A Woman with Recurrent Anaemia and Jaundice

BMJ 2019;364:k5168 doi: 10.1136/bmj.k5168 (Published 27 February 2019) Page 1 of 4 BMJ: first published as 10.1136/bmj.k5168 on 27 February 2019. Downloaded from

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CASE REVIEW A woman with recurrent anaemia and jaundice

Muhajir Mohamed consultant haematologist 1 associate professor of medicine 1, Wan Danial Noor trainee resident 1

1Department of Medicine, Launceston General Hospital, Launceston, Tasmania, Australia; 2Launceston Clinical School, University of Tasmania, Tasmania, Australia;

A 41 year old white woman presented to the emergency 3.How is this condition managed? 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. Answers She had experienced three similar episodes in the past five years. 1. Each episode resolved completely after treatment with What is the likely diagnosis? antibiotics prescribed by her general practitioner. She had no http://www.bmj.com/ Hereditary spherocytosis presenting with haemolytic crisis. other notable medical conditions or family history. There is marked spherocytosis and polychromasia on peripheral She appeared pale and had scleral icterus. Her spleen was blood smear (fig 2). The negative direct antiglobulin test and enlarged and palpable below the left costal margin, firm in splenomegaly are suggestive of hereditary spherocytosis. In consistency, and mildly tender on palpation. Results of patients with hereditary spherocytosis, development of anaemic laboratory investigations are shown in table 1. symptoms and jaundice in association with a rapid drop in Examination of peripheral blood film revealed abnormalities in

haemoglobin and increase in indirect bilirubin and lactate on 17 June 2019 by Anne Meneghetti. Protected copyright. red blood cell morphology (fig 1). dehydrogenase are suggestive of haemolytic crisis.

Blood film 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 Ultrasonography of the abdomen confirmed splenomegaly with (blue arrows) spleen size of 16 cm.

Questions Hereditary spherocytosis is the most common inherited 1.What is the most likely diagnosis? haemolytic anaemia in white people and has an estimated prevalence between 1:2000 and 1:5000. In approximately 75% 2.How can you diagnose this condition? of cases the inheritance is autosomal dominant.1 The condition

Correspondence to M Mohamed [email protected]

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is characterised by deficiency or defect of one or more red cell as growth retardation and extramedullary erythropoiesis causing BMJ: first published as 10.1136/bmj.k5168 on 27 February 2019. Downloaded from membrane proteins, which results in decreased red cell bony changes and hepatosplenomegaly.3 2 membrane stability. Red cells therefore lose their normal Splenectomy is recommended in symptomatic patients with bi-concave disc shape and transform into dense, spherical cells moderate and severe hereditary spherocytosis and is avoided in known as spherocytes. In hereditary spherocytosis, extravascular asymptomatic patients with mild hereditary spherocytosis. haemolysis occurs primarily in the spleen, where these Splenectomy improves anaemia and reduces the risk of spherocytes are selectively trapped and removed prematurely gallstones, haemolytic crises, and aplastic crises. by the splenic sinusoids.3 Before undertaking splenectomy, give vaccinations against Patients with hereditary spherocytosis can develop serious encapsulated organisms such as pneumococcus, meningococcus, complications such as and Haemophilus influenza b. •Haemolytic crises: rapid worsening of anaemia and After splenectomy, spherocytes persists in the blood film and jaundice, triggered by infection there is an increased risk of life threatening sepsis from •Aplastic crises: rapid fall in haemoglobin concentration encapsulated organisms.3 7 Splenectomy is generally not and low reticulocyte count, precipitated by parvovirus B19 recommended in children under 6 because of their higher risk infection of sepsis. •Megaloblastic crises: worsening anaemia resulting from Lifelong penicillin prophylaxis is recommended in asplenic severe folate deficiency caused by increased bone marrow patients under 16, over 50, and in those with a previous episode requirement in haemolysis.3 of invasive pneumococcal disease, or for whom pneumococcal 8 Other complications include pigmented gall stones, growth vaccination had been ineffective. failure, skeletal abnormalities, and leg ulcers.3 Patient outcome 2. Our patient experienced recurrent episodes of acute haemolysis, How can you diagnose this condition? which were triggered by infections. During the earlier episodes Initial investigations include full blood counts, reticulocyte her symptoms were mild, which resolved after treatment for count, peripheral blood smear, bilirubin, lactate dehydrogenase infections and hence went unnoticed. Despite the negative family and direct antiglobin test. Haemoglobin, reticulocyte, and history, the possibility of hereditary spherocytosis was raised bilirubin levels are used to determine severity.4 Anaemia is due to the presence of spherocytes in peripheral blood smear typically mild to moderate, and if compensated haemolysis and negative direct antiglobulin test. Flow cytometric analysis by EMA binding test revealed reduced EMA staining on the occurs, the haemoglobin concentration may be within normal http://www.bmj.com/ range (reticulocyte count remains high). red blood cells, thus confirming the diagnosis of hereditary spherocytosis. She started folic acid 5 mg daily and was planned Diagnosis is usually confirmed by flow cytometric analysis of for elective splenectomy. She received pneumococcal, eosin-5-maleimide (EMA) labelled intact red blood cells (EMA meningococcal and Haemophilus influenza b vaccines. binding test).5 6 Red cell membrane protein analysis by sodium dodecyl sulphate Learning Points polyacrylamide gel electrophoresis of erythrocyte membranes 7 •Hereditary spherocytosis is an inherited disorder commonly is useful as a confirmatory test in atypical cases. on 17 June 2019 by Anne Meneghetti. Protected copyright. manifesting as mild or moderate haemolytic anaemia. Hereditary spherocytosis disease severity varies from asymptomatic carrier state to symptomatic severe haemolytic •This condition is diagnosed by the presence of spherocytes anaemia. It often presents in childhood with anaemia (50%), in blood smear, negative direct antiglobulin test, along with splenomegaly or jaundice; but may be diagnosed at any time of a positive family history. life.1 •Moderate to severe cases require treatment with folic acid and splenectomy. 3. How is this condition managed? The BMJ has judged that there are no disqualifying financial ties to commercial There is no specific treatment for hereditary spherocytosis. If companies. the patient is asymptomatic, no treatment is required. In more The authors declare the following other interests: none. severe cases supplementation with folic acid and splenectomy Further details of The BMJ policy on financial interests is here: https://www.bmj. are required to minimise complications of chronic haemolysis com/about-bmj/resources-authors/forms-policies-and-checklists/declaration- and anaemia. Infections can precipitate haemolytic crises in competing-interests people with the condition, so investigate and treat any infection Patient consent obtained. as necessary. Provenance and peer review: not commissioned; externally peer reviewed. Folic acid supplementation is necessary to prevent worsening of anaemia from folate deficiency, which occurs as a result of 1 Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis.Lancet increased marrow erythropoietic response to haemolysis. The 2008;372:1411-26. 10.1016/S0140-6736(08)61588-3 2 Delaunay J.The molecular basis of hereditary red cell membrane disorders.Blood Rev recommended dose of folic acid is a 2 to 3 mg tablet daily until 2007;21:1-20. 10.1016/j.blre.2006.03.005 3 the age of 5 years and 5 mg daily thereafter. Despite low 3 Mariani M, Barcellini W, Vercellati C, etal Clinical and hematologic features of 300 patients haemoglobin, older children and adults generally do not require affected by hereditary spherocytosis grouped according to the type of the membrane protein defect.Haematologica 2008;93:1310-7. 10.3324/haematol.12546 regular blood transfusions because of compensated 4 Bolton-Maggs PH, Stevens RF, Dodd NJ, Lamont G, Tittensor P, King MJ; General erythropoietic response by the bone marrow. In younger children Haematology Task Force of the British Committee for Standards in Haematology. Guidelines for the diagnosis and management of hereditary spherocytosis.Br J Haematol with severe hereditary spherocytosis, regular transfusions may 2004;126:455-74. 10.1111/j.1365-2141.2004.05052. be required before splenectomy to prevent complications such 5 Bianchi P, Fermo E, Vercellati C, etal. Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. Haematologica 2012;97:516-23. 10.3324/haematol.2011.052845

