Question
A 22-year-old man is being evaluated before planned gallbladder surgery after several attacks of symptomatic gallstones. He has also had recurrent episodes of anaemia severe enough to require blood transfusion. He takes no regular medication. His mother has occasionally developed mild jaundice during illnesses, while his father reportedly has an unspecified blood disorder.
Examination shows conjunctival pallor and mild splenomegaly. Investigations reveal:
- Hb: 110 g/L
- MCV: 84.1 fL
- MCHC: 391 g/L — markedly elevated
- Platelets: 389 × 10⁹/L
- WBC: 8.2 × 10⁹/L
- Bilirubin: 22 µmol/L
- Liver enzymes: normal
- Renal function: normal
Which disorder best explains the combination of chronic anaemia, splenomegaly, and recurrent gallstones?
A. Autoimmune haemolytic anaemia
B. Vitamin B12 deficiency
C. Pyruvate kinase deficiency
D. Beta-thalassaemia trait
E. Hereditary spherocytosis
Answer
Hereditary spherocytosis
Explanation
The key clue is the combination of chronic haemolytic anaemia + splenomegaly + pigment gallstones + markedly raised MCHC.
Hereditary spherocytosis (HS) is an inherited red-cell membrane disorder, most commonly due to abnormalities involving proteins such as spectrin, ankyrin, band 3, or protein 4.2. The red cells lose their normal biconcave shape and become spherical.
These spherocytes are less deformable and therefore become trapped in the splenic cords, where they are destroyed by macrophages. This produces extravascular haemolysis.
Why this case strongly suggests HS
1. Raised MCHC:
An increased MCHC is a classic laboratory clue for hereditary spherocytosis. An MCHC of 391 g/L is particularly striking.
2. Splenomegaly:
The spleen continuously removes abnormal spherocytes, leading to enlargement.
3. Recurrent gallstones at age 22:
Chronic haemolysis increases bilirubin production, leading to black pigment gallstones at a young age.
4. Normocytic anaemia:
The MCV is normal at 84.1 fL, which is compatible with HS.
5. Family history:
HS is commonly autosomal dominant, so a family history of a blood disorder supports the diagnosis.
Blood film
The characteristic finding is:
Spherocytes → small, round red cells lacking central pallor.
Reticulocytosis would also usually be present due to compensatory bone-marrow activity.
Diagnosis
In a typical patient with:
family history + haemolysis + spherocytes + raised MCHC + reticulocytosis
additional specialised testing may not be required.
When confirmation is necessary, the preferred test is the:
EMA (eosin-5-maleimide) binding test
Flow cytometry demonstrates reduced EMA binding to abnormal red-cell membrane proteins.
The osmotic fragility test is the traditional examination answer but is now considered less reliable and is generally not the preferred modern diagnostic test.
Important complications
- Pigment gallstones
- Aplastic crisis, classically precipitated by parvovirus B19
- Haemolytic crises during infections
- Folate deficiency due to increased erythropoiesis
Treatment
Mild cases may require little specific treatment apart from monitoring and folic acid when appropriate.
Patients with clinically significant haemolysis may undergo splenectomy, which markedly reduces haemolysis because the spleen is the main site of red-cell destruction. Splenectomy does not correct the membrane defect, so spherocytes remain on the blood film.
Patients undergoing splenectomy require appropriate vaccination against encapsulated organisms, particularly Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis.
Gallbladder surgery may also be required for symptomatic pigment stones.
Why the alternatives are less likely
Vitamin B12 deficiency typically causes a macrocytic anaemia rather than a normal MCV with high MCHC.
Beta-thalassaemia trait generally produces marked microcytosis, often disproportionate to the degree of anaemia. More severe thalassaemia can cause splenomegaly and gallstones, but this blood pattern is not typical.
Pyruvate kinase deficiency can cause chronic haemolysis and gallstones, but the markedly increased MCHC and classic combination of splenomegaly and spherocytosis point much more strongly toward HS.
Autoimmune haemolytic anaemia can also produce spherocytes, but would usually be acquired rather than showing this longstanding familial pattern; the direct antiglobulin (Coombs) test helps distinguish it from HS.
Summary for Quick Exam Revision
Hereditary spherocytosis is an inherited red-cell membrane disorder, usually transmitted in an autosomal dominant fashion. Commonly affected membrane proteins include spectrin, ankyrin, band 3, and protein 4.2. Loss of membrane causes red cells to become spherical rather than biconcave. Spherocytes are poorly deformable and become trapped and destroyed in the spleen, producing extravascular haemolysis. The classic clinical triad is anaemia, jaundice, and splenomegaly. Chronic bilirubin production predisposes young patients to black pigment gallstones. A particularly important laboratory clue is an increased MCHC. The blood film shows spherocytes without central pallor, and reticulocytes are usually increased. Spherocytes can also occur in autoimmune haemolytic anaemia, but the direct antiglobulin test is positive in autoimmune disease and generally negative in hereditary spherocytosis. The preferred confirmatory investigation when the diagnosis is uncertain is the EMA binding test. Osmotic fragility testing is historically important but is no longer the preferred diagnostic method. Parvovirus B19 can precipitate an aplastic crisis, producing a sudden severe fall in haemoglobin with reticulocytopenia. Folate requirements may increase because of chronic erythropoiesis. Severe or symptomatic disease may be treated with splenectomy, which reduces haemolysis but does not remove the underlying red-cell membrane abnormality. Before splenectomy, appropriate vaccination against encapsulated organisms is essential. In an exam question, think hereditary spherocytosis whenever you see young patient + haemolytic anaemia + splenomegaly + pigment gallstones + raised MCHC.