HEREDITARY

SPHEROCYTOSIS

DR. AHLA JASIM

RESIDENT LAB HEMATOLOGY
 INTRODUCTION:
A type of congenital hemolytic anemia in which erythrocytes are unable to
maintain their normal biconcave shape due to genetic mutations in
membrane/cytoskeletal proteins that play a role in structural morphologic
stability. Deficient or abnormal proteins may include spectrin, ankyrin, band
3, and band 4.2, encoded by different genes.
Structure of Erythrocytes:
• Normal erythrocytes have a biconcave shape and possess relatively
high plasticity. A lipid bilayer forms their membrane with proteins that
adhere to the cytoskeleton and confer a normal biconcave shape
providing optimal surface/volume relationship and adequate
malleability, maintaining structural integrity and proper ion
permeability.
• With biconcave shape, normal erythrocytes are able to buffer for
small changes in osmolarity along with other changes in the
intravascular environment.
Spherocytes:
• Hereditary spherocytosis results from a deficiency in one or more proteins
involved in maintaining adequate adherence between the cytoskeleton and bilipid
membrane. As the cellular surface is unable to be adequately supported by the
cytoskeleton, the cell adopts an abnormal sphere shape that decreases surface to
volume relationship. As the abnormal red blood cell membrane holds a higher
tension, their structure is increasingly fragile and unable to buffer for several
intravascular imbalances, such as a decrease in osmolarity.

• Spherocytes also have an abnormal ionic permeability that increases the influx of
sodium to the intracellular space, which increases ATP requirements as the activity
of the Na/K pump increases to compensate for the rise in intracellular sodium.
Epidemiology:
• Hereditary spherocytosis is the most common genetic hemolytic
disease. While it is more common in Northern Europe and North
America, it may present in various racial populations. It is diagnosed
in 1 out of every 2000 individuals, although a substantial number of
asymptomatic cases may remain undiagnosed.[
Inheritance:
• Deficiency of RBC membrane proteins (mostly spectrin) results in
defective linkage of RBC inner membrane cytoskeleton to its outer
lipid bilayer. This defect results in loss of RBC membrane stability and
deformability with progressive membrane lipid bilayer loss in the
microvasculature. Membrane loss results in spherocytosis, a drop in
mean corpuscular volume (MCV), an increase in mean corpuscular
hemoglobin concentration (MCHC), and increased osmotic fragility of
RBCs. Spherocytes are destroyed and cleared from circulation during
passage through the spleen.[1][4]
• The differential diagnosis for patients with hereditary spherocytosis is
broad and includes other red blood cell disorders including elliptocytosis
and its variants, hereditary stomatocytosis, pyropoikilocytosis, and
ovalocytosis. Additionally, red blood cell enzymes disorders should also be
considered, such as glucose-6-phosphate dehydrogenase (G6PD)
deficiency or pyruvate kinase deficiency.

• Autoimmune hemolytic anemia (AIHA) is a common cause of hemolysis,

and it commonly presents in adult patients. Unlike elliptocytosis, however,
patients with AIHA commonly test positive for Coombs, and this disease
does not commonly correlate with a positive family history.
Peripheral smear:
• In microscopical blood smear evaluation, spherocytic red blood cells
appear as smaller round cells lacking the normal central pale area due
to the absence of a normal biconcave shape. Spherocytes may also be
present in other types of hemolytic anemia, although more
commonly in hereditary spherocytosis.[2][6]