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6 Kar R, Mishra P, Pati HP. Evaluation of eosin-5-maleimide flow cytometric test in diagnosis Haemato-Oncology task force.Br J Haematol 2011;155:308-17. BMJ: first published as 10.1136/bmj.k5168 on 27 February 2019. Downloaded from of hereditary spherocytosis.Int J Lab Hematol 2010;32:8-16. 10.1111/j.1365-2141.2011.08843. 10.1111/j.1751-553X.2008.01098. 9 Da Costa L, Galimand J, Fenneteau O, Mohandas N. Hereditary spherocytosis, 7 Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ. Task Force of the British elliptocytosis, and other red cell membrane disorders.Blood Rev 2013;27:167-78. Committee for Standards in Haematology. Guidelines for the diagnosis and management 10.1016/j.blre.2013.04.003 of hereditary spherocytosis—2011 update.Br J Haematol 2012;156:37-49. 10 Hayag-Barin JE, Smith RE, Tucker FCJr. Hereditary spherocytosis, thrombocytosis, and 10.1111/j.1365-2141.2011.08921. chronic pulmonary emboli: a case report and review of the literature.Am J Hematol 8 Davies JM, Lewis MP, Wimperis J, Rafi I, Ladhani S, Bolton-Maggs PH. British Committee 1998;57:82-4. 10.1002/(SICI)1096-8652(199801)57:1<82::AID-AJH15>3.0.CO;2-B for Standards in Haematology. Review of guidelines for the prevention and treatment of Published by the BMJ Publishing Group Limited. For permission to use (where not already infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British Committee for Standards in Haematology by a working party of the granted under a licence) please go to http://group.bmj.com/group/rights-licensing/ permissions http://www.bmj.com/ on 17 June 2019 by Anne Meneghetti. Protected copyright.

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Table BMJ: first published as 10.1136/bmj.k5168 on 27 February 2019. Downloaded from

Table 1| Results of laboratory investigations

Result Reference range Haemoglobin concentration 96 g/L 130 to 180 g/L Mean corpuscular volume 87 fL 80 to 100 fL Mean corpuscular haemoglobin concentration 368 g/L 320 to 360 g/L White cell count 14.5 × 109/L 4.0 to 11.0 × 109/L Absolute reticulocyte count 354 × 109/L 50 to 100×109/L Lactate dehydrogenase 540 U/L 125 to 240 U/L Indirect bilirubin 64 µmol/L 0 to 18 µmol/L Haptoglobin <0.01 g/L 0.3 to 2.0 g/L Liver enzymes Normal Direct antiglobulin Negative Platelet count Normal http://www.bmj.com/ on 17 June 2019 by Anne Meneghetti. Protected copyright.

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