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Micronutrients, the critical components consumed in the diet that help run the metabolic reactions of the body, including iron, are known to be commonly deficient in the US population.^1,2 While it is well known that certain populations are at risk for iron deficiency, including children and people who are menstruating or pregnant, the prevalence of this mineral deficiency in the rest of the healthy adult population is usually assumed to be low. Now a new study provides evidence that even in the absence of any frank morbidities related to low iron, the prevalence of iron deficiency among US adults is nearly one in three.³

In the study, a cross-sectional nationally representative survey of over 8,000 US adults in the NHANES cohort (mean age 48 years; 52% female), researchers measured serum ferritin levels, serum iron levels, and unsaturated iron-binding capacity. Measures of iron stores and availability frequently use the proteins ferritin and transferrin. Ferritin is an iron storage protein found mostly inside cells, but its levels in the serum has long been used as a reliable measure of iron stores in the body, while transferrin is a liver-produced plasma protein that transports iron between cells. The researchers calculated transferrin saturation by dividing serum iron levels by total iron-binding capacity (sum of serum iron and unsaturated iron-binding capacity) multiplied by 100. They defined absolute iron deficiency as a serum ferritin level less than 30 ng/mL regardless of transferrin saturation and functional iron deficiency (in which iron stores are normal but available iron is low) as transferrin saturation less than 20% with a serum ferritin level greater than or equal to 30 ng/mL.³

The researchers found that absolute iron deficiency affects an estimated 14% (95% CI, 13%-15%) of adults in the US, and functional iron deficiency affects an estimated 15% (95% CI, 14%-17%), with absolute iron deficiency most often affecting young women and functional iron deficiency affecting women and men of all ages. This was true even among those without conditions often screened for iron deficiency such as anemia, chronic kidney disease, heart failure, or current pregnancy, in which the prevalence of absolute iron deficiency was 11% (95% CI, 10%-11%) and that of functional iron deficiency was 15% (95% CI, 14%-17%). The prevalence of functional iron deficiency exceeded that of absolute iron deficiency in all US adults except women younger than 50 years.³

Why is this important? While frank anemia and its associated health risks are well known, iron deficiency has health effects in other tissues, including skeletal and cardiac muscle, even in the absence of anemia.^4,5 The study authors also note that iron deficiency has been associated with restless leg syndrome, decreased physical capacity, impaired neurocognitive function, heart failure, all-cause mortality, and other adverse outcomes, all independent of anemia.⁴

What’s Inflammation Got to Do With It?

This study suggests that absolute iron deficiency may impact about one in seven adults and closer to one in three reproductive-aged women, and while this type of deficiency may often be addressed by iron repletion via diet or supplementation, functional iron deficiency may not be as straightforward. In functional iron deficiency, which the study similarly suggests affects about one in seven adults, the body seems to have adequate iron stores, leading some clinicians to conclude that an individual is iron replete when in fact they are not. One of the primary drivers of functional iron deficiency is inflammation, which can cause iron to be redistributed mostly into macrophages.⁶ Obesity-related inflammation increases expression of a molecule called hepcidin,^7,8 which inhibits iron transport by binding to the iron export channel ferroportin. Indeed, the researchers in the present study found that higher body mass index was associated with a higher risk of functional iron deficiency and lower transferrin saturation.³ The researchers note that higher body mass index may explain the high prevalence of functional iron deficiency, especially in younger adults without other inflammatory comorbidities. Strategies for lowering inflammation may be effective in preventing the effects of functional iron deficiency, and studies show that diet-induced weight loss improves iron status in patients with obesity and iron deficiency anemia.^7,8

Another important point the authors makes is that in inflammatory states, absolute iron deficiency can be masked because ferritin acts as an acute phase reactant. They found lower mean red blood cell volumes, mean red blood cell hemoglobin levels, and red blood cell distribution widths, which suggest that some individuals within the functional iron deficiency category also had absolute iron deficiency that was likely masked by inflammation.³

Conclusions

While it remains to be seen whether this study will change the guideline for testing iron levels, it does provide some important things to think about from a functional medicine standpoint. It might be worth considering testing more patients for iron deficiency even in the absence of signs of anemia, especially if they have any symptoms that suggest it, as the tests are cheap and widely available. For repletion, consider suggesting increasing dietary intake of iron and judicious supplementation where indicated. Finally, addressing the underlying causes of inflammation in patients with functional iron deficiency may be helpful, but it may also unmask an absolute iron deficiency that may subsequently be addressed with repletion.

References

1. US Department of Health and Human Services and US Department of Agriculture. 2020-2025 Dietary Guidelines for Americans. 9^th USDA and HHS; 2020. Accessed September 26, 2024. https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials
2. Bird JK, Murphy RA, Ciappio ED, McBurney MI. Risk of deficiency in multiple concurrent micronutrients in children and adults in the United States. Nutrients. 2017;9(7):E655. doi:10.3390/nu9070655
3. Tawfik YMK, Billingsley H, Bhatt AS, et al. Absolute and functional iron deficiency in the US, 2017-2020. JAMA Netw Open. 2024;7(9):e2433126. doi:10.1001/jamanetworkopen.2024.33126
4. Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. Iron deficiency. Lancet. 2021;397(10270):233-248. doi:10.1016/S0140-6736(20)32594-0
5. Camaschella C, Girelli D. The changing landscape of iron deficiency. Mol Aspects Med. 2020;75:100861. doi:10.1016/j.mam.2020.100861
6. Marques O, Weiss G, Muckenthaler MU. The role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation. Blood. 2022;140(19):2011-2023. doi:10.1182/blood.2021013472
7. Alshwaiyat NM, Ahmad A, Wan Hassan WMR, Al-Jamal HAN. Association between obesity and iron deficiency. Exp Ther Med. 2021;22(5):1268. doi:10.3892/etm.2021.10703
8. Alshwaiyat NM, Ahmad A, Al-Jamal HAN. Effect of diet-induced weight loss on iron status and its markers among young women with overweight/obesity and iron deficiency anemia: a randomized controlled trial. Front Nutr. 2023;10:1155947. doi:10.3389/fnut.2023.1155947