Red Blood Cell Metabolism

What are the primary functions of red blood cells (RBCs)?

RBCs have several essential functions, including:

• Transporting oxygen from the lungs to tissues and removing carbon dioxide.
• Maintaining cellular shape and flexibility for optimal circulation.
• Keeping essential constituents in reduced, active form.
• Protecting against oxidative stress.
• Producing energy through anaerobic glycolysis.

How long do RBCs circulate, and what makes their circulation unique?

RBCs circulate for approximately 120 days, traveling about 300 miles (483 km) and making 170,000 circuits through the heart. Their deformability is crucial for passing through capillaries and splenic sinusoids.

Why do RBCs rely solely on anaerobic metabolism?

RBCs lack nuclei and cytoplasmic organelles, including mitochondria, so they cannot undergo aerobic respiration. They rely on anaerobic glycolysis (Embden-Meyerhof pathway) to generate ATP, which is necessary for:

• Phosphorylation of membrane and signaling components.
• Fueling ion pumps and channels.
• Maintaining phospholipid levels.

What are the key metabolic pathways in RBCs?

RBCs depend on three major metabolic pathways:

1. Embden-Meyerhof Pathway (Glycolysis) – Converts glucose to lactate, generating 2 ATP per glucose molecule.
2. Rapaport-Luebering Shunt – Generates 2,3-Diphosphoglyceric acid (2,3-DPG), which decreases hemoglobin's affinity for oxygen, facilitating oxygen delivery to tissues.
3. Hexose Monophosphate (HMP) Shunt – Produces glutathione, a reducing agent that protects RBCs from oxidative damage.
4. Methemoglobin Reductase Pathway – Maintains hemoglobin in its reduced state (Fe²⁺), preventing the accumulation of non-functional methemoglobin.

What are the genetic components involved in RBC metabolism?

Several genes encode enzymes crucial for RBC metabolism, including:

• Glycolysis: PKLR (Pyruvate Kinase), HK1 (Hexokinase), GPI (Glucose-6-phosphate isomerase), PFKM (Phosphofructokinase), PGK1 (Phosphoglycerate kinase).
• Glutathione metabolism: G6PD (Glucose-6-phosphate dehydrogenase), GSR (Glutathione reductase), GSS (Glutathione synthase).
• Purine metabolism: NT5C3A (Pyrimidine 5 nucleotidase).

What are the consequences of enzyme defects in RBC metabolism?

RBC enzyme deficiencies can lead to inherited hemolytic anemias, such as:

• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency – The most common RBC metabolic disorder, affecting males primarily due to its X-linked inheritance. Leads to episodic hemolysis triggered by oxidative stress (e.g., infections, drugs, fava beans). Causes Heinz body formation.
• Pyruvate Kinase Deficiency – Affects glycolysis by impairing ATP generation, leading to RBC membrane instability and chronic, non-spherocytic hemolytic anemia with splenomegaly and gallstones.
• Methemoglobinemia – Caused by defects in the Methemoglobin Reductase Pathway, leading to an accumulation of methemoglobin (Fe³⁺), which cannot bind oxygen effectively.

How does the HMP shunt protect RBCs from oxidative stress?

The Hexose Monophosphate (HMP) shunt generates NADPH, which maintains glutathione in its reduced form. Reduced glutathione neutralizes reactive oxygen species (ROS), preventing oxidative damage to RBC membranes and hemoglobin.

What is the role of the Rapaport-Luebering Shunt in oxygen delivery?

The Rapaport-Luebering Shunt generates 2,3-DPG, which binds to hemoglobin and decreases its affinity for oxygen, thereby facilitating oxygen unloading in tissues.

Where are RBCs destroyed, and how does this occur?

Aged or damaged RBCs are removed in the spleen and liver. The reticuloendothelial system phagocytoses RBCs, breaking them down into:

• Heme, which is converted into bilirubin and excreted via bile.
• Globin, which is degraded into amino acids and recycled.
• Iron, which is stored or transported via transferrin.

What triggers hemolysis in G6PD deficiency?

RBCs with G6PD deficiency are highly susceptible to oxidative stress. Hemolysis is triggered by:

• Infections (e.g., due to hydrogen peroxide production by neutrophils).
• Drugs (e.g., sulfa drugs, primaquine, aspirin).
• Fava bean consumption, which contains oxidizing compounds.
  Oxidative damage leads to hemoglobin precipitation and Heinz body formation, followed by RBC destruction.

Why do pyruvate kinase-deficient RBCs undergo hemolysis?

Pyruvate kinase deficiency reduces ATP production, impairing RBC membrane integrity. This results in:

• Chronic hemolytic anemia (non-spherocytic).
• Splenomegaly, due to excessive RBC sequestration and destruction.
• Gallstones, composed of calcium bilirubinate from chronic hemolysis.

How does methemoglobinemia affect oxygen transport?

In methemoglobinemia, Fe²⁺ in hemoglobin is oxidized to Fe³⁺, which cannot bind oxygen. This leads to:

• Hypoxia and cyanosis (bluish skin discoloration).
• Chocolate-brown blood.
• Treatment includes methylene blue, which helps reduce Fe³⁺ back to Fe²⁺.

Why can't RBCs synthesize new enzymes?

Since mature RBCs lack nuclei and organelles, they cannot produce new proteins or repair damaged enzymes. Any enzyme deficiency will persist for the RBC’s 120-day lifespan, leading to chronic metabolic deficiencies.