Page 78 - Haematologica May 2020

N.U. Stoffel et al.
for the lower increase in SHep in response to oral iron in anemic women compared to iron deficient non-anemic women is that hepatic hepcidin expression is more strongly suppressed by ID and erythropoetic drive; the latter mechanism may be particularly important in our subjects who had recently donated blood.16
The strengths of this study are that we used a cross- over design providing two high oral iron doses (100 and 200 mg) to women with IDA together with a standard- ized diet, and precisely quantified iron absorption using multiple iron stable isotopic labels on multiple days, with each subject acting as her own control. SHep and iron sta- tus parameter profiles were accurately and repeatedly quantified using an immunoassay with high sensitivity over two to six days; tolerability and gastrointestinal side effects were assessed by a standardized interview. Furthermore, study participants were otherwise healthy and free of comorbidities. Limitations of the study are that our subjects were only mildly, or for some, border- line, anemic, with Hb values ranging from 8.6 to 12.5 g/dL. Confirmation of these findings in women with more severe anemia (with Hb <8 g/dL) would require fur- ther study. At inclusion, most of the participants had just donated blood, which contributed to their anemia. The recent loss of 500 mL blood during donation could have influenced the response to the supplemental iron doses: for example, acute blood loss can stimulate renal EPO production which can suppress hepatic hepcidin synthe- sis.29,30 However, despite prevailing high EPO concentra- tions (Table 2), we saw clear increases in SHep in response to the iron doses. Whether the response of SHep would differ in subjects with chronic anemia cannot be
concluded from our data. However, chronic anemia would also increase the chance for gastrointestinal or other inflammatory conditions affecting iron absorption, and we can exclude that these had an effect in the current study. Finally, based on our study design, it is unclear if the effect of iron supplement dosing on consecutive days (day 2, 3) prior to the alternate day dosing (day 3, 5) effected our comparisons. To address this, an alternate design could have been to test consecutive day dosing and then have a washout period and then test the alter- nate day dosing. However, a disadvantage of this approach would be an increase in the number of test meals and subject burden, as well as potential changes in subjects’ inflammatory and/or iron status during the washout period that would increase variability.
In conclusion, as in our previous studies using a daily dose of 60 mg in iron-depleted non-anemic women, our data show that with higher doses of 100 to 200 mg iron in women with IDA, alternate day dosing results in high- er FIA and a trend for lower incidence of gastrointestinal side effects compared to consecutive day dosing. These potential benefits need to be confirmed in long-term intervention studies in anemic women with clinical end- points, such as change in Hb, iron status and side effects, as primary outcomes. If confirmed, this dosing regimen may allow the use of lower iron doses, which may reduce side effects and improve compliance.
Acknowledgments
The authors thank the participating women, the nursing staff, Bérénice Hansen, Dr. Reinhard Henschler and Dr. Beat Frey for their support of the study.
References
1. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014; 123(5):615-624.
2. Cogswell ME, Looker AC, Pfeiffer CM, et al. Assessment of iron deficiency in US pre- school children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003-2006. Am J Clin Nutr. 2009;89(5):1334-1342.
3. Cook JD. Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol. 2005;18(2):319-332.
4. Camaschella C. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015;2015:8-13.
5. CDC. Recommendations to Prevent and Control Iron Deficiency in the United States. Atlanta: Centers for Disease Control and Prevention (CDC). 1998 [cited 2018 21.09]; Available from: https://www.cdc.gov/mmwr/preview/mm wrhtml/00051880.htm
6. Stoltzfus RJ, Dreyfuss ML. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia: International Nutritional Anemia Consultative Group (INACG), 1998. Available from: mother- childnutrition.org/nutrition-protection-pro- motion/pdf/mcn-guidelines-for-iron-sup- plementation.pdf
7. Pavord S, Myers B, Robinson S, et al. UK
guidelines on the management of iron defi- ciency in pregnancy. Br J Haematol. 2012; 156(5):588-600.
8. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;22;126(17):1981- 1989.
9. Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementa- tion causes significant gastrointestinal side- effects in adults: a systematic review and meta-analysis. PloS One. 2015;10(2): e0117383.
10. Kortman GA, Raffatellu M, Swinkels DW, Tjalsma H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol Rev 2014; 38(6):1202-1234
11. Lund EK, Fairweather-Tait SJ, Wharf SG, Johnson IT. Chronic exposure to high levels of dietary iron fortification increases lipid peroxidation in the mucosa of the rat large intestine. J Nutr. 2001;131(11):2928-2931.
12. Lund EK, Wharf SG, Fairweather-Tait SJ, Johnson IT. Oral ferrous sulfate supple- ments increase the free radical-generating capacity of feces from healthy volunteers. Am J Clin Nutr. 1999;69(2):250-255.
13. Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med. 2005;118(10):1142-1147.
14. Jaeggi T, Kortman GA, Moretti D, et al.
Iron fortification adversely affects the gut microbiome, increases pathogen abun- dance and induces intestinal inflammation in Kenyan infants. Gut. 2015;64(5):731-742.
15. Paganini D, Uyoga MA, Kortman GAM, et al. Prebiotic galacto-oligosaccharides miti- gate the adverse effects of iron fortification on the gut microbiome: a randomised con- trolled study in Kenyan infants. Gut. 2017;66(11):1956-1967.
16. Sangkhae V, Nemeth E. Regulation of the iron homeostatic hormone hepcidin. Adv Nutr. 2017;8(1):126-136.
17. Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supple- ments given on consecutive versus alter- nate days and as single morning doses ver- sus twice-daily split dosing in iron-depleted women: two open-label, randomised con- trolled trials. Lancet Haematol. 2017;4(11): e524-e533.
18. Schaap CC, Hendriks JC, Kortman GA, et al. Diurnal rhythm rather than dietary iron mediates daily hepcidin variations. Clin Chem. 2013;59(3):527-535.
19. Troutt JS, Rudling M, Persson L, et al. Circulating human hepcidin-25 concentra- tions display a diurnal rhythm, increase with prolonged fasting, and are reduced by growth hormone administration. Clin Chem. 2012;58(8):1225-1232.
20. Camaschella C. New insights into iron deficiency and iron deficiency anemia. Blood Rev. 2017;31(4):225-233.
21. Pena-Rosas JP, De-Regil LM, Gomez
1238
haematologica | 2020; 105(5)