Pathophysiology
Summary
G6PD is the rate-limiting enzyme in the pentose phosphate pathway, a biochemical route responsible for the synthesis of fatty acids and cholesterols, as well as the generation of NADPH, a crucial cofactor for cellular redox reactions.
In G6PD deficiency, the decreased production of NADPH leads to inhibition of the recycling of active glutathione, an antioxidant that helps protect RBCs from oxidative damage. As a result, RBCs are left vulnerable to oxidative stress, especially during times of physiological stress such as infection.
G6PD deficiency is X-linked recessive and therefore predominantly affects males. The oxidative stress exposes hemoglobin to denaturation, leading to the formation of insoluble clumps known as Heinz bodies. Heinz bodies cause damage to the RBC membrane and are visible as small dots within the cytoplasm. Upon reaching the spleen, red blood cells with Heinz bodies and damaged membranes are targeted by splenic macrophages, which remove the defective portions and create characteristic 'bite cells’. This process is a hallmark of extravascular hemolysis, the predominant form of hemolysis in G6PD deficiency, although a lesser degree of intravascular hemolysis is also present.
Clinically, hemolysis in G6PD deficiency presents with dark urine, jaundice, & abdominal/back pain from renal injury. Stressors such as infections, certain drugs like dapsone & trimethoprim-sulfamethoxazole, and fava beans can trigger hemolysis in G6PD deficiency. G6PD deficiency confers some level of protection against malaria.
Autoimmune hemolytic anemia (AIHA) occurs in two primary forms: cold AIHA and warm AIHA, differentiated by the type of autoantibodies and their temperature sensitivity.
In cold AIHA, IgM autoantibodies target RBC surface antigens but only bind at temperatures below 30ºC. This low-temperature binding leads to agglutination of RBCs. Clinically, this manifests as blue, painful extremities that are more susceptible to cold temperatures.
In contrast, warm AIHA involves IgG autoantibodies that bind to RBC surface antigens at body temperature.
Both forms of AIHA activate the complement system, as immunoglobulins bind to RBC surfaces. The surface-bound immunoglobulins and complement act as opsonins, marking the cells for phagocytosis by macrophages.
Both cold and warm AIHA lead to bite cells and spherocytes, resulting from macrophages removing parts of the complement-coated cell membrane. This change results in extravascular hemolysis in the spleen and, to a lesser extent, intravascular hemolysis through membrane attack complexes (MAC).
Diagnosis commonly involves a direct Coombs test, using a Coombs reagent that binds to antibodies on the RBC surface. A positive test results from agglutination of these coated cells.
Etiological factors differ for each subtype. Warm AIHA is commonly triggered by viral infections in children, autoimmune diseases like lupus, and drugs such as penicillin. Cold AIHA triggers include Mycoplasma pneumoniae and Epstein-Barr virus (EBV). Certain lymphomas, particularly chronic lymphocytic leukemia (CLL), can cause either form of AIHA.
Lesson Outline
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FAQs
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway, which is responsible for generating NADPH and synthesizing fatty acids and cholesterols. In G6PD deficiency, the production of NADPH is compromised, leading to a decrease in active glutathione. Glutathione is essential for protecting red blood cells (RBCs) from oxidative damage, and its deficiency makes RBCs more susceptible to oxidative stress, resulting in both intravascular and extravascular hemolysis.
In G6PD deficiency, a blood smear typically reveals 'bite cells,' which are formed when splenic macrophages remove damaged portions of the RBC membrane and Heinz bodies. Heinz bodies are aggregates of denatured hemoglobin that occur due to oxidative stress—a consequence of reduced glutathione levels. These Heinz bodies appear as small dots within the RBC cytoplasm and contribute to membrane damage.
Clinical manifestations of hemolysis in G6PD deficiency include dark urine and jaundice, both due to elevated bilirubin levels, as well as abdominal or back pain related to renal injury. Hemolysis can be precipitated by various factors such as infections, and exposure to specific substances like dapsone, trimethoprim-sulfamethoxazole, and fava beans.
In cold AIHA, IgM autoantibodies target RBC surface antigens and bind at low temperatures, leading to RBC agglutination and symptoms like blue, painful extremities. In warm AIHA, IgG autoantibodies form against RBC surface antigens. Both types can activate the complement system and facilitate phagocytosis by macrophages, resulting in intravascular and extravascular hemolysis. However, warm AIHA is more likely to produce 'bite cells' on a blood smear.
Diagnosis of AIHA often involves a combination of clinical findings and laboratory tests. The direct Coombs test is a key diagnostic tool that detects antibodies or complement proteins attached to the surface of red blood cells. A positive result indicates that the immune system is attacking RBCs. Additional tests may include a complete blood count (CBC) to assess anemia, and serum lactate dehydrogenase levels to evaluate the extent of hemolysis.
