What is hereditary spherocytosis, its diagnosis, management, and treatment options?

Hereditary Spherocytosis: Comprehensive Overview

Definition and Pathophysiology

Hereditary spherocytosis (HS) is a genetic disorder characterized by intrinsic red blood cell membrane defects that cause erythrocytes to assume an abnormal spherical shape, leading to premature destruction primarily in the spleen and resulting in hemolytic anemia 1, 2. The fundamental pathophysiology involves defective membrane proteins (most commonly spectrin, ankyrin, band 3, or protein 4.2) that compromise the structural integrity of the red blood cell membrane, causing loss of membrane surface area and spherocyte formation 3, 4.

• The spherical shape reduces red blood cell deformability, leading to splenic sequestration and destruction as these rigid cells cannot navigate the narrow splenic sinusoids 2, 5.
• HS is most common in Northern European populations and represents the most frequent hereditary hemolytic anemia caused by congenital membrane defects 4, 5.

Genetic Basis and Inheritance

HS is primarily inherited in an autosomal dominant pattern in approximately 75% of cases, though autosomal recessive and de novo mutations account for the remainder 4.

• The most commonly implicated genes include ANK1 (ankyrin), SPTA1 (alpha-spectrin), SPTB (beta-spectrin), SLC4A1 (band 3), and EPB42 (protein 4.2) 3, 4.
• Novel mutations continue to be identified, such as the c.790C>T (p.Gln264Ter) nonsense mutation in ANK1 and the c.7134+5G>A intronic variant in SPTA1, which may determine disease severity when combined with other pathogenic variants 3, 4.
• Compound heterozygous mutations, particularly in SPTA1, can result in severe clinical manifestations requiring lifelong transfusions from infancy 3.

Clinical Presentation

The clinical spectrum of HS ranges from asymptomatic carriers to severe forms presenting in early infancy 5.

Classic Triad

• Hemolytic anemia with variable severity 1, 4
• Jaundice (often intermittent, worsening during hemolytic crises) 1, 4
• Splenomegaly (present in most symptomatic cases) 1, 2

Additional Clinical Features

• Gallstones (cholelithiasis) develop in many patients due to chronic hyperbilirubinemia 1, 3
• Aplastic crises triggered by parvovirus B19 infection 4
• Hemolytic crises precipitated by infections 4
• Neonatal jaundice requiring phototherapy or exchange transfusion 4
• Growth retardation in severe untreated cases 3

Severe Presentations

• Some patients require monthly transfusions from six months of age 3
• Complications include alloimmunization (development of red blood cell antibodies), secondary hemochromatosis from chronic transfusions, and severe cholestasis 1, 3

Diagnostic Approach

Initial Laboratory Evaluation

Begin with complete blood count showing normocytic or slightly macrocytic anemia, elevated reticulocyte count (indicating compensatory erythropoiesis), and peripheral blood smear demonstrating spherocytes 1, 5.

• Hemoglobin levels vary from normal (in compensated cases) to severely reduced (in transfusion-dependent patients) 1, 3
• Mean corpuscular hemoglobin concentration (MCHC) is characteristically elevated above 36 g/dL 5
• Indirect (unconjugated) hyperbilirubinemia reflects ongoing hemolysis 1
• Lactate dehydrogenase (LDH) and haptoglobin levels confirm hemolysis (elevated LDH, decreased haptoglobin) 1

Specific Diagnostic Tests

The eosin-5'-maleimide (EMA) binding test by flow cytometry is the preferred confirmatory test, demonstrating reduced fluorescence due to decreased membrane protein content 1, 5.

• EMA testing has superior sensitivity and specificity compared to older methods 1, 5
• The osmotic fragility test (OFT) shows increased fragility of spherocytes in hypotonic solutions, though it is less specific and may be normal in mild cases 3, 5
• The acidified glycerol lysis time (AGLT) test is an alternative when EMA testing is unavailable 5

Genetic Testing

When classical features are absent or diagnosis remains uncertain, whole-exome sequencing (WES) or targeted gene panel testing for ANK1, SPTA1, SPTB, SLC4A1, and EPB42 should be performed 3, 4.

