TOMAS GANZ (LOS ANGELES)
IRON-RESTRICTED ERYTHROPOIESIS
Tomas Ganz, PhD, MD
University of California, Los Angeles
Definition—Iron-restricted erythropoiesis is a condition in which the supply of iron to the
erythropoietic marrow is impaired. Systemic iron deficiency also results in iron-restricted
erythropoiesis but the supply of iron to all other tissues is also diminished. In this
presentation, I will focus on situations where iron restricted erythropoiesis occurs
selectively, without systemic iron deficiency.
Erythropoiesis requires holotransferrin—The plasma protein transferrin delivers iron to the
erythropoietic compartment where it is taken up by erythroid precursors via transferrin
receptor-1 (TfR1) and is used for heme and hemoglobin synthesis. The final common
pathway for the effect of iron restriction on erythropoiesis is decreased concentration of
iron-transferrin in blood plasma, especially that of diferric (holo)transferrin. In principle, this
can also reflect transferrin deficiency, as in the very rare genetic disorder atransferrinemia1,
but much more commonly iron restriction is a result of iron retention in the macrophages in
the iron-recycling organs (primarily the spleen and the liver). These macrophages normally
contribute most of the iron in transferrin with the rest originating through iron absorption in
the duodenum and release from hepatocyte stores.
Iron restriction affects predominantly the erythroid lineage—The erythroid lineage is
uniquely sensitive to restriction of iron supply, in comparison to the megakaryocytic or
myeloid lineages 2. Even in diseases in which iron restriction is very severe, such as iron-refractory
iron deficiency anemia3, in which affected children can have transferrin
saturations as low as 2%, the effects appeared to be predominantly on erythropoiesis, with
characteristic severe microcytic anemia and resistance to not only iron administration but
also to endogenous or exogenous erythropoietin (Epo). Because most of the iron in plasma
is destined for the marrow, the decreased utilization of iron for erythropoiesis during iron
restriction may serve to protect the iron supply to the brain, heart and other vital organs.
Regulation of erythropoiesis by iron—What mechanisms mediate the sensitivity of
erythropoiesis to iron restriction? The answer is far from self-evident and requires
consideration of how erythroid precursors respond to either selective iron deprivation or the
resulting cellular stress. Two mechanisms have been analyzed in detail. The first is the
regulatory effect of heme-regulated inhibitor, HRI. During iron restriction, heme synthesis in
erythroid cells is inhibited. HRI responds to heme deficiency by decreasing the translation of
globins and a number of other erythroid proteins4. Importantly, during iron restriction HRI
also inhibits Epo receptor signaling to mTorc1, a major metabolic control pathway required
for erythroblast proliferation, slowing erythropoiesis. The second mechanism affects EpoR
signaling through the iron-sensing enzyme aconitase5 and controls the activity and display
of EpoR on erythroid cell membranes through the scaffold protein Scribble6. Scribble is
decreased during iron restriction by its interactions with transferrin receptor 2, which acts as
a sensor of holotransferrin concentration. In effect, during iron restriction all these
mechanisms induce resistance to Epo.
Anemia of inflammation—Other than systemic iron deficiency, the most prevalent cause of
iron-restricted erythropoiesis is anemia of inflammation (AI, formerly called anemia of