Introduction to Anemia

Classification Iron Metabolism Iron Deficiency Anemia of Chronic Disease

Anemia
Definition Subnormal hemoglobin concentration Subnornal red cell count Subnormal volume of packed red cells

Classifying Anemia
Morphologic approach Kinetic approach

Erythrocyte Indices
Mean corpuscular volume (MCV) 79-94 fL 27-33 pg 32-36 g/dL

Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin (MCHC) concentration

ANEMIA

Erythrocyte Indices

MCV > 100 Macrocytic

MCV 80-100 Normocytic

MCV < 80 Microcytic

Outline
Iron metabolism Iron deficiency Anemia of chronic disease

Total Body Iron Stores

MALE Hemoglobin iron Myoglobin iron Storage iron Other 3.0 g 0.3 g 1.0 g 0.1 g 4.4 g FEMALE 2.4 g 0.2 g 0.4 g 0.1 g 3.1 g

Iron Balance
Dietary Iron Iron Absorbed Iron Lost 20-25 mg 1 mg 1 mg

GUT LUMEN INTESTINAL ABSORPTION PLASMA TRANSFERRIN IRON MACROPHAGE LIVER CIRCULATING ERYTHROCYTES MARROW ERYTHROID PRECURSORS

The Players
CELLS Enterocyte Macrophage Hepatocyte Erythrocyte

Enterocyte
++

Hepatocyte
++

Macrophage
++

Hp

1 mg
+++

5 mg
++

22 mg
++

Cp
+++

Tf

The Players
PROTEINS
Plasma
Ceruloplasmin Transferrin Ferritin Hepcidin

Cell Associated
Iron reductase DMT1 Ferroportin Hephaestin Tf receptor Ferritin (Hepcidin)

Iron Absorption
Lumen ++ Reductase +++
N N

N N

DMT1
++ Cytoplasm Ferritin

HEME OX

++

Transfer of Iron to Plasma

Cytosol

++

++

Plasma

++

Hp

Cp +++

+++

Tf

Transferrin Saturation
Women Men

10

20

30

40

50

% transferrin saturation

RBC Iron Uptake

+ H
+++ ++

DMT1
++

++ ++ ++

++ ++

Cell Surface Endosome

Ferrochelatase

Iron
N N Fe N N

Protoporphyrin

The Macrophage
Uptake of senescent red cells Lysis of senescent red cells Release of heme from globin Heme oxygenase reaction Storage of iron in ferritin Release of iron to plasma

Heme Oxygenase
O2 Iron
N N Fe N N

Carbon monoxide Biliverdin

Macrophage Iron Export

++

CYTOPLASM

++

Cp

+++

PLASMA

Tf

Hepatocyte

Hepcidin Fe Ferritin Fe

Hepcidin
1. Antimicrobial peptide secreted by the liver during inflammation 2. Member of family of defensins 3. Highly disulfide linked

The Effects of Hepcidin on Iron Export

Hepcidin Controls:
LIVER
in id pc he

hepcidin

SPLEEN

he pc id in

Absorption Recycling (release from stores) Placental transfer

idin hepc

PLACENTA
DUODENUM

IL-6

Ferroportin-GFP is Internalized by Hecidin

control + 1 g/ml hepcidin

Iron Deficiency
Causes Blood Loss
Hemoglobinuria Rapid growth

GUT LUMEN INTESTINAL ABSORPTION PLASMA TRANSFERRIN IRON MACROPHAGE LIVER CIRCULATING ERYTHROCYTES MARROW ERYTHROID PRECURSORS

Clinical Manifistations of Iron Deficiency Anemia

Fatigue and other non-specific symptoms Bizarre food cravings (pica) Spoon-shaped nails (koilonychia) Esophageal webs (Plummer-Vinson)

Dignosis of Iron Deficiency

Microcytic anemia Low serum iron High serum transferrin Low transferrin saturation Low ferritin Marrow iron stores absent

Treatment of Iron Deficiency

Identify and correct the source of blood loss Iron replacement

Oral Iron Therapy

Ferrous sulfate tablets 1 with dinner for 3 days 1 with dinner and lunch for 3 days 1 with dinner, lunch and breakfast Final dose: 3 tablets daily ~1 year

Parenteral Iron Therapy

Rarely required Sodium ferric gluconate Given I.V.

Calculating I.V. Iron Dose

How many ml of RBC must be made ? If blood volume 6 L, Hct=20% (1200 ml RBC) Desired Hct=40% (2400 ml RBC) 1 ml RBC= 1 mg iron 1200 ml RBC=1.2 g iron Stores: need 1.0 g Total dose 2.2 g

Anemia of Chronic Disease

Usually normocytic 30% microcytic Must distinguish from iron deficiency

Anemia of Chronic Disease

Mechanism
Impaired release of iron from the macrophage Mediated by hepcidin Iron limited erythropoiesis

Anemia of Chronic Disease

JENSEN WN, GUBLER CJ, CARTWRIGHT GE, WINTROBE MM. Proc Soc Exp Biol Med. 1952 May;80(1):33-6.

Comparison: ACD vs Fe Def

MCV Serum Fe TIBC Tf Sat. Ferritin Marrow ACD Low (30%) Low Low Low Normal Fe in M None in RBC Fe Def Low Low High Low Low None