Abstract
Introduction
Several studies on obese youths and adults have reported increased hepcidin levels, which seems to be related to metabolic and iron metabolism alterations. The complete mechanisms involved in hepcidin increase remain to be elucidated, and particularly its role in the development of other known complications such as Nonalcoholic Fatty Liver Disease (NAFLD). NAFLD in prepubertal children might be of special interest in understanding the underlying mechanisms.
Methods
Anthropometric measurements, liver ultrasonography, lipid profile, liver function, oxidative stress, inflammatory state, and iron metabolism were studied in 42 obese prepubertal children and 33 healthy controls. We, therefore, evaluated the presence of possible correlations between Hepcidin and the other metabolic variables, and the possible association between NAFLD and iron metabolism.
Results
Hepcidin levels were significantly increased in the obese prepubertal children (p=0.001) with significant differences between obese children with and without NAFLD (p=0.01). Blood iron was lower in obese children (p=0.009). In the obese group, a negative correlation between hepcidin and both blood iron levels (p=0.01) and LagPHASE (p=0.02) was found. In addition, a positive association between hepcidin and NAFLD (p=0.03) was detected.
Conclusions
We suggest that an increase in hepcidin levels may represent an early step in iron metabolism derangements and metabolic alterations, including NAFLD, in prepubertal obese children.
Acknowledgments
(If applicable).
-
Research funding: None declared.
-
Author contribution: Each author has made substantial contributions to the conception or design of the study, participated in drafting the study or revising it critically for important intellectual content, approved the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
1. Katsarou, A, Pantopoulos, K. Basics and principles of cellular and systemic iron homeostasis. Mol Aspect Med 2020;75:100866. https://doi.org/10.1016/j.mam.2020.100866.Search in Google Scholar PubMed
2. Bekri, S, Gual, P, Anty, R, Luciani, N, Dahman, M, Ramesh, B, et al.. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 2006;131:788–96. https://doi.org/10.1053/j.gastro.2006.07.007.Search in Google Scholar PubMed
3. Tussing-Humphreys, L, Pusatcioglu, C, Nemeth, E, Braunschweig, C. Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin. J Acad Nutr Diet 2012;112:391–400. https://doi.org/10.1016/j.jada.2011.08.038.Search in Google Scholar PubMed PubMed Central
4. Yanoff, LB, Menzie, CM, Denkinger, B, Sebring, NG, McHugh, T, Remaley, AT, et al.. Inflammation and iron deficiency in the hypoferremia of obesity. Int J Obes 2007;31:1412–9. https://doi.org/10.1038/sj.ijo.0803625.Search in Google Scholar PubMed PubMed Central
5. Nemeth, E, Rivera, S, Gabayan, V, Keller, C, Taudorf, S, Pedersen, BK, et al.. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271–6. https://doi.org/10.1172/jci200420945.Search in Google Scholar
6. Aigner, E, Feldman, A, Datz, C. Obesity as an emerging risk factor for iron deficiency. Nutrients 2014;6:3587–600. https://doi.org/10.3390/nu6093587.Search in Google Scholar PubMed PubMed Central
7. Reichert, CO, da Cunha, J, Levy, D, Maselli, LMF, Bydlowski, SP, Spada, C. Hepcidin: homeostasis and diseases related to iron metabolism. Acta Haematol 2017;137:220–36. https://doi.org/10.1159/000471838.Search in Google Scholar PubMed
8. Schwimmer, JB, Deutsch, R, Kahen, T, Lavine, JE, Stanley, C, Behling, C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388–93. https://doi.org/10.1542/peds.2006-1212.Search in Google Scholar PubMed
9. Datz, C, Müller, E, Aigner, E. Iron overload and non-alcoholic fatty liver disease. Minerva Endocrinol 2017;42:173–83. https://doi.org/10.23736/S0391-1977.16.02565-7.Search in Google Scholar PubMed
10. Ma, B, Sun, H, Zhu, B, Wang, S, Du, L, Wang, X, et al.. Hepatic steatosis is associated with elevated serum iron in patients with obesity and improves after laparoscopic sleeve gastrectomy. Obes Facts 2021;14:64–71. https://doi.org/10.1159/000511736.Search in Google Scholar PubMed PubMed Central
