro-opiomelanocortin (POMC), leptin (LEP), leptin receptor (LEPR) and single-minded homologue 1 (SIM1) (Table 1). Polygenic obesity is the more common form of obesity due to interplay between genetic susceptibility, environmental pathogens and epigenetics [16].

Syndromes

A number of syndromes are associated with obesity, including Prader–Willi Syndrome (PWS), Alström (ALMS), Bardet–Biedl (BBS), Beckwith–Wiedemann, achondroplasia, Bannayan–Riley–Ruvalcaba, Borjeson–Forssman–Lehmann, Carpenter, Cohen, Pseudohypoparathyroidism 1a (PHP 1a) [17] (Table 2).

Environmental

The term ‘obesogenic environment’ refers to the influences that the surroundings, opportunities or conditions of life have on promoting obesity in individuals and populations [18]. A meta-analysis of 74,168 pooled participants ages 2–19 in the United States found that rural children have 26 % greater risk of obesity, compared to urban children (OR 1.26; 95 % CI, 1.21–1.32) [19], although this pattern was inverted in other studies investigating different populations such as the United Arab Emirates [20] and India [21]. Indisputably, socioeconomic status (SES) is a strong social determinant in all areas, with low status linked with obesity in high resource settings like the United Kingdom and United States, but higher social status in low resource countries [22]. A higher burden of obesity could, therefore, be seen as an indicator of pervasive health inequalities within a population.

Behavioural factors such as maternal smoking in pregnancy [23], infant formula feeding [24], television viewing/sedentary lifestyles and low levels of physical activity [25] have all been implicated in playing a role in the development of childhood obesity, although individual behaviours should be considered in the context of environmental constraints and wider social context. Within the United Kingdom, proximity to convenience stores and takeaway premises in inner city areas is strongly associated with a higher burden of obesity in those areas, where access to healthy foods such as fresh fruit and vegetables is more limited, as well as access to safe green spaces conducive to active lifestyles [26]. Those of lower SES, or without means to access healthier foods, may be more likely to opt for readily available and cheap energy-rich, nutrient poor foods [27]. There are disproportionately high levels of obesity and accelerated metabolic complications such as Type 2 Diabetes among ethnic minority groups in the United Kingdom.

Social and parental factors

There is a correlation between psychosocial experiences in early life and the development of obesity [28]. People who experience one or more adverse childhood experiences (ACEs) are more likely to develop obesity in adult life. More recent studies have identified ACEs as a causal factor in paediatric obesity, particularly among girls, with sexual abuse identified as the single biggest risk factor [29]. The likelihood of developing obesity has been shown to increase with an accumulation of such experiences through the person’s life course [30]. It is now becoming increasingly recognised that as well as causing social disruption and dysregulated health behaviours, genes and environment interact during these critical early stages of child development, creating a situation of ‘toxic’ or chronic stress, causing remodelling of brain architecture and neurotransmitter release, leading to long-term dysregulated metabolism [31].

The family’s dietary choices and lifestyle have a crucial role in influencing the child’s weight, food preferences and appetite-related behaviours [32]. Authoritative parenting style (responding to hunger cues) has been found to be protective against childhood obesity [33]. Portion sizes at home also affect the child’s weight, especially if large portion sizes of calorie dense food are served. Family practices like ordering takeaways frequently or dining out and excessive consumption of JUNCS (Junk foods – foods high in fats, especially saturated and trans-fats, sugars and salts, and foods lacking in micronutrients/minerals, U – Ultra processed foods, N – Nutritionally inappropriate foods, C – Caffeinated/coloured/carbonated beverages, S – Sugar sweetened beverages) [34] has been shown to be associated with higher energy intake in both children and adults, leading to excess weight gain. Children exposed to environmental smoking are also at risk of obesity [35].

