Novel technology for the diagnosis and monitoring
of iron toxicity, iron overload, in body fluids

The Technology

Introduction

Thalassemia, Hereditary Hemochromatosis and other health conditions associated with deranged metabolism or handling of iron often result in the development of acute and/or chronic Iron Overload. This condition is characterized by elevated serum iron, transferrin saturation and serum ferritin, and in many cases by the appearance of non-transferrin bound iron (NTBI). In many iron-overloaded patients, a fraction of the NTBI is redox active and may catalyze the formation of reactive oxygen species (ROS) in the circulation and in iron overloaded cells. The accumulation of oxidized proteins and metabolites could ultimately lead to damage in sensitive tissues such as liver, pancreas and especially the heart.

NTBI, which encompasses all forms of serum iron that are not tightly associated with tranferrin, is chemically and functionally heterogeneous.

LPI (Labile Plasma Iron) represents a component of NTBI that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload. LPI measurement can serve not only as indicators of impending iron overload but also as measures of the efficacy of iron chelation in eliminating a potentially toxic agent from plasma. LPI measures the iron-specific capacity of a given sample to produce reactive oxygen species (ROS).

Principle of the LPI Test (FeROS™)

The FeROS™ assay measures the redox activity of iron in serum. A reducing agent, (ascorbate) and an oxidizing agent (atmospheric O2) cause the Labile iron in the tested sample to oscillate between its oxidized (Fe3+) and reduced (Fe2+) form, generating Reactive Oxygen Species (ROS) via the Fenton reaction. The ROS are detected by an oxidation-sensitive probe (DHR), which becomes fluorescent when oxidized by ROS.

The assay employs a selective iron chelator that blocks redox cycling of iron to specifically identify iron-mediated ROS generation. Comparison of the fluorescence generated in the reaction in the presence and absence of the iron chelator translates into an accurate estimate of the quantity of LPI in the tested sample.

Literature

  • Esposito, BP., Breuer, W., Sirankapracha, P. Pootrakul, P., Hershko, C. and Cabantchik, Z.I. (2003). Labile plasma iron in iron overload: redox activity and susceptibility to chelators. Blood. 2003;102: 2670-2677. download PDF download.
  • Pootrakul, P., Breuer, W., Sametband, M., Sirankapracha P., Hershko, C. and Cabantchik, Z.I. (2004) Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron overloaded beta-thalassaemia/HbE patients treated with an oral chelator. Blood 104: 1504 – 1510. download PDF download.
  • Cabantchik ZI  and Breuer, W. (2005). LPI-Labile plasma in iron overload. Best Practice & Research in Clinical Haematology Vol. 18, No. 2, pp. 277–287. download PDF download.
  • Le Lan, c ,  O Loréal T Cohen, M Ropert, H Glickstein, M Pouchard, Y Deugnier, A Le Treut,W Breuer,  ZI Cabantchik, P Brissot (2005). Association between hepatic damage, iron overload and incidence of redox-active iron in the plasma.  Blood. 105: 4527-4531 download PDF download.
  • Hershko, C, Link, G , Konijn AM  and Cabantchik. Z.I. (2005). Iron Chelation Therapy.  Curr, Hematol. 4:110-116 download PDF download.
  • van der A, D.J.; Marx, JJM, Grobbee, DE, Kamphuis, MH; Georgiou, N; van Kats-Renaud, JH; Breuer, W., Cabantchik, Z.I.; Roest, M, Voorbij, HAM; van der Schouw, YH (2006) Non–Transferrin-Bound Iron and Risk of Coronary Heart Disease in Postmenopausal Women Circulation. 113:1942-1949. download PDF download.
  • Rachmilewitz E.A, Weizer-Stern, O., Adamsky, K., Amariglio, N., Rechavi, R., Barda, L., Rivella S.and  Cabantchik, Z.I. (2005). Role of Iron in Inducing Oxidative Stress in Thalassemia: Can It Be Prevented by Inhibition of Absorption and by Antioxidants? Ann. N.Y. Acad. Sci. 1054: 118–123. download PDF download.
  • Cabantchik Z.I., Fibach, E. and Bruer, W. 2009. Can labile plasma iron (LPI) and labile cell iron (LCI) levels serve as early indicators of chelation efficacy in iron overload? BloodMed.com. Retrieved July 15 2009. http://www.bloodmed.com/800000/mini-reviews1.asp?id=254 download PDF download.
  • Zanninelli, G., Breuer, W. and Cabantchik, Z.I. (2009). Daily labile plasma iron as an indicator of chelator activity in Thalassemia major patients. Br. J. Hematol. 147, 744–751 doi:10.1111/j.1365-2141.2009.07907.x download PDF download.

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