PowerPoint-Präsentation

Iron Metabolism in Anaemia of Chronic Disease Guenter Weiss, MD Professor of Medicine Department of Internal Medicine, Clinical Immunology, and Infectious Diseases Medical University of Innsbruck Innsbruck, Austria

Anaemia of Chronic Disease (ACD) • Most frequent anaemia among hospitalised patients • Mild to moderate, normo-/normochromic • Develops in patients with cellular immune activation • Degree of anaemia correlated to immune activation

Inflammatory Diseases Associated with the Development of ACD I. Infections (acute and chronic) A. B. C. D. E.

Viral infections including HIV Bacterial Parasitic Fungal Helminth

II. Malignancies A. B.

Haematologic Solid tumor

III. Autoimmune A. B. C. D.

Rheumatoid arthritis Systemic lupus erythematosus and connective tissue diseases Vasculitis Inflammatory bowel disease

IV. Chronic kidney disease and inflammation

Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Impairment of erythrocyte progenitor formation • Inadequate formation and function of erythropoietin

Intestinal Iron Absorption Enterocyte

Fe3+

Tf Fe3+ DcytB

Hephaestin

Fe2+

Fe2+ DMT1 Heme

Hemeoxygenase Fe2+

Fe Luminal

Ferroportin

+

HCP-1

Slide courtesy of G. Weiss, MD Hentze MW, et al. Cell. 2010;142:24-28.

-

Fe2+ Hepcidin

Baso-lateral

Hepcidin Master Regulator of Iron Homeostasis • 20-,22-,25- AA peptide with antimicrobial potential • Expression induced by iron in the liver • Stimulated also by LPS and IL-6 by an iron independent pathway—acute phase protein (blocked by TNF-a) • Hepcidin over-expression leads to iron-deficient anaemia and hepcidin knock-out to iron overload • Hepcidin inhibits duodenal iron absorption and macrophage iron release • Mechanism of action: interferes with ferroportin, thereby leading to ferroportin degradation and blockage of iron export

Control of Body Iron Homeostasis by Hepcidin Luminal

Baso-lateral

Enterocyte

Macrophage

Tf Fe3+

Fe3+ DcytB

HO-1

Heph Fe2+

Fe2+ DMT1

Heme

Fpn1

-

Fe2+

Fe2+

-

HCP-1?

Heph

Fe

Fpn1

Fe2+ + HO-1

Hepcidin Tf-Fe+3

Fe2+

-

Hepcidin

+

+ Tf-Fe+3

Liver

Slide courtesy of Dr. G. Weiss. Hentze MW, et al. Cell. 2010;142:24-28

Tf Fe3+

Inflammation (IL-6, LPS)

Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Inadequate formation and function of erythropoietin • Impairment of erythrocyte progenitor formation

Pathways for Iron Retention in ACD A collaborative work of acute phase proteins (Hepcidin) and cytokines Hepcidin

Hepcidin

+

ACD is an immunity driven disease

Fe+2 Duodenum

-

Liver

Fe+2

b

+ LPS

Monocyte

CD3+

IL-6 IL-1 TNFα IL-10 IFN-γ

+

+

Tf/TfR

Fe+2 FP-1

a

Ferritin

Macrophage

+

Fe+2 Hepcidi n

Slide courtesy of Dr. G. Weiss. Weiss G. Biochim Biophys Acta. 2009;1790:682-693.

c

Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Impairment of erythrocyte progenitor formation • Inadequate formation and function of erythropoietin

Cytokine Effects on Epo Production IL-6 LPS

Monocyte

IL-1 TNF-α IL-10

CD3+

IFN-γ

-

-

?

Epo

Kidneys Bone marrow Fe+2

Slide courtesy of Dr. G. Weiss. Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.

