Spherocytosis: Causes, Genes and Tests

What spherocytes are

Normal red blood cells are biconcave discs, thinner in the middle, which makes them flexible enough to squeeze through tiny spaces in the spleen. Their shape depends on a scaffold of proteins under the cell membrane, mainly spectrin, ankyrin, band 3 and protein 4.2.

A spherocyte has lost part of its membrane, so it rounds up into a sphere: the smallest shape for its volume. On a stained blood smear, spherocytes look small, dense and evenly dark, without the normal pale center. Because they are rigid, the spleen traps and destroys them. Lab reports often show a raised MCHC (mean corpuscular hemoglobin concentration), a clue to spherocytes.

Hereditary spherocytosis

Hereditary spherocytosis is an inherited defect in the red cell membrane proteins. It is the most common inherited hemolytic anemia in people of Northern European descent, affecting about 1 in 2,000. About 3 in 4 families show dominant inheritance; the rest are recessive or new mutations.

Genes involved

SLC4A1 (band 3) spherocytosis

SLC4A1 encodes band 3, the main protein linking the membrane to its scaffold and the cell's chloride-bicarbonate exchanger. Band 3-deficient spherocytosis usually causes:

• mild to moderate hemolytic anemia, often first noticed in childhood or adulthood rather than at birth
• jaundice and gallstones
• a modestly enlarged spleen
• distinctive "pincered" red cells on the smear

The same gene, through different variants, can also cause distal renal tubular acidosis (a kidney acid-handling disorder) and Southeast Asian ovalocytosis. Rare people have both spherocytosis and kidney acidosis. Severity varies between families and sometimes within them.

Acquired causes of spherocytes

A small number of spherocytes can also appear in hemolytic anemias of other causes. G6PD deficiency and elliptocytosis cause different cell shapes but can be confused with spherocytosis.

Symptoms

Hereditary and acquired spherocytosis cause similar effects of hemolysis:

• tiredness, paleness, shortness of breath on exertion
• jaundice (yellow skin or eyes), often worse during infections
• dark urine during hemolytic episodes
• an enlarged spleen, felt as fullness under the left ribs
• gallstones, which can cause pain after meals; they develop in about half of people with hereditary spherocytosis by adulthood
• in newborns, jaundice that may need light therapy or exchange transfusion

Crises

• Aplastic crisis: parvovirus B19 (the cause of fifth disease) temporarily stops red cell production, causing severe anemia over days. See aplastic crisis.
• Hemolytic crisis: a surge in destruction during viral infections, causing more jaundice and anemia.

Tests

1. Complete blood count: low hemoglobin, high MCHC, and a high reticulocyte count (young red cells) as the marrow compensates.
2. Blood smear: confirms spherocytes and looks for other shapes.
3. Hemolysis markers: raised bilirubin and LDH, low haptoglobin.
4. Direct antiglobulin (Coombs) test: positive in autoimmune and immune-mediated causes; negative in hereditary spherocytosis.
5. EMA binding test (flow cytometry): reduced in hereditary spherocytosis; the preferred screening test.
6. Osmotic fragility test: cells burst more easily in dilute salt solutions; less used now.
7. Genetic testing: a red cell membrane gene panel identifies ANK1, SPTB, SLC4A1 and other variants, helpful in unclear or severe cases and for family planning.
8. Ultrasound for gallstones and spleen size.

Treatment

Hereditary spherocytosis

• Folic acid supplements in moderate to severe disease.
• Blood transfusions during crises, and in some infants.
• Splenectomy (often partial in children) for moderate to severe disease, usually after age 6. It stops most hemolysis but raises lifelong infection risk, so vaccines and sometimes preventive antibiotics are needed.
• Gallbladder removal for symptomatic gallstones, sometimes at the same time as splenectomy.

Acquired spherocytosis

Treat the cause: steroids and other immune treatments for autoimmune hemolytic anemia, phototherapy for newborn jaundice, and urgent treatment of sepsis, burns or envenomation.

Frequently asked questions

What does it mean if spherocytes are seen on a blood smear?

It means some red cells have lost membrane and become round and rigid, which usually indicates they are being destroyed faster than normal. The two main causes are hereditary spherocytosis and autoimmune hemolytic anemia. A Coombs test and family history usually distinguish them.

What are the symptoms of SLC4A1 spherocytosis?

SLC4A1 (band 3) spherocytosis usually causes mild to moderate anemia, intermittent jaundice, a modestly enlarged spleen and gallstones. Some people have few symptoms until an infection triggers a crisis. Rarely, variants in the same gene also affect the kidneys, causing distal renal tubular acidosis.

How is hereditary spherocytosis different from acquired spherocytosis?

Hereditary spherocytosis is an inborn membrane defect, often with a family history and a negative Coombs test. Acquired spherocytosis develops later, most often because antibodies coat red cells in autoimmune hemolytic anemia, giving a positive Coombs test. Treatment differs completely.

Is spherocytosis serious?

It varies. Many people with mild hereditary spherocytosis live normal lives with occasional jaundice. Severe forms need transfusions or splenectomy. Acquired spherocytosis can be serious when caused by sepsis or severe autoimmune hemolysis. Regular follow-up keeps complications such as gallstones in check.

Can spherocytosis be cured?

Hereditary spherocytosis cannot be cured, but splenectomy controls hemolysis in most people. Acquired spherocytosis often resolves once the cause is treated, for example with steroids for autoimmune hemolytic anemia.