Anemia:- Part 7 – Hereditary Spherocytosis

Hereditary Spherocytosis

Sample

1. EDTA blood may be needed.

Definition of Hereditary Spherocytosis:

1. Hereditary spherocytosis anemia is quite common and transmitted as an autosomal dominant trait in the caucasian population.
2. Rarely it may be autosomal recessive.
   1. 75% of the cases are autosomal dominant inheritance patterns, and 25% are sporadic, and in most cases 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.

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 protein4.2.
   2. Defect in the spectrin.
   3. Defect in the ankyrin.
2. This basic defect is a partial deficiency of a protein called spectrin needed for the RBCs membrane’s cytoskeleton. Spectrin deficiency autosomal dominant pattern is the most common cause.
   1. The patients with the autosomal dominant pattern have 60% to 80% of normal spectrin, while recessive forms have 30% to 70% of the normal level.
3. This is usually caused by the defect in the proteins involved in the vertical interaction between the membrane skeleton and the RBCs’ lipid bilayers.
4. Spherocytes are not destroyed in the blood circulation, but these 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.

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 membrane and become more spherical where there is a loss of surface area compared to volume.

Hereditary spherocytosis (RBC) 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.
      

      Clinical parameters	Minor HS	Moderate HS	Moderate to severe	Severe HS
      Hemoglobin	Normal	>80%	60% to 80%	<60%
      Reticulocytes	<6%	6% to 10%	>10%	>10%
      Peripheral blood smear	Few spherocytes	Spherocytes	Spherocytes	Microspherocytes and poikilocytosis
      Osmotic fragility at 37 °C	Increased	Increased	Increased	Increased
      Splenectomy	Rarely needed	Depending upon certain cases	Necessary >5 years old	necessary > 2 to 3 years old
      Inheritance	Autosomal dominant	Autosomal dominant, de novo	Autosomal dominant, de novo	Autosomal recessive

Differential diagnoses of hereditary spherocytosis:

1. May be seen in 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.

Signs and symptoms of Hereditary Spherocytosis:

1. Hereditary spherocytosis is quite a common cause of hemolytic anemias, more than the hemoglobinopathies and G-6-PD deficiency.
   1. There is hemolysis and is present in >90% of the cases.
   2. 50% to 60% of the cases are compensated by the hyperplasia of the bone marrow, and no anemia may be seen except in the crises.
2. The prominent features of hereditary spherocytosis:
   1. Chronic hemolysis.
   2. Jaundice is found in 50% of the cases, and it is intermittent.
   3. Splenomegaly was found in 50% of the cases of young children. It is found in 80% of older children and adults (In the literature reported as 72% to 95%).
3. Anemia is mild and usually is unnoticed and diagnosed at an adult age.
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.
   1. The jaundice is fluctuating. It is marked if it is associated with Gilbert’s syndrome.
6. Chronic hemolysis leads to pigment. Gall stones are quite common in these patients. In old patients, 55% to 75% develop gall stones, and it may be seen even in young children.
7. In the spleen, these cells, by removing the membrane, changed into microspherocytes and are ultimately sequestered and will lead to splenomegaly.
   1. Spenemegally is quite common in these patients.
8. These patients ultimately develop anemia, splenomegaly, and ulcer legs.
9. Aplastic crises are usually seen in patients with parvovirus infection. This will leads to the severity of anemia.
10. Megaloblastic anemia is due to folate depletion owing to the overactivity of the bone marrow.
11. Autohemolysis is increased, and this can be corrected by glucose.
12. Gallstones develop in 55%  to 75% of the patients by the time of old age and may be seen in even young children.

Lab. findings of Hereditary Spherocytosis:

1. There is evidence of hemolysis in 90% of the cases.
   1. 50% to 60% of the patients can compensate for the bone marrow hyperplasia and do not show anemia except in crises.
2. There is mild to moderate anemia (8 to 12 G/dL).
3. MCV is normal or slightly low, or even maybe high due to reticulocytosis.
4. MCHC is high.
   1. MCV and MCHC are within the normal range in about 80% of the cases; for the rest, in 20% this value may be increased or decreased.
   2. MCHC is usually in the normal range, but it is increased in 20% to 50% of the cases.
   3. Increased MCHC value indicates congenital spherocytosis.
5. Increased reticulocytes, 5 to 7% (another reference 5% to 20%). Reticulocytes are raised in 98% of the cases, and the mean count is 9%.
6. 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.
   2. Procedure:
   3. Keep the normal saline with decreasing dilution in different tubes.
   4. In diluted saline, normal RBCs start hemolysis.
   5. Spherocytes are more susceptible to hypotonic saline for hemolysis than normal RBCs.
   6. Spherocytes start hemolysis at a concentration above the normal range.
7. Bilirubin slightly increased. 50% of the patients develop jaundice which is intermittent.
8. There is detectable urine urobilinogen.
9. Raised LDH level.
10. Urine urobilinogen is increased.
11. Haptoglobin low.
12. 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 staining with a smaller diameter than the normal RBCs.
    4.  Spherocytes are uniform round RBCs with more intensely staining hemoglobin, and there is no central pallor.

Anemia showing spherocytosis

1. 1. There is increased polychromatophilia.
   2. Reticulocytes are seen.
2. Bone marrow shows erythroid hyperplasia.
3. Direct coomb’s test is negative.
4. The differential diagnosis for the immune-mediated hemolysis:
   1. In HS, a direct antiglobulin test is negative.
   2. In immune-mediated hemolysis the MCV is low.

Complications of Hereditary Spherocytosis:

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

Differential diagnosis of anemia:

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

Treatment of Hereditary Spherocytosis :

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