Makindo Medical Notes

Related Subjects: |Iron deficiency Anaemia |Haemolytic anaemia |Macrocytic anaemia |Megaloblastic anaemia |Microcytic anaemia |Myelodysplasia |Myelofibrosis

Overview of Haemoglobins

Haemoglobin is a vital protein found in red blood cells that is responsible for transporting oxygen from the lungs to tissues and facilitating the return of carbon dioxide from tissues to the lungs for exhalation. It plays a critical role in maintaining tissue oxygenation and overall metabolic function.

Structure of Haemoglobin

• Haemoglobin is a tetrameric protein composed of four subunits:
  • Each subunit contains a heme group and a globin chain.
  • Heme group: A porphyrin ring with an iron (Fe²⁺) ion at its centre, capable of binding one molecule of oxygen (O₂).
  • Globin chains: Polypeptide chains that provide structural support and help regulate oxygen binding and release.
• The most common form of haemoglobin in adults is Haemoglobin A (HbA), composed of two alpha (α) and two beta (β) globin chains (α₂β₂).

Formation of Haem

Haem is a crucial component of haemoglobin, myoglobin, and various enzymes, such as cytochromes. The biosynthesis of haem occurs primarily in the bone marrow and liver, involving several enzymatic steps that convert simpler molecules into haem.

Steps in Haem Synthesis

1. Formation of δ-Aminolevulinic Acid (ALA):
   • The first step in haem synthesis occurs in the mitochondria. Glycine and succinyl-CoA are combined by the enzyme ALA synthase to form δ-aminolevulinic acid (ALA).
   • This step is the rate-limiting step in haem synthesis and is regulated by the levels of free haem in the cell.
   • Vitamin B6 (pyridoxal phosphate) is a necessary cofactor for ALA synthase.
2. Conversion of ALA to Porphobilinogen (PBG):
   • ALA is transported to the cytoplasm, where two molecules of ALA are condensed to form porphobilinogen (PBG), catalysed by the enzyme ALA dehydratase.
   • This step is sensitive to heavy metals like lead, which can inhibit ALA dehydratase, leading to disorders like lead poisoning.
3. Formation of Uroporphyrinogen III:
   • Four molecules of porphobilinogen are linked together by the enzyme uroporphyrinogen I synthase to form hydroxymethylbilane.
   • Hydroxymethylbilane is converted to uroporphyrinogen III by uroporphyrinogen III cosynthase.
4. Conversion to Coproporphyrinogen III:
   • Uroporphyrinogen III is then decarboxylated by uroporphyrinogen decarboxylase to form coproporphyrinogen III.
5. Formation of Protoporphyrinogen IX:
   • Coproporphyrinogen III is transported back into the mitochondria, where it is converted into protoporphyrinogen IX by coproporphyrinogen oxidase.
6. Formation of Protoporphyrin IX:
   • Protoporphyrinogen IX is further oxidized by protoporphyrinogen oxidase to form protoporphyrin IX.
7. Insertion of Iron into Protoporphyrin IX:
   • The final step involves the insertion of ferrous iron (Fe²⁺) into protoporphyrin IX by the enzyme ferrochelatase, producing haem.
   • This step also occurs in the mitochondria.

Regulation of Haem Synthesis

• Haem synthesis is tightly regulated, primarily at the first step where ALA synthase is involved.
• When haem levels are high, it inhibits ALA synthase, reducing the production of more haem.
• Conversely, low levels of haem (e.g., during anaemia) increase the activity of ALA synthase, boosting haem production.

Clinical Relevance

• Porphyrias: Disorders of haem biosynthesis, such as acute intermittent porphyria and porphyria cutanea tarda, arise from enzyme deficiencies in the haem pathway.
• Lead Poisoning: Lead inhibits enzymes like ALA dehydratase and ferrochelatase, leading to anaemia and neurological symptoms due to impaired haem production.

Types of Haemoglobin

• Haemoglobin A (HbA):
  • Composed of two alpha and two beta chains (α₂β₂).
  • Accounts for approximately 97% of adult haemoglobin.
• Haemoglobin A2 (HbA2):
  • Composed of two alpha and two delta chains (α₂δ₂).
  • Accounts for about 2-3% of adult haemoglobin.
• Haemoglobin F (HbF) (Fetal Haemoglobin):
  • Composed of two alpha and two gamma chains (α₂γ₂).
  • Predominant form of haemoglobin in the fetus and newborns, with a higher affinity for oxygen than adult haemoglobin.
  • Gradually replaced by HbA after birth.
• Abnormal Haemoglobins:
  • Haemoglobin S (HbS): Associated with sickle cell disease, resulting from a mutation in the beta chain.
  • Haemoglobin C (HbC): Results from a different mutation in the beta chain, leading to haemoglobin C disease.
  • Thalassemias: Genetic disorders characterized by reduced or absent production of one of the globin chains.

Function of Haemoglobin

• Oxygen Transport:
  • Haemoglobin binds oxygen in the lungs, where oxygen concentration is high, forming oxyhaemoglobin (HbO₂).
  • Oxygen is released in tissues where oxygen concentration is low, facilitating cellular respiration.
• Carbon Dioxide Transport:
  • Haemoglobin helps transport carbon dioxide (CO₂) from tissues to the lungs for exhalation.
  • CO₂ binds to the amino groups of the globin chains, forming carbaminohaemoglobin.
• Buffering:
  • Haemoglobin acts as a buffer by binding hydrogen ions (H⁺) and helping maintain blood pH within a narrow range.

Oxygen-Haemoglobin Dissociation Curve

• The oxygen-haemoglobin dissociation curve is a sigmoidal graph that describes the relationship between the partial pressure of oxygen (pO₂) and haemoglobin saturation with oxygen.
  • Right Shift:
    • Indicates decreased affinity of haemoglobin for oxygen, facilitating oxygen release to tissues.
    • Caused by increased CO₂, increased H⁺ (lower pH), increased temperature, and increased 2,3-bisphosphoglycerate (2,3-BPG).
  • Left Shift:
    • Indicates increased affinity of haemoglobin for oxygen, facilitating oxygen binding in the lungs.
    • Caused by decreased CO₂, decreased H⁺ (higher pH), decreased temperature, and decreased 2,3-BPG.

Clinical Relevance

• Anaemias:
  • Conditions characterized by a decrease in the number of red blood cells or haemoglobin, leading to reduced oxygen-carrying capacity.
  • Causes include nutritional deficiencies (iron, vitamin B12, folate), genetic disorders (thalassemias, sickle cell disease), and chronic diseases.
• Haemoglobinopathies:
  • Genetic disorders affecting the structure or production of haemoglobin, such as sickle cell disease and thalassemias.
  • Lead to various clinical complications, including anaemia, pain, and organ damage.
• Carbon Monoxide Poisoning:
  • Carbon monoxide (CO) binds to haemoglobin with a much higher affinity than oxygen, forming carboxyhaemoglobin and reducing oxygen delivery to tissues.
  • Symptoms include headache, dizziness, confusion, and, in severe cases, death.
• Methaemoglobinemia:
  • A condition where iron in the heme group is oxidized to Fe³⁺, forming methaemoglobin, which cannot bind oxygen effectively.
  • Causes include genetic mutations, exposure to certain drugs or chemicals, and nitrate-contaminated water.

Summary

Haemoglobin is an essential protein in red blood cells, responsible for oxygen and carbon dioxide transport, as well as buffering blood pH. It has a complex structure that allows it to perform these functions effectively. Variations in haemoglobin structure and function can lead to various clinical conditions, highlighting its critical role in human physiology and health.