Body iron stores and the risk for non-communicable disease in Indian children

High body iron stores have been associated with a higher risk for diabetes, dyslipidaemia and even hypertension in adults, with defined pathophysiological mechanisms. This association has not been described in iron supplemented children, and is relevant in India with universal iron fortification.
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 Background:

There are at least three threads that weave together to form the basis of the question asked in this study. First, India is considered to have profound levels of anaemia, but that consideration may be suspect. Recent rigorous surveys (1) have shown that anaemia in children is not as high as previously thought. As an aside, anaemia itself may be over-diagnosed, since surveys using capillary blood will overestimate the prevalence of anaemia (2) and there is some doubt that the haemoglobin cut-off to diagnose anaemia is incorrectly high (3), overestimating its prevalence.

The second thread comes from the assumption that dietary iron deficiency is a major problem, particularly in Indians. Indeed, only a third of the anaemia prevalence is due to iron deficiency (1). Other nutrients like vitamin B12, folate and protein are also important for haemoglobin synthesis. Coming to the issue of iron deficiency, the iron density of the average Indian diet is ~8.5 mg iron/1000 Kcal energy. For women who eat adequately for a sedentary lifestyle, the diet should provide nearly about 15 mg iron/day, matching their iron requirement of 15 mg/day. Those who have a lower iron requirement, like adult men, or those who eat more food energy as a result of an active lifestyle, will more easily meet their dietary iron requirement. Therefore, dietary iron deficiency is not the major problem. Nevertheless, based on this incorrect iron deficiency narrative, the policy in India has been to universally fortify rice with iron to increase the diet iron density, meaning that all the rice supplied in government feeding programs will be fortified; there will be no individual choice in this matter.

The third and troubling thread, is that excess iron in the diet is not safe for the individual, at many levels. There has been a lot of research in this area, particularly linked to chronic non-communicable disease (NCD) like diabetes, but also to hypercholesterolemia, and even high blood pressure. For the link with diabetes, there have been extensive reviews that offer mechanistic explanations for a disordered glucose metabolism (4), epidemiological investigations from the NHANES data that shows that increased serum ferritin (SF, the body iron storage molecule) is associated with a high risk for diabetes (5), or even simple interventions, like blood donations, that will decrease the body iron content, can improve the body glucose control (6). The counter-narrative here, is the assumption that there is a very tight regulation of iron absorption at the intestinal mucosa, but even this regulation cannot shut off iron absorption completely, such that net iron absorption will still be present. This does not consider those who have no way to excrete body iron (like men and post-menopausal women), in whom, over a long period of exposure to increased iron intake, the risk of a high body iron is increased. Finally, even the unabsorbed iron makes its way down to the colon, where it can alter the colonic microbiome (7), which as we are coming to realize, has consequences for good health over a lifetime. And that last, is the point. Once the policy for large scale iron fortification of staple foods is in place, it will last for a lifetime, or more.

These threads weave together a hypothesis, which taken together with the fact that India has an inordinately high number of people with diabetes, suggests that in a population that is getting iron supplementation (through pills), there could be a link between enhanced body iron stores (SF) and markers of risk for NCD, like high blood glucose or lipids. Further, could this be occurring early, for example in adolescent children? If so, the burden of later adult diabetes, hypercholesterolaemia or hypertension will be high, and offers a glimpse of potential unintended consequences of long-term, universal iron fortification.

What did we do?

In our manuscript (9) entitled “Is iron status associated with markers of non-communicable disease in adolescent Indian children?”, we set out to evaluate this hypothesis in a well-conducted national survey of Indian children, in data from the Indian Comprehensive National Nutrition Survey (8). We examined the association of NCD markers such as fasting blood glucose (FBG), blood pressure (HTN) and serum total cholesterol (TC) with SF (corrected for inflammation by Serum C-Reactive Protein), using logistic additive models in adolescent children (10-19 years), and further adjusted these analyses for confounders such as age, sex, body size, the presence of inflammation, and existing haemoglobin levels. We also examined the interaction of these associations with wealth and co-existing prediabetes. Finally, we also performed a scenario analysis to forecast the potential impact of iron fortification of cereals on the prevalence of NCD among Indian adolescents. ”

What did we find out?

We found that the odds ratio (OR) of high FBG, HTN and TC were 1.05 (95% CI 1.01-1.08), 1.02 (95% CI: 1.001-1.03) and 1.04 (95% CI: 1.01-1.06) respectively for every 10µg/L increase in SF. The odds for high TC increased with co-existing prediabetes. The scenario analysis showed that providing 10 mg of iron/day by fortification could increase the prevalence of high FBG by 2%-14% across states of India. Although with this cross-sectional observational design, causality cannot be inferred with any certainty, the adjustment for several important confounders does suggest plausibility. Nevertheless, these are worrying findings, indicating that the enhancing of iron intake in anaemia prevention programs should consider what the impact would be on the risk for later NCD.

 

References

  1. Avina Sarna, Akash Porwal, Sowmya Ramesh, et al. Characterisation of the types of anaemia prevalent among children and adolescents aged 1–19 years in India: a population-based study. Lancet Child & Adolescent Health. 2020;4:515-525.
  2. Neufeld LM, Larson LM, Kurpad A, et al. Hemoglobin concentration and anemia diagnosis in venous and capillary blood: biological basis and policy implications. Ann N Y Acad Sci. 2019;1450:172-189.
  3. Sachdev HS, Porwal A, Acharya R, et al. Haemoglobin thresholds to define anaemia in a national sample of healthy children and adolescents aged 1-19 years in India: a population-based study. Lancet Glob Health. 2021;9:e822-e31.
  4. Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17:329-341. 
  5. Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among US adults. Diabetes Care. 1999; 22:1978–1983.
  6. Houschyar KS, Ludtke R, Dobos GJ, et al. Effects of phlebotomy induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial. BMC Med. 2012;10: 54.
  7. Paganini D, Zimmermann MB. The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr. 2017;106(Suppl 6):1688S-1693S.
  8. Ministry of Health and Family Welfare (MoHFW), Government of India, UNICEF and Population Council. Comprehensive National Nutrition Survey (CNNS). National Report 2016–2018. New Delhi, India: MoHFW, Government of India, UNICEF and Population Council; 2019 [accessed September 2022].
  9. Ghosh S, Thomas T, Kurpad A, et al. Is iron status associated with markers of non-communicable disease in adolescent Indian children? Eur J Clin Nutr. 2022. In Press.

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