Hemoglobin and Gas Exchange Quiz

Biochemistry 8

• This Biochemistry course covers globular proteins, hemoglobin and myoglobin structure and function, the Bohr effect, and hemoglobinopathies.

• The course material is from Lippincott Illustrated Reviews Biochemistry, 8th edition, 2021, chapters 58-89, "Globular Proteins".

Hemoglobin

• Hemoglobin is a protein composed of globin chains (alpha, beta, gamma, delta) and heme molecules.
• It contains four globin chains in 2 pairs.
• A heme molecule has an iron atom in the center surrounded by a porphyrin ring; oxygen binds to the iron atom.

Hemoglobin Types

• Hemoglobin A (α2β2): the most common type found in adults (95%).
• Hemoglobin A2 (α2δ2): a less common type in adults (2-3%).
• Hemoglobin F (α2γ2): the predominant type in fetal hemoglobin.

Oxygen-Dissociation Curves

• The Y-axis represents the percentage of hemoglobin bound to oxygen.
• The X-axis represents the partial pressure of oxygen (PaO2).
• The curve is S-shaped due to positive cooperativity (binding of one oxygen molecule increases the affinity of the next molecule).

Oxygen-Hemoglobin Binding

• Four heme groups do not oxygenate simultaneously.
• First oxygen increases affinity for the second molecule.
• The third oxygen molecule increases affinity for the fourth molecule.
• The last oxygen has 300 times greater affinity compared to the first.
• Positive cooperativity produces an S-shaped dissociation curve.

Allosteric Proteins

• Allosteric proteins have an "other site" where binding at one site influences other sites.
• Hemoglobin is an allosteric protein.
• Oxygen cooperativity is a positive allosteric effect.

Taut and Relaxed Forms of Hemoglobin

• Globin chains can exist in two forms: taut (T) and relaxed (R).
• The T form tends to release oxygen and is favored in tissues.
• The R form holds onto oxygen and is favored in the lungs.

Peripheral Tissue

• Carbon dioxide (CO2) enters red blood cells (RBCs).
• CO2 + H2O ⇌ H2CO3 ⇌ H+ + HCO3-
• Hydrogen ions (H+) bind to hemoglobin, releasing oxygen.
• Chloride shift: Chloride ions (Cl-) move into RBCs to balance the negative charge.

Bohr Effect

• The affinity of O2-Hb is inversely proportional to the CO2 content and H+ concentration.
• High CO2 and H+ concentration in peripheral tissues lead to decreased O2 affinity, promoting O2 release to tissues
• The O2-Hb dissociation curve is shifted to the right.

Haldane Effect

• The CO2 affinity of Hb is inversely proportional to the oxygenation of Hb.
• Oxygenated Hb (higher O2 levels) has lower affinity for CO2, releasing CO2 from the blood.
• Oxygen uptake is facilitated when Hb is deoxygenated, typically seen in peripheral tissues.
• When Hb is oxygenated, CO2 affinity decreases, resulting in CO2 release.

Shifts in Oxyhemoglobin Curves

• Hgb's oxygen affinity fluctuates in response to environmental changes within RBCs.
• The dissociation curves shift either right or left.

Right Curve Shifts

• Favors a taut form
• Causes include elevated CO2, lower pH, and increased temperature.
• Increases P50.

Left Curve Shifts

• Hgb binds to oxygen more readily.
• Causes include decreased CO2, higher pH, and lower temperature.
• Lower P50 values are observed.

2,3-Biphosphoglycerate (2,3-BPG)

• 2,3-BPG is a negative allosteric effector in RBCs.
• It's produced from diverted 1,3-BPG in glycolysis and produces ATP.
• Elevated 2,3-BPG decreases hemoglobin's oxygen affinity, promoting oxygen release to tissues.
• 2,3-BPG increases with chronic hypoxia, COPD, high altitude, and chronic anemia.

Fetal Hemoglobin

• Hgb F is predominant after 8 weeks of pregnancy.
• Hgb F is up to 90% of fetal hemoglobin until after birth.
• Hgb F is higher affinity for oxygen than HgbA.
• Fetal pO2 is 40 mmHg, which requires higher O2 affinity for oxygen transfer to the fetus.

Myoglobin

• Myoglobin is a single peptide chain found in skeletal muscle and heart.
• It binds one molecule of oxygen.
• It has a higher oxygen affinity at all pressures compared to hemoglobin.

Carbon Monoxide

• Carbon monoxide (CO) binds to iron in heme 240 times more strongly than oxygen.
• Forms carboxyhemoglobin (HbCO), blocking oxygen binding sites.
• Shifts the O2-Hb dissociation curve to the left, impairing oxygen transport.
• CO poisoning causes functional anemia.

Carbon Monoxide Poisoning

• Symptoms can be non-specific: Headache, malaise, nausea, dizziness are common symptoms.
• The classic (but rare) sign is cherry red lips.
• No cyanosis is observed in CO poisoning.
• Standard pulse oximetry is normal in CO poisoning.
• Diagnosis: HbCO level.
• Treatment: oxygen.

Methemoglobinemia

• Caused by reduced iron in hemoglobin converted to ferric iron (Fe3+).
• Fe3+ methemoglobin cannot bind oxygen.
• Excess methemoglobin leads to hypoxia.
• Drugs (local anesthetics, nitric oxide, dapsone) can cause acquired methemoglobinemia.
• Treatment: methylene blue (reducing agent) to convert Fe3+ to Fe2+.

