Defects of Hemoglobin Synthesis

Iron Deficiency Anemia

Of the iron (Fe) content in the body (2 g in fe-males, 5 g in males) ca.⅔ is bound to hemoglo-bin (Hb), ¼ is stored iron (ferritin, hemosider-in), the rest is iron with diverse functions (myo-globin, Fe-containing enzymes). Loss of iron is ca. 1 mg/d in males and up to 2 mg/d in females (menstruation, pregnancy, birth). Of Fe taken up in food, 3–15% is absorbed in the duode-num (→A); in cases of Fe deficiency it can be up to 25 % (see below). Iron intake with food should therefore be at least 10–20 mg/d (women > children > men).

Iron absorption (→A 1). Fe can be absorbed relatively efficiently by the heme transporter HCP1 as heme-Fe²⁺(found in meat and fish).

The Fe (split off from heme) enters the blood or remains in the mucosa as ferritin-Fe³⁺and re-turns to the lumen on mucosal cell disintegra-tion. Non-heme Fe can be absorbed only in the form of Fe²⁺, which is absorbed by a Fe²⁺-H⁺ -symport carrier (DCT1). A low pH of the chyme is essential for absorption, because it will 1) in-crease the H⁺gradient that drives Fe²⁺into the cell via DCT1, and 2) release Fe from compounds in food. Non-heme Fe³⁺in food must be reduced by ferrireductase (+ ascorbate) to Fe²⁺on the surface of the luminal mucosa (→A 1, FR). Fe up-take into blood requires the oxidation of Fe²⁺to Fe³⁺by the multi-copper ferroxidase hephaestin (for uptake from intestinal mucosa) or by ceru-loplasmin (for uptake from macrophages). Fe²⁺ exit from the cells is mediated by the Fe-trans-porter ferroportin in the membrane of duodenal epithelial cells, hepatocytes, and macrophages.

Ferroportin is internalized and thus downregu-lated by the hepatic peptide hormone hepcidin.

In blood, two Fe³⁺interact with one apotrans-ferrin to form transapotrans-ferrin, which accomplishes the Fe transport in plasma (→A) and delivers Fe³⁺to transferrin receptors in erythroblasts, he-patocytes, and cells of further tissues (e.g., pla-centa). Following release of Fe³⁺, apotransferrin is free to take up Fe again from intestinal cells and macrophages (see below).

Iron storage (→A 2, p. 270) is accomplished by ferritin (rapidly available Fe) and

hemosider-in. For Fe recycling, Hb-Fe and heme-Fe, re-leased from malformed erythroblasts ( “ineffi-cient erythropoiesis”) and hemolyzed erythro-blasts, is bound to haptoglobin and hemopexin respectively, and taken up by the macrophages in bone marrow or by liver and spleen by endo-cytosis, 97 % being reused. Transferrin, which has been filtered in renal glomerula, is retrieved by renal tubular reabsorption involving cubilin.

In iron deficiency the intestinal Fe-absorp-tion is increased by inhibiFe-absorp-tion of the mucosal ferritin translation (by binding of the Fe-regu-lating protein IRP1 to ferritin mRNA) and of the hepcidin formation. Clinically overt iron deficiency (serum Fe < 0.4 mg/L; serum ferritin

↓) inhibits Hb synthesis (→p. 40) so that hypo-chromic microcytic anemia develops: MCH

< 26 pg, MCV < 70 fL, Hb < 110 g/L. Its causes are (→A and Table):

◆Blood loss (gastrointestinal tract, increased menstrual bleeding) in adults is the most com-mon cause of iron deficiency (0.5 mg Fe lost with each mL of blood).

◆Fe recycling is decreased; this form of anemia (the second most common worldwide) occurs with chronic infections, whereby inflammatory cytokines (IL-1 and IL-6, TNF-α etc.) stimulate the hepcidin synthesis leading to decreased formation of ferroportin and thus insufficient reuse of Fe taken up by the macrophages.

◆Fe uptake is too low (malnutrition, especially in the developing countries).

