Hereditary Spherocytosis

Introduction and Epidemiology

Hereditary spherocytosis (HS) is a common inherited abnormality of the red blood cell (RBC) membrane, representing the most frequent cause of inherited hemolytic anemia in individuals of Northern European descent.
The estimated prevalence of the disorder is approximately 1 in 2,000 to 5,000 individuals.
The disease is transmitted as an autosomal dominant trait in approximately 75% of cases.
As many as 25% of patients present with no prior family history, representing either autosomal recessive inheritance or de novo genetic variants.

Pathophysiology and Genetics

Cellular Pathophysiology

The underlying pathophysiology of HS involves an intrinsic structural defect of the erythrocyte membrane combined with an intact spleen that selectively traps, damages, and removes the abnormal RBCs.
Qualitative or quantitative defects in key membrane proteins lead to the uncoupling of "vertical" interactions between the lipid bilayer and the underlying membrane skeleton.
This instability results in the progressive release of membrane microvesicles and a depletion of membrane lipid, causing a loss of surface area without a proportional reduction in cell volume.
The resulting decreased surface-area-to-volume ratio produces the characteristic spherocytic shape and severely reduces erythrocyte deformability.
Non-deformable spherocytes are unable to effectively navigate from the splenic cords into the splenic sinuses, leading to erythrostasis and trapping.
Splenic conditioning—characterized by low pH, low glucose, and high macrophage contact—further exacerbates rapid ATP utilization and membrane loss, culminating in premature RBC destruction.
Hemolysis may be particularly prominent in the newborn period because fetal hemoglobin (HbF) binds 2,3-diphosphoglycerate (2,3-DPG) poorly; the resulting increased free 2,3-DPG destabilizes the spectrin-actin-protein 4.1 complex, worsening membrane instability.

Genetic Mutations

Ankyrin-1 (ANK1): Mutations in ankyrin are the most common defect, accounting for 50–67% of HS cases, and are mostly inherited in an autosomal dominant fashion.
Band 3 (AE1/SLC4A1): Mutations account for 15–20% of cases and are inherited in an autosomal dominant pattern, usually presenting with mild to moderate disease.
$β$ -Spectrin (SPTB): Mutations account for 15–20% of cases and exhibit an autosomal dominant inheritance.
$α$ -Spectrin (SPTA1): Mutations account for <5% of cases, are inherited in an autosomal recessive pattern, and typically result in severe disease.
Protein 4.2 (EPB42): Mutations account for <5% of cases, possess an autosomal recessive inheritance, and present with mild to moderate symptoms.

Clinical Manifestations

Disease Severity Classification

Mild HS (20–30%): Patients are frequently asymptomatic into adulthood, presenting with a well-compensated mild anemia where reticulocyte production matches erythrocyte destruction.
Moderate HS (60–70%): Patients experience partially compensated hemolytic anemia with reticulocytosis, often displaying symptoms of fatigue, pallor, and intermittent jaundice.
Severe HS (3–5%): Patients suffer from life-threatening anemia and require regular, ongoing blood transfusions.

General and Neonatal Features

Splenomegaly is a hallmark finding that becomes common after infancy and is present in almost all HS patients by young adulthood.
Bilirubin gallstones develop as a function of age due to chronic hemolysis; they can form as early as 4 to 5 years of age and are present in most affected adults.
In the neonatal period, HS can manifest with severe anemia and hyperbilirubinemia requiring phototherapy or exchange transfusion to prevent kernicterus.
The need for transfusions in early infancy does not predict severe disease later in life, as infants are typically slow to mount an adequate compensatory reticulocyte response.
Unlike older children, neonates with HS rarely present with splenomegaly.

Complications

Aplastic Crisis: Frequently triggered by Parvovirus B19 infection, which targets and infects colony-forming unit-erythroid progenitors, causing a transient maturation arrest and cessation of RBC production. This leads to a precipitous drop in hemoglobin and reticulocytes, potentially causing high-output heart failure, cardiovascular collapse, and death. Bone marrow analysis during the recovery phase often reveals giant pronormoblasts.
Hypoplastic Crisis: Can occur in association with other non-parvovirus infections.
Megaloblastic Crisis: Develops due to concurrent dietary folate deficiency, driven by the increased metabolic demands of brisk, continuous erythropoiesis.
Hemolytic Crisis: Features accelerated hemolysis and more pronounced jaundice, often precipitated by intercurrent viral infections.
Rare Complications: Include splenic sequestration crises, gout, cardiomyopathy, priapism, chronic leg ulcers, and spinocerebellar degeneration.

