Download pathophysiology of iron overload

Z. Ioav Cabantchik, William Breuer and Eitan Fibach
Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
PATHOPHYSIOLOGY OF IRON OVERLOAD
Symposium 6, 11th International Conference on Thalassaemia & Haemoglobinopathies
Iron overload is a pathophysiological condition of excessive systemic iron accumulation,
characterized by the appearance of redox-active iron forms in extracellular fluids and toxic
levels of iron in specific tissues and cell types.
Among the various pathologies leading to iron overload are impaired functioning of humoral
factors (hepcidin), mutations in genes of cell iron metabolism (HFE, ferroportin,
hemojuvelin), or a combination of these together with the massive intake of iron via repeated
transfusions (thalassemia). In hereditary haemochromatosis and transfusion-dependent
anaemias, the continual influx iron into the circulation ultimately surpasses the transferriniron-binding-capacity of plasma, leading to the formation of labile plasma iron (LPI) (a labile
component of non-transferrin-bound iron=NTBI). This form of iron may gain access to cells
opportunistically, via pathways for uptake of other metals (possibly calcium channels) or
adsorptive endocytosis, leading to increased levels of cytosolic labile (redox-active) cell iron
(LCI). The participation of LCI in generating reactive oxygen species is a key factor leading
to compromised functional integrity of key organs such as the liver, heart and endocrine
tissues.
The goal of iron chelation are to confer protection from constantly re-emerging LPI and relief
from tissue iron overload by removing accumulated cell iron while avoiding overchelation
and damage to essential functions. In chronic iron overload, it might take months to safety
reduce body iron levels, because at any given time only a small proportion of body iron is
labile (LPI or LCI) and hence chelatable. Systematic monitoring of labile iron forms
appearing in body fluids (LPI) and/or in circulating cells (LCI) of iron overloaded patients
has provided an analytical platform for assessing the adequacy of chelation treatment and the
screening of chelation efficiency in clinical and experimental settings.
Supported by the Israel Science Foundation via the Israel Academy of Sciences, Novartis
Pharma (Switzerland), and Apopharma (Canada).