11. Ahmed, U, Latham, PS, Oates, PS. Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis. World J Gastroenterol 2012;18:4651–8. https://doi.org/10.3748/wjg.v18.i34.4651.Search in Google Scholar PubMed PubMed Central
12. Manco, M, Alisi, A, Real, JF, Equitani, F, DeVito, R, Valenti, L, et al.. Early interplay of intrahepatic iron and insulin resistance in children with non-alcoholic fatty liver disease. J Hepatol 2011;55:647–53. https://doi.org/10.1016/j.jhep.2010.12.007.Search in Google Scholar PubMed
13. Cacciari, E, Milani, S, Balsamo, A, Spada, E, Bona, G, Cavallo, L, et al.. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 2006;29:581–93. https://doi.org/10.1007/bf03344156.Search in Google Scholar PubMed
14. D’Adamo, E, Giannini, C, Chiavaroli, V, de Giorgis, T, Verrotti, A, Chiarelli, F, et al.. What is the significance of soluble and endogenous secretory receptor for advanced glycation end products in liver steatosis in obese prepubertal children? Antioxidants Redox Signal 2011;14:1167–72. https://doi.org/10.1089/ars.2010.3719.Search in Google Scholar PubMed
15. Flynn, JT, Falkner, BE. New clinical practice guideline for the management of high blood pressure in children and adolescents. Hypertension 2017;70:683–6. https://doi.org/10.1161/hypertensionaha.117.10050.Search in Google Scholar
16. Chan, DF, Li, AM, Chu, WC, Chan, MH, Wong, EM, Liu, EK, et al.. Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord 2004;28:1257–63. https://doi.org/10.1038/sj.ijo.0802734.Search in Google Scholar PubMed
17. Yeckel, CW, Weiss, R, Dziura, J, Taksali, SE, Dufour, S, Burgert, TS, et al.. Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents. J Clin Endocrinol Metab 2004;89:1096–110. https://doi.org/10.1210/jc.2003-031503.Search in Google Scholar PubMed
18. Foreman, JR, Karlin, JB, Edelstein, C, Juhn, DJ, Rubenstein, AH, Scanu, AM. Fractionation of human serum lipoproteins by single-spin gradient ultracentrifugation: quantification of apolipoproteins B and A-1 and lipid components. J Lipid Res 1977;18:759–67. https://doi.org/10.1016/s0022-2275(20)41594-9.Search in Google Scholar
19. Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–75. https://doi.org/10.1016/s0021-9258(19)52451-6.Search in Google Scholar
20. Belcher, JD, Balla, J, Balla, G, Jacobs, DRJr, Gross, M, Jacob, HS, et al.. Vitamin E, LDL, and endothelium. Brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro. Arterioscler Thromb 1993;13:1779–89. https://doi.org/10.1161/01.atv.13.12.1779.Search in Google Scholar PubMed
21. Esterbauer, H, Striegl, G, Puhl, H, Rotheneder, M. Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun 1989;6:67–75. https://doi.org/10.3109/10715768909073429.Search in Google Scholar PubMed
22. Simon, BC, Cunningham, LD, Cohen, RA. Oxidized low density lipoproteins cause contraction and inhibit endothelium-dependent relaxation in the pig coronary artery. J Clin Invest 1990;86:75–9. https://doi.org/10.1172/jci114718.Search in Google Scholar
23. Mezzetti, A, Guglielmi, MD, Pierdomenico, SD, Costantini, F, Cipollone, F, De Cesare, D, et al.. Increased systemic oxidative stress after elective endarterectomy: relation to vascular healing and remodeling. Arterioscler Thromb Vasc Biol 1999;19:2659–65. https://doi.org/10.1161/01.atv.19.11.2659.Search in Google Scholar PubMed
24. Nemeth, E, Tuttle, MS, Powelson, J, Vaughn, MB, Donovan, A, Ward, DM, et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090–3. https://doi.org/10.1126/science.1104742.Search in Google Scholar PubMed
25. Dandona, P, Aljada, A, Bandyopadhyay, A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004;25:4–7. https://doi.org/10.1016/j.it.2003.10.013.Search in Google Scholar PubMed
26. Hutchinson, C. A review of iron studies in overweight and obese children and adolescents: a double burden in the young? Eur J Nutr 2016;55:2179–97. https://doi.org/10.1007/s00394-016-1155-7.Search in Google Scholar PubMed
