In this cross-sectional study, 103 children and adolescents with obesity were divided according to the criteria proposed by Damanhoury et al to either having MHO or MUO [15]. Several obesity-related clinical and laboratory parameters were compared between these two groups of youth with obesity and a third group of age-, sex-, and Tanner-matched NW children. As anticipated, most of the examined parameters were affected in children with MUO compared to NW, including the parameters used as criteria to differentiate MHO and MUO phenotypes (i.e. HDL-C, TG, SBP, DBP, and FBG) as well as indicators of visceral adiposity, insulin sensitivity, hepatic steatosis, thrombosis, immune system and inflammation. What was not anticipated though, was the finding that several of the examined parameters were found to be affected also in children with MHO compared to NW.
Concerning glucose metabolism, no significant difference was observed regarding FPG levels among youth with NW, youth with MHO, and youth with MUO (88.1 ± 8 vs 87.9 ± 7 vs 88.4 ± 10 mg/dL). Such an observation could be explained by the fact that FBG usually remains within normal range in children, despite obesity and changes in insulin sensitivity and secretion [31], especially in children with relatively short obesity duration such as our study participants [32]. In addition, possible differences in the genetic predisposition of each child to develop hyperglycemia could also play a role. Fasting insulin levels (8.4 ± 3.5 vs 12.4 ± 7.6 vs 14.7 ± 13.5 μU/mL) and HOMA-IR (1.85 ± 0.8 vs 2.7 ± 1.7 vs 3.3 ± 3.7) were lower and QUICKI (0.36 ± 0.032 vs 0.33 ± 0.05 vs 0.33 ± 0.03) was higher in NW compared to both children with MHO and MUO indicating that a state of insulin resistance and a consequent hyperinsulinemia characterize both groups of children with obesity compared to NW peers. In addition, a relative overlapping was observed when cutoff values of insulin, HOMA-IR, and QUICKI were calculated to differentiate between groups of children.
Regarding subclinical inflammation and atherogenesis, hsCRP (2.1 ± 1.2 vs 4.7 ± 3.8 vs 5.4 ± 3.9 mg/L), fibrinogen (296 ± 50 vs 361 ± 109 vs 381 ± 76 mg/dL), and UA (4.4 ± 0.9 vs 5.4 ± 2 vs 5.02 ± 1.4 mg/dL) were found to be lower in NW compared to both children with MHO and MUO while they did not differ significantly between the latter two groups. A recent study in adults showed that pro-inflammatory monocyte subsets were lower in adults with MHO compared to those with MUO but higher than NW suggesting a sub-clinical inflammation in individuals with MHO [33]. To the best of our knowledge, no studies have been published linking hsCRP or fibrinogen levels with MHO phenotype in children, while increased UA levels have recently been linked to MUO in youth [34]. Our results show that obesity is associated with subclinical inflammation and a pro-atherogenic milieu, even in children with the MHO phenotype.
Regarding adipokines, adiponectin was higher (11.9 ± 5.8 vs 9.8 ± 5.8 vs 9.4 ± 5 μg/mL), and leptin was lower (10.5 ± 7 vs 31 ± 19 vs 34 ± 15 ng/mL) in controls compared to both children with MHO and MUO. Visfatin was higher in children with MUO compared to NW (12.9 ± 7 vs 9.8 ± 5 ng/mL, p<0.01) but showed no difference between children with MHO and NW (11.7 ± 6 vs 9.8 ± 5 ng/mL). IL-6 did not differ between the three groups of children (9.4 ± 10 vs 8.3 ± 6.4 vs 9.9 ± 9.5 pg/mL). Visfatin showed a tendency to increase between patients with MHO and MUO (11.7 ± 6 vs 12.9 ± 7, p=0.10) while the other three adipokines did not differ between the two groups of children with obesity. Similar to our results, studies have shown that children with MHO may present with lower adiponectin levels compared to NW, and higher leptin levels [35, 36]. Regarding visfatin and the MHO phenotype, data have been conflicting thus far [37, 38], while, to the best of our knowledge, there have been no studies investigating IL‐6 levels in children with MHO and MUO. These results point toward a pro-inflammatory milieu that could gradually lead to metabolic derangements not only in children with MUO but also in those with MHO compared to NW.
Regarding liver transaminases, ALT, which is considered to be the best screening tool to detect NAFLD in children [39], was higher in youth with both MHO and MUO compared to NW [(23.6 ± 13) vs (26.5 ± 15) vs (18.7 ± 8) U/L respectively, p<0.001]. In addition, children with MUO had mean ALT values (26.5 ± 15 U/L) above the upper limit of normal in children (22 U/L for girls and 26 U/L for boys) according to the latest NASPGHAN Clinical Practice Guideline [39]. These findings imply that mainly children with MUO but also those with MHO are at increased risk of developing liver dysfunction and possibly NAFLD, in agreement with other studies in both adolescents and adults with obesity [40–42]. Fortunately, only one of all youth included in the study, a prepubertal child with MUO, had ALT>80 U/L, a finding that has been linked with increased risk of fibrosis in children with non-alcoholic steatohepatitis [39].
The uncertainties that still exist regarding pediatric MHO definition may imply that MHO does not represent a biologically defined distinct subgroup of individuals with obesity and that it might not be a totally benign condition after all [16, 43]. Indeed, evidence is gradually accumulating, both in adults and children, that individuals with MHO have a worse metabolic profile compared to their lean counterparts and are at increased risk of obesity complications. In a recent study for example, Caleyachetty et al showed that adults with MHO had a higher risk of coronary heart disease, CVD, and heart failure than NW counterparts [17]. In youth, individuals with MHO have shown increased risk of hepatic steatosis, higher degree of visceral fat accumulation, higher inflammatory biomarkers and higher carotid intima-media thickness, a proxy of CVD, compared to NW [35, 41, 44, 45]. The findings of our study corroborate the notion that MHO is not a totally benign condition that can be clearly differentiated from MUO but rather, obesity represents a continuum-increased risk for complications and CVD.
This study has some limitations, namely the relatively small sample size from an epidemiological point of view, and the lack of information regarding long-term outcomes (e.g., obesity complications and related morbidities) due to the study’s cross-sectional design. In addition, it could be speculated that there may have been subtle differences in fat composition or fat distribution between the study groups, since reference methods of adiposity estimation were not used. Further, information on children’s birth, diet, lifestyle habits, and family history is lacking. The strengths of this study were that all three groups were age-, sex- and Tanner-matched as well as of the same ethnicity, that several obesity-related biochemical parameters were measured and that the differences observed were statistically strong making the results more reliable.
In conclusion, it was shown that children and adolescents with obesity diagnosed as having MHO show a better metabolic profile than their peers with MUO, but a worse profile compared to NW. These findings question the benign nature of the pediatric MHO. More comprehensive and stringent criteria could possibly better define children and adolescents with obesity that are metabolically healthy, but still, the clinical significance and the long-term outcome of such a phenotype are highly debatable. Until more data are gathered, children with MHO should be considered as having a vaguely defined and possibly unstable phenotype and should therefore be treated as all children with obesity.