◆Fe absorption is reduced due to: a) achlor-hydria (atrophic gastritis, after gastrectomy;

→p. 154, 160); and b) malabsorption in dis-eases of the upper small intestine or in the presence of Fe-binding food components (phy-tate in cereals and vegetables; tannic acid in tea, oxalates, etc.).

◆Fe requirement is increased (growth, preg-nancy, breast-feeding).

◆An apotransferrin defect (rare).

If Fe overloading occurs in the body, damage is caused mainly to the liver, pancreas and myo-cardium (hemochromatosis) (→p. 270).

42

Normal Fe deficiency Apotrans-ferrin defect

Fe utilization defect

Fe recycling defect

Serum Fe : Fe binding capacity Transferrin saturation

1 mg/L : 3.3 mg/L ca. 33%

↓: ↓

< 10%

↓:↓ 0

↓: normal

> 50 %

↓:↓

> 10%

3Blood

Plate3.6IronDeficiencyAnemia

43 1

Fe

2 Fe

Fe³⁺Fe³⁺

Fe³⁺

Fe²⁺Fe³⁺

Fe²⁺

H⁺

Fe Fe

HCI Fe

Fe

Hb synthesis

Malnutrition etc.

Stomach

Malabsorption Disease in upper

small intestine, Fe-binding food

Fe deficiency anemia

Transferrin deficiency, transferrin defect

Achlorhydria, gastrectomy

Lumen

Ferritin

Blood

Lyso-some turnoverCell Mucosal transferrin

Apo- transferrin HemeFe²⁺

Mucosal cells (duodenum)

Liver

Fe uptake

Trans- ferrin

Absorption Nonabsorbed Fe in stool normal: 85–97% of uptake

Fe deficiency Heme

Fe storage

Systemic blood Liver

Bonemarrow

Hemo-siderin Ferritin Heme

Hb

throcytes Ery- Hemo-pexin

Hapto-globin Ferritin

Growth, pregnancy, breast feeding

Fe demand

Fe recycling Chronic infections

Hemo-siderin

Storage, loss and recycling

Trans- ferrin

Macrophages in spleen, liver and bone marrow (extravasal) Blood loss

(GI-tract, menstruation)

Fe loss

Fe absorption:

3–15% of Fe uptake FR

To liver

Fe absorption

Already in bone marrow Fe³⁺

Normal Fe uptake:

10–20 mg/d 5–10 mg/d HCP1

DCT1

Ferroportin

Ferro-portin Hepcidin

Hepcidin

Ferro-portin Hep-cidin

Ferroportin Hepcidin synthesis A. Iron (Fe) Deficiency Inhibits Hemoglobin Synthesis

Hemolytic Anemias

Erythrocytes can only attain their normal life-span when their flexibility, their ability to withstand osmotic and mechanical stress, their reductive potential, and their energy supply are normal (→p. 34). Defects in these proper-ties lead to a shorter life-span (in some cases to just a few days [corpuscular hemolytic ane-mia]). There are, however, many other causes that shorten the life-span of normal erythro-cytes (extracorpuscular hemolytic anemia). A common feature of these anemias is an in-creased concentration of erythropoietin, which provides compensatory stimulation of eryth-ropoiesis (→p. 37, A and B3).

Causes of corpuscular hemolytic anemia (→A) are usually genetic defects:

◆One of the membrane diseases is hereditary spherocytosis (spherocyte anemia). It is caused by a functional abnormality (defective ankyrin) or deficiency of spectrin, which, as an impor-tant constituent of the cytoskeleton, is essential for its stability (→A 1). The volume of sphero-cytes is normal, but the defect in the cytoskele-ton results in erythrocytes being spherical, in-stead of having a normal flexible discoid shape.

The osmotic resistance of these cells is reduced, i.e., they hemolyse when the hypotonicity of the external medium is still low. As they are prematurely segregated in the spleen, splenec-tomy is therefore therapeutically effective.