Obstructive sleep apnoea

Obstructive sleep apnoea (OSA) may be defined as recurrent events of partial or complete upper airway obstruction during sleep resulting in abnormal ventilation and sleep patterns [37]. Obesity in children is associated with a significantly increased risk of OSA, occurring in up to 60 % of children with obesity [38]. Untreated OSA may lead to cardiovascular complications, impaired growth, learning and behaviour problems and problems with glucose metabolism [39].

It is important to ask about potential symptoms of OSA such as snoring, witnessed apnoea, nocturnal enuresis, morning headaches and daytime sleepiness or fatigue [37]. If a patient has a history suggestive of obstructive sleep apnoea, a formal sleep study should be undertaken. If obstructive sleep apnoea is confirmed, initiation of non-invasive ventilation may be required. Patients with obesity and suspected or proven OSA should be advised and supported to lose weight as this may enable reversal of the condition [40].

Metabolic-dysfunction associated steatotic liver disease

Metabolic-dysfunction associated steatotic liver disease (MASLD) is characterised by the presence of moderate to severe hepatic steatosis, confirmed by imaging or histology, in the absence of alternative aetiologies [41]. In children and adolescents with obesity, it is estimated that the prevalence of MASLD is around 35 % [42]. If childhood MASLD persists into adulthood, it is associated with an increased risk of a range of conditions, e.g. cirrhosis, hepatocellular carcinoma, T2DM, cardiovascular disease and chronic kidney disease [43]. It is important to screen for MASLD when assessing CYP living with obesity, for example by measuring levels of liver enzymes (alanine transferase, aspartate aminotransferase and gamma-glutamyl transferase) in the blood and undertaking liver ultrasound scans (with elastography if available) if any of the enzymes are elevated above the normal range for the individual laboratory.

Weight loss is the only proven effective treatment for MASLD and has the potential to reverse the condition [43]. There is no evidence supportive of the use of medication to treat MASLD [43]. Rarely, bariatric surgery may be considered in adolescent patients with MASLD and may have the potential to reverse the condition through weight loss.

Hypertension

Obesity is a known cause of hypertension in children, and it has been shown that adolescents who are overweight are more than 8 times as likely to develop hypertension compared to those with a healthy BMI [44]. Hypertension may be defined as systolic or diastolic blood pressure≥95th centile by blood pressure for sex, age and height with an appropriately sized cuff and should be diagnosed with confirmed blood pressure readings≥95th percentile at three different visits [45].

If a patient is found to be hypertensive, it is recommended to perform an early morning urine sample measuring protein:creatinine and albumin:creatinine ratio to screen for renal damage. Blood tests to assess renal function and to look for underlying causes of hypertension are recommended, including urea and electrolytes, thyroid function tests, bicarbonate, bone profile and magnesium. Lifestyle changes are recommended for children with either hypertension including weight loss, physical activity, dietary sodium restriction and optimising other cardiovascular risk factors such as lipid and glycaemic control in diabetes. Pharmacological therapy for hypertension secondary to obesity may be required during childhood and adolescence to reduce the risk of end organ damage.

Dyslipidaemia

Obesity in childhood is known to increase the risk of dyslipidaemia. Therefore, it is important that a lipid profile is measured in CYP living with obesity, to include total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides (if fasted sample). Reference data for normal lipid values in paediatrics are limited and are based on cohort studies, such as in the Netherlands [46]. If LDL-cholesterol levels are persistently elevated after 3 months above 3.0 mmol/L despite dietary changes, the initiation of pharmacological therapy such as statins may be considered. Treatment of persistently elevated triglycerides may require referral to a specialist lipid clinic.

