What Is Hereditary Nonspherocytic Hemolytic Anemia?
Hereditary nonspherocytic hemolytic anemia (HNSHA) refers to a subtype of hemolytic disorder where there is premature destruction of red blood cells (RBC). The characteristic features of these hemolytic disorders are as follows:
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They are inherited (transferred through genes).
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Hemolysis is not immediate by the immune mechanism.
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There is a deficiency of enzymes that are required for the normal functioning of red blood cells.
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These enzyme defects affect the cellular metabolism inside the red blood cells.
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There is no change in the shape of the red blood cells (non spherocytosis).
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The genetic defect is in the genes coding for red blood cell enzymes.
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They are also referred to as hereditary red blood cell enzymopathies.
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Splenectomy is not the treatment of choice for these disorders.
Various Types of Hereditary Nonspherocytic Hemolytic Anemia
There are different numbers (over 20) of RBC enzyme defects with various degrees of severity. The most commonly reported red blood cell enzymopathies are:
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Glucose-6- phosphate-dehydrogenase (G6PD) deficiency.
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Pyruvate kinase (PK) deficiency.
Other Rare Enzyme Defects:
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Glucose phosphate isomerase (GPI) deficiency.
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Cytochrome b5 reductase (b5R) deficiency.
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Hexokinase deficiency.
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Adenylate kinase 1 deficiency.
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Phosphoglycerate kinase 1 deficiency.
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Glutathione reductase deficiency.
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5-nucleotidase pyrimidine deficiency.
What Are the Causes of Hereditary Nonspherocytic Hemolytic Anemia?
Hereditary nonspherocytic hemolytic anemias are caused by a mutational change in a specific gene sequence that codes for certain RBC (red blood cells) enzyme production. The exact type and severity of hemolytic anemia depend on the specific type of gene involved and its pattern of inheritance. The different inheritance patterns are as follows:
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X-Linked Inheritance (Transferred Through X Chromosome) - It is seen in G6PD deficiency where females are asymptomatic and are carriers. Carrier females have a 25 percent chance of transferring it to their offspring.
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Autosomal Recessive Trait - Recessive genes are inherited and expressed if both parents carry defective genes.
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Autosomal Dominant Inheritance - Here a single copy of a defective non-working gene expresses the disease condition. The risk of transferring the defective genes to the offspring is 50 percent. Both males and females have an equal chance of carrying the genetic defect.
What Happens in Hereditary Nonspherocytic Hemolytic Anemia?
The primary function of red blood cells is to carry oxygen throughout the body. RBCs do not have cell organelles like the nucleus and mitochondria to produce energy (ATP molecules) on their own. They are dependent on various metabolic pathways that supply energy (ATP molecules) for their normal functioning.
Any defect in the enzyme systems or block in the pathways affects the proper working of red blood cells. Their oxygen-carrying capacity is reduced resulting in anemia. Also, RBCs exist in reduced form for oxygen transport. Failure in RBC enzyme complexes causes oxidative stress leading to premature hemolysis. Pathogenesis differs for each genetic defect. Some of them are as follows:
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Decreased production of the required enzymes.
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Fragile membrane of the red blood cells resulting in premature lysis.
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Some gene defects block the energy pathway by which red blood cells get energy and function properly.
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Some genetic defects produce non-working genes that get triggered following any illness, administration of medication, or other oxidative stress-inducing factors.
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In G6PD deficiency, hemolysis is due to oxidative stress from dehydration, infections (bacterial and viral), drugs (Aspirin, antimalarial agents), and certain foods like fava beans.
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In PK deficiency, the cellular activities in RBCs stop due to the unavailability of energy molecules (block in the anaerobic glycolytic pathway).
Clinical Manifestations of Hereditary Nonspherocytic Hemolytic Anemia
The clinical symptoms of hemolytic anemia in these enzymopathies vary in severity; ranging from mild to moderate, to severe and fatal anemia according to the severity of enzyme deficiencies. The symptoms could be seen at birth in some cases or expressed in adulthood in other cases. Some individuals are asymptomatic and only exhibit hemolytic conditions on exposure to infections or drugs. The following are the common signs and symptoms of HNSHA:
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Jaundice (yellowish discoloration of the skin).
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Tiredness.
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Splenomegaly (enlargement of the spleen).
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Hepatomegaly (enlargement of the liver).
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Hyperbilirubinemia (increased bilirubin - pigment produced during RBC breakdown).
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Severe pallor.
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High-colored urine with febrile illness.
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Cardiac insufficiency.
Who Is Affected by Hereditary Nonspherocytic Hemolytic Anemia?
The most common form, G6PD deficiency is seen in more than 400 million people across the world. Most of these disorders are rare and still remain underdiagnosed. Generally, males are affected more than females. Also, the prevalence of hereditary nonspherocytic hemolytic anemia is more frequent in consanguineous marriages (marriage between cousins).
How Is Hereditary Nonspherocytic Hemolytic Anemia Diagnosed?
Diagnosis of HNSHA is often confused with other hemolytic disorders due to its rare occurrence. Cases with low hemoglobin levels in spite of normocytic anemia, elevated reticulocyte counts, negative direct coombs test, normal hemoglobin electrophoresis, and normal osmotic fragility tests should be suspected from the presence of hereditary nonspherocytic hemolytic anemia disorders. The important diagnostics to detect HNSHA are as follows:
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Increased reticulocyte (immature red blood cells) count.
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Decreased red blood cell count (anemia).
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Decreased hemoglobin levels.
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Increase in lactate dehydrogenase (high enzyme levels indicate tissue destruction).
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Increased bilirubin (metabolic byproducts from the breakdown of heme molecule).
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Peripheral blood smear shows normochromic (no change in color) and normocytic (no change in size and shape) red blood cells.
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Immunoassay to identify the defective enzyme.
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Genetic sequencing (next-generation gene sequence) to detect gene mutations.
What Are the Treatment Strategies for Hereditary Nonspherocytic Hemolytic Anemia?
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No specific treatment is needed for individuals who show mild symptoms of hereditary nonspherocytic hemolytic anemia disorders.
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Regular blood transfusions are recommended for moderate to severe hemolytic conditions.
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Red blood cell concentrates are preferred in patients with cardiac insufficiency.
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Since RBC destruction is due to enzyme defects and not due to structural abnormality, splenectomy (removal of spleen) is not the treatment of choice in hereditary nonspherocytic hemolytic anemia. But partial splenectomy is considered in very severe cases.
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Stem cell therapy is under investigation for a few types of HNSHA.
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Gene therapies to activate deficient enzymes are under experimental trial.
How to Prevent Hereditary Nonspherocytic Hemolytic Anemia?
These are rare hereditary disorders where most of their existence remains undiagnosed. Extended awareness is essential among family members where there are occurrences of such unidentified hemolytic episodes. Genetic counseling facilitates a better understanding of genetic tests for inheritance analysis. Drugs and foods that trigger hemolytic disorders are to be avoided.
Conclusion
Hereditary nonspherocytic hemolytic anemia is a group of rare red blood cell disorders that remains usually asymptomatic. Supportive care and management are needed for moderate and several hemolytic conditions. Specific diagnostics and enhanced treatment strategies would prevent fatal complications.
