Spherocytosis

Overview

Spherocytosis, also known as hereditary spherocytosis, is a genetic blood disorder that affects the shape and flexibility of red blood cells. In this condition, red blood cells lose their normal biconcave disc shape and become spherical, making them more fragile and prone to destruction by the spleen. This leads to chronic hemolytic anemia, where red blood cells are broken down faster than they can be replaced.

The condition is caused by mutations in genes that produce proteins essential for maintaining the red blood cell membrane structure. These proteins include spectrin, ankyrin, band 3, and protein 4.2. When these proteins are defective or missing, the red blood cell membrane becomes unstable, leading to the characteristic spherical shape and increased fragility.

Spherocytosis is the most common inherited cause of hemolytic anemia in people of Northern European descent, affecting approximately 1 in 5,000 individuals. The severity can vary widely, from very mild cases that may go undiagnosed to severe forms requiring medical intervention. Early diagnosis and appropriate management can significantly improve quality of life and prevent complications.

Types of Spherocytosis

Spherocytosis can be classified based on severity, inheritance pattern, and underlying genetic defects:

By Severity

• Mild Spherocytosis: Minimal symptoms, may remain undiagnosed
• Moderate Spherocytosis: Noticeable anemia and jaundice, especially during stress
• Severe Spherocytosis: Significant anemia requiring medical management
• Life-threatening: Severe anemia with complications from birth

By Inheritance Pattern

• Autosomal Dominant (75%): One parent passes the defective gene
• Autosomal Recessive (25%): Both parents carry the defective gene
• De novo mutations: New mutations not inherited from parents

By Genetic Defect

• Spectrin deficiency: Most common, affecting membrane flexibility
• Ankyrin deficiency: Affects membrane protein anchoring
• Band 3 deficiency: Impacts ion transport and membrane stability
• Protein 4.2 deficiency: Less common, affects membrane integrity

Clinical Variants

• Typical spherocytosis: Classic presentation with spherical cells
• Atypical spherocytosis: May have mixed cell shapes
• Compensated hemolysis: Normal hemoglobin despite ongoing cell destruction

Symptoms

Symptoms of spherocytosis can vary greatly in severity and may not appear until later in life, even in people with the genetic mutation.

Primary Symptoms

Additional Symptoms

• Pallor - Pale skin and mucous membranes
• Shortness of breath during physical activity
• Weakness and reduced exercise tolerance
• Dizziness or lightheadedness
• Rapid heartbeat (tachycardia)
• Dark urine from hemoglobin breakdown
• Gallstones from excess bilirubin
• Leg ulcers in severe cases

Symptoms During Hemolytic Crisis

• Severe fatigue and weakness
• Worsening jaundice
• Abdominal pain from spleen enlargement
• Dark or red-colored urine
• Fever (may indicate infection)
• Rapid breathing and heart rate
• Confusion or difficulty concentrating

Age-Related Presentations

• Newborns: Severe anemia, jaundice, may require transfusion
• Children: Growth delays, recurrent infections, spleen enlargement
• Adults: Chronic fatigue, gallstone formation, gradual worsening
• Pregnancy: May worsen anemia and require closer monitoring

Causes

Spherocytosis is caused by genetic mutations that affect proteins essential for maintaining normal red blood cell membrane structure and function.

Genetic Basis

• Inherited mutations: Passed from parents to children
• De novo mutations: New mutations occurring spontaneously
• Gene dosage effects: Severity depends on number of defective genes
• Penetrance variation: Same mutation may cause different severity

Affected Proteins and Genes

Spectrin (ANK1, SPTB genes)

• Most common cause (65% of cases)
• Forms cytoskeleton network beneath cell membrane
• Deficiency leads to membrane instability
• Usually autosomal dominant inheritance

Ankyrin (ANK1 gene)

• Second most common cause (20-25% of cases)
• Links spectrin to membrane proteins
• Deficiency causes membrane protein loss
• Autosomal dominant inheritance pattern

Band 3 Protein (SLC4A1 gene)

• Accounts for 15-20% of cases
• Major membrane protein for ion transport
• Deficiency affects membrane stability
• Can be dominant or recessive inheritance

Protein 4.2 (EPB42 gene)

• Rare cause (5% of cases)
• Stabilizes band 3 protein complex
• More common in Japanese populations
• Usually autosomal recessive inheritance

Pathophysiology

• Membrane loss: Defective proteins cause membrane instability
• Shape change: Cells lose biconcave shape, become spherical
• Decreased deformability: Spherical cells can't pass through spleen
• Splenic sequestration: Spleen removes defective cells
• Hemolysis: Accelerated red blood cell destruction

Modifying Factors

• Coinherited traits: Other genetic factors affecting severity
• Environmental triggers: Infections, stress, certain medications
• Age factors: Symptoms may worsen with age
• Hormonal influences: Pregnancy may exacerbate symptoms

Risk Factors

Since spherocytosis is a genetic condition, the primary risk factor is family history, though several factors can influence disease severity:

