Hereditary Spherocytosis

What is hereditary spherocytosis?

Hereditary spherocytosis is the most common hereditary (inherited) hemolytic anemia in northern Europeans. Hemolytic anemias are defined as those anemias that result from an increase in red cell destruction rate. There are two main mechanisms whereby red cells are destroyed in hemolytic anemia. There may be excessive removal of red cells by cells of the reticuloendothelial system or they may be broken down directly in the circulation in a process known as intravascular hemolysis. Hereditary hemolytic anemias are the result of ‘intrinsic’ red cell defects whereas acquired hemolytic anemias are usually the result of an extracorpuscular or environmental change. Paroxysmal nocturnal haemoglobinuria is the exception because although it is an acquired disorder, the red cells have an intrinsic effect. 

Normal red cell destruction

A red blood cell’s normal life span is 120 days, after which the cells will be removed extravascularly by the macrophages in the reticuloendothelial system. The heme iron will be recycled to to produce more erythrocytes (red cells) in the bone marrow and the protoporphyrin is broken down into bilirubin and goes through a process and eventually excreted as urobilinogen in the urine and stercobilinogen in the feces. Globin chains are broken down to amino acids which are reutilized for general protein synthesis in the body. 

What causes hereditary spherocytosis?

Hereditary spherocytosis  is usually caused by defects in the membrane proteins involved in the vertical interactions between the membrane skeleton and the lipid bilayer of the red cell, for example mutations found in the band 3 protein, ankyrin, protein 4.2 or alpha spectrin. The inheritance pattern of this disorder is autosomal dominant. Only 1 mutant allele needs to be inherited for the patient to be symptomatic. 

Pathophysiology of hereditary spherocytosis

As the RBC travels at a very high speed in the vascular lumen, the RBC inadvertently knocks against  the vascular lumen wall and also other cells. This causes multiple loss of the phospholipid bilayer. The loss of membrane may be caused by the release of parts of the lipid bilayer that are not supported by the skeleton. The marrow produces red cells that are normal biconcave shapes but these lose membrane and become increasingly spherical as they circulate through the spleen and the rest of the reticuloendothelial system. These spherocytes are rigid and inflexible. Ultimately, the spherocytes will be unable to pass through the splenic microcirculation where they are prematurely phagocytosed and destroyed by the splenic macrophages. 

Features of hereditary spherocytosis

The anemia can present at any age with fluctuating jaundice. Splenomegaly is common as well as pigment gallstones. Aplastic crises may cause a sudden increase in severity of anemia when precipitated by a parvovirus infection. 

How do I test for hereditary spherocytosis?

General laboratory tests

Laboratory investigations show decreased hemoglobin level with reticulocytosis in the full blood count. The blood films reveal anemia with numerous polychromatic spherocytes. The bone marrow smear indicates a hypercellular bone marrow with erythroid hyperplasia.  

Specific laboratory tests

In specific tests, the cells are fragile thus have an increased osmotic fragility, with increased serum bilirubin levels and urine urobilinogen. Coombs’ test is negative as it is not an immune disorder and there should be a positive family history. 

How is hereditary spherocytosis treated or managed?

Treatment and management of hereditary spherocytosis include prophylactic folic acid supplementation in severe cases to prevent folate deficiency. Splenectomy is indicated if in anemia or gallstones. Lifelong prophylactic penicillin is given post-splenectomy to prevent infections.  

Key points of hereditary spherocytosis

Definition 

An inherited hemolytic anemia due to a defect in a red cell membrane protein. Mainly autosomal dominant.

Signs and symptoms

  • Mild to moderate anemia
  • Intermittent jaundice precipitated by pregnancy, fatigue or infection
  • Moderate splenomegaly
  • Presence of pigment gallstones
  • Aplastic crises triggered by an acute parvovirus B19 infection. 

Causes of hereditary spherocytosis

Genetic mutations. Most common mutations are mutations found in the ankyrin, spectrin, band 3 or band protein 4.2.