Diagnostic Evaluation

Laboratory Findings

The classic presentation includes a mild to moderate anemia, reticulocytosis (typically 3–15%), indirect hyperbilirubinemia, elevated lactate dehydrogenase (LDH), and decreased serum haptoglobin.
Red cell indices typically show a low-normal or decreased mean corpuscular volume (MCV), an elevated red cell distribution width (RDW), and an increased mean corpuscular hemoglobin concentration (MCHC > 35 g/dL).
The combination of an elevated RDW and an elevated MCHC provides very high specificity for the diagnosis of HS.
Peripheral blood smear examination reveals spherocytes (which are hyperchromic, smaller in diameter, and lack central pallor), microspherocytes, and polychromatophilic reticulocytes.
The direct antiglobulin test (DAT or Coombs test) is characteristically negative, distinguishing HS from immune-mediated hemolysis.

Specific Diagnostic Tests

Eosin-5-maleimide (EMA) Binding Test: A flow cytometry-based assay demonstrating decreased binding of the fluorescent EMA dye to band 3 and other membrane proteins; it is considered the screening test of choice due to its high diagnostic sensitivity and specificity.
Incubated Osmotic Fragility Test: RBCs are incubated at 37°C for 24 hours in progressive dilutions of sodium chloride. HS erythrocytes lyse at lower dilutions compared to normal cells due to their reduced surface-area-to-volume ratio. This test has poor sensitivity for mild cases of HS.
Other Assays: The cryohemolysis test, acidified glycerol lysis test, and osmotic gradient ektacytometry are also utilized but are frequently restricted to specialized reference laboratories.
Genetic/Molecular Analysis: Can definitively identify the underlying mutation and is increasingly available; some experts recommend molecular confirmation prior to proceeding with splenectomy.

Differential Diagnosis

Immune Hemolytic Anemia: Isoimmune hemolytic disease of the newborn (e.g., ABO incompatibility) and acquired autoimmune hemolytic anemia (AIHA) strongly mimic HS morphology but are distinguished by a positive DAT (Coombs test).
Transient Spherocytosis: Can be caused by thermal injury (severe burns), clostridial sepsis (due to hemolytic clostridial toxins), severe hypophosphatemia, Wilson disease, and envenomation by snakes, bees, or wasps.

Management and Treatment

Supportive Care

Lifelong daily folic acid supplementation (1 mg/day) is recommended for patients with moderate to severe HS to support the hyperactive erythropoietic state and prevent megaloblastic crises.
Routine clinical surveillance should include monitoring of growth, exercise tolerance, and spleen size.
Screening for gallbladder disease using abdominal ultrasound should commence around 4 years of age and be repeated every 3 to 5 years.
Leukocyte-depleted packed red blood cell transfusions are indicated for symptomatic neonatal anemia, severe erythroblastopenic (aplastic) crises, or in cases of severe transfusion-dependent HS.

Splenectomy

Splenectomy is curative for the clinical manifestations of HS; it markedly improves erythrocyte lifespan, corrects the anemia and hyperbilirubinemia, and eliminates the ongoing risk of gallstone formation.
The procedure is strongly indicated for patients with severe HS and should be considered for patients with moderate HS who experience frequent hypoplastic crises, cardiomegaly, or poor growth. It is generally not recommended for mild HS.
Surgery should ideally be delayed until the child is at least 5 to 6 years old to mitigate the heightened risk of overwhelming postsplenectomy infection (OPSI).
The laparoscopic approach is currently the surgical technique of choice as it significantly decreases operative morbidity, shortens hospital stays, and reduces analgesic requirements.
Partial/Subtotal Splenectomy: Involves the removal of 85–95% of the splenic volume. It successfully decreases the hemolytic rate while preserving some residual splenic phagocytic immune function, making it an attractive option for children under 5 years of age who suffer from severe, transfusion-dependent HS.
If bilirubin gallstones are present, a concomitant cholecystectomy should be performed during the splenectomy.

Post-Splenectomy Care and Complications

Prior to splenectomy, patients must receive requisite vaccinations against encapsulated bacteria, specifically pneumococcus, meningococcus, and Haemophilus influenzae type b.
Post-operatively, prophylactic oral penicillin must be administered; this is typically continued until the patient is at least 5 years of age or for a minimum of 2 years post-splenectomy.
While splenectomy resolves the anemia, spherocytosis persists on the peripheral blood smear, and the procedure introduces long-term risks including OPSI, arterial and venous thrombosis, and idiopathic pulmonary hypertension.
Post-splenectomy thrombocytosis is a common, expected finding that usually resolves spontaneously and does not require specific treatment.
Splenectomy Failure: The recurrence of hemolysis and the disappearance of Howell-Jolly bodies from the peripheral smear suggest a failed splenectomy, which may be caused by an unremoved accessory spleen, accidental autotransplantation of splenic tissue (splenosis), or a misdiagnosis.