◆Enzyme defects disturb the glucose metabo-lism of erythrocytes (→A 2): 1) if pyruvate ki-nase is affected, ATP to Na⁺-K⁺-ATPase supply is stopped, the cells swell up so that they be-come vulnerable and hemolyse early; 2) defec-tive glucose‑6-phosphate dehydrogenase (gluc‑

6-PDH;→A 3) slows the pentose phosphate cy-cle, so that oxidized glutathione (GSSG), formed under oxidative stress, can no longer be ade-quately regenerated to the reduced form (GSH).

As a result, free SH groups of enzymes and membrane proteins as well as phospholipids are no longer sufficiently protected against oxi-dation, leading to premature hemolysis. Eating horsebeans (Vicia faba major, causing favism) or certain drugs (e.g., primaquin or sulfon-amides) increase oxidative stress and thus

ag-gravate the situation; 3) a defect of hexokinase results in a deficiency of both ATP and GSH (→A2, 3).

◆Sickle cell anemia and thalassemias (→p. 40) also have a hemolytic component (→A 4).

◆In (acquired) paroxysmal nocturnal hemo-globinuria (PNH) some of the erythrocytes (de-rived from somatically mutated stem cells) have increased complement sensitivity. It is based on a defect of the membrane anchor (glycosyl-phosphotidylinositol) of proteins that protect erythrocytes against the comple-ment system (especially the decay accelerating factor [DAF], [CD55] or the membrane inhibitor of reactive lysis [CD59];→A 5). The disorder leads to complement activation with eventual perforation of the erythrocyte membrane.

Examples of the causes of extracorpuscular hemolytic anemia are:

◆Mechanical causes, such as damage to the erythrocytes by collision with artificial heart valves or vascular prostheses, especially if car-diac output (CO) is raised;

◆Immunological causes, for example, in ABO blood group transfusion mismatches, or Rh in-compatibility between mother and fetus;

◆Toxins, for example, certain snake poisons.

In most hemolytic anemias the erythrocytes will, as would occur normally, be phagocytized and“digested” in bone marrow, the spleen and liver (extravascular hemolysis), and Fe is reused (→p. 42). A small amount of Hb released intra-vascularly is bound to haptoglobin (→p. 42). In massive acute intravascular hemolysis (→B) haptoglobin is, however, overloaded and free Hb is filtered in the kidneys. This results not only in hemoglobinuria (dark urine), but can also through tubular occlusion lead to acute re-nal failure (→p. 118). Chronic hemoglobinuria additionally causes Fe deficiency anemia, car-diac output rises and the resulting mechanical hemolysis creates a vicious circle (→B). Finally, the erythrocytic fragments produced in intra-vascular hemolysis may cause thrombi and em-boli, which can result in ischemia in the brain, cardiac muscle, kidneys, and other organs.

44

3Blood

Plate3.7HemolyticAnemias

45

+

Gluc–6–PDH

1

2

3 4

5

Cl^–/HCO3–

Na⁺ K⁺

ATP Hb

Hemoglobinuria Renal filtration

of Hb

Fe deficiency Hb deficiency

CO

Haptoglobin overload Free Hb Erythrocyte

Horse beans, primaquine, sulfonamides, etc.

Defect Enzyme defects

deficiencyATP

swellingCell

Acute renal failure Corpuscular causes

(e.g. PNH)

Acute intravascular hemolysis

Thrombosis, embolism Erythrocyte fragments

Extracorpuscular causes immunological

(e.g. transfusion reaction)

toxic

(e.g. snake poison) mechanical (e.g. artificial

heart valve)

Ischemia

Favism Hemolysis Ankyrin

Spectrin

Glucose

Hexokinase Glucose–6–P

Pentose–P cycle

2 GSH GSSG

R1–SS–R2

Oxidative stress Carrier

Glycolysis Pyruvate

kinase

R1–SH,R2–SH DAF defect

Complement activation

Paroxysmal nocturnal hemo-globinuria (PNH) Osmotic

resistance Deficiency or functional disorder of spectrin

Hereditary spherocytosis

Gene defects

Thalassemia Sickle-cell anemia

CD55or CD59