Anemia:- Part 7 – Hereditary Spherocytosis

Hereditary Spherocytosis

What sample is needed for Hereditary Spherocytosis?

1. EDTA blood may be needed.

How will you define Hereditary Spherocytosis?

1. Hereditary spherocytosis anemia is quite common and transmitted as an autosomal dominant trait in the caucasian population.
2. Rarely is it autosomal recessive.
   1. 75% of the cases have autosomal dominant inheritance patterns, 25% are sporadic, and in most cases, they have a recessive inheritance.
3. This is the most common hereditary hemolytic anemia in northern Europe, 1 in 5000.
4. Inheritance is autosomal dominant in 75% of the cases.
5. Cardinal features are:
   1. Chronic hemolysis.
   2. Jaundice.
   3. Splenomegaly.

How will you discuss the pathogenesis of Hereditary Spherocytosis?

1. Molecular abnormality of the cytoskeletal proteins has been identified in some cases; these defects may be:
   1. Cytoskeletal proteins like band3 or protein 4.2.
   2. Defect in the spectrin.
   3. Defect in the ankyrin.
2. This basic defect is a partial deficiency of a spectrin protein needed for the RBCs’ membrane cytoskeleton.
3. Spectrin deficiency, an autosomal dominant pattern, is the most common cause.
   1. The patients with the autosomal dominant pattern have 60% to 80% of normal spectrin, while those with the recessive form have 30% to 70% of the normal level.
4. This is usually caused by a defect in the proteins involved in the vertical interaction between the membrane skeleton and the RBCs’ lipid bilayers.
5. Spherocytes are not destroyed in the blood circulation but are sequestered and removed in the spleen.
   1. This condition will lead to splenomegaly.
   2. In these cases, splenectomy will cure the patients because the bone marrow can compensate.

What is the basic defect of Hereditary Spherocytosis?

1. It is the loss of RBCs’ membrane caused by the release of parts of the lipid bilayer that is not supported by the skeleton, resulting in decreased surface area.
2. This will produce RBCs with the lowest surface-area-to-volume ratio, called spherocytes.
3. The marrow produces normal biconcave RBCs, but these lose their membranes and become more spherical, resulting in a loss of surface area compared to volume.

Heriditary spherocytosis mechanism

4. These RBCs can not change their shape easily, so they can not move through the microcirculation, particularly through the spleen reticuloendothelial system, where they will die permanently.
5. In one of the articles, hereditary spherocytosis is classified into four subtypes.
   1. Minor HS.
   2. Moderate HS.
   3. Moderate to severe HS.
   4. Severe HS.

What are the features of various types of Hereditary spherocytosis?

What are the causes of hereditary spherocytosis?

1. It may be seen in the ABO transfusion reaction.
2. These are seen in widespread malignancy.
3. These are seen in Clostridium welchii septicemia.
4. Seen in severe burns.
5. Sometimes seen in autoimmune hemolytic anemia.

What are the signs and symptoms of Hereditary Spherocytosis?

1. Hereditary spherocytosis is quite a common cause of hemolytic anemias, more than hemoglobinopathies and G-6-PD deficiency.
   1. There is hemolysis, which is present in >90% of the cases.
   2. Hyperplasia of the bone marrow compensates for 50% to 60% of the cases, and no anemia may be seen except in crises.
2. The prominent features of hereditary spherocytosis:
   1. Chronic hemolysis.
   2. Jaundice is found in 50% of the cases and is intermittent.
   3. Splenomegaly was found in 50% of young children’s cases. It is found in 80% of older children and adults (the literature reports it as 72% to 95%).
3. Anemia is mild and usually goes unnoticed, and is diagnosed in adulthood.
4. Anemia may be present at any age, from infancy to old age.
   1. Anemia may be mild to moderate, and Hb is >8 g/dL.
5. There is an increased tendency for the bilirubin levels.
6. The jaundice is fluctuating. It is marked if it is associated with Gilbert’s syndrome.
7. Chronic hemolysis leads to pigment. Gallstones are quite common in these patients. In old patients, 55% to 75% develop gallstones, which may be seen even in young children.
8. In the spleen, these cells, by removing the membrane, change into microspherocytes and are ultimately sequestered, leading to splenomegaly.
   1. Spenemegally is quite common in these patients.
9. These patients ultimately develop anemia, splenomegaly, and ulcers on their legs.
10. Aplastic crises are usually seen in patients with parvovirus infection. This will lead to the severity of anemia.
11. Megaloblastic anemia is due to folate depletion, caused by the bone marrow’s overactivity.
12. Autohemolysis is increased, and this can be corrected by glucose.
13. Gallstones develop in 55%  to 75% of patients by old age and may be seen in even young children.

