February 10, 2010 (Umeå, Sweden) – Obesity, glucose intolerance, and hypertension in childhood are strongly linked with premature death from endogenous causes in young adulthood and middle age, according to the results of a new epidemiological study in a cohort of American Indian children.
Elevated cholesterol levels, on the other hand, were not associated with early mortality, although investigators caution against concluding that hypercholesterolemia in childhood is not harmful.
"The linking factor here is almost certainly the obesity," lead investigator Dr Paul Franks (Umeå University Hospital, Sweden) told heartwire .
"When we adjusted the risk associated with glucose levels and blood pressure for obesity, the effect of those risk factors substantially diminished.
We also know the causal mechanisms with blood pressure, glucose, and obesity suggest that obesity is probably the primary metabolic derangement that causes hyperglycemia and high blood pressure, and not the other way around."
The results of the study are published in the February 11, 2010 issue of the New England Journal of Medicine.
BMI Associated With Increased Risk of Premature Death From Endogenous Causes
Speaking with heartwire , Franks noted that his group previously published studies examining the association between glucose levels during pregnancy and the risk of obesity and diabetes in the offspring, as well as studies linking clinical risk factors in children with diabetes in adulthood. The purpose of this study was to study the effect of childhood risk factors for cardiovascular disease on adult mortality.
In a cohort of 4857 American Indian children aged five to 19 years without diabetes, body-mass index (BMI), glucose tolerance, blood pressure, and cholesterol levels were assessed to determine the extent to which they predicted premature death. The analyses included data from the date of the baseline examination until the person's death, their 55th birthday, or the end of 2003. During a median follow-up of 24 years, there were 166 deaths, 3.4% of the cohort, from endogenous causes. Of these deaths, 59 were attributed to alcoholic liver disease, 22 to cardiovascular disease, 21 to infections, 12 to cancer, 10 to diabetes or diabetic nephropathy, nine to alcoholic poisoning or drug overdose, and 33 to other causes.
BMI was associated with a significantly increased risk of premature death from endogenous causes, with those in the highest quartile having a mortality rate 230% greater than those in the lowest BMI quartile.
The two-hour plasma glucose level assessed during an oral glucose-tolerance test was not associated with premature death, but children with elevated blood glucose, those in the highest quartile, had a 73% greater risk of premature death than those in the lowest quartile.
Incidence-Rate Ratios for Premature Death (Quartile 4 vs Quartile 1) Variable Premature death from endogenous causes, incidence-rate ratio (95% CI)
BMI 2.30 (1.46–3.62)
2-h glucose 1.73 (1.09–2.74)
Total cholesterol 1.28 (0.81–2.02)
Systolic blood pressure 1.34 (0.83–2.15)
Diastolic blood pressure1 1.40 (0.89–2.19)
In models looking only at children with impaired glucose tolerance, there was no significant association with premature death.
"That might sound slightly counterintuitive, that these children with impaired glucose tolerance, those at the top end, are not the ones really driving mortality," explained Franks. "My feeling is that this is a population with a well-known risk for diabetes, so children diagnosed with the highest glucose levels, even though they are not diabetic, might have been picked up by the medical services early on and treated, which would make them less prone to the consequences of hyperglycemia. The children just below that level, they still have high glucose, they're the ones really driving the mortality rate in this study. The take-home message from this is that having a threshold for high glucose and saying that we're only going to intervene when it is above that threshold might not be good enough."
There was no significant association observed between systolic and diastolic blood pressure and premature death, but when investigators used a childhood definition of hypertension, one that takes three measurements and is standardized for height, there was a 57% increase in the risk of premature death among hypertensive children.
Regarding the absence of an association between childhood hypercholesterolemia and premature mortality, Franks told heartwire that only total-cholesterol levels were measured and that they did not have access to a full lipid profile. Moreover, a limited number of cardiovascular events might have influenced this finding, and as a result clinicians should err on the side of caution about concluding that there is no risk associated with elevated cholesterol levels.
"I would say that the absence of a statistically significant effect does not mean that high cholesterol levels in childhood are not harmful," he said. "It could mean that we did not observe enough events related to cardiovascular death to produce a statistically significant association between cholesterol in childhood and early death. Possibly, if this cohort is followed until later in life and more cardiovascular deaths occur, it's possible that one would observe an association between childhood cholesterol and mortality rates."
How Should the Findings Be Put Into Practice?
In an editorial accompanying the study , Dr Edward Gregg (Centers for Disease Control, Atlanta, GA) notes that the causes of obesity and diabetes appear to be rooted in culture--inactivity and large portion sizes of calorie-dense fast food--and that fighting these diseases with "clinical and adult-based approaches" is akin to "pasting a small bandage on a gaping wound."
While future approaches might target young people as a means of preventing these metabolic disorders, it should not be assumed that targeting youths will be effective for reducing their prevalence. "Bridging the wide gap between risk factors in youth and the prevention of illness in adults needs not only evidence that risk factors track strongly from childhood to adulthood but also efficient interventions with sustainable effects across different life stages," he writes.
"What we don't know is, if we intervene in these children, would we decrease the mortality rates; and we don't yet know the best way to intervene," he told heartwire . "Weight loss is not normally considered an appropriate strategy in children; instead, we try to get them to migrate toward a healthy growth trajectory. The message for frontline therapists is healthy diet and physically active lifestyles."
In highlighting one of the limitations of the study, Gregg points out that many deaths occurred before individuals were 45 years of age and were influenced by a large number of deaths from liver disease, something that warrants further study. He said the clinicians should not assume that follow-up into later life, when people die of typical causes, would yield similar associations with impaired glucose, obesity, and death. Like Gregg, Franks noted the cohort is unique, but that trends with respect to obesity and diabetes have mirrored trends in the US population in the past few decades.
No conflicts of interest reported.