27. Langer, AL, Ginzburg, YZ. Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation. Hemodial Int 2017;21:S37–46. Suppl 1. https://doi.org/10.1111/hdi.12543.Search in Google Scholar PubMed PubMed Central
28. Gajewska, J, Ambroszkiewicz, J, Klemarczyk, W, Głąb-Jabłońska, E, Weker, H, Chełchowska, M. Ferroportin-hepcidin Axis in prepubertal obese children with sufficient daily iron intake. Int J Environ Res Publ Health 2018;15:2156. https://doi.org/10.3390/ijerph15102156.Search in Google Scholar PubMed PubMed Central
29. Bussler, S, Penke, M, Flemming, G, Elhassan, YS, Kratzsch, J, Sergeyev, E, et al.. Novel insights in the metabolic syndrome in childhood and adolescence. Horm Res Paediatr 2017;88:181–93. https://doi.org/10.1159/000479510.Search in Google Scholar PubMed
30. Nelson, JE, Klintworth, H, Kowdley, KV. Iron metabolism in nonalcoholic fatty liver disease. Curr Gastroenterol Rep 2012;14:8–16. https://doi.org/10.1007/s11894-011-0234-4.Search in Google Scholar PubMed
31. Aeberli, I, Hurrell, RF, Zimmermann, MB. Overweight children have higher circulating hepcidin concentrations and lower iron status but have dietary iron intakes and bioavailability comparable with normal weight children. Int J Obes 2009;33:1111–7. https://doi.org/10.1038/ijo.2009.146.Search in Google Scholar PubMed
32. Del Giudice, EM, Santoro, N, Amato, A, Brienza, C, Calabrò, P, Wiegerinck, ET, et al.. Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency. J Clin Endocrinol Metab 2009;94:5102–7. https://doi.org/10.1210/jc.2009-1361.Search in Google Scholar PubMed
33. Deugnier, Y, Bardou-Jacquet, É, Lainé, F. Dysmetabolic iron overload syndrome (DIOS). Presse Med 2017;46:e306–e311. https://doi.org/10.1016/j.lpm.2017.05.036.Search in Google Scholar PubMed
34. Mörwald, K, Aigner, E, Bergsten, P, Brunner, SM, Forslund, A, Kullberg, J, et al.. Serum ferritin correlates with liver fat in male adolescents with obesity. Front Endocrinol 2020;11:340. https://doi.org/10.3389/fendo.2020.00340.Search in Google Scholar PubMed PubMed Central
35. Sal, E, Yenicesu, I, Celik, N, Pasaoglu, H, Celik, B, Pasaoglu, OT, et al.. Relationship between obesity and iron deficiency anemia: is there a role of hepcidin? Hematology 2018;23:542–8. https://doi.org/10.1080/10245332.2018.1423671.Search in Google Scholar PubMed
36. Hamza, RT, Hamed, AI, Kharshoum, RR. Iron homeostasis and serum hepcidin-25 levels in obese children and adolescents: relation to body mass index. Horm Res Paediatr 2013;80:11–7. https://doi.org/10.1159/000351941.Search in Google Scholar PubMed
37. Nicolas, G, Chauvet, C, Viatte, L, Danan, JL, Bigard, X, Devaux, I, et al.. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037–44. https://doi.org/10.1172/jci0215686.Search in Google Scholar
38. Mohn, A, Catino, M, Capanna, R, Giannini, C, Marcovecchio, M, Chiarelli, F. Increased oxidative stress in prepubertal severely obese children: effect of a dietary restriction-weight loss program. J Clin Endocrinol Metab 2005;90:2653–8. https://doi.org/10.1210/jc.2004-2178.Search in Google Scholar PubMed
39. Fujita, B, Strodthoff, D, Fritzenwanger, M, Pfeil, A, Ferrari, M, Goebel, B, et al.. Altered red blood cell distribution width in overweight adolescents and its association with markers of inflammation. Pediatr Obes 2013;8:385–91. https://doi.org/10.1111/j.2047-6310.2012.00111.x.Search in Google Scholar PubMed
40. Messner, DJ, Rhieu, BH, Kowdley, KV. Iron overload causes oxidative stress and impaired insulin signaling in AML-12 hepatocytes. Dig Dis Sci 2013;58:1899–908. https://doi.org/10.1007/s10620-013-2648-3.Search in Google Scholar PubMed PubMed Central
41. Demircioğlu, F, Görünmez, G, Dağıstan, E, Göksügür, SB, Bekdaş, M, Tosun, M, et al.. Serum hepcidin levels and iron metabolism in obese children with and without fatty liver: case-control study. Eur J Pediatr 2014;173:947–51. https://doi.org/10.1007/s00431-014-2268-8.Search in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston