Hereditary Spherocytosis (HS)

Definition & Epidemiology

• Most common inherited abnormality of erythrocyte associated with inherited hemolytic anemia.
• Highest prevalence in Northern European ancestry (1 in 2000–5000).
• Genetic transmission: Autosomal dominant (75%); Autosomal recessive or de novo variant (25%).

Pathophysiology & Genetics

Molecular Defect

• Primary defect involves erythrocyte membrane instability.
• Uncoupling of “vertical” interactions between lipid bilayer and underlying membrane skeleton.
• Results in release of membrane microvesicles.
• Loss of membrane surface area without proportional loss of cell volume causes decreased surface-to-volume ratio.
• Erythrocytes become spherical, rigid, and less deformable.

Splenic Destruction

• Decreased deformability impairs passage from splenic cords to splenic sinuses.
• Abnormal HS erythrocytes trapped and selectively destroyed by intact spleen (splenic conditioning).

Genetic Variants

Affected Protein	Gene	Inheritance Pattern	Prevalence in HS	Disease Severity
Ankyrin-1	ANK1	Autosomal Dominant (rarely recessive)	50–67%	Mild to moderate.
Band 3	AE1 / SLC4A1	Autosomal Dominant	15–20%	Mild to moderate.
$\beta$-Spectrin	SPTB	Autosomal Dominant	15–20%	Mild to moderate.
Protein 4.2	EPB42	Autosomal Recessive	<5%	Mild to moderate.
$\alpha$-Spectrin	SPTA1	Autosomal Recessive	<5%	Severe.

Clinical Manifestations

Neonatal Presentation

• Significant cause of hemolysis in newborns.
• Manifests as anemia and/or hyperbilirubinemia.
• May require phototherapy, simple transfusion, or exchange transfusion.
• Splenomegaly typically absent in neonates.

Childhood & Adulthood Presentation

• Chronic compensated or uncompensated hemolytic anemia.
• Symptoms include fatigue, pallor, and intermittent jaundice.
• Splenomegaly present in almost all patients by young adulthood.
• Pigment gallstones (cholelithiasis) develop as early as 4–5 years of age.

Acute Crises

• Aplastic Crisis: Precipitated primarily by Parvovirus B19 infection. Virus infects erythroid progenitors, halting production. Presents with profound anemia, absent reticulocytes, high-output heart failure, and potential cardiovascular collapse.
• Hypoplastic Crisis: Associated with other concomitant infections.
• Megaloblastic Crisis: Due to dietary folate deficiency amidst high erythroid marrow demands.
• Hemolytic Crisis: Accelerated hemolysis, often precipitated by viral infections, leading to pronounced jaundice.

Disease Severity Classification

Feature	Mild	Moderate	Severe
Proportion of Cases	20–30%	60–70%	3–5%.
Hemoglobin (g/dL)	11–15	8–12	<8 (Transfusion dependent).
Reticulocytes (%)	3–6	$\ge$ 6	$\ge$ 10.
Bilirubin (mg/dL)	1–2	$\ge$ 2	$\ge$ 3.
Splenectomy Indication	Rarely needed	Consider partial splenectomy	Highly recommended (>5 years age).

Diagnostic Investigations

Primary Hematologic Indices

• Hemoglobin/Hematocrit: Normal to severely decreased.
• Mean Corpuscular Volume (MCV): Low-normal or slightly decreased.
• Mean Corpuscular Hemoglobin Concentration (MCHC): Characteristically elevated (>35 g/dL) due to cellular dehydration.
• Red Cell Distribution Width (RDW): Elevated.
• Screening utility: MCHC >35.4 g/dL combined with RDW >14% highly specific for HS.
• Reticulocyte Count: Elevated (3–15%), reflecting marrow response.

Peripheral Blood Smear

• Spherocytes: Hyperchromic, lacking central pallor, smaller diameter.
• Other findings: Polychromatophilic reticulocytes.

Hemolysis Markers

• Elevated indirect bilirubin.
• Decreased serum haptoglobin.
• Elevated lactate dehydrogenase (LDH).

Specific Confirmatory Tests

• Eosin-5-Maleimide (EMA) Binding Test: Flow cytometry-based test detecting decreased fluorescent dye binding to band 3 membrane protein. High diagnostic sensitivity and specificity. Test of choice.
• Osmotic Fragility Test: HS erythrocytes lyse at lower dilutions (higher sodium chloride concentrations) due to reduced surface-to-volume ratio. Incubation at 37°C for 24 hours required to maximize sensitivity. Poor sensitivity for mild HS.
• Direct Antiglobulin Test (DAT / Coombs): Negative. Crucial for excluding immune-mediated hemolysis.
• Autohemolysis Test: Increased lysis at 24 and 48 hours; corrected by glucose addition.

Differential Diagnosis

Condition	Distinguishing Features
Isoimmune Hemolytic Disease	ABO incompatibility in neonates. Mimics HS. DAT (Coombs test) positive.
Autoimmune Hemolytic Anemia	Older children. Positive DAT. History of previously normal hemoglobin/reticulocyte counts.
Transient Spherocytosis Causes	Thermal injury, clostridial sepsis, severe hypophosphatemia, Wilson disease, snake/wasp envenomation.

Management

General & Medical Therapy

• Folic Acid Supplementation: Daily requirement (1 mg/day) to support brisk erythropoiesis and prevent megaloblastic crisis. Recommended in moderate and severe HS.
• Transfusion Support:
  • Neonates: May require packed red blood cell (pRBC) transfusion, phototherapy, or exchange transfusion.
  • Older children: Intermittent pRBC transfusions during aplastic/hypoplastic crises or severe baseline anemia.
• Monitoring: Annual hematology follow-up. Monitor growth, spleen size, and exercise tolerance. Interval ultrasonography screening for gallstones starting around age 4 (repeated every 3–5 years).

Surgical Intervention

Splenectomy

• Rationale: Erythrocytes destroyed almost exclusively in spleen. Splenectomy halts premature destruction, resolving anemia and reducing gallstone risk.
• Indications: Strongly recommended for severe HS. Considered for moderate HS with frequent crises, poor growth, or cardiomegaly. Not recommended for mild HS.
• Timing: Delayed until age >5–6 years to mitigate high risk of overwhelming post-splenectomy infection (OPSI).
• Technique: Laparoscopic approach preferred due to reduced surgical morbidity.
• Concomitant Cholecystectomy: Performed simultaneously if symptomatic gallstones present.

Partial Splenectomy

• Removal of 85–95% of spleen volume.
• Advantage: Decreases hemolytic rate while preserving residual splenic phagocytic immune function.
• Indication: Attractive alternative for children <5 years old with severe, transfusion-dependent HS.

Post-Splenectomy Care

• Vaccinations: Mandatory preoperative immunization against encapsulated organisms (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b).
• Prophylaxis: Daily oral penicillin prophylaxis required post-splenectomy (typically until adulthood).
• Complications: Increased lifelong risk of sepsis. Increased risk for cardiovascular diseases, including venous/arterial thrombosis and pulmonary hypertension.