Haemoglobin, Iron and Red Cell Metabolism

Haemaglobin

carries oxygen, binds and releases hydrogen ions, contributes to acid-base balance

Haemaglobin structure

4 globulin chains with one heam group within an iron core. 2 alpha globulins, 2 beta globulins

Haem structure

a ring of carbon, hydrogen and nitrogen atoms (protoporphorin IX) with a central atom of divalent ferrous iron (Fe2+). ferrous iron in each haem reversible binds to one oxygen molecule.

protoporphorin IX

is a key intermediate in the heme biosynthetic pathway, serving as a precursor for heme

Haemologbin synthesis

Occurs in mitochondria and cytosol of bone marrow erythrocyte precursors. Proerythroblast to reticulocyte stage. Synthesis occurs in early stages of erythroblast so there are still ribosomes

why can mature erythrocytes not make haemaglobin

they have lost their ribosomes and mitochondria

haem synthesis

Ferric iron (Fe3+ ) is delivered to the cell by transferrin via transferrin receptors. Transferrin is recycled, Fe3+ enters the mitochondria where it is reduced to Fe2+ and united with protoporphyrin IX to form haem.

globin synthesis

Occurs in the cytosol on ribosomes. Chromosome 16 (α chains) and Chromosome 11 (non-α) control the synthesis of the globin chains.

Normally, in adults, α chains and β chains are produced in equal quantities.

2 α and 2 β chains combine. happens the same time as haem synthesis

Actions of Erythropoietin

increase number of committed progenitors which are then stimulated to proliferate, differentiate and synthesize Hb

Hb affinity for oxygen

related to the partial pressure of oxygen. The affinity of Hb for O2 is defined by the amount of O2 needed to saturate 50% of Hb (P50 value)

PO2

(PO2 ) measured in mmHg

PO2 determines the amount of oxygen needed to saturate 50% of Hb (P50 value)

high O2 tension

Hb has high affinity for O2

low O2 tension

Hb has low affinity for oxygen

Haemoglobin Oxygen Dissociation Curve

A change in pH shifts the Hb O2 saturation curve (Bohr effect).

This facilitates the ability of Hb to exchange O2 and CO2. a decreased pH in tissues shifts curve to the right

so there is lower affinity for O2

2,3-bisphosphoglycerate (2,3-BPG) concentration

molecule that stabilises the deoxygenated form of Hb

tense state

stabilises the deoxygenated form of Hb by binding between the β-globin chains, favouring O2 release;

relaxed state

Binding of O2 releases 2,3-BPG and the Hb molecules rotates into the relaxed "R" state when it is fully oxygenated

Haemaglobin function In venous blood

CO2 diffuses into RBC and combines with water. carbonic acid (H2CO3 ), then dissociates to H+ and HCO3-. H+ binds oxygenated Hb and the oxygen is released

Haemaglobin function in lungs

O2 diffuses into RBC, binds to deoxygenated Hb, release H+ of from Hb. H+ combines with HCO3 - to form carbonic acid which is converted to water and CO2

Haemoglobin Function - Nitric oxide transport

helps with relaxation of vascular smooth muscles and vasodilation

Dyshaemoglobins

Dysfunctional Hb unable to transport oxygen

Mostly acquired (drugs or toxins), some hereditary

Methemoglobin (MetHb)

Circulating Hb present with iron in oxidised Fe3+ instead of usual Fe2+ state which cannot bind to oxygen

Haemoglobin Catabolism

Is a normal process at the end of the RBC lifespan

Hb broken down to globin, iron and protoporphyrin.

Globin and iron are recycled. protoporphyrin is disposed of

iron deficiency

reduced availability of iron for haem synthesis.

thalassaemia

reduced production of globin chains (α or β) and the accumulation of the excess globins

Haemoglobinopathy

point mutations in the globin chains that lead to unstable haemoglobins.

iron distribution compartments

functional, storage and transport

functional compartment

Contains all iron that is functioning within cells

storage compartment

Iron that is not currently functioning but is available when needed

transport compartment

Iron that is in transit in the plasma (transferrin)

iron chemistry

The metabolic function of iron depends on its ability to change its valence state from reduced ferrous iron to oxidised ferric iron. In cells, ferrous iron can react with peroxide and from highly reactive oxygen molecules (including free radicals) that can damage proteins, lipids and nucleic acids

iron stores

Iron not required for erythropoiesis is stored in hepatocytes and macrophages.

Ferritin is the storage form of iron. It is mobilised to BM when required.

hepcidin

regulates iron transport to cells.

Hepcidin synthesis (in the liver ) is affected by: Hb levels Inflammation, Iron stores, Erythropoietic activity, Oxygen content

iron metabolism in other tissues

10 - 15% of iron is in myoglobin and cytochromes.

Myoglobin is the oxygen carrying molecule for muscles and resembles haemoglobin

full blood count assessment

RBCC, HGB, MCV and RDW. also checks size, colour and shape

serum iron studies

indicator of available transport iro

transferrin studies

indicator of available transport iron and transferrin level

ferritin

indicator of available storage iron

loss of deformability

decreased mean cell haemoglobin concentration means deformability compromised shortened red cell life span

deformability

process of RBCs to stretch undamaged up to 2.5 times their resting diameter as they pass through narrow capillaries and splenic pores

RBC energy generation

produce ATP (adenosine triphosphate) through anaerobic glycolysis. ATP also required to slow down the oxidation of proteins and iron by environmental peroxides and superoxide anions to maintain haemoglobin function and membrane integrity

Embden Meyerhof pathway

RBC lack mitochondria so rely on anaerobic glycolysis for energy generation.

Metabolism of glucose to pyruvate.

2 ATPs produced per glucose molecule. energy is used to maintain volume shape and flexibilty. NADH also produced, necessary for activation of non-functional MetHb

Hexose Monophosphate pathway

G6PD produces NAD and NADH (antioxidants prevents iron from getting oxidized). G6PD is pivotal as it is the only means for the RBC to generate NADPH which reduces glutathione.

Reduced glutathione reduces peroxide to water