Intended for healthcare professionals

Endgames Case Review

A woman with recurrent anaemia and jaundice

BMJ 2019; 364 doi: https://doi.org/10.1136/bmj.k5168 (Published 27 February 2019) Cite this as: BMJ 2019;364:k5168
  1. Muhajir Mohamed, consultant haematologist, associate professor of medicine12,
  2. Wan Danial Noor, trainee resident1
  1. 1Department of Medicine, Launceston General Hospital, Launceston, Tasmania, Australia
  2. 2Launceston Clinical School, University of Tasmania, Tasmania, Australia;
  1. Correspondence to M Mohamed muhajirbm{at}yahoo.com

A 41 year old white woman presented to the emergency department. She described fever, cough, and exercise intolerance, yellowish discolouration of her eyes, and pain in the left upper quadrant that had been ongoing for three days. She had experienced three similar episodes in the past five years. Each episode resolved completely after treatment with antibiotics prescribed by her general practitioner. She had no other notable medical conditions or family history.

She appeared pale and had scleral icterus. Her spleen was enlarged and palpable below the left costal margin, firm in consistency, and mildly tender on palpation. Results of laboratory investigations are shown in table 1.

Table 1

Results of laboratory investigations

View this table:

Examination of peripheral blood film revealed abnormalities in red blood cell morphology (fig 1).

Ultrasonography of the abdomen confirmed splenomegaly with spleen size of 16 cm.

Questions

  1. What is the most likely diagnosis?

  2. How can you diagnose this condition?

  3. How is this condition managed?

Answers

1. What is the likely diagnosis?

Hereditary spherocytosis presenting with haemolytic crisis.

There is marked spherocytosis and polychromasia on peripheral blood smear (fig 2). The negative direct antiglobulin test and splenomegaly are suggestive of hereditary spherocytosis. In patients with hereditary spherocytosis, development of anaemic symptoms and jaundice in association with a rapid drop in haemoglobin and increase in indirect bilirubin and lactate dehydrogenase are suggestive of haemolytic crisis.

Fig 2
Fig 2

Spherocytes (red arrows) appear as dense spherical red cells with loss of central pallor, and polychromasia is an indication of increase in reticulocytes in the blood smear (blue arrows)

Hereditary spherocytosis is the most common inherited haemolytic anaemia in white people and has an estimated prevalence between 1:2000 and 1:5000. In approximately 75% of cases the inheritance is autosomal dominant.1 The condition is characterised by deficiency or defect of one or more red cell membrane proteins, which results in decreased red cell membrane stability.2 Red cells therefore lose their normal bi-concave disc shape and transform into dense, spherical cells known as spherocytes. In hereditary spherocytosis, extravascular haemolysis occurs primarily in the spleen, where these spherocytes are selectively trapped and removed prematurely by the splenic sinusoids.3

Patients with hereditary spherocytosis can develop serious complications such as

  • Haemolytic crises: rapid worsening of anaemia and jaundice, triggered by infection

  • Aplastic crises: rapid fall in haemoglobin concentration and low reticulocyte count, precipitated by parvovirus B19 infection

  • Megaloblastic crises: worsening anaemia resulting from severe folate deficiency caused by increased bone marrow requirement in haemolysis.3

Other complications include pigmented gall stones, growth failure, skeletal abnormalities, and leg ulcers.3

2. How can you diagnose this condition?

Initial investigations include full blood counts, reticulocyte count, peripheral blood smear, bilirubin, lactate dehydrogenase and direct antiglobin test. Haemoglobin, reticulocyte, and bilirubin levels are used to determine severity.4 Anaemia is typically mild to moderate, and if compensated haemolysis occurs, the haemoglobin concentration may be within normal range (reticulocyte count remains high).

Diagnosis is usually confirmed by flow cytometric analysis of eosin-5-maleimide (EMA) labelled intact red blood cells (EMA binding test).56

Red cell membrane protein analysis by sodium dodecyl sulphate polyacrylamide gel electrophoresis of erythrocyte membranes is useful as a confirmatory test in atypical cases.7

Hereditary spherocytosis disease severity varies from asymptomatic carrier state to symptomatic severe haemolytic anaemia. It often presents in childhood with anaemia (50%), splenomegaly or jaundice; but may be diagnosed at any time of life.1

3. How is this condition managed?

There is no specific treatment for hereditary spherocytosis. If the patient is asymptomatic, no treatment is required. In more severe cases supplementation with folic acid and splenectomy are required to minimise complications of chronic haemolysis and anaemia. Infections can precipitate haemolytic crises in people with the condition, so investigate and treat any infection as necessary.

Folic acid supplementation is necessary to prevent worsening of anaemia from folate deficiency, which occurs as a result of increased marrow erythropoietic response to haemolysis. The recommended dose of folic acid is a 2 to 3 mg tablet daily until the age of 5 years and 5 mg daily thereafter.3 Despite low haemoglobin, older children and adults generally do not require regular blood transfusions because of compensated erythropoietic response by the bone marrow. In younger children with severe hereditary spherocytosis, regular transfusions may be required before splenectomy to prevent complications such as growth retardation and extramedullary erythropoiesis causing bony changes and hepatosplenomegaly.3

Splenectomy is recommended in symptomatic patients with moderate and severe hereditary spherocytosis and is avoided in asymptomatic patients with mild hereditary spherocytosis. Splenectomy improves anaemia and reduces the risk of gallstones, haemolytic crises, and aplastic crises.

Before undertaking splenectomy, give vaccinations against encapsulated organisms such as pneumococcus, meningococcus, and Haemophilus influenza b.

After splenectomy, spherocytes persists in the blood film and there is an increased risk of life threatening sepsis from encapsulated organisms.37 Splenectomy is generally not recommended in children under 6 because of their higher risk of sepsis.

Lifelong penicillin prophylaxis is recommended in asplenic patients under 16, over 50, and in those with a previous episode of invasive pneumococcal disease, or for whom pneumococcal vaccination had been ineffective.8

Patient outcome

Our patient experienced recurrent episodes of acute haemolysis, which were triggered by infections. During the earlier episodes her symptoms were mild, which resolved after treatment for infections and hence went unnoticed. Despite the negative family history, the possibility of hereditary spherocytosis was raised due to the presence of spherocytes in peripheral blood smear and negative direct antiglobulin test. Flow cytometric analysis by EMA binding test revealed reduced EMA staining on the red blood cells, thus confirming the diagnosis of hereditary spherocytosis. She started folic acid 5 mg daily and was planned for elective splenectomy. She received pneumococcal, meningococcal and Haemophilus influenza b vaccines.

Learning Points

  • Hereditary spherocytosis is an inherited disorder commonly manifesting as mild or moderate haemolytic anaemia.

  • This condition is diagnosed by the presence of spherocytes in blood smear, negative direct antiglobulin test, along with a positive family history.

  • Moderate to severe cases require treatment with folic acid and splenectomy.

Footnotes

References

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