Physiology Of Hemoglobin

Hemoglobin is a iron containing protein in the red blood cells that carries oxygen in the blood from the lungs to the rest of the body tissues. A normal hemoglobin level is necessary for the normal function of the body. If there is decreased or abnormal hemoglobin synthesis it results in number of different diseases.

Here we will discuss the brief physiology of hemoglobin in the human body which helps in understanding the diseases related to abnormal hemoglobin.

Hemoglobin Synthesis

• Erythropoietic activity is regulated by erythropoietin.
• The mitochondria of the developing erythroblast are the main sites for the sythesis of haem.
• The globin protein part is synthesized in the ribosomes .
• There are number of complex series of steps for the synthesis of hemoglobin.
• The Vitamin B6 acts as a cofactor in the process of synthesis.
• The Fe is supplied by the circulating transferrin.
• A tetramer of four globin chains, each with its own haem group attached, is formed to make a molecule of hemoglobin.

Structure and Different Types of hemoglobin
Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins. This structure comes from its four subunits arranged roughly in a tetrahedral pattern.

HbA: In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called hemoglobin A, consisting of two alpha and beta subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as alpha2beta2. The subunits are structurally similar and about the same size. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

HbF: In human infants, the hemoglobin molecule is made up of 2 alpha chains and 2 gamma chains. The gamma chains are gradually replaced by beta chains as the infant grows. Hemoglobin F has a higher oxygen affinity and in normal adults it is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in certain diseases like sickle cell or thalassaemia.

HbA2: (alpha2delta2) – delta chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%.

Hb in the Embryo:
Gower 1
Gower 2
Hemoglobin Portland

Hemoglobin Variant that cause disease:

Hemoglobin H (beta4) – A variant form of hemoglobin, formed by a tetramer of beta chains, which may be present in variants of alpha thalassemia.

Hemoglobin Barts (gamma4) – A variant form of hemoglobin, formed by a tetramer of gamma chains, which may be present in variants of alpha thalassemia.

Hemoglobin S (alpha2betaS2) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the beta-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.

Hemoglobin C (alpha2betaC2) – Another variant due to a variation in the beta-chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin E (alpha2betaE2) – Another variant due to a variation in thebeta-chain gene. This variant causes a mild chronic hemolytic anemia.

Hemoglobin AS – A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease gene

Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding hemoglobin C.

Red Blood Cell Physiology
Red blood cells also known as erythrocytes are are oval and flexible biconcave disks. They lack a cell nucleus and most organelles to accommodate maximum space for haemoglobin. The cells develop in the bone marrow and circulate for about 100–120 days in the body. RBC’s cytoplasm is rich in haemoglobin that can bind oxygen and is responsible for the blood’s red color. The functions of red blood cells is:

• To pass through microcirculation of capillaries
• To maintain hemoglobin in the reduced state.
• To maintain an osmotic equilibrium.

Oxygen Dissociation Curve
When oxygen is unloaded from a molecule of oxygenated Hb, the beta-chains open up allowing, 2-3 DPG to enter. This results in the deoxygenated Hb having a low affinity for oxygen, preventing haemoglobin from stealing the oxygen back from the tissues. This 2-3 DPG related affinity for the oxygen dissociation curve is sigmoidal in appearance rather than a straight line.

The factors that cause the curve to shift are summarized as below:

Shift to the Right( Decreased Oxygen Affinity)

• Acidosis
• Increased CO2
• Increased temperature
• Increased 2,3 DPG
• Excersise
• Hb S

Shift to the Left (Increased Oxygen Affinity)

• Alkalosis
• Decreased CO2
• Decreased temperature
• Decreased 2,3 DPG
• Hb F