Anaemia that isn’t due to iron deficiency

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Anaemia that isnt due to iron deficiency

• Dr Annette Nicolle
• Consultant Haematologist
• Queen Elizabeth Hospital/ Sunderland Royal
  Hospital

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Objectives

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

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Thought for the day

• Many of us talk in our sleep. The distinctive
  achievement of lecturers is to talk in other
  peoples sleep
• Raymond Tallis

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Laboratory results suggestive of anaemia

• Hblt11.5 g/dl for females
• Hblt13.0 g/dl for males
• Hblt11.0 g/dl for F with rheumatoid arthritis
• Hblt11.0 g/dl for M with rheumatoid arthritis
• NB take into account previous Hb level

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The Med School Version
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Iron deficiency
EXERCISE How many causes of anaemia can you come
up with? Ive started you off
Bone Marrow
Blood vessels
Intravascular Haemolysis
Antibodies
Liver and spleen
Causes of Anaemia
Pooling
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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
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Case 1

• See envelope set 1
• Personnel
• Patient Mike Tucker 56 years old
• GP
• BMS in the lab (Multitalented)
• Greek Chorus everybody else

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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

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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

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Microcytic anaemia

• MCVlt80
• Iron deficiency
• Reduced Iron availability
• Anaemia of chronic disease
• Small print
• Reduced Haem synthesis
• Lead poisoning
• Reduced globin production
• Thalassaemia
• Other haemoglobinopathies

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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?
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Case 2

• Ferritin 73
• Next step?
• Haemoglobinopathy screen
• HbA/A
• HbA2 4.0
• Consistent with Beta thal trait
• Significance?

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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

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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

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Macrocytic Anaemia

• MCVgt100
• Abnormal RBC maturation
• DRUGS
• Alcohol abuse
• Liver disease
• MDS, Leukaemia
• Hypothyroidism
• Abnormal DNA Synthesis
• B12 and Folate deficiency
• Mild macrocytosis
• Reticulocytosis

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Aetiology of macrocytosis in 300 patients with an
MCV gt99fl
BMJ 20093381644
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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

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Renal Anaemia

• GFR lt60 CKD possible cause of anaemia
• GFR lt30 (lt45 in diabetics) CKD is likely to be
  the cause
• Should not be assessed until iron deficiency
  corrected
• Can measure serum erythropoietin in clinic

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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

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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

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Lab pitfalls
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Ferritin

• SERUM FERRITIN is now a standard diagnostic test
  for Iron deficiency anaemia
• only iron deficiency will give a low result.
• A value lt15 µg/L is diagnostic of IDA.

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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

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SERUM IRON and TOTAL IRON BINDING CAPACITY (TIBC)

• In iron deficiency the serum iron is low (lt10
  µmol/L) and the TIBC is usually raised (gt70
  µmol/L).
• Erythropoiesis is