• Genetic testing is particularly valuable in atypical presentations, severe cases requiring early intervention, and for family counseling 3, 4
• Identification of specific mutations helps predict disease severity and inheritance patterns 3, 4

Diagnostic Pitfalls

• Spherocytes may not be prominent on blood smear in mild cases or during aplastic crises 3
• OFT can be falsely negative in compensated HS or when performed during transfusion therapy 3
• Autoimmune hemolytic anemia can mimic HS with spherocytes on smear; direct antiglobulin test (Coombs test) should be negative in HS 3
• In resource-limited settings without access to EMA testing or genetic analysis, diagnosis may be significantly delayed 3

Management and Treatment

Conservative Management

Folic acid supplementation (1 mg daily) is recommended for all patients with HS to support increased erythropoiesis 5.

• Monitor hemoglobin levels, reticulocyte counts, and bilirubin regularly (frequency depends on disease severity) 5
• Avoid oxidative stressors and ensure prompt treatment of infections to prevent hemolytic crises 4
• Vaccinate against encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis) before any splenectomy 2, 5

Transfusion Therapy

Red blood cell transfusions are reserved for severe anemia during aplastic or hemolytic crises, or for transfusion-dependent patients with severe HS 3.

• Chronic transfusion therapy carries risks of alloimmunization, iron overload requiring chelation therapy, and transfusion reactions 3
• Monitor for secondary hemochromatosis with serum ferritin and transferrin saturation in chronically transfused patients 3

Surgical Management: Splenectomy

Total splenectomy is the definitive treatment for moderate to severe HS, eliminating the primary site of red blood cell destruction and normalizing hemoglobin levels in most patients 2, 5.

Indications for Splenectomy

• Moderate to severe HS with symptomatic anemia 2, 5
• Transfusion-dependent patients 3, 5
• Growth retardation or failure to thrive 2
• Recurrent hemolytic crises 5
• Development of complications (severe gallstones, leg ulcers) 5

Timing of Splenectomy

• Defer splenectomy until at least 5-6 years of age when possible to minimize infection risk 2, 5
• Earlier intervention may be necessary in severe transfusion-dependent cases, but increases lifelong infection risk 2
• Mild HS may not require splenectomy at all 2, 5

Total vs. Partial Splenectomy

Partial (subtotal) splenectomy is an alternative approach that aims to preserve splenic immune function while reducing hemolysis, though long-term outcomes remain less well-established than total splenectomy 2, 5.

• Partial splenectomy typically removes 80-90% of splenic tissue, leaving a remnant to maintain immunologic function 5
• Advantages include reduced risk of overwhelming post-splenectomy infection (OPSI) and preservation of some immune surveillance 2, 5
• Disadvantages include potential for incomplete resolution of anemia, risk of splenic regrowth requiring reoperation, and technical complexity 2, 5
• Total splenectomy provides more complete and predictable resolution of anemia but exposes patients to lifelong risk of potentially lethal infections 2, 5

Post-Splenectomy Outcomes

• Hemoglobin normalizes in the majority of patients 5
• Reticulocyte count decreases to near-normal levels 2
• Transfusion requirements are eliminated or dramatically reduced 3, 5
• Spherocytes persist on blood smear but without clinical hemolysis 2

Post-Splenectomy Infection Prevention

Lifelong antibiotic prophylaxis with penicillin or equivalent is recommended following total splenectomy, particularly in children 2.

• Ensure vaccination against Streptococcus pneumoniae (both PCV13 and PPSV23), Haemophilus influenzae type b, and Neisseria meningitidis before splenectomy 2, 5
• Educate patients about the risk of overwhelming post-splenectomy infection (OPSI) and the need for immediate medical attention with fever 2
• Consider annual influenza vaccination 2

Critical Management Pitfalls

• Performing splenectomy in young children with mild HS who do not require intervention exposes them to unnecessary lifelong infection risk 2
• Failing to vaccinate before splenectomy leaves patients vulnerable to encapsulated bacterial infections 2, 5
• Not screening for and treating gallstones before or during splenectomy may necessitate additional surgery 1, 5
• Inadequate genetic counseling in families with HS may result in delayed diagnosis of affected siblings 3, 4

Prognosis

With appropriate management, including splenectomy when indicated, most patients with HS have normal life expectancy and quality of life 5.

• Mild HS may require no intervention beyond folic acid supplementation 2, 5
• Moderate to severe cases benefit significantly from splenectomy with resolution of anemia 2, 5
• The main long-term risks are post-splenectomy infection and complications from chronic hemolysis (gallstones, iron overload in transfusion-dependent patients) 3, 2