To our knowledge, this is the first study to demonstrate a strong and consistent association among inflammatory markers and obesity in a large, recent nationally representative sample of US children across the full childhood age range. Although associations between inflammatory markers and obesity were greatest for older children, this relationship was observed among children as young as age 3 and was consistently demonstrated for 3 different measures of inflammation. Our analysis also provides national prevalence estimates of elevated inflammatory markers in children at varying weight statuses and age groups.
In the present era of an obesity epidemic, when 14% of preschool-aged children (2–5 years) are overweight,17
our study is an important addition to the literature. Previous research used ultrasound techniques to show that increased CRP seems to be related to vascular intima media thickness in children and early atherosclerotic changes related to inflammation.11,34
Taken together with these pathophysiologic findings in small clinic samples, the results of our work raise concerns about the entire population of overweight children’s risk for long-term cardiovascular disease. Ford et al analyzed NHANES 1999–2000 and demonstrated associations between BMI percentile and increases in CRP.35
Since that study, the definitions of overweight/obesity have changed, and the epidemic of obesity has progressed within all age groups of the population. Our study, in which we used larger, more recent nationally representative data with a broader age range and multiple inflammatory markers, therefore extends earlier work by Ford et al and other authors.10–15,36
Our study results also demonstrated the persistence of the relationship between weight status and inflammation despite using inflammatory markers based on different terminal inflammatory pathways. The weak correlations between the measures suggest that each is measuring a somewhat different process yet is independently and similarly associated with weight status. Each inflammatory pathway may have different effects on health outcomes. Future research will need to examine their usefulness, individually or combined, in predicting future cardiovascular and other health outcomes.
Whereas our study has important strengths, there are also limitations. First, we were unable to fully control for pubertal age, which may affect cardiovascular risk factors including inflammation. NHANES no longer includes Tanner staging for measurement of puberty, and there are also few other sexual development proxies available. However, our results are similar for age groups in which there may be significant variation in puberty and for age groups in which the great majority of children have likely begun puberty, strongly suggesting that the lack of control for puberty had minimal impact on our analyses. Second, given the cross-sectional design, we are unable to determine the direction of association between inflammation and obesity. Although there is evidence that adipose tissue acts as an active endocrine organ that stimulates inflammatory cascades,5,6,37
it is possible that inflammation could also incite obesity. More importantly, although the relationship between inflammation and adiposity is evident in very young children, the cross-sectional design does not permit us to comment on whether the relationship is maintained for individual children across time or certainly into adulthood. Third, because inflammatory markers do vary somewhat according to age, our use of the same cutoff for all ages may obscure subtle relationships. However, using age-specific 95th percentile as cutoffs for abnormal values did not significantly change the results. Finally, we used 2 less-established markers of chronic inflammation, in addition to the more accepted and conventional marker, CRP. Whereas the F/T marker (described here for the first time) may ultimately be a novel way to examine ferritin while controlling for iron status, there are currently no descriptions of its distribution in the population, and its use here is based on face validity alone.
Why we did not identify a relationship between elevated inflammatory markers and obesity in infants and children younger than 3 years of age is unclear, although very obese 1- to 2-year-olds did have a trend toward elevated inflammatory markers. It is possible that inflammatory markers are not elevated immediately with obese status, and therefore obese children in the youngest age range would not yet have elevated markers. Longitudinal study would better test this hypothesis. Possibly, the weight-for-length percentile used for the youngest children altered the relationship between weight status (otherwise assessed via BMI) and inflammatory markers. Because the number of 1- to 2-year-old children in our sample was smaller, it is possible that a more balanced sample distribution would have conferred statistically significant differences at all ages.
It is also unclear why the association between obesity and inflammatory markers seems to peak at ages 9 to 11. One possibility is that the lack of pubertal controls disguises a more complex relationship between adiposity changes in the early pubertal period and inflammation perhaps related to insulin resistance.38
In addition to specific puberty-based differences, there may be biological or physiologic differences in this developmental period that we are unable to elucidate using our data.
Our research brings to the forefront many important questions. First, with so many children potentially at risk for health-related sequelae from obesity, does the presence of increased inflammatory markers predict those who will fare poorest? Future research needs to focus on the ability to use inflammatory markers to predict cardiovascular risk in children, as has been done in adults. In this way, inflammatory markers could be used as a second layer of screening to determine who would most benefit from obesity interventions. Although cardiovascular screening of adults by using CRP is debated,39
it is clear that there is a relationship between CRP level and future cardiovascular morbidity.40,41
In addition, there is evidence that treating older adults with an elevated CRP but normal lipid levels using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces mortality.42
To be enrolled in the 3-hydroxy-3-methylglutaryl coenzyme A reductase treatment trial (JUPITER trial), subjects had to have a CRP level of > 2 mg/L,42
which makes it concerning that a significant proportion of obese children have CRP levels of > 4 mg/L. Although current recommendations and debate about statin use in children focus on the reduction of hyperlipidemia, the JUPITER trial may stimulate researchers to investigate the benefits of statin usage in children beyond cholesterol reduction alone.
Another question is whether biomarkers could change quickly with lifestyle change and thereby be useful to motivate and support patients early in the course of improved lifestyles. Because there is evidence that physical activity, specific dietary behaviors, and other environmental factors play a role in the inflammatory process,37,43
could counseling that focuses on improved diet and activity improve inflammation even before weight decreases?