OVERVIEW

What is hereditary spherocytosis?

Hereditary spherocytosis (HS) is, as the name suggests, a genetic disorder caused by defects in erythrocyte membrane skeleton genes. The resulting spherical red blood cells are excessively destroyed in the spleen, leading to hemolytic anemia.

Typical patients exhibit general manifestations of hemolytic disease: anemia, hepatosplenomegaly, and jaundice. Peripheral blood smears reveal numerous spherocytes, which show increased osmotic fragility. Patients often have a clear family history.

Splenectomy is usually highly effective. The prognosis is generally favorable.

Is there a gender difference in hereditary spherocytosis?

Hereditary spherocytosis shows no significant gender difference in incidence.

Is hereditary spherocytosis common?

Relatively common.
The incidence in Northern European families is about 1 in 1,000. Some literature suggests an incidence of over 1 in 5,000.

SYMPTOMS

What are the common manifestations of hereditary spherocytosis patients?

Due to differences in inheritance patterns and the degree of protein variation, the clinical manifestations of hereditary spherocytosis vary greatly. Some patients may be asymptomatic, serving only as gene carriers.

Severe cases may exhibit significant anemia, massive splenomegaly, frequent jaundice, dependence on blood transfusions for survival, growth retardation, and skeletal deformities, resembling thalassemia.

Patients may also experience hemolytic crisis (acute exacerbation of chronic hemolysis, leading to renal tubular cell necrosis and lumen obstruction due to massive hemolysis products, resulting in acute renal failure) or aplastic crisis (sudden cessation of hematopoiesis during chronic hemolysis, causing worsened anemia or bleeding).

The most typical clinical manifestations of HS patients are anemia, intermittent jaundice, and varying degrees of splenomegaly. Most patients report a similar family history of the disease.

What other diseases are commonly caused by hereditary spherocytosis?

About half of the patients develop secondary gallstones, with a high incidence among those aged 10–30.

Other rare complications include recurrent lower limb ulcers and chronic erythematous dermatitis, which can resolve after splenectomy.

Additionally, patients with severe clinical manifestations often experience various crises triggered by infections:

• Hemolytic crisis (most common, self-limiting);
• Aplastic crisis (life-threatening, often associated with parvovirus B19 infection);
• Megaloblastic anemia crisis (may occur if folic acid is not replenished promptly during recurrent hemolysis).

CAUSES

What are the causes of hereditary spherocytosis?

Most patients have autosomal dominant inheritance, while a minority show autosomal recessive inheritance. Patients without family history may result from spontaneous gene mutations.

Abnormalities in red blood cell membrane skeletal protein genes lead to deficiencies in these proteins, loss of membrane lipids, and reduced cell surface area, transforming normal biconcave disc-shaped red blood cells into spherical forms. Additionally, defects in membrane skeletal proteins trigger a series of secondary metabolic changes (primarily involving ion transport and energy metabolism within red blood cells).

The resulting spherocytes exhibit significantly reduced deformability and flexibility, making them highly susceptible to destruction when passing through the spleen, thereby causing hemolysis.

DIAGNOSIS

What tests are needed for hereditary spherocytosis?

• Complete blood count (CBC): Patients usually have normal or slightly reduced hemoglobin levels, which may drop significantly during acute episodes. Reticulocyte count is elevated, typically ranging from 5% to 20%. However, it may sharply decrease or even disappear during aplastic crisis. Over half of patients exhibit increased MCHC and decreased MCV, presenting as typical microcytic hyperchromic anemia.

• Peripheral blood smear: Uniform, small, spherical red blood cells are observed. Normally, such abnormal spherocytes account for <5%, but in hereditary spherocytosis, they often exceed 10% and may reach 60%-70%. However, a small subset of patients may lack typical spherocytes.

• Osmotic fragility test (OF): Spherocytes show increased osmotic fragility and are prone to hemolysis. However, this test has a sensitivity of only about 66%, meaning some patients (e.g., those without typical spherocytes) may show normal results. False positives can also occur in immune-mediated hemolytic anemia.

• Acidified glycerol lysis test (AGLT): Measures the rate of red blood cell lysis in a glycerol solution. In hereditary spherocytosis, lysis occurs significantly faster than in normal individuals. This test is often used as a screening tool with higher sensitivity than OF but lower specificity.

• Flow cytometry: Uses fluorescent labeling to quantify erythrocyte membrane proteins. Patients with spherocytosis show markedly reduced fluorescence intensity. This test offers high sensitivity and specificity.

