Abstract
The identification of hemoglobin (Hb) biological determinants is of primary clinical interest, in particular in the elderly because of the well-documented relationship between anemia and cognitive and functional decline. Ceruloplasmin (Cp) and non-Cp ferroxidase activity might influence Hb production because of its role in modulating iron mobilization. This potential connection has never been explored so far. Therefore, in the present study, we evaluated the possible association between serum ferroxidase activity (sFeOx) and Hb in a sample of 136 apparently healthy older individuals. The results revealed that nonlinear (quadratic) regression explained the relationship between the two variables of interest better than did the linear one (R 2 = 0.09 vs. R 2 = 0.03). The same analysis highlighted a linear behavior for the relationship between Hb and sFeOx, for two separate subsamples stratified on the basis of the Hb value (141 g/L) corresponding to the parabola vertex. In the subset with higher Hb (high Hb), sFeOx was positively associated (r = 0.44, p = 0.003) while in the low Hb subset, the association was negative (r = −0.26, p = 0.01). Notably, we found that the concentration of Cp was significantly higher in Low Hb compared to High Hb subsample (p < 0.05), with this multicopper oxidase selectively contributing to sFeOx in the former group (r = 0.348, p = 0.001). Collectively, this exploratory study suggests that ferroxidases might play a role in dispatching the body’s iron toward erythropoietic tissues, with Cp contribution that might become more important in stress-like conditions.
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References
Beutler E, Waalen J (2006) The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 107:1747–1750. doi:10.1182/blood-2005-07-3046
Makipour S, Kanapuru B, Ershler WB (2008) Unexplained anemia in the elderly. Semin Hematol 45:250–254. doi:10.1053/j.seminhematol.2008.06.003
Onem Y, Terekeci H, Kucukardali Y et al (2010) Albumin, hemoglobin, body mass index, cognitive and functional performance in elderly persons living in nursing homes. Arch Gerontol Geriatr 50:56–59. doi:10.1016/j.archger.2009.01.010
Atti AR, Palmer K, Volpato S et al (2006) Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging 27:278–284. doi:10.1016/j.neurobiolaging.2005.02.007
Go AS, Yang J, Ackerson LM et al (2006) Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure—the anemia in chronic heart failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation 113:2713–2723. doi:10.1161/CIRCULATIONAHA.105.577577
Guralnik JM (2004) Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 104:2263–2268. doi:10.1182/blood-2004-05-1812
Halfdanarson TR, Kumar N, Li C-Y et al (2008) Hematological manifestations of copper deficiency: a retrospective review. Eur J Haematol 80:523–531. doi:10.1111/j.1600-0609.2008.01050.x
Prohaska JR (2011) Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases). Adv Nutr An Int Rev J 2:89–95. doi:10.3945/an.110.000208
Collins JF, Prohaska JR, Knutson MD (2010) Metabolic crossroads of iron and copper. Nutr Rev 68:133–147. doi:10.1111/j.1753-4887.2010.00271.x
Osaki S, Johnson DA, Frieden E (1971) The mobilization of iron from the perfused mammalian liver by a serum copper enzyme, ferroxidase I. J Biol Chem 246:3018–3023
Gray LW, Kidane TZ, Nguyen A et al (2009) Copper proteins and ferroxidases in human plasma and that of wild-type and ceruloplasmin knockout mice. Biochem J 419:237–245. doi:10.1042/BJ20081983
De Domenico I, Ward DM, di Patti MCB et al (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26:2823–2831. doi:10.1038/sj.emboj.7601735
Xu X, Pin S, Gathinji M et al (2004) Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci 1012:299–305
Zuliani G, Ranzini M, Guerra G et al (2007) Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 41:686–693. doi:10.1016/j.jpsychires.2006.02.008
Erel O (1998) Automated measurement of serum ferroxidase activity. Clin Chem 44:2313–2319
Cervellati C, Romani A, Fainardi E et al (2014) Serum ferroxidase activity in patients with multiple sclerosis: a pilot study. In Vivo 28:1197–1200
Cervellati C, Romani A, Bergamini CM et al (2015) PON-1 and ferroxidase activities in older patients with mild cognitive impairment, late onset Alzheimer’s disease or vascular dementia. Clin Chem Lab Med 53:1049–1056. doi:10.1515/cclm-2014-0803