Type 2 diabetes mellitus

Paediatric obesity is associated with an increased risk of prediabetes and T2DM [47]. Obesity increases insulin resistance in the skeletal muscles, liver and adipose tissues, thereby decreasing glucose disposal in the skeletal muscles and building up free fatty acids and inflammatory cytokines. Glucotoxicity, lipotoxicity, mitochondrial dysfunction and endoplasmic reticular stress cause a steady decline of beta cell number and function [48]. ADA (American Diabetes association) and ISPAD (International society of Paediatric and adolescent diabetes) recommend screening for overweight or obese children with one or more of the following risk factors (maternal or family history of type 2 diabetes, insulin resistance, hypertension, dyslipidaemia, born small for gestational age, race/ethnicity predilection and pubertal/≥10 years of age). Screening tests include fasting plasma glucose, glycated haemoglobin (HbA_1c) and 2-h plasma glucose after an oral glucose tolerance test [49] with a follow-up annually if normal. It is important to note that where HbA_1c is used for diagnosis this should be a Diabetes Control and Complications Trial (DCCT) aligned, National Glycohemoglobin Standardization Program (NGSP) certified methodology, rather than a point-of-care method, and if hyperglycaemic symptoms are not present, then laboratory testing should be confirmed using a different test or on a different day [50]. Multi-disciplinary management of T2DM in CYP should incorporate support to lose weight, pharmacotherapy to improve glycaemic control and pro-active management of complications due to the aggressive nature of the disease when diagnosed in adolescence.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH) also known as primary pseudotumor cerebri syndrome (PTCS) is a condition with unknown aetiology that causes increased intracranial pressure (ICP [51]). In a large study, prevalence of IIH among 1,058 obese children and adolescents was 1.32 %, more commonly in pubertal age [52]. The signs and symptoms of IIH can be from transient visual loss, photophobia (‘shimmering lights with coloured centres’) and headache (2/3rd of cases but difficult to elicit in younger children) to mimicking clinical symptoms of a lesion in the posterior fossa. Investigations for IIH include a formal ophthalmology examination, a cranial magnetic resonance imaging (MRI) scan and lumbar puncture. Management for IIH includes weight loss and pharmacological agents such as acetazolamide and topiramate.

Musculoskeletal

Musculoskeletal difficulties encountered by children and young people with obesity include slipped upper femoral epiphysis (SUFE), which is a non-traumatic displacement (epiphyseal plate disruption) of the proximal femoral epiphysis. It has been reported that the risk of SUFE in severe obesity, compared to individuals with a normal BMI, is increased 6-fold at 5–6 years and 17-fold at 11–12 years [53]. Blount disease in obesity is due to increased pressure on proximal-posteromedial portion of the tibial physis resulting in non-physiologic varus deformity with internal tibial torsion and procurvatum [54]. The risk of fracture also appears to be increased in children due to low bone mineral density secondary to reduced physical activity. Obesity may lead to a delay in diagnosis and may alter the natural history of Legg–Calvé–Perthes disease and adolescent idiopathic scoliosis due to the increased body mass [55].

Puberty

Childhood obesity due to nutritional causes is associated with normal or accelerated linear growth during pre-puberty and early puberty. The high insulin level found in obesity due to insulin resistance stimulates gonadotropin-releasing hormone (GnRH) axis causing luteinising hormone (LH) secretion, increasing 5-alpha, 21-hydroxylase activity and 11 beta-hydroxysteroid dehydrogenase 1 activity stimulating ovarian and adrenal steroidogenesis [56], which is responsible for premature adrenarche. Leptin is increased in obesity, also stimulates kisspeptin activating hypothalamic–pituitary–gonadal axis, increasing sex steroids (both oestrogen and androgens) [57]; therefore, this may result in early puberty.

Psychosocial

Obesity during childhood and adolescence can have significant implications for social and psychological health [58]. Low self-esteem, anxiety, depression and lower quality of life scores are common in young people living with obesity [59]. Obesity in childhood and adolescence increased the change of adverse psychological and social outcomes, including poorer academic achievement, disordered eating and high levels of stress. Therefore, it is beneficial for children and young people living with severe obesity to have access to psychological support.