Image depicts a schematic diagram of a red blood cell membrane, highlighting the locations of common hereditary spherocytosis (HS) mutation sites, including spectrin, ankyrin, band 3, and protein 4.2
This illustration provides a visual guide, highlighting the common sites for hereditary spherocytosis (HS) mutations including the specific locations of spectrin, ankyrin, band 3, and protein 4.2, proteins that play critical roles in maintaining membrane integrity.

Pathophysiology

Normal-shaped young RBCs are produced by the bone marrow → repeated passage through the spleen and circulation leads to loss of membrane surface area releasing bilayer lipids in the form of cytoskeleton-free vesicles → spherocytes (rigid, inflexible and less deformable) → premature  destruction of spherocytes by splenic macrophages (extravascular hemolysis).

Image depicting a microscopic view of red blood cells undergoing hemolysis in hereditary spherocytosis, highlighting the role of membrane defects and mechanical stress
At the heart of hereditary spherocytosis lies a collection of genetic mutations that disrupt the structure and function of red blood cell membranes. As these RBCs traverse the narrow capillaries of the spleen, they encounter mechanical stress, forcing them to squeeze through constricted spaces. This mechanical assault further compromises the already fragile membrane, leading to its rupture and the release of cellular contents. The release of cellular contents triggers a cascade of events that culminate in the destruction of the spherocyte. Macrophages, the resident phagocytes of the spleen, engulf the damaged cells, further contributing to the progressive hemolytic process.

Laboratory Investigations

Full blood count and Peripheral blood characteristics

Full blood count: variable hemoglobin level and reticulocytosis. 

Peripheral blood smear: Numerous polychromatic spherocytes.

Image displaying a peripheral blood smear of hereditary spherocytosis, showcasing the presence of numerous spherocytes, characterized by their small size, dense staining, and lack of central pallor
The presence of spherocytes in a peripheral blood smear serves as a telltale sign of HS, providing valuable diagnostic clues for clinicians. These abnormal red blood cells, characterized by their small size, dense staining, and lack of central pallor, are the result of membrane defects that disrupt their normal structure and function.

Bone marrow characteristics

Markedly hypercellular with erythroid hyperplasia

Specific investigations and expected results

  • ↑ serum bilirubin.
  • ↑ urine urobilinogen. 
  • ↓ serum haptoglobin.
  • Negative direct antiglobulin (Coombs) test. 
  • ↑ Osmotic fragility test
  • ↓ fluorescent signal in flow cytometric analysis of eosin-5-maleimide binding.
  • Positive family history

Treatment and management of hereditary spherocytosis

  • Folic acid supplement
  • Splenectomy in severe cases
  • Prophylactic penicillin V lifelong post splenectomy

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

  1. Anemia: Diagnosis and Treatment (Willis, 2016).
  2. Management of Anemia: A Comprehensive Guide for Clinicians (Provenzano et al., 2018)
  3. Goldberg S, Hoffman J. Clinical Hematology Made Ridiculously Simple, 1st Edition: An Incredibly Easy Way to Learn for Medical, Nursing, PA Students, and General Practitioners (MedMaster Medical Books). 2021.

Related Diseases

Systemic Approach to Anemia

Systemic Approach to Anemia

Introduction A systemic approach to anemia is a comprehensive strategy that tackles the condition from multiple angles, aiming for accurate diagnosis, effective treatment, and long-term management. It involves several steps that consider various factors to pinpoint...

Hereditary Hemochromatosis

Hereditary Hemochromatosis

Introduction Hereditary hemochromatosis is a genetic disorder that affects the body's ability to regulate iron metabolism. This leads to excessive iron absorption from the diet, resulting in a buildup of iron in the body's tissues and organs. Iron is a mineral that is...

Sideroblastic Anemia

Sideroblastic Anemia

Introduction Sideroblastic anemia is a type of anemia characterized by abnormal iron metabolism within red blood cell precursors. It belongs to a category called refractory anemia, which means the bone marrow has difficulty producing healthy red blood cells. The...