Physiology of haemoglobin

Red blood cells contain haemoglobin (Hb). Haemoglobin binds oxygen when partial pressures of oxygen are high (for example at the lungs) and releases it when partial pressures of oxygen are low (for example at body tissues). It is responsible for the majority of oxygen transport in the body.

The structure of haemoglobin is adapted to it’s function. Haemoglobin is a tetramer of four proteins (globins) each of which carry a haem group. Haem consists of an iron molecule held in a porphyrin ring structure. It is the iron molecule which binds oxygen, thus each haemoglobin molecule has the capacity to carry four oxygen molecules. In addition the binding of one oxygen molecule causes a structural or conformational change in the haemoglobin molecule which increases the affinity of the remaining haem units for oxygen. This cooperativity gives rise to the classical sigmoid-shaped oxygen-dissociation curve.

Ferrous and Ferric iron

The majority of iron in haem is in the form of Fe2+ (ferrous ion); this functional form can bind oxygen. Fe2+ can be oxidised to Fe3+ (ferric ion); Fe3+ is non-functional and cannot bind oxygen. Haemoglobin containing Fe3+ is called Methaemoglobin (MetHb).

Furthermore the presence of Fe3+ alters the structure of the whole haemoglobin molecule to increase the affinity of the remaining Fe2+ ions for oxygen (i.e. a left shift of the oxygen-dissociation curve).

Therefore the presence of Fe3+ has a dual impact on oxygen carriage – haemoglobin can carry less oxygen AND oxygen release at the tissues is impaired – causing a more profound tissue hypoxia than indicated by the SaO2.

When protective mechanisms fail, methaemoglobinaemia results

Red blood cells are continuously exposed to oxidative stresses which convert haemoglobin to MetHb. In health, levels of MetHb are maintained at < 1% by a host of protective reduction pathways that restore Fe3+ to Fe 2+.

Foremost of these is the cytochrome-b5-reductase (also called NADH-methaemoglobin-reductase) pathway. This pathway is responsible for 99% of MetHb reduction under normal conditions.

Other minor pathways involve other reducing agents including NADPH-methaemoglobin-reductase (which requires functioning G6PD), ascorbic acid and glutathione. These minor pathways offer options for the treatment of methaemoglobinaemia, as will be discussed later.

When the physiological balance of iron oxidation and reduction is upset, either by an increase in oxidative stresses (causing increased MetHb production) or by ineffective reduction (causing reduced clearance of MetHb), methaemoglobinaemia results and oxygen delivery falls.

Learning bite

Hb can be oxidised to MetHb. MetHb does not carry oxygen efficiently. In health, protective enzymes reverse Hb oxidation to keep MetHb levels at < 1%. The major enzyme involved is cytochrome-b5-reductase. When these protective mechanisms fail, MetHb levels rise and hypoxia results

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