Presentation on theme: "Anaemia that isn’t due to iron deficiency"— Presentation transcript:
1 Anaemia that isn’t due to iron deficiency Dr Annette NicolleConsultant HaematologistQueen Elizabeth Hospital/ Sunderland Royal Hospital
2 Objectives Look at the wide differential diagnosis of anaemia Discuss some clinical casesLook 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 TallisAmerican Author
4 Laboratory results suggestive of anaemia Hb<11.5 g/dl for femalesHb<13.0 g/dl for malesHb<11.0 g/dl for F with rheumatoid arthritisHb<11.0 g/dl for M with rheumatoid arthritisNB – take into account previous Hb level
5 Taught at med school – not terribly helpful in cases that aren’t straightforward The Med School Version
6 How many causes of anaemia can you come up with? Iron deficiencyEXERCISEHow many causes of anaemia can you come up with?I’ve started you offBone MarrowBlood vesselsIntravascular HaemolysisAntibodiesI give this one to the SpRs I teach – you can probably do betterLiver and spleenCauses of Anaemia“Pooling”
7 Anaemia of chronic disease Shortage of raw materialsExternal insultsRenal systemReduced ErythropoeitinBone Marrow“Abnormal Genes”Blood LossIntrinsic Marrow ProblemsBlood vesselsRapid turnoverIntravascular HaemolysisAntibodiesI use this to try to encourage the junior docs to think laterally….Mechanical damageLiver and spleenCauses of AnaemiaExtravascular Haemolysis“Pooling”
8 Case 1 See envelope set 1 Personnel: Patient: Mike Tucker – 56 years oldGP: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 informationThe 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 tirednessMicrocytic anaemiaHigh ESRInflammatory features – high platelets, raised immunoglobulinsRetics low – indicate reduced marrow outputAnaemia of Chronic disease
11 Microcytic anaemia MCV<80 Iron deficiency Reduced Iron availability Anaemia of chronic diseaseSmall print:Reduced Haem synthesisLead poisoningReduced globin productionThalassaemiaOther haemoglobinopathies
12 Case 2Helen Archer - first pregnancy antenatal screening bloods:WBC 7.2Hb 12.9MCV (80-102)MCH 19.2 (27-32)Plt 251Any thoughts?
13 Case 2 Ferritin 73 Next step? Haemoglobinopathy screen Significance? HbA/AHbA2 4.0%Consistent with Beta thal traitSignificance?
14 Case 3 Envelope set 2 Personnel: Patient: Linda Snell 63 years old GP: BMS in the lab (Multitalented)“Greek Chorus” – everybody elseSame rules apply
15 Case 3 discussionMacrocytic anaemia which had a wide differential diagnosis from historyInsidious onsetFamily historyPancytopeniaNote other clinical features of pernicious anaemia– not often present, but very useful when they areHowever – need sense of perspective when investigating macrocytic anaemia
16 Macrocytic Anaemia Abnormal RBC maturation Abnormal DNA Synthesis MCV>100Abnormal RBC maturationDRUGSAlcohol abuseLiver diseaseMDS, LeukaemiaHypothyroidismAbnormal DNA SynthesisB12 and Folate deficiencyMild macrocytosis:Reticulocytosis
17 Aetiology of macrocytosis in 300 patients with an MCV >99fl Prevalence (%)Drugs (cytotoxics, anticonvulsants, anti-retrovirals )37Alcohol (+/- liver disease)26Reticulocytosis (haemolysis or bleeding)8Vit B12 or folate deficiency6Non-alcoholic liver diseasePrimary bone marrow disorders (eg MDS, AML)Hypothyroidism0.6BMJ 2009;338:1644
18 Normocytic Anaemia Early iron deficiency Acute blood loss Anaemia of chronic disease (may be microcytic)Renal FailureCancerHaemolysis (or may be macrocytic)Bone marrow suppression/ disordersCombined haematinic deficiencies
19 Renal Anaemia GFR <60 = CKD possible cause of anaemia GFR <30 (<45 in diabetics) = CKD is likely to be the causeShould not be assessed until iron deficiency correctedCan measure serum erythropoietin in clinic
20 Anaemia of Chronic Disease Protective mechanism to reduce availability of iron where it may have a detrimental effectReduced availability of essential nutrient for bacteria and tumour cellsAnaemia limits oxygen transport which affects rapidly proliferating tissues/ organismsReduced serum iron also increases immune response
21 Anaemia of Chronic Disease Reduced erythropoietin responsiveness and productionReduced transferrin synthesisReduced Fe mobilisation from macrophagesLow serum iron despite adequate tissue storesReduced iron re-utilization in erythropoiesisRaised serum ferritinReticulocytopenia
23 FerritinSERUM FERRITIN is now a standard diagnostic test for Iron deficiency anaemiaonly iron deficiency will give a low result.A value <15 μg/L is diagnostic of IDA.
