Skip to main content
Top
Published in: Arthritis Research & Therapy 4/2012

Open Access 01-08-2012 | Research article

Inflammation associated anemia and ferritin as disease markers in SLE

Authors: Kamala Vanarsa, Yujin Ye, Jie Han, Chun Xie, Chandra Mohan, Tianfu Wu

Published in: Arthritis Research & Therapy | Issue 4/2012

Login to get access

Abstract

Introduction

In a recent screening to detect biomarkers in systemic lupus erythematosus (SLE), expression of the iron storage protein, ferritin, was increased. Given that proteins that regulate the storage, transfer and release of iron play an important role in inflammation, this study aims to determine the serum and urine levels of ferritin and of the iron transfer protein, transferrin, in lupus patients and to correlate these levels with disease activity, inflammatory cytokine levels and markers of anemia.

Methods

A protein array was utilized to measure ferritin expression in the urine and serum of SLE patients and healthy controls. To confirm these results as well as the role of the iron transfer pathway in SLE, ELISAs were performed to measure ferritin and transferrin levels in inactive or active SLE patients and healthy controls. The relationship between ferritin/transferrin levels and inflammatory markers and anemia was next analyzed.

Results

Protein array results showed elevated ferritin levels in the serum and urine of lupus patients as compared to controls, which were further validated by ELISA. Increased ferritin levels correlated with measures of disease activity and anemia as well as inflammatory cytokine titers. Though active SLE patients had elevated urine transferrin, serum transferrin was reduced.