Dietary

Children and young people living with obesity consume excessive calories for a range of reasons and exploring the individual reasons behind this and supporting targeted change is of paramount importance [65]. It is also important to explore non-hunger eating patterns and the family set up along with care provision, offering a more thorough view of what is eaten and what food is provided in the different environments [66]. The dietary aim for any changes would be to achieve a nutritionally balance diet whilst always lowering the calorie intake in a holistic and culturally acceptable way [65]. It is important to address meal structure, snacks and the lack of fruit and vegetables, and it may be necessary to provide tailored calorific goals or meal replacement plans. Although there is limited paediatric data to support the use of very-low-energy-diets (VLED), there is some accumulating evidence that these diets are efficacious and safe in adolescents with obesity but meal-replacement drinks are not always tolerated due to taste [67].

Exercise

Physical activity is linked to a variety of benefits in terms of physical health as well as psychosocial well-being and mental health. In itself, exercise is not a central component of weight reduction, which requires dietary change [58]. It is recommended that all children should exercise to strengthen their muscles and bones aiming for an average of at least 60 min of moderate or vigorous intensity physical activity every day across the week [58].

In the weight management setting, advice about physical activity should be tailored specifically to the individual and their family, considering cost, mobility limitations or musculoskeletal issues. It is important to explore ways in which physical activity can be incorporated in daily routines, such as using stairs instead of a lift, walking to school or part of the way to school and active play. Sedentary behaviours and screen time should be limited [68]. According to the AAP (American Academy of Paediatrics) recommendations, children less than 18 months should have no exposure to screen except for video chatting occasionally with relatives [69]. Children above 18 months to 5 years can have up to 1 h per day of screen time but limit to quality and educational screen time. Children above 5 years till adulthood should not have more than 2 h of non-academic/non-work-related screen time per day [69].

It is important to identify specific, modifiable factors in the built environment to facilitate physical activity in childhood and adolescence. Not only does prevention of obesity require behavioural modifications, so does the treatment. Self-monitoring, goal setting individually and in group sessions, use of technologies, setting diet and physical activity patterns are equally important and needs reinforcement [70]. There is paucity of data in measuring energy expenditure versus intake; hence, we need to maximise on knowing how to use objective measures of energy expenditure (accelerometer or doubly labelled water) or energy intake [71].

Psychology

Psychological and behavioural interventions are highly beneficial in supporting children and young people living with obesity. Psychosocial dysregulation and heightened stress responses put young people at risk of obesity with those who have experience ACEs particularly at risk [72]. Psychological input in paediatric weight management may enable the identification of underlying causes of eating behaviours that contribute to and maintain obesity. Psychological assessment may also help to identify binge eating behaviours, which may contribute to obesity and significant emotional distress. Psychological interventions may focus on helping young people improve emotional regulation and develop ways to manage stress as well as understanding non-hunger eating patterns, and motivational interviewing may be used to help enact behavioural change. In children and young people with neurodiversity or learning difficulties, such as autism spectrum disorder and attention deficit hyperactivity disorder, psychological strategies may be tailored to focus on dietary habits such as rigid food routines and sensory differences that mediate the increased risk of obesity [73].

Pharmacological interventions

A range of pharmacological agents have been used for managing obesity in children in whom lifestyle interventions have been unsuccessful (Table 4). Orlistat, an intestinal lipase inhibitor, has been approved for use in adolescents in the United Kingdom with evidence of BMI reduction of 0.5–5kg/m² compared to placebo [74], but likely due to high rates of gastrointestinal side effects, it has been shown to be associated with high likelihood of treatment discontinuation. Topiramate [75] and phentermine combined with topiramate [76] have also been demonstrated to lead to weight loss in adolescents. It should be noted that phentermine is not an NHS-approved drug in the United Kingdom and is not prescribed for weight loss by itself or in combination.

