Functional Iron Deficiency in Obesity

Iron is essential for numerous bodily functions not least the production of the red blood cell oxygen transporter hemoglobin and myoglobin, a related molecule essential for muscle function. Iron deficiency is one of the most common nutritional deficiencies, especially in, but not limited to, premenopausal women.

Clinical signs of iron deficiency include anemia, difficulty in concentration, poor memory, depression, dizziness, weakness, labored breathing, anginal pain, brittle lusterless, flattened or spoon-shaped nails, swollen ankles, hair loss, pale skin, and exhaustion.

Paradoxically, obesity, a state more commonly considered in the context of over- than under-nutrition, is associated with a higher risk of iron deficiency compared to normal-weight individuals.

Several hypotheses have been suggested for this paradox including dilutional (pseudo) hypoferremia, poor dietary iron intake, increased iron requirements (in part due to the earlier onset and often more severe periods associated with excess weight), and/or impaired iron absorption in obese individuals.

However, there is now accumulating data that iron deficiency in obesity may also be mediated by the low-grade chronic inflammation commonly seen in individuals with excess weight.

This topic is elegantly reviewed by Ana Cepeda-Lopez and colleagues from the Netherlands, Mexico and Switzerland, in a paper just published in the International Journal of Vitamin and Nutrition Research.

The article summarizes the abundant data from epidemiological studies, dating as far back as 1962, documenting the inverse associations between adult and childhood adiposity and poor iron status (defined in most studies as low serum iron concentration).

With regard to possible mechanisms, the authors describe their own work in obese volunteers demonstrating decreased intestinal iron absorption using stable iron isotopes.

Iron absorption from the gut is dependent on both a divalent metal transporter and the iron exporter ferroportin, which delivers enteral iron to the blood stream and appears to be the rate-limiting step in this process.

Ferroportin in turn is largely regulated by hepcidin, a 25-amino acid peptide hormone, which is both an inhibitor of intestinal iron absorption as well as macrophage iron release.

Hepcidin is produced both in the liver and in fat tissue and is modulated by body iron stores and hypoxia, but also, as recently recognised, by proinflammatory cytokines, which are commonly elevated in individuals with excess weight and can promote hepcidin formation.

In addition, lipocalin 2, an iron binding protein is also produced by fat cells and could lead to sequestration of iron stores making them unavailable for hemoglobin or myoglobin formation.

Thus, irrespective of actual iron intake, a ‘low’ iron status in obese individuals may result both from reduced absorption and functional iron deficiency – the latter perhaps being more important than the former.

The authors conclude their article by summarizing the findings from three recent intervention studies: one in 15 obese children, where weight loss resulted both in a decrease in hepcidin levels and improved enteral iron absorption as well as two studies in bariatric surgical patients showing reduction in inflammation markers, decrease in hepcidin levels and improved iron status.

These findings are important as both low ‘absolute’ and ‘functional’ iron deficiency have been associated not only with anemia but also a wide range of other health problems including myocardial dysfunction and heart failure.

Clinicians should monitor obese patients for both absolute and functional iron deficiency and be aware that iron deficiencies may well be independent of and unresponsive to enteral iron intake.

Edmonton, Alberta

Cepeda-Lopez AC, Aeberli I, & Zimmermann MB (2010). Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition, 80 (4-5), 263-70 PMID: 21462109