Zakai NA, French B, Arnold AM et al (2013) Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. Am J Hematol 88:5–9. doi:10.1002/ajh.23336
Zakai NA, McClure LA, Prineas R et al (2009) Correlates of anemia in American blacks and whites: the REGARDS Renal Ancillary Study. Am J Epidemiol 169:355–364. doi:10.1093/aje/kwn355
Cervellati C, Wood PL, Romani A et al (2016) Oxidative challenge in Alzheimer’s disease: state of knowledge and future needs. J Investig Med 64:21–32. doi:10.1136/jim-2015-000017
Hentze MW, Muckenthaler MU, Andrews NC (2004) Balancing Acts. Cell 117:285–297. doi:10.1016/S0092-8674(04)00343-5
Logan JI, Harveyson KB, Wisdom GB et al (1994) Hereditary caeruloplasmin deficiency, dementia and diabetes mellitus. QJM 87:663–670
Morita H, Ikeda S, Yamamoto K et al (1995) Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann Neurol 37:646–656. doi:10.1002/ana.410370515
Kosman DJ (2013) Iron metabolism in aerobes: managing ferric iron hydrolysis and ferrous iron autoxidation. Coord Chem Rev 257:210–217. doi:10.1016/j.ccr.2012.06.030
Wong BX, Ayton S, Lam LQ et al (2014) A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe(2+) under physiologically relevant conditions. Biochim Biophys Acta 1840:3299–3310. doi:10.1016/j.bbagen.2014.08.006
Meyer LA, Durley AP, Prohaska JR, Harris ZL (2001) Copper transport and metabolism are normal in aceruloplasminemic mice. J Biol Chem 276:36857–36861. doi:10.1074/jbc.M105361200
Prohaska JR (1981) Comparison between dietary and cenetic copper deficiency in mice: copper-dependent anemia. Nutr Res 1:159–167. doi:10.1016/S0271-5317(81)80098-X
Martin F, Linden T, Katschinski DM et al (2005) Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood 105:4613–4619. doi:10.1182/blood-2004-10-3980
Sarkar J, Seshadri V, Tripoulas NA et al (2003) Role of ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem 278:44018–44024. doi:10.1074/jbc.M304926200
Ranganathan PN, Lu Y, Jiang L et al (2011) Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake. Blood 118:3146–3153. doi:10.1182/blood-2011-05-352112
Guyatt GH, Patterson C, Ali M et al (1990) Diagnosis of iron-deficiency anemia in the elderly. Am J Med 88:205–209
Nowak M, Wielkoszyński T, Marek B et al (2010) Antioxidant potential, paraoxonase 1, ceruloplasmin activity and C-reactive protein concentration in diabetic retinopathy. Clin Exp Med 10:185–192. doi:10.1007/s10238-009-0084-7
Artz AS, Xue Q-L, Wickrema A et al (2014) Unexplained anaemia in the elderly is characterised by features of low grade inflammation. Br J Haematol 167:286–289. doi:10.1111/bjh.12984
Olivieri S, Conti A, Iannaccone S et al (2011) Ceruloplasmin oxidation, a feature of Parkinson’s disease CSF, inhibits ferroxidase activity and promotes cellular iron retention. J Neurosci 31:18568–18577. doi:10.1523/JNEUROSCI.3768-11.2011
Ayton S, Lei P, Duce JA et al (2013) Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 73:554–559. doi:10.1002/ana.23817
Acknowledgments
The authors want to thank Monica Squezanti, Manuela Spagnolo, and Juana M Sanz for their meaningful contribution in data collection and elaboration.
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This study conforms to the Code of Ethics of the World Medical Association (Declaration of Helsinki) and was conducted according to the guidelines for Good Clinical Practice (European Medicines Agency, http://www.ema.europa.eu). Signed informed consent, which was written in compliance with local and national ethical guidelines, was obtained from each patient prior to the inclusion into the study. Personal data and medical history were collected by a structured interview from participants.
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The study was supported by “Local Research Project” grant from University of Ferrara.
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The authors declare that they have no conflict of interest.
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Romani, A., Trentini, A., Passaro, A. et al. Mutual relationship between serum ferroxidase activity and hemoglobin levels in elderly individuals. Ann Hematol 95, 1333–1339 (2016). https://doi.org/10.1007/s00277-016-2709-8
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DOI: https://doi.org/10.1007/s00277-016-2709-8