Anaemia that isn’t due to iron deficiency

Dr Annette NicolleConsultant Haematologist

Queen Elizabeth Hospital/ Sunderland Royal Hospital

Objectives

• Look at the wide differential diagnosis of anaemia

• Discuss some clinical cases

• Look at laboratory pitfalls, and questions commonly asked

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

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

The Med School Version

Blood vessels

Liver and spleen

Bone Marrow

Intravascular Haemolysis

Causes of Anaemia “Pooling”

Antibodies

Iron deficiencyEXERCISE

How many causes of anaemia can you come up with?

I’ve started you off

Blood vessels

Liver and spleen

Bone Marrow

Shortage of raw materials

Blood Loss

Intravascular Haemolysis

Extravascular Haemolysis

External insults

Intrinsic Marrow Problems

Reduced Erythropoeitin

Renal system

Rapid turnover

Causes of Anaemia “Pooling”

Mechanical damage

Antibodies

“Abnormal Genes”

Anaemia of chronic disease

Case 1

See envelope set 1

Personnel:

Patient: Mike Tucker – 56 years old

GP:

BMS in the lab (Multitalented)

“Greek Chorus” – everybody else

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

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

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

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?

Case 2

• Ferritin 73

• Next step?

• Haemoglobinopathy screen– HbA/A

– HbA2 4.0%

– Consistent with Beta thal trait

• Significance?

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

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

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

Aetiology of macrocytosis in 300 patients with an MCV >99fl

Prevalence (%)

Drugs (cytotoxics, anticonvulsants, anti-retrovirals )

37

Alcohol (+/- liver disease) 26

Reticulocytosis (haemolysis or bleeding) 8

Vit B12 or folate deficiency 6

Non-alcoholic liver disease 6

Primary bone marrow disorders (eg MDS, AML)

6

Hypothyroidism 0.6

BMJ 2009;338:1644

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

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

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

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

Lab pitfalls

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.

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

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%.

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

Type of anaemia

Blood film Ferritin Iron TIBC sTfR –ferritin ratio

Anaemia of chronic disease

Normocytic, normochromic

Normal or raised

Low Low <1

Early Iron Deficiency

Hypochromic, mild anisocytosis

Normal or Low

Low Raised >2

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

Problems setting the B12 range…

• B12 assay curve– Setting lower end of

range is difficult

Normal distribution curve

-applies to most lab tests

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

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

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

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

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

Case 4 – Kate Aldridge

• 1 week history of flu-like illness• Fainted a couple of times• Now dizzy every time she stands up

WBC 7.6Hb 4.1Plt 282

Further investigations?

Further investigations

• MCV 80• Iron 9.0• Bilirubin 10• Retics 10• LDH 200• Normal renal function

• Now what do you do?

Blood film

Normal film

Patient’s film

More results

Spherocytes on film

No evidence of malignancy/ marrow infiltration

• How does that fit with your differential diagnoses?

• Other tests?

Other tests

• Parvovirus serology

• Confirm Hereditary spherocytosis

• Family history?

“Aplastic” crisis

• Parvovirus B19 IgM positive• Treatment

– transfused as very symptomatic– Folic acid, iron (tests showed iron 9.0)

24/12/08 25/12/08 26/12/08 29/12/08

Hb 4.1 8.3 7.8 10.1

Retics 10.3 27.2 106 425

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

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…….

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

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

Any Questions?

Thankyou

Blood vessels

Liver and spleen

Bone Marrow

Intravascular Haemolysis

Causes of Anaemia “Pooling”

Antibodies

Iron deficiency

Other abnormal Haematology results

When to refer and when to relax…

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 possible• If erythrocytosis persists, consider referral

• If 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)

Haematology laboratory results

• White cells

• Neutrophils < 1.5• Consider whether secondary to medication, auto-

immune disorder, hypersplenism, race or viral infection• If 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

Haematology laboratory results

• White cells

• Neutrophils > 10.0, persisting for at least one month• Exclude 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

Haematology laboratory results

• White cells

• Lymphocytes > 10.0, persistent for at least one month• Consider infection, esp. IM or pertussis• Laboratory will arrange cell markers when appropriate,

and may then advise referral

• Monocytes >2.0, persistent for at least one month• Consider chronic infection, e.g. TB• If accompanied by anaemia and/or neutropenia,

neutrophilia or thromoboctyopenia, refer to haematology

Haematology laboratory results

• Platelets

• Platelets >600, persistent for at least one month• Exclude blood loss, chronic infection or inflammation, prescribe low

dose aspirin if no contra-indication• If no obvious cause, refer to haematology

• Platelets 100-150 - do not refer, monitor to detect trend

• Platelets 50-100 - consider medication, auto-immune disorder, hypersplenism. Do not refer to haematology unless symptomatic

• Platelets <50 - consider referral to haematology unless cause is clear and/or more relevant to another speciality

Haematology laboratory results

• Coagulation tests

• Consider referral to haematology if patient symptomatic (bruising or bleeding) and abnormalities not secondary to anticoagulation, dietary deficiency or known liver disease:

• PT > 18 secs• APTT > 40 secs - N.B. exclude lupus “anticoagulant”• Fibrinogen <1.0g/l• Any combination of abnormal coagulation results

accompanied by relevant symptoms