24 FerritinIron deficiency anaemia can occur with a normal or high ferritin:Liver dysfunction: ferritin is released when hepatocytes are damagedIncreased 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%.TIBC can be affected by nutritional status
26 Soluble transferrin receptor ratio Available in some hospitals in the regionSerum transferrin receptor-ferritin ratiobetter for distinguishing between iron deficiency and anaemia of chronic diseaseRatio <1 suggests Anaemia of chronic disease and >2 iron deficiencySTR derived from bone marrow cells, inversely increased in iron deficiency26
27 Type of anaemiaBlood filmFerritinIronTIBCsTfR –ferritin ratioAnaemia of chronic diseaseNormocytic, normochromicNormal or raisedLow<1Early Iron DeficiencyHypochromic, mild anisocytosisNormal or LowRaised>2
29 Problems with B12 levelsSerum B12 is not a good indicator of total body storesLow serum levels without a true deficiencyOCP, pregnancy, iron deficiency, atrophic gastritisFalse normal B12 levelsMyeloproliferative disease, hepatoma, acute liver disease, high titre IF AbsHave to use the result in clinical contextManufacturers warning that results should be interpreted in clinical contextHigh titre intrinsic factor abs can give false normal B12 levels
30 Problems setting the B12 range… B12 assay curveSetting lower end of range is difficultNormal distribution curve-applies to most lab tests
31 ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS B12 > 197 pg/ml. No need for commentpg/ml. Borderline low B12 - probably not clinically significantpg/ml - Low B12. Not macrocytic:Check IFA: if positive, treat as PAIf negative, consider oral Rx (unless gastric or ileal resection) and check response
32 ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS pg/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 tabletsFalse low serum folate – recent alcoholFalse normal red cell folate – recent transfusionFalse low red cell folate – primary B12 deficiency
34 ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS Folate > 4.0ng/ml - no need for commentng/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 ReticulocytesThe 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
40 More results Spherocytes on film No evidence of malignancy/ marrow infiltrationHow 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 24/12/08 transfused as very symptomaticFolic acid, iron (tests showed iron 9.0)24/12/0825/12/0826/12/0829/12/08Hb126.96.36.1990.1Retics10.327.2106425
44 Lab evidence of haemolysis Increased reticulocyte countIncreased bilirubinDAT (Direct Antibody test) – Coombs testlow serum haptoglobinIncreased LDHFilm appearancesHaemoglobinemia/ HaemoglobinuriaHaemosiderinuriaNB – Red cell autoantibodies are common 3% over 70s have a positive DAT – it does not necessarily cause haemolysisFancy tests requested by haematology – osmotic fragility etc
45 Marrow Problems Anaemia may be secondary to Marrow infiltration Cancer, Leukaemia, Lymphoma, inflammatory conditions, infections, fibrosis,Ineffective/ reduced productionMDS, Aplastic anaemia, Inflammatory conditions, infections, DRUGS, anorexiaCall your friendly local Haematologist…….
46 Case 5: Adam Macy Blood film – What is causing his anaemia
47 SummaryUseful pointsRemember anaemia of chronic disease – infection/ inflammationRenal ImpairmentReticulocyte count – tells you marrow functionCombined haematinic deficiencies - can mask each otherHistorical results are useful, and rate of changeLab tests are not infallible
49 Causes of Anaemia Bone Marrow Blood vessels Liver and spleen Iron deficiencyBone MarrowBlood vesselsIntravascular HaemolysisAntibodiesSlide for “brainstorm”Liver and spleenCauses of Anaemia“Pooling”
50 Other abnormal Haematology results When to refer and when to relax…
51 Haematology laboratory results Haemoglobin (erythrocytosis)Hb > 18.5, Hct >0.55 (M), Hb > 16.5, Hct > 0.50 (F)If only Hb raised, consider hypoxia, smoking, alcohol, dehydration and correct if possibleIf erythrocytosis persists, consider referralIf accompanied by raised neutrophils and/or platelets, check if itching, sweating, splenic discomfort, gout, etc.Refer to haematology if PRV/MPD seems likely (JAK2, etc)
52 Haematology laboratory results White cellsNeutrophils < 1.5Consider whether secondary to medication, auto-immune disorder, hypersplenism, race or viral infectionIf remains unexplained, refer to haematology (possible need for bone marrow biopsy)Low lymphocyte or monocyte count - no specific referral criteria, but consider HIV if lymphocytes reduced, with appropriate clinical history
53 Haematology laboratory results White cellsNeutrophils > 10.0, persisting for at least one monthExclude latent infection or inflammation, medication (esp. steroids)If accompanied by raised eosinophils and/or basophils, consider referral (? CML)If accompanied by monocytosis, consider referral (? CMMoL)If isolated neutrophilia but unexplained upward trend, consider referral
54 Haematology laboratory results White cellsLymphocytes > 10.0, persistent for at least one monthConsider infection, esp. IM or pertussisLaboratory will arrange cell markers when appropriate, and may then advise referralMonocytes >2.0, persistent for at least one monthConsider chronic infection, e.g. TBIf accompanied by anaemia and/or neutropenia, neutrophilia or thromoboctyopenia, refer to haematology
55 Haematology laboratory results PlateletsPlatelets >600, persistent for at least one monthExclude blood loss, chronic infection or inflammation, prescribe low dose aspirin if no contra-indicationIf no obvious cause, refer to haematologyPlatelets do not refer, monitor to detect trendPlatelets consider medication, auto-immune disorder, hypersplenism. Do not refer to haematology unless symptomaticPlatelets <50 - consider referral to haematology unless cause is clear and/or more relevant to another speciality
56 Haematology laboratory results Coagulation testsConsider referral to haematology if patient symptomatic (bruising or bleeding) and abnormalities not secondary to anticoagulation, dietary deficiency or known liver disease:PT > 18 secsAPTT > 40 secs - N.B. exclude lupus “anticoagulant”Fibrinogen <1.0g/lAny combination of abnormal coagulation results accompanied by relevant symptoms