How is hereditary spherocytosis diagnosed?

The diagnosis is confirmed based on typical clinical manifestations of hemolytic anemia, laboratory findings (e.g., >10% spherocytes in peripheral blood, increased osmotic fragility), and a family history of similar conditions.

For patients without a family history, other causes of hemolytic anemia (e.g., secondary spherocytosis due to autoimmune hemolytic anemia) must be ruled out. Genetic testing may be used if necessary.

What diseases can hereditary spherocytosis be confused with?

Hereditary spherocytosis typically presents with uniform, small, spherical red blood cells without significant poikilocytosis.

Other hemolytic anemias may show varied spherocytes alongside other abnormal red cell shapes. Clinically, distinguishing hereditary spherocytosis from autoimmune hemolytic anemia can be challenging. However, the latter is more common, and Coombs testing or response to steroid therapy can aid differentiation.

What is the Coombs test for hereditary spherocytosis?

The Coombs test, named after British immunologist Coombs, diagnoses autoimmune hemolytic anemia. It is often used to differentiate hereditary spherocytosis from autoimmune hemolytic anemia.

Two types exist:

• Direct Coombs test: Detects incomplete antibodies on red blood cell surfaces.
• Indirect Coombs test: Detects free incomplete antibodies in serum.

Autoimmune hemolytic anemia yields a positive Coombs test.

Is genetic testing necessary for hereditary spherocytosis despite its high cost?

Most cases are diagnosed via clinical presentation, lab tests, and family history, making genetic testing unnecessary for the majority. Only rare cases require erythrocyte membrane protein or gene analysis for confirmation.

TREATMENT

Which department should patients with hereditary spherocytosis visit?

Hematology.

How should hereditary spherocytosis be treated?

Since spherocytes are easily destroyed when passing through the spleen, leading to hemolysis, splenectomy is the primary treatment for this condition. After surgery, 90% of patients show significant improvement in clinical symptoms such as anemia and jaundice. Splenectomy also reduces or eliminates the need for blood transfusions, and studies indicate a decreased incidence of gallstones post-surgery.

There are currently no effective medications for HS. During the chronic phase, symptomatic treatment involves using membrane stabilizers and replenishing hematopoietic nutrients. During hemolytic crises, treatment includes blood transfusions, fluid replacement, anti-infection measures, and folic acid supplementation to prevent worsening anemia or triggering a crisis.

Which patients with hereditary spherocytosis should undergo splenectomy?

• All severe HS patients with significant anemia symptoms and signs: growth impairment, skeletal deformities, leg ulcers, or extramedullary hematopoiesis;
• Elderly HS patients with vascular damage in vital organs;
• The treatment for mild to moderate HS patients remains inconclusive;
• Infants and young children face a high risk of sepsis post-splenectomy, so the procedure should be delayed until after age 10 if possible.

What should be considered before splenectomy for hereditary spherocytosis?

The spleen is an immune organ, and the main complication after splenectomy is infection, which can be fatal in severe cases. Therefore, weeks before surgery, especially for young patients, preventive measures such as vaccinations or oral antibiotics should be taken.

What complications may arise from splenectomy in hereditary spherocytosis?

Common complications include localized infections, bleeding, and pancreatitis.

Why might treatment fail after splenectomy in hereditary spherocytosis patients?

• The patient may have an accessory spleen;
• Splenic rupture during surgery may lead to splenic tissue implantation in the abdominal cavity, forming a regenerated spleen;
• Severe or atypical forms of hereditary spherocytosis;
• Misdiagnosis or co-occurrence with other hemolytic diseases.

Can hereditary spherocytosis be cured?

There is currently no cure for hereditary spherocytosis, but splenectomy often yields excellent results. Supportive treatments such as folic acid supplementation and blood transfusions when necessary can alleviate symptoms.

DIET & LIFESTYLE

What is the prognosis of hereditary spherocytosis after treatment?

Patients with this disease often have a good prognosis, with only a few dying from hemolytic crisis or complications after splenectomy.

What lifestyle and dietary precautions should patients with hereditary spherocytosis take?

Patients should maintain a balanced diet and supplement with folic acid appropriately to prevent worsening anemia symptoms. In daily life, they should pay attention to rest, avoid overexertion, and particularly focus on preventing infections.

PREVENTION

Can hereditary spherocytosis be prevented? Is prenatal screening useful?

Patients with a family history of genetic predisposition should undergo genetic counseling and prenatal testing, including fetal umbilical vein blood sampling or amniotic fluid cell gene testing.