• Howell-Jolly bodies are frequently present in post-splenectomy blood

smear microscopic evaluation; their absence after splenectomy may
be a sign of residual functioning splenic tissue.
History:
• Most patients with hereditary spherocytosis have a positive family
history.
• Patients may also present with asymptomatic cholelithiasis of
undetermined etiology, commonly with a positive family history.
Sign and Symptoms:
• Approximately 50% of patients with hereditary spherocytosis present
with anemia, and 10 to 15% with splenomegaly or jaundice. The
majority of patients will present partially compensating hemolysis in
addition to mild anemia.
• This disease should be suspected in any child presenting with
splenomegaly, anemia, and hyperbilirubinemia.
Clinical Course:
Hereditary spherocytosis has a broad severity spectrum, and patients
will have different clinical courses.
The degree of anemia categorizes as:
• severe for patients with hemoglobin lower than 8 g/dL.
• moderate for 8 to 10 g/dL.
• mild with hemoglobin 10 to 11.5 g/dL in females, or 10 to 13.5 g/dL in
males.
Presentation in neonates:
• The classic triad of jaundice, anemia, and splenomegaly is rare in
neonates. The most common finding in this population is jaundice.
• Thus hereditary spherocytosis should be considered in neonates with
hyperbilirubinemia of unknown cause. Additionally, spherocytes are
seen less often in newborns along with several markers of the
hemolysis that are typically present in older infants or adults.[9]
• Most neonates with hereditary spherocytosis have a positive family
history; this should increase suspicion and aid in the diagnostic
workup of patients with an unknown cause of jaundice.[9]
Diagnostic basis revolves around history, clinical presentation, and
laboratory results.
Investigations should include
• blood smear.
• reticulocyte count.
• complete blood count.
• bilirubin level.
• red cell osmotic fragility tests.
Diagnosis:
• Coombs-negative hemolysis.
• Increased mean corpuscular hemoglobin concentration (MCHC).
• Positive history for hereditary spherocytosis.
• Spherocytes on microscopy, or by a positive result in a specialized
test such as osmotic fragility, eosin-5-maleimide (EMA), or acidified
glycerol lysis test (AGLT).
Management:
• Treatment centers on improving quality of life, avoiding the
complications of hereditary spherocytosis, and treating them
appropriately when present.
• For pediatric population hemoglobin is generally kept above 7 to
8g/dL; however, for newborns, there is no clear consensus regarding
hemoglobin threshold to transfuse red blood cells.
• The decision to transfuse neonates focuses on their hemodynamic
stability and degree of hemolysis.
• Erythropoietin treatment is beneficial for most infants with hereditary
spherocytosis to increase hemoglobin levels and possibly decrease
the need for red blood cell transfusion.
• Neonates with hyperbilirubinemia due to hereditary spherocytosis
should be promptly treated to avoid kernicterus. The decision to
perform blood exchange transfusion therapy should result from the
consideration of several factors including gestational and
chronological age, and level of indirect bilirubin in addition to the rate
of increase.
• Splenectomy largely improves symptomatology in most patients as the
spleen is the principal organ where erythrocyte destruction takes place.
• However, while most patients show a positive outcome after surgical
excision of the spleen, a study showed that clinical response to
splenectomy correlates with the degree of spectrin deficiency.
• The indication for splenectomy generally focuses on improving the
quality of life. However, while the indication is clear for patients with
severe hereditary spherocytosis, for patients with moderate disease
there is no clear consensus and the decision for splenectomy in these
patients is controversial.
• Due to the increase in erythropoietic activity compensating for
hemolysis, patients with hereditary spherocytosis have increased
consumption of folate. For this reason, adequate supplementation is
necessary, particularly in patients with moderate to severe disease.[8]
Prognosis:
• The overall prognosis for patients with hereditary spherocytosis is
considered good. However, it may vary depending on the disease
severity.
• Complications:

• Aplastic crisis secondary to parvovirus B19 infection

• Pigment gallstones more frequent in the second and third decades of
life and may result in obstructive jaundice.
• Gout, ulcer, and growth retardation (less common)
• Patients who undergo splenectomy are at risk of sepsis. The most common causing organisms are
encapsulated and include Streptococcus pneumoniae with the highest incidence, Neisseria meningitides, and
Haemophilus influenzae. The risk of sepsis is associated with the age of the patient.
• Cholelithiasis is one of the most common complications and usually presents in patients between the ages of
10 and 30 years, although younger patients may also present with cholelithiasis.
• Some patients may also present with hematologic crises, which may be hemolytic, aplastic, or megaloblastic.
[19]Hemolytic crisis is the most common of these and presents with fever; it may be triggered by viral
infections, although it may present spontaneously.
• Aplastic crises are generally worse than hemolytic crises and may be the cause of acute heart failure; it has
correlations with parvovirus B19. Children commonly present with chills and fever, abdominal pain, myalgias,
and generalized maculopapular rash. The clinical course of aplastic crisis usually starts with a decrease in
hemoglobin and reticulocytes, followed by a reduction in bone marrow erythroblasts and bilirubin. During
recovery neutrophils and platelets increase first, then subsequently by reticulocytosis and gradual increase in
hemoglobin levels.
• Megaloblastic crises are infrequent and usually caused by a deficiency in folate levels. These complications are
treatable with adequate folate supplementation.
Patient Education:

• Patients with hereditary spherocytosis, especially parents of younger children will

benefit from comprehensive educational supplementation. These patients will require
periodical follow up, and monitoring. Ideally, they should be able to identify early signs
and symptoms of disease complications such as aplastic crises or cholelithiasis.

• Affected patients who undergo splenectomy will require additional prophylactic

vaccination against encapsulated organisms and follow-up to monitor for complications.

• For patients who have moderate disease, the decision to perform splenectomy is
controversial and extensive counseling, and educational plan are warranted before
drawing a conclusion, there should be a consensus should between the patient, family,
and physicians.