Anaemia that isn’t due to iron deficiency

1. Anaemia that isn’t due to iron deficiency Dr Annette Nicolle Consultant Haematologist Queen Elizabeth Hospital/ Sunderland Royal Hospital

2. Objectives • Look at the wide differential diagnosis of anaemia • Discuss some clinical cases • Look at laboratory pitfalls, and questions commonly asked

3. Thought for the day • “Many of us talk in our sleep. The distinctive achievement of lecturers is to talk in other people’s sleep” • Raymond Tallis

4. Laboratory results suggestive of anaemia • Hb<11.5 g/dl for females • Hb<13.0 g/dl for males • Hb<11.0 g/dl for F with rheumatoid arthritis • Hb<11.0 g/dl for M with rheumatoid arthritis • NB – take into account previous Hb level

5. The Med School Version

6. Iron deficiency EXERCISE How many causes of anaemia can you come up with? I’ve started you off Bone Marrow Blood vessels Intravascular Haemolysis Antibodies Liver and spleen Causes of Anaemia “Pooling”

7. Anaemia of chronic disease Shortage of raw materials External insults Renal system Reduced Erythropoeitin Bone Marrow “Abnormal Genes” Blood Loss Intrinsic Marrow Problems Blood vessels Rapid turnover Intravascular Haemolysis Antibodies Mechanical damage Liver and spleen Causes of Anaemia Extravascular Haemolysis “Pooling”

8. Case 1 See envelope set 1 Personnel: Patient: Mike Tucker – 56 years old GP: BMS in the lab (Multitalented) “Greek Chorus” – everybody else

9. The rules • The consultation exercise is run by the GP and patient • The BMS in the lab can only answer questions – he/she cannot volunteer information • The GP can refer to the Greek chorus to seek opinions at any stage by calling a time-out

10. Case 1 Summary • Polymyalgia Rheumatica • Key features • History – limb girdle stiffness, extreme tiredness • Microcytic anaemia • High ESR • Inflammatory features – high platelets, raised immunoglobulins • Retics low – indicate reduced marrow output • Anaemia of Chronic disease

11. Microcytic anaemia MCV<80 • Iron deficiency • Reduced Iron availability • Anaemia of chronic disease Small print: • Reduced Haem synthesis • Lead poisoning • Reduced globin production • Thalassaemia • Other haemoglobinopathies

12. Case 2 • Helen Archer - first pregnancy antenatal screening bloods: • WBC 7.2 • Hb 12.9 • MCV 62.3 (80-102) • MCH 19.2 (27-32) • Plt 251 Any thoughts?

13. Case 2 • Ferritin 73 • Next step? • Haemoglobinopathy screen • HbA/A • HbA2 4.0% • Consistent with Beta thal trait • Significance?

14. Case 3 Envelope set 2 Personnel: Patient: Linda Snell 63 years old GP: BMS in the lab (Multitalented) “Greek Chorus” – everybody else Same rules apply

15. Case 3 discussion • Macrocytic anaemia which had a wide differential diagnosis from history • Insidious onset • Family history • Pancytopenia • Note other clinical features of pernicious anaemia– not often present, but very useful when they are • However – need sense of perspective when investigating macrocytic anaemia

16. Macrocytic Anaemia MCV>100 Abnormal RBC maturation DRUGS Alcohol abuse Liver disease MDS, Leukaemia Hypothyroidism Abnormal DNA Synthesis B12 and Folate deficiency Mild macrocytosis: Reticulocytosis

17. Aetiology of macrocytosis in 300 patients with an MCV >99fl BMJ 2009;338:1644

18. Normocytic Anaemia Early iron deficiency Acute blood loss Anaemia of chronic disease (may be microcytic) Renal Failure Cancer Haemolysis (or may be macrocytic) Bone marrow suppression/ disorders Combined haematinic deficiencies

19. Renal Anaemia • GFR <60 = CKD possible cause of anaemia • GFR <30 (<45 in diabetics) = CKD is likely to be the cause • Should not be assessed until iron deficiency corrected • Can measure serum erythropoietin in clinic

20. Anaemia of Chronic Disease Protective mechanism to reduce availability of iron where it may have a detrimental effect Reduced availability of essential nutrient for bacteria and tumour cells Anaemia limits oxygen transport which affects rapidly proliferating tissues/ organisms Reduced serum iron also increases immune response

21. Anaemia of Chronic Disease Reduced erythropoietin responsiveness and production Reduced transferrin synthesis Reduced Fe mobilisation from macrophages Low serum iron despite adequate tissue stores Reduced iron re-utilization in erythropoiesis Raised serum ferritin Reticulocytopenia

22. Lab pitfalls

23. Ferritin • SERUM FERRITIN is now a standard diagnostic test for Iron deficiency anaemia • only iron deficiency will give a low result. • A value <15 μg/L is diagnostic of IDA.