More recently, glucagon-like peptide-1 (GLP-1) agonist analogues such as daily liraglutide or weekly semaglutide have been introduced as potential therapeutic options for weight loss in obesity. GLP-1 agonists given by subcutaneous injection, act by increasing insulin release, inhibiting glucagon release, slowing gastric motility and suppressing appetite. GLP-1 agonists have been demonstrated to achieve effective weight loss in adolescence. A randomised, controlled trial showed that liraglutide was associated with significantly greater weight loss in adolescence than placebo with a reduction in BMI of at least 5 % observed in 43.3 % of participants taking liraglutide versus 18.7 % treated with placebo after 56 weeks [77]. Similarly, in a randomised, controlled trial, semaglutide in adolescence was associated with greater weight loss than placebo, with 73 % of participants taking semaglutide losing 5 % or more of body weight compared to 18 % in the placebo group after 68 weeks [78]. A further study demonstrated that after 68 weeks treatment with semaglutide more than 40 % of adolescents BMI dropped to below the obesity threshold [79]. Side effects commonly found with GLP-1 agonists are nausea and vomiting; however, this is reduced by slow dose escalation. Extreme caution is required in those with a history of pancreatitis and GLP-1 agonists should not be prescribed to those with a family history of Multiple Endocrine Neoplasia-2 syndrome or thyroid cancer. Although initial safety data are positive, further studies are needed to demonstrate long-term safety of GLP-1 receptor agonists in the paediatric population [80].

Newer combination drugs, such as GLP-1 with glucose-dependent insulinotropic polypeptide (GIP) receptor analogues, are now being developed and undergoing trials [81]. Additionally, medications are being developed to target specific forms of genetic obesity. Setmelanotide, an MC4R agonist, has been shown to be highly effective in the treatment of severe obesity due to LEPR or POMC deficiency. In a randomised, controlled trial combining both paediatric and adult patients 80 % participants with POMC deficiency and 45 % with LEPR deficiency achieved at least 10 % weight loss at approximately 1 year [82]. Commonly, encountered side effects of setmelanotide include hyperpigmentation, nausea and site reactions.

It is an exciting time for the development of pharmacotherapy for the treatment of severe obesity in adolescents. It is important that pharmacological therapy is used as an adjunct to diet and lifestyle interventions to achieve effective weight loss and, therefore, maximal benefit for longer term health.

Bariatric surgery

There is an increasing international trend for patients to undergo bariatric surgery to treat obesity. However, as per latest guidelines, bariatric surgery could be considered in adolescents with BMI>40 kg/m2 or > 35 kg/m2 with significant comorbidities (T2DM, moderate-extreme OSA, IIH, debilitating orthopaedic problems, and non-alcoholic steatohepatitis with advanced fibrosis) including extreme psychological distress related to obesity (but no underlying psychiatric illness and a stable supportive family) despite rigorous lifestyle modification. Surgery can be malabsorptive, restrictive, or combination procedures.

The most common current operative procedures include vertical sleeve gastrectomy (VSG), laparoscopic adjustable gastric banding (LAGB) and Roux-en Y gastric bypass surgery (RYGB). In terms of choice of intervention, VSG is preferred in adolescents as there is no rearrangement of the anatomy, less likely malabsorption or postoperative bowel obstruction, as compared with RYGB. In addition to the anatomical effects of the procedures, both RYGB and VSG decrease ghrelin and increase the anorexigenic incretins, thus decreasing appetite and improving insulin sensitivity [83]. There are limited reviews on the efficacy of bariatric surgery and its long-term outcome in adolescents making it difficult to comment on its advantageous or disadvantages. Studies that support the role of bariatric surgery are ongoing; one of the most significant of these is the teen-LABS study, which showed that at 3-year follow-up, mean weight decreased by 27 % in the intervention group which was maintained in the 5-year follow-up [84]. In addition to the effect on weight, a reduction in complications related to excess weight, including T2DM [85], hypertension and MASLD [86] and improvement in quality of life has also been reported in adolescent bariatric surgery.

Side effects following bariatric surgery include dumping syndrome, severe gastro-oesophageal reflux, cholelithiasis and surgery-related complications and weight regain [87]. Multidisciplinary team monitoring the adherence to nutritional guidelines is essential for all patients postoperatively because low levels of minerals (iron, zinc, copper, selenium, calcium and phosphate) and vitamins (cholecalciferol, B12, B1 and folate) can occur due to restricted nutrient intake, decreased gastric acid production, decreased production of intrinsic factor and digestive enzymes, or food intolerance [88].