Putative molecular mechanisms: • TNF-α/IL-1 induce NF-kB/GATA-2 with suppression of Epo gene promotor • Cytokine mediated radical formation negatively affects Epo-producing cells in the kidney • Interaction with Epo/EpoR signal transduction (JAK2/STAT5/MAPK/PKC) • Reduction of EpoR expression on CFU-e • Impaired Epo function because of reduced iron availabiltiy • Impaired Epo function due to impaired erythroid progenitor proliferation

Pathophysiology—Cornerstones • Iron retention within the reticulo-endothelial system • Inadequate formation and function of erythropoietin • Impairment of erythrocyte progenitor formation

Cytokine Effects on Erythroid Progenitor Cell Proliferation LPS

Monocyte

IL6 IL1 TNF-a IL-10

CD3+

IFN-abg

Putative molecular mechanisms: • TNF-α -inhibitory effect via stroma cells • IL-1 acts primarily via IFN-g induction • IFN-γ induces apotposis of CFU-e • IFN-γ: caspase mediated apoptosis involving ceramide

Epo

• IFN-γ induces NO; inhibits heme synthesis • Cytokines (IFN-γ) inhibit Epo and SCF formation and functionality

-

Kidneys

Bone marrow Fe+2

Slide courtesy of Dr. G. Weiss. Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.

• Iron restriction due to cytokines/hepcidin

ACD Is an Immunity-Driven Disease Hepcidin Hepcidin

+

Duodenum Fe+2

-

Liver LPS

IL-1

Monocyte

Spleen

Fe+2

IL-6

++ Fe

TNF-α

2

IL-10 IFN-γ

CD4+

DMT1

+

Fe+2

Ferritin

Tf/TfR

-

-

Macrophage

-

Epo Bone marrow -

-

FP-1

Fe+2 Fe+ 2

Slide courtesy of Dr. G. Weiss.

+

Hepcidin

Positive Effects of ACD? • Withholding iron from infectious pathogens in order to limit their growth1 – Iron acquisition linked to pathogenicity in microbes, fungi? • Reducing the supply of oxygen to rapid proliferating tissues • Strengthening of immune response

Weinberg ED. Biochim Biophys Acta. 2009;1790:600-605.

Iron Loading of Macrophages Impairs Their Ability to Kill Intracellular Pathogens by IFN- Mediated Pathways

IFN-

IFNMEF, macrophage effector function

MEF

Macrophage

Fe

+

Fe

MEF

Macrophage

Slide courtesy of Dr. G. Weiss. Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023. Nairz M, et al. Cell Microbiol. 2009;11:13651381. Wessling-Resnick M. Annu Rev Nutr. 2010;30:105-122.

Iron, Immunity, and Infection • Iron affects cell-mediated immune function and thus host responses towards pathogens • Microbes need iron for proliferation and pathogenicity • Cytokines and acute-phase proteins regulate iron metabolism genes under inflammatory conditions, leading to – Development of anaemia of chronic disease – Iron limitation for pathogens

• Thus, ACD may result from the endeavour of the body to limit the availability of iron for invading pathogens and to strengthen antimicrobial immune effector pathways

ACD Diagnosis Parameter

ACD

IDA

Serum iron concentration Transferrin levels Transferrin saturation Ferritin Serum transferrin receptor sTfR/log ferritin Zinc protoporphyrin IX Percentage hypochromic RBC Cytokines (TNF, IL-1, IL-6)

Reduced to normal Reduced to normal Reduced to normal Normal to increased Normal Low (2) High High Normal

Cytokine levels are inversely correlated with the degree of anaemia Sole iron determination in serum is clinically not useful Slide courtesy of Dr. G. Weiss.

Several Patients Suffer from a Combination of ACD and Iron Deficiency (ACD/IDA) as a Consequence of Inflammatory Anaemia and Blood Loss (Mostly on the Basis of Gastrointestinal or Urogenital Bleeding) Parameter

ACD

Both (ACD + IDA)

Reduced

Reduced

Reduced to normal

Reduced

Reduced

Reduced

Normal to increased

Reduced to normal

Normal

Normal to increased

sTfR/log ferritin

Low (2) ?

Cytokine levels

Increased

Increased

Serum iron Transferrin levels TfS Ferritin sTfR

Why Is the Differential Diagnosis Between ACD and ACD + IDA Important?

Because these patients need contrasting therapies!

Differential Diagnosis Between ACD and ACD Plus IDA Anaemia Biochemical or clinical evidence of inflammation Transferrin saturation 2

ACD/IDA

ACD/IDA

sTfR/log ferritin