Conclusion

Urine ferritin and transferrin levels are elevated significantly in SLE patients and correlate with disease activity, bolstering previous reports. Most importantly, these changes correlated with the inflammatory state of the patients and anemia of chronic disease. Taken together, altered iron handling, inflammation and anemia of chronic disease constitute an ominous triad in SLE.
Appendix
Available only for authorised users
Literature
1.
go back to reference Uppal SS, Al-Mutairi M, Hayat S, Abraham M, Malaviya A: Ten years of clinical experience with adult onset Still's disease: is the outcome improving?. Clin Rheumatol. 2007, 26: 1055-1060. 10.1007/s10067-006-0440-x.CrossRefPubMed Uppal SS, Al-Mutairi M, Hayat S, Abraham M, Malaviya A: Ten years of clinical experience with adult onset Still's disease: is the outcome improving?. Clin Rheumatol. 2007, 26: 1055-1060. 10.1007/s10067-006-0440-x.CrossRefPubMed
2.
go back to reference Da Costa R, Szyper-Kravitz M, Szekanecz Z, Csepany T, Danko K, Shapira Y, Zandman-Goddard G, Orbach H, Agmon-Levin N, Shoenfeld Y: Ferritin and prolactin levels in multiple sclerosis. Isr Med Assoc J. 2011, 13: 91-95.PubMed Da Costa R, Szyper-Kravitz M, Szekanecz Z, Csepany T, Danko K, Shapira Y, Zandman-Goddard G, Orbach H, Agmon-Levin N, Shoenfeld Y: Ferritin and prolactin levels in multiple sclerosis. Isr Med Assoc J. 2011, 13: 91-95.PubMed
3.
5.
go back to reference Yildirim K, Karatay S, Melikoglu MA, Gureser G, Ugur M, Senel K: Associations between acute phase reactant levels and disease activity score (DAS28) in patients with rheumatoid arthritis. Ann Clin Lab Sci. 2004, 34: 423-426.PubMed Yildirim K, Karatay S, Melikoglu MA, Gureser G, Ugur M, Senel K: Associations between acute phase reactant levels and disease activity score (DAS28) in patients with rheumatoid arthritis. Ann Clin Lab Sci. 2004, 34: 423-426.PubMed
6.
go back to reference Nishiya K, Hashimoto K: Elevation of serum ferritin levels as a marker for active systemic lupus erythematosus. Clin Exp Rheumatol. 1997, 15: 39-44.PubMed Nishiya K, Hashimoto K: Elevation of serum ferritin levels as a marker for active systemic lupus erythematosus. Clin Exp Rheumatol. 1997, 15: 39-44.PubMed
7.
go back to reference Lim MK, Lee CK, Ju YS, Cho YS, Lee RS, Yoo B, Moon HB: Serum ferritin as a serologic marker of activity in systemic lupus erythematosus. Rheumatol Int. 2001, 20: 89-93. 10.1007/s002960000083.CrossRefPubMed Lim MK, Lee CK, Ju YS, Cho YS, Lee RS, Yoo B, Moon HB: Serum ferritin as a serologic marker of activity in systemic lupus erythematosus. Rheumatol Int. 2001, 20: 89-93. 10.1007/s002960000083.CrossRefPubMed
8.
go back to reference Beyan E, Beyan C, Demirezer A, Ertugrul E, Uzuner A: The relationship between serum ferritin levels and disease activity in systemic lupus erythematosus. Scand J Rheumatol. 2003, 32: 225-228. 10.1080/03009740310003712.CrossRefPubMed Beyan E, Beyan C, Demirezer A, Ertugrul E, Uzuner A: The relationship between serum ferritin levels and disease activity in systemic lupus erythematosus. Scand J Rheumatol. 2003, 32: 225-228. 10.1080/03009740310003712.CrossRefPubMed
9.
go back to reference Nishiya K, Kawabata F, Ota Z: Elevated urinary ferritin in lupus nephritis. J Rheumatol. 1989, 16: 1513-1514.PubMed Nishiya K, Kawabata F, Ota Z: Elevated urinary ferritin in lupus nephritis. J Rheumatol. 1989, 16: 1513-1514.PubMed
10.
go back to reference Theil EC: Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem. 1987, 56: 289-315. 10.1146/annurev.bi.56.070187.001445.CrossRefPubMed Theil EC: Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem. 1987, 56: 289-315. 10.1146/annurev.bi.56.070187.001445.CrossRefPubMed
11.
go back to reference Picard V, Epsztejn S, Santambrogio P, Cabantchik ZI, Beaumont C: Role of ferritin in the control of the labile iron pool in murine erythroleukemia cells. J Biol Chem. 1998, 273: 15382-15386. 10.1074/jbc.273.25.15382.CrossRefPubMed Picard V, Epsztejn S, Santambrogio P, Cabantchik ZI, Beaumont C: Role of ferritin in the control of the labile iron pool in murine erythroleukemia cells. J Biol Chem. 1998, 273: 15382-15386. 10.1074/jbc.273.25.15382.CrossRefPubMed