Genetic Risk Factors

• Family history: Having a parent with spherocytosis (50% risk)
• Ethnicity: More common in people of Northern European descent
• Gene mutation type: Some mutations cause more severe disease
• Inheritance pattern: Recessive forms tend to be more severe

Factors Affecting Severity

• Type of mutation: Complete vs. partial protein deficiency
• Compound heterozygosity: Having two different mutations
• Modifier genes: Other genetic factors influencing severity
• Environmental factors: Infections, oxidative stress

Triggers for Hemolytic Crisis

• Infections: Viral infections (parvovirus B19, EBV)
• Physical stress: Surgery, trauma, extreme exercise
• Medications: Certain antibiotics, antimalarials
• Pregnancy: Increased metabolic demands
• Dehydration: Concentrates damaged cells in spleen

Complications Risk Factors

• Age: Gallstone risk increases with age
• Severity: More severe anemia increases complication risk
• Delayed diagnosis: Untreated disease may lead to complications
• Spleen size: Larger spleen increases risk of rupture

Population-Specific Factors

• Northern Europeans: Highest prevalence globally
• Mediterranean populations: Certain mutations more common
• Japanese populations: Higher frequency of protein 4.2 deficiency
• African populations: Different mutation spectrum

Diagnosis

Diagnosing spherocytosis involves a combination of clinical evaluation, family history, laboratory tests, and specialized studies to confirm the presence of spherical red blood cells and hemolysis.

Clinical Evaluation

Healthcare providers will assess:

• Personal and family history of anemia, jaundice, or gallstones
• Physical examination for pallor, jaundice, and spleen enlargement
• Symptom patterns and triggers
• Response to previous treatments
• Ethnic background and family ancestry

Laboratory Tests

Complete Blood Count (CBC)

• Low hemoglobin levels (anemia)
• Elevated reticulocyte count (young red blood cells)
• Normal or slightly low white blood cell count
• Normal or elevated platelet count

Blood Smear Examination

• Spherocytes (round cells without central pallor)
• Polychromasia (blue-tinged young red blood cells)
• Absence of central pallor in affected cells
• Variable cell size (anisocytosis)

Hemolysis Markers

• Elevated bilirubin: Indirect (unconjugated) form
• Low haptoglobin: Protein that binds free hemoglobin
• Elevated LDH: Enzyme released from damaged cells
• Elevated urinary urobilinogen: Bilirubin breakdown product

Specialized Tests

Osmotic Fragility Test

• Gold standard diagnostic test
• Measures red blood cell fragility in salt solutions
• Spherocytes break down in less concentrated salt
• May be normal in mild cases

Incubated Osmotic Fragility

• More sensitive than standard osmotic fragility
• Cells incubated for 24 hours before testing
• Detects mild forms of spherocytosis
• Used when standard test is borderline

EMA Binding Test

• Eosin-5'-maleimide binding test
• Flow cytometry-based screening test
• Measures membrane protein density
• Highly sensitive and specific

Advanced Testing

Genetic Testing

• DNA analysis for specific mutations
• Useful for family planning and counseling
• May identify specific protein deficiency
• Not always necessary for diagnosis

Protein Studies

• SDS-PAGE gel electrophoresis
• Quantifies specific membrane proteins
• Identifies which protein is deficient
• Research and specialized centers only

Differential Diagnosis

Other conditions that may cause similar symptoms:

• Autoimmune hemolytic anemia
• Glucose-6-phosphate dehydrogenase deficiency
• Pyruvate kinase deficiency
• Thalassemia
• Elliptocytosis
• Wilson's disease

Treatment Options

Treatment for spherocytosis depends on the severity of symptoms and complications. Many people with mild forms require no treatment, while severe cases may need surgical intervention.

Conservative Management

Monitoring and Supportive Care

• Regular blood counts and monitoring
• Annual physical examinations
• Monitoring for complications (gallstones, leg ulcers)
• Patient education about the condition

Folic Acid Supplementation

• Essential for all patients with active hemolysis
• Supports increased red blood cell production
• Typical dose: 1-5 mg daily
• Especially important during growth, pregnancy

Preventive Measures

• Vaccination against encapsulated bacteria
• Pneumococcal, meningococcal, and Haemophilus vaccines
• Annual influenza vaccination
• Prompt treatment of infections

Medical Interventions

Blood Transfusions

• For severe anemia or hemolytic crises
• Temporary measure to improve symptoms
• May be needed during infections or surgery
• Risk of iron overload with repeated transfusions

Iron Chelation Therapy

• For patients receiving frequent transfusions
• Prevents iron overload complications
• Various agents available (deferoxamine, deferasirox)
• Requires regular monitoring

Surgical Treatment

Splenectomy (Spleen Removal)

• Indications: Severe anemia, growth retardation, frequent crises
• Benefits: Eliminates hemolysis, improves anemia
• Timing: Usually after age 5-6 years
• Types: Total splenectomy or partial splenectomy

Laparoscopic Splenectomy

• Minimally invasive approach
• Shorter recovery time
• Less postoperative pain
• Preferred method when possible

Partial Splenectomy

• Removes part of spleen, preserves immune function
• Considered for children when possible
• May need repeat procedures
• Balances benefits with infection risk