24. Ferritin Iron deficiency anaemia can occur with a normal or high ferritin: • Liver dysfunction: ferritin is released when hepatocytes are damaged • Increased haem turnover: haemolysis and trauma (including surgery) • Inflammatory lesions: malignancy, infection and inflammation

25. SERUM IRON and TOTAL IRON BINDING CAPACITY (TIBC) In iron deficiency the serum iron is low (<10 μmol/L) and the TIBC is usually raised (>70 μmol/L). Erythropoiesis is iron-deficient when the transferrin saturation (SI  TIBC x 100%) falls below 15%.

26. Soluble transferrin receptor ratio Available in some hospitals in the region • Serum transferrin receptor-ferritin ratio • better for distinguishing between iron deficiency and anaemia of chronic disease • Ratio <1 suggests Anaemia of chronic disease and >2 iron deficiency

29. Problems with B12 levels Serum B12 is not a good indicator of total body stores Low serum levels without a true deficiency OCP, pregnancy, iron deficiency, atrophic gastritis False normal B12 levels Myeloproliferative disease, hepatoma, acute liver disease, high titre IF Abs Have to use the result in clinical context

30. B12 assay curve Setting lower end of range is difficult Problems setting the B12 range… Normal distribution curve -applies to most lab tests

31. ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS • B12 > 197 pg/ml. No need for comment • 150 - 197pg/ml. Borderline low B12 - probably not clinically significant • 100 - 150pg/ml - Low B12. Not macrocytic: Check IFA: if positive, treat as PA If negative, consider oral Rx (unless gastric or ileal resection) and check response

32. ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS • 100 - 150pg/ml - Low B12. If macrocytic: Advise trial of IM B12. If response, continue as for PA • < 100pg/ml - Low B12. Advise IM B12 therapy, check response. Diagnosis: ? PA (check IFA), ? Crohn’s, ? gastric or ileal resection

33. Problems with folate levels (Labs do either serum or red cell folate) False normal serum folate -folate deficient patient who has had a few folic acid tablets False low serum folate – recent alcohol False normal red cell folate – recent transfusion False low red cell folate – primary B12 deficiency

34. ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS • Folate > 4.0ng/ml - no need for comment • 2.2 - 4.0ng/ml - no need for treatment unless macrocytic and B12 normal, in which case advise trial of treatment and check response • < 2.2ng/ml – trial of treatment • ? dietary deficiency. • Consider coeliac or other small bowel disorder or resection, anti-folate medication

35. Reticulocytes The reticulocyte count (retics) reflects the bone marrow's response to anaemia. A low retic count indicates bone marrow hypoplasia. Reticulocytosis (high retic count) indicates the marrow is still responding

37. Case 4 – Kate Aldridge 1 week history of flu-like illness Fainted a couple of times Now dizzy every time she stands up WBC 7.6 Hb 4.1 Plt 282 Further investigations?

38. Further investigations • MCV 80 • Iron 9.0 • Bilirubin 10 • Retics 10 • LDH 200 • Normal renal function • Now what do you do?

39. Blood film Normal film Patient’s film

40. More results Spherocytes on film No evidence of malignancy/ marrow infiltration How does that fit with your differential diagnoses? Other tests?

41. Other tests • Parvovirus serology • Confirm Hereditary spherocytosis • Family history?

42. “Aplastic” crisis Parvovirus B19 IgM positive Treatment transfused as very symptomatic Folic acid, iron (tests showed iron 9.0)

44. Lab evidence of haemolysis Increased reticulocyte count Increased bilirubin DAT (Direct Antibody test) – Coombs test low serum haptoglobin Increased LDH Film appearances Haemoglobinemia/ Haemoglobinuria Haemosiderinuria NB – Red cell autoantibodies are common 3% over 70s have a positive DAT – it does not necessarily cause haemolysis

45. Marrow Problems Anaemia may be secondary to • Marrow infiltration • Cancer, Leukaemia, Lymphoma, inflammatory conditions, infections, fibrosis, • Ineffective/ reduced production • MDS, Aplastic anaemia, Inflammatory conditions, infections, DRUGS, anorexia Call your friendly local Haematologist…….

46. Case 5: Adam MacyBlood film – What is causing his anaemia

47. Summary • Useful points • Remember anaemia of chronic disease – infection/ inflammation • Renal Impairment • Reticulocyte count – tells you marrow function • Combined haematinic deficiencies - can mask each other • Historical results are useful, and rate of change • Lab tests are not infallible

48. Any Questions? Thankyou

49. Iron deficiency Bone Marrow Blood vessels Intravascular Haemolysis Antibodies Liver and spleen Causes of Anaemia “Pooling”

50. Other abnormal Haematology results When to refer and when to relax…