How will you diagnose Hereditary Spherocytosis?

1. There is evidence of hemolysis in 90% of the cases.
2. 50% to 60% of the patients can compensate for the bone marrow hyperplasia and do not show anemia except in crises.
3. There is mild to moderate anemia (8 to 12 G/dL).
4. MCV is normal, slightly low, or even high due to reticulocytosis.
5. MCHC is high.
   1. MCV and MCHC are within the normal range in about 80% of cases; in the remaining 20%, these values may be increased or decreased.
   2. MCHC is usually in the normal range, but increases in 20% to 50% of cases.
   3. Increased MCHC value indicates congenital spherocytosis.
6. Increased reticulocytes, 5% to 7% (another reference 5% to 20%). Reticulocytes are raised in 98% of the cases, and the mean count is 9%.
7. Osmotic fragility is very high, and this is a confirmatory test.
   1. This test needs 24 hours of incubation at 37 °C to become prominent, particularly in newborns.
8. How will you perform the osmotic fragility test?
   1. Keep the normal saline with decreasing dilution in different tubes.
   2. In diluted saline, normal RBCs start hemolysis.
   3. Spherocytes are more susceptible to hypotonic saline for hemolysis than normal RBCs.
   4. Spherocytes start hemolysis at a concentration above the normal range.
9. Bilirubin slightly increased. 50% of the patients develop intermittent jaundice.
10. There is detectable urine urobilinogen.
11. Raised LDH level.
12. Urine urobilinogen is increased.
13. Haptoglobin low.
14. Peripheral blood shows prominent spherocytes.  The classic spherocyte is smaller or just near the size of normal RBCs. It is round and does not show a central clear area.
    1. Smaller spherocytes are called microspherocytes and are seen in other types of hemolytic anemia, e.g., hemolytic transfusion reaction.
    2. 20% to 25% of the cases show few spherocytes.
    3. Spherocytes are densely stained with a smaller diameter than the normal RBCs.
    4.  Spherocytes are uniform, round RBCs with more intensely staining hemoglobin and no central pallor.

Anemia and the presence of spherocytosis

15. There is increased polychromatophilia.
16. Reticulocytes are seen.
17. Bone marrow shows erythroid hyperplasia.
18. Direct Coombs’ test is negative.
19. The differential diagnosis for immune-mediated hemolysis:
    1. In HS, a direct antiglobulin test is negative.
    2. In immune-mediated hemolysis, the MCV is low.

What are the complications of Hereditary Spherocytosis?

1. Hemolytic crises are usually associated with viral infections. The Hb level decrease is not severe.
   1. The Hb level drops in this situation, and WBCs, RBCs, and platelet production are stopped.
2. Aplastic crises usually accompany abdominal pain and fever, lasting 6 to 14 days.
3. Bone marrow production of WBCs, RBCs, and platelets is stopped, and there is low hemoglobin.
4. Megaloblastic deficiency leads to megaloblastic changes, which have been seen in congenital spherocytosis.
5. With increasing age, there is a risk of pigmented gallstones, which may be seen in 50% of the cases.

What is the differential diagnosis of Hereditary spherocytosis anemia?

1. This hereditary spherocytic anemia needs to be differentiated from:
   1. Immune hemolytic anemia.
   2. G6PD deficiency.
   3. Thermal injury.
   4. Toxins due to the infection of Clostridium.
   5. Snake venom.
   6. Bee and spider venom.

How will you treat Hereditary Spherocytosis?

1. For the treatment of symptomatic patients, splenectomy is the choice.
2. Because increased bone marrow production of RBCs can compensate for the presence of spherocytes, which have a shorter life span than the normal RBCs.
3. The patient should be kept on folic acid prophylaxis to prevent aplastic crises.