Hereditary Hemolytic Anemias: G6PD, PK, and Enzyme Deficiencies

What is Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency?

A hereditary condition where the body lacks the enzyme G6PD, leading to hemolytic anemia, particularly after exposure to certain drugs or stress.

How is G6PD deficiency inherited?

It is transmitted by a mutant gene located on the X chromosome, affecting heterozygous men and homozygous women.

What is the most common form of G6PD enzyme?

GdB, which is normally active and exists in 99% of whites in the United States.

What is the G6PD Mediterranean variant associated with?

It is associated with acute hemolytic anemia and favism, a severe reaction to fava beans.

What triggers a hemolytic episode in G6PD deficiency?

Oxidative stress, which can be caused by certain drugs, chemicals, or ingestion of fava beans.

What are Heinz bodies?

Irreversibly denatured hemoglobin that precipitates in G6PD-deficient erythrocytes due to oxidation.

List some drugs that can cause hemolytic anemia in G6PD deficiency.

Chloramphenicol, Methylene blue, Nalidixic acid, Primaquine, and Trinitrotoluene (TNT).

What are the clinical manifestations of G6PD deficiency?

Most individuals are asymptomatic, but symptoms can include decreased RBC count, normocytic/normochromic anemia, and back pain during hemolytic episodes.

What laboratory tests are used to diagnose G6PD deficiency?

Tests include hemoglobin levels, Heinz body visualization, methemoglobin reduction test, ascorbate-cyanide test, and fluorescent spot test.

What does a fall in hemoglobin indicate in G6PD deficiency?

It indicates a hemolytic episode, often occurring 2-3 days after exposure to an offending agent.

What is the role of G6PD in erythrocytes?

G6PD catalyzes the first step in the hexose monophosphate shunt, providing reduced glutathione to protect hemoglobin from oxidative damage.

What happens to G6PD activity with cell aging?

G6PD activity decreases with the aging of erythrocytes.

What is favism?

A severe hemolytic reaction that occurs in G6PD-deficient individuals after ingesting fava beans.

What is the significance of reticulocyte count in G6PD deficiency?

An increase in reticulocytes indicates the body's attempt to compensate for the loss of red blood cells during hemolytic episodes.

What is the GdA- variant of G6PD?

A variant with reduced enzymatic activity, leading to a higher risk of hemolytic episodes.

What is the clinical significance of G6PD deficiency in different racial groups?

The highest incidence of G6PD deficiency is found in darkly pigmented racial and ethnic groups, with varying enzyme variants.

What is the role of reduced glutathione (GSH) in erythrocytes?

GSH protects hemoglobin from oxidative denaturation, crucial for maintaining red blood cell integrity.

What are the symptoms of a hemolytic episode in G6PD deficiency?

Symptoms can include fatigue, jaundice, dark urine, and back pain, depending on the severity of hemolysis.

What is the mechanism of hemolysis in G6PD deficiency?

Hemolysis occurs due to oxidative stress leading to the formation of Heinz bodies, which compromise cell deformability and lead to premature destruction.

What is the significance of the fluorescent spot test?

It detects G6PD deficiency by measuring the conversion of NADP to NADPH in erythrocytes under fluorescent light.

What is the prognosis for individuals with mild G6PD deficiency?

Most individuals with mild deficiency remain asymptomatic and can function normally unless exposed to oxidative stress.

What is the primary consequence of PK deficiency in red blood cells?

Diminished capacity to generate ATP, leading to cell membrane fragility and hemolytic anemia.

How is PK deficiency inherited?

As an autosomal recessive trait.

Which population has a high frequency of PK deficiency?

The Pennsylvania Amish, traced back to a single immigrant couple.

What role does PK play in red blood cells?

PK catalyzes a reaction step in the Embden-Meyerhof pathway of anaerobic glycolysis.

Why are mature red blood cells dependent on anaerobic glycolysis?

They lack mitochondria.

What are the consequences of decreased ATP generation in red blood cells?

Cell water loss, shrinkage, distortion of cell shape, and increased membrane rigidity.

What clinical manifestations are associated with PK deficiency?

Anemia and jaundice at birth, increased hemolysis during infections, and increased incidence of pigmented gallstones.

What is the significance of increased 2,3-DPG levels in PK deficiency?

It decreases the affinity for O2, allowing for more oxygen release to tissues.

What does laboratory testing typically reveal in PK deficiency?

Normocytic, normochromic anemia with reticulocytosis and possible polychromasia, poikilocytosis, and nucleated red blood cells.

What laboratory findings indicate hemolysis in PK deficiency?

Moderate increase in unconjugated bilirubin and decreased or absent haptoglobin levels.

What is the osmotic fragility test used for in PK deficiency?

To assess the structural integrity of red blood cells, which shows increased fragility.

What is the autohemolysis test?

A test where normal erythrocytes show lysis in their serum, while PK-deficient erythrocytes show increased autohemolysis.

How is the diagnosis of PK deficiency confirmed?

Through specific testing for the PK enzyme, including fluorescence screening tests.

What is methemoglobin?

Hemoglobin oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state.

What is the role of NADH-methemoglobin reductase?

It maintains the balance between methemoglobin formation and reduction.

What is the major clinical feature of methemoglobinemia?

Cyanosis.

How is severe cyanosis treated in methemoglobinemia?

By administering methylene blue intravenously.

What enzyme deficiency is involved in the Ender-Meyerhof pathway?

Glucose phosphate isomerase (GPI).

What is a common response of individuals with GPI deficiency?

They show a partial response to splenectomy.