12.
go back to reference Ferreira C, Bucchini D, Martin ME, Levi S, Arosio P, Grandchamp B, Beaumont C: Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem. 2000, 275: 3021-3024. 10.1074/jbc.275.5.3021.CrossRefPubMed Ferreira C, Bucchini D, Martin ME, Levi S, Arosio P, Grandchamp B, Beaumont C: Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem. 2000, 275: 3021-3024. 10.1074/jbc.275.5.3021.CrossRefPubMed
13.
go back to reference Chow JK, Werner BG, Ruthazer R, Snydman DR: Increased serum iron levels and infectious complications after liver transplantation. Clin Infect Dis. 2010, 51: E16-E23. 10.1086/654802.PubMedCentralCrossRefPubMed Chow JK, Werner BG, Ruthazer R, Snydman DR: Increased serum iron levels and infectious complications after liver transplantation. Clin Infect Dis. 2010, 51: E16-E23. 10.1086/654802.PubMedCentralCrossRefPubMed
14.
go back to reference Torti FM, Torti SV: Regulation of ferritin genes and protein. Blood. 2002, 99: 3505-3516. 10.1182/blood.V99.10.3505.CrossRefPubMed Torti FM, Torti SV: Regulation of ferritin genes and protein. Blood. 2002, 99: 3505-3516. 10.1182/blood.V99.10.3505.CrossRefPubMed
15.
go back to reference Torti SV, Kwak EL, Miller SC, Miller LL, Ringold GM, Myambo KB, Young AP, Torti FM: The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J Biol Chem. 1988, 263: 12638-12644.PubMed Torti SV, Kwak EL, Miller SC, Miller LL, Ringold GM, Myambo KB, Young AP, Torti FM: The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J Biol Chem. 1988, 263: 12638-12644.PubMed
16.
go back to reference Muntane-Relat J, Ourlin JC, Domergue J, Maurel P: Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995, 22: 1143-1153.CrossRefPubMed Muntane-Relat J, Ourlin JC, Domergue J, Maurel P: Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995, 22: 1143-1153.CrossRefPubMed
17.
go back to reference Rovin BH, Zhang X: Biomarkers for lupus nephritis: the quest continues. Clin J Am Soc Nephrol. 2009, 4: 1858-1865. 10.2215/CJN.03530509.CrossRefPubMed Rovin BH, Zhang X: Biomarkers for lupus nephritis: the quest continues. Clin J Am Soc Nephrol. 2009, 4: 1858-1865. 10.2215/CJN.03530509.CrossRefPubMed
18.
go back to reference Zandman-Goddard G, Orbach H, Agmon-Levin N, Boaz M, Amital H, Szekanecz Z, Szucs G, Rovensky J, Kiss E, Corocher N, Doria A, Stojanovich L, Ingegnoli F, Meroni PL, Rozman B, Gomez-Arbesu J, Blank M, Shoenfeld Y: Hyperferritinemia is associated with serologic antiphospholipid syndrome in SLE patients. Clin Rev Allergy Immunol. 2011 Zandman-Goddard G, Orbach H, Agmon-Levin N, Boaz M, Amital H, Szekanecz Z, Szucs G, Rovensky J, Kiss E, Corocher N, Doria A, Stojanovich L, Ingegnoli F, Meroni PL, Rozman B, Gomez-Arbesu J, Blank M, Shoenfeld Y: Hyperferritinemia is associated with serologic antiphospholipid syndrome in SLE patients. Clin Rev Allergy Immunol. 2011
19.
go back to reference Zandman-Goddard G, Peeva E, Shoenfeld Y: Gender and autoimmunity. Autoimmun Rev. 2007, 6: 366-372. 10.1016/j.autrev.2006.10.001.CrossRefPubMed Zandman-Goddard G, Peeva E, Shoenfeld Y: Gender and autoimmunity. Autoimmun Rev. 2007, 6: 366-372. 10.1016/j.autrev.2006.10.001.CrossRefPubMed
20.
go back to reference You SA, Wang Q: Ferritin in atherosclerosis. Clin Chim Acta. 2005, 357: 1-16. 10.1016/j.cccn.2005.02.001.CrossRefPubMed You SA, Wang Q: Ferritin in atherosclerosis. Clin Chim Acta. 2005, 357: 1-16. 10.1016/j.cccn.2005.02.001.CrossRefPubMed
21.
go back to reference Thomson AM, Rogers JT, Leedman PJ: Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol. 1999, 31: 1139-1152. 10.1016/S1357-2725(99)00080-1.CrossRefPubMed Thomson AM, Rogers JT, Leedman PJ: Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int J Biochem Cell Biol. 1999, 31: 1139-1152. 10.1016/S1357-2725(99)00080-1.CrossRefPubMed
22.
go back to reference Eisenstein RS: Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu Rev Nutr. 2000, 20: 627-662. 10.1146/annurev.nutr.20.1.627.CrossRefPubMed Eisenstein RS: Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu Rev Nutr. 2000, 20: 627-662. 10.1146/annurev.nutr.20.1.627.CrossRefPubMed
23.