Clinical Scenario

• Endoscopy patients receiving benzocaine may develop methemoglobinemia.
• Patients may present with post-procedural shortness of breath and chocolate-colored blood, associated with variable O2 saturation.
• Typical PaO2 levels are normal.
• Methemoglobin levels are measured to confirm the diagnosis.

Thalassemia

• Decreased or absent globin chain production (alpha or beta).
• There is a diverse spectrum of severity in thalassemia.
• Thalassemia minor is commonly asymptomatic.
• Thalassemia major results in a severe loss of globin production, requiring lifelong transfusions or potentially leading to death.

HbH Disease

• Characterized by severe reduction of alpha globin production.
• Increased production of beta globin leads to the formation of unstable tetramers (HbH).
• Associated with hypochromic, microcytic anemia, which results in abnormally shaped red blood cells.
• Leads to extravascular hemolysis and abnormal red blood cell deformability.
• Diagnosis may involve DNA testing and Hb electrophoresis, which may be insensitive to HbH production.
• Treatment strategies include splenectomy and transfusions.

Hgb Barts

• No alpha globin leads to the formation of Hgb Barts tetramers.
• These tetramers form in utero.
• Causes massive total body edema and high output heart failure, resulting in fetal death shortly after birth.

Beta Thalassemia

• Characterized by reduced or absent beta globin chain synthesis.
• Reduced beta globin production may result from mutations and not deletions.
• Varying degrees in disease severity, depending on the mutation type.

Beta Thalassemia Minor

• Also known as beta thalassemia trait.
• Heterozygous condition resulting in reduced beta globin production.
• Patients are typically asymptomatic or have mild anemia, noticeable on routine blood work.
• Diagnosis can be made through electrophoresis, showing a significant increase in HgbA2 levels, which do not require beta chains for formation.

Beta Thalassemia Major

• Characterized by severely limited beta globin production.
• Leads to significant and potentially life-threatening anemia starting during the first year of life.
• HgbF production wanes throughout the disease, leading to ineffective erythropoiesis.
• Alpha-chains aggregate to form damaging tetramers that cause significant red blood cell damage.
• Splenomegaly and extramedullary hematopoiesis often occur in response to the disease.

Basophilic Stippling

• Characterized by the presence of residual RNA in red blood cells.
• Often seen in patients with thalassemia or lead poisoning.

Target Cells

• Red blood cell shape abnormality characterized by a central pallor.
• Result of increased cell surface area relative to the cell volume.
• An expansion of the cell membrane, resulting in red blood cells having a characteristic target appearance.

Extramedullary Hematopoiesis

• Hematopoiesis outside the bone marrow.
• Primarily a consequence of severe anemia, such as in beta major.
• Often involves the liver and spleen, resulting in hepatosplenomegaly.
• Nucleated red blood cells are frequently encountered.

Parvovirus B19

• Viral infection that can cause aplastic crisis in beta-thalassemia major patients.
• Characterized by a temporary cessation of red blood cell production.
• The virus causes significant marrow dependence in beta major patients.

Sickle Cell Anemia

• An autosomal-recessive disorder.
• Abnormally shaped beta-hemoglobin chains, causing the characteristic sickle cell morphology.
• HbS accounts for approximately 95% of total hemoglobin.

Sickle Cell Anemia Disease Characteristics

• A heterogeneous disease with multiple symptoms and conditions potentially impacting various organs.
• Includes hemolytic anemia and vaso-occlusion of small blood vessels, both influenced by the sickled RBC shape.
• Characterized by hemolysis, often involving extravascular hemolysis causing premature RBC destruction.
• Potentially painful and damaging.
• Potential complications: increased risk of infection.
• Also encompasses symptoms such as splenic failure, characterized by functional asplenia.
• Common complication, often affecting children, includes splenic sequestration crisis.
• Chest syndrome is a serious condition involving vaso-occlusion in pulmonary microvasculature, often triggered by infection, increasing sickling and potentially leading to death.
• Additional complications include renal dysfunction, specifically characterized by occlusion of vasa recta in the renal medulla and impairment of concentrating ability.
• Also implicated is acute pain crisis, affecting various organs.

Sickle Cell Anemia Treatment

• Immunizations and preventative measures are crucial, especially for infections.
• Hydroxyurea is used to increase fetal hemoglobin production.
• Bone marrow transplants may be curative.

Sickle Cell Trait

• A condition in which the patient has a single mutated beta-globin gene.
• Characterized by the absence of sickling in most normal conditions.
• Exception in the renal medulla, where concentrating ability may be impaired (potentially increasing the possibility of renal medullary carcinoma).

Sickle Cell Diagnosis

• Electrophoresis is a diagnostic test and shows varying amounts of HbS depending on the disease or trait.
• A sickling test uses sodium metabisulphite to reduce oxygen tension, causing HbS to precipitate as a turbid suspension for easier visualization of HbS.

Hemoglobin C

• Characterized by a rare beta-gene mutation.
• Replacement of glutamic acid with lysine.
• Results in mild anemia and extravascular hemolysis in heterozygotes.
• Microscopic examination of a blood sample can demonstrate crystals characteristic of hemoglobin C.
• Associated with dehydration-induced red blood cell changes.

Test your knowledge on the functions of hemoglobin and its role in gas exchange. This quiz covers the Bohr effect, Haldane effect, and the structural differences between hemoglobin and myoglobin. Explore the physiological consequences of CO2 and oxygen interactions.