Post-Splenectomy Care

• Lifelong antibiotic prophylaxis consideration
• Education about infection risks
• Immediate medical attention for fever
• Travel precautions and malaria prophylaxis
• Annual blood count monitoring

Management of Complications

Gallstone Management

• Often performed with splenectomy
• Cholecystectomy for symptomatic stones
• Laparoscopic approach preferred
• Ursodeoxycholic acid for prevention

Leg Ulcer Treatment

• Wound care and dressing changes
• Treatment of underlying anemia
• Compression therapy when appropriate
• Surgical intervention for severe cases

Special Situations

Pregnancy Management

• Close monitoring throughout pregnancy
• Increased folic acid supplementation
• Management of worsening anemia
• Coordination with maternal-fetal medicine

Pediatric Considerations

• Delayed splenectomy when possible
• Aggressive vaccination schedule
• Monitoring for growth and development
• School activity modifications if needed

Prevention

Since spherocytosis is a genetic condition, primary prevention is not possible. However, genetic counseling and screening can help families make informed decisions, and secondary prevention focuses on preventing complications.

Genetic Counseling

• Family planning consultation for affected individuals
• Explanation of inheritance patterns and risks
• Genetic testing options for family members
• Prenatal diagnosis and testing options
• Support for families making reproductive decisions

Prenatal Screening

• Available for families with known mutations
• Chorionic villus sampling or amniocentesis
• Cordocentesis for severe cases
• Allows for early preparation and planning

Preventing Complications

Infection Prevention

• Complete vaccination schedules
• Extra vaccines for encapsulated bacteria
• Annual influenza vaccination
• Good hygiene practices
• Prompt treatment of infections

Hemolytic Crisis Prevention

• Avoid known triggers when possible
• Maintain adequate hydration
• Stress management techniques
• Regular medical follow-up
• Early treatment of illnesses

Gallstone Prevention

• Maintain healthy weight
• Regular exercise
• Balanced diet with adequate fiber
• Avoid rapid weight loss
• Consider ursodeoxycholic acid

Lifestyle Modifications

• Regular, moderate exercise as tolerated
• Balanced nutrition with iron-rich foods
• Adequate rest and sleep
• Stress reduction techniques
• Avoiding extreme physical demands

Health Monitoring

• Regular blood count monitoring
• Annual abdominal ultrasound
• Monitoring for growth and development in children
• Regular ophthalmologic examinations
• Screening for complications

Education and Awareness

• Understanding the condition and its implications
• Recognizing signs of complications
• Medication adherence importance
• When to seek medical attention
• Family screening recommendations

When to See a Doctor

Seek Emergency Medical Care

• Severe weakness or inability to perform normal activities
• Difficulty breathing or chest pain
• Severe abdominal pain (may indicate gallstone complications)
• Signs of severe infection (high fever, chills, confusion)
• Rapid heart rate with weakness or dizziness
• Fainting or near-fainting episodes
• Severe, sudden worsening of jaundice

Schedule Urgent Appointment

• Fever over 101°F (38.3°C), especially if spleen removed
• Persistent vomiting or inability to keep fluids down
• Worsening fatigue or weakness over days
• New or worsening abdominal pain
• Changes in urine color (very dark or red)
• Persistent headaches or confusion
• Increased bruising or bleeding

Routine Medical Consultation

• Family history of anemia, jaundice, or early gallbladder removal
• Persistent fatigue without obvious cause
• Recurring episodes of jaundice
• Enlarged spleen found on examination
• Chronic anemia of unknown cause
• Planning pregnancy and have family history

Regular Follow-up Care

• Annual comprehensive evaluation
• Monitoring blood counts and hemolysis markers
• Abdominal ultrasound for gallstone screening
• Growth and development monitoring in children
• Vaccination updates and preventive care
• Assessment for potential complications

Genetic Counseling Consultation

• Planning to have children
• Family members wanting screening
• Questions about inheritance patterns
• Prenatal testing options
• Understanding genetic test results

Specialist Referrals

• Hematologist: For diagnosis confirmation and management
• Genetic counselor: For family planning and testing
• Surgeon: For splenectomy evaluation
• Gastroenterologist: For gallstone management
• Pediatric hematologist: For children with the condition

Related Conditions

Several conditions share similar features with spherocytosis or commonly occur alongside it:

Other Hereditary Hemolytic Anemias

• Pyruvate kinase deficiency - Enzyme disorder
• Stomatocytosis - Membrane permeability defect
• Thalassemia - Hemoglobin production disorder
• Sickle cell disease - Hemoglobin structure abnormality

Associated Complications

• Cholelithiasis - Gallstone formation
• Splenomegaly - Enlarged spleen
• Iron deficiency anemia - May coexist
• Aplastic crisis - Temporary bone marrow failure

Conditions with Similar Symptoms

• Wilson's disease - Can cause hemolysis
• Paroxysmal nocturnal hemoglobinuria - Acquired membrane defect
• Microangiopathic hemolytic anemia - Mechanical cell destruction

Frequently Asked Questions