go back to reference LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, Drake SK, Miller G, Abu-Asab M, Tsokos M, Switzer R, Grinberg A, Love P, Tresser N, Rouault TA: Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001, 27: 209-214. 10.1038/84859.CrossRefPubMed LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, Drake SK, Miller G, Abu-Asab M, Tsokos M, Switzer R, Grinberg A, Love P, Tresser N, Rouault TA: Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001, 27: 209-214. 10.1038/84859.CrossRefPubMed
24.
go back to reference Hirayama M, Kohgo Y, Kondo H, Shintani N, Fujikawa K, Sasaki K, Kato J, Niitsu Y: Regulation of iron metabolism in HepG2 cells: a possible role for cytokines in the hepatic deposition of iron. Hepatology. 1993, 18: 874-880. 10.1002/hep.1840180420.CrossRefPubMed Hirayama M, Kohgo Y, Kondo H, Shintani N, Fujikawa K, Sasaki K, Kato J, Niitsu Y: Regulation of iron metabolism in HepG2 cells: a possible role for cytokines in the hepatic deposition of iron. Hepatology. 1993, 18: 874-880. 10.1002/hep.1840180420.CrossRefPubMed
25.
go back to reference Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner-Felmayer G, Wachter H, Hentze MW: Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 1993, 12: 3651-3657.PubMedCentralPubMed Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner-Felmayer G, Wachter H, Hentze MW: Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 1993, 12: 3651-3657.PubMedCentralPubMed
26.
go back to reference Carraway MS, Ghio AJ, Taylor JL, Piantadosi CA: Induction of ferritin and heme oxygenase-1 by endotoxin in the lung. Am J Physiol. 1998, 275: L583-592.PubMed Carraway MS, Ghio AJ, Taylor JL, Piantadosi CA: Induction of ferritin and heme oxygenase-1 by endotoxin in the lung. Am J Physiol. 1998, 275: L583-592.PubMed
27.
go back to reference Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A, Galy B, Hentze MW, Lazaro FJ, Rouault TA, Meyron-Holtz EG: Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010, 116: 1574-1584. 10.1182/blood-2009-11-253815.CrossRefPubMed Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang DL, Crooks DR, Sougrat R, Morgenstern A, Galy B, Hentze MW, Lazaro FJ, Rouault TA, Meyron-Holtz EG: Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010, 116: 1574-1584. 10.1182/blood-2009-11-253815.CrossRefPubMed
28.
go back to reference Morikawa K, Oseko F, Morikawa S: A role for ferritin in hematopoiesis and the immune system. Leuk Lymphoma. 1995, 18: 429-433. 10.3109/10428199509059641.CrossRefPubMed Morikawa K, Oseko F, Morikawa S: A role for ferritin in hematopoiesis and the immune system. Leuk Lymphoma. 1995, 18: 429-433. 10.3109/10428199509059641.CrossRefPubMed
29.
go back to reference Harada T, Baba M, Torii I, Morikawa S: Ferritin selectively suppresses delayed-type hypersensitivity responses at induction or effector phase. Cell Immunol. 1987, 109: 75-88. 10.1016/0008-8749(87)90293-0.CrossRefPubMed Harada T, Baba M, Torii I, Morikawa S: Ferritin selectively suppresses delayed-type hypersensitivity responses at induction or effector phase. Cell Immunol. 1987, 109: 75-88. 10.1016/0008-8749(87)90293-0.CrossRefPubMed
30.
go back to reference Gray CP, Arosio P, Hersey P: Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells. Blood. 2002, 99: 3326-3334. 10.1182/blood.V99.9.3326.CrossRefPubMed Gray CP, Arosio P, Hersey P: Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells. Blood. 2002, 99: 3326-3334. 10.1182/blood.V99.9.3326.CrossRefPubMed
31.
go back to reference Baker JF, Ghio AJ: Iron homoeostasis in rheumatic disease. Rheumatology (Oxford). 2009, 48: 1339-1344. 10.1093/rheumatology/kep221.CrossRef Baker JF, Ghio AJ: Iron homoeostasis in rheumatic disease. Rheumatology (Oxford). 2009, 48: 1339-1344. 10.1093/rheumatology/kep221.CrossRef
Metadata
Title
Inflammation associated anemia and ferritin as disease markers in SLE
Authors
Kamala Vanarsa
Yujin Ye
Jie Han
Chun Xie
Chandra Mohan
Tianfu Wu
Publication date
01-08-2012
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 4/2012
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4012

Other articles of this Issue 4/2012

Arthritis Research & Therapy 4/2012 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine