1.

Liver:
o Hepcidin Production: The liver is central to ACD due to its role in producing
hepcidin, a peptide hormone that regulates iron metabolism. Hepcidin levels
increase in response to inflammation, impacting iron availability.
2. Bone Marrow:
o Erythropoiesis: The bone marrow is the primary site of erythropoiesis. In ACD,
the bone marrow's ability to produce red blood cells is impaired due to the effects
of inflammatory cytokines and altered iron availability.
3. Spleen and Reticuloendothelial System:
o Iron Recycling: The spleen and other reticuloendothelial tissues are involved in
the recycling of iron from old or damaged red blood cells. In ACD, iron is
sequestered within macrophages, reducing its availability for new red blood cell
production.
4. Kidneys:
o Erythropoietin Production: The kidneys produce erythropoietin (EPO), a
hormone that stimulates erythropoiesis. In ACD, the inflammatory milieu can
blunt the kidney's production of EPO, contributing to reduced red blood cell
production.

Cellular and Molecular Mechanisms

1. Inflammatory Cytokines:
o Interleukin-6 (IL-6): IL-6 is a key cytokine that upregulates hepcidin production
in the liver. Elevated hepcidin levels lead to decreased iron absorption from the
gut and reduced iron release from macrophages.
o Tumor Necrosis Factor-alpha (TNF-α) and Interferon-gamma (IFN-γ): These
cytokines contribute to the suppression of erythropoiesis by inhibiting the action
of erythropoietin on erythroid progenitor cells in the bone marrow.
2. Hepcidin and Iron Metabolism:
o Hepcidin Function: Hepcidin binds to ferroportin, a protein that transports iron
from inside cells to the plasma. When hepcidin binds to ferroportin, it causes its
internalization and degradation, reducing iron efflux from enterocytes in the gut
and macrophages in the reticuloendothelial system.
o Iron Sequestration: Elevated hepcidin levels result in iron being sequestered
within macrophages and reduced serum iron levels, limiting the availability of
iron for erythropoiesis.
3. Red Blood Cell (RBC) Life Span:
o Reduced RBC Survival: Chronic inflammation can lead to a shortened lifespan
of red blood cells, though the exact mechanisms are not fully understood. Factors
such as increased oxidative stress and altered red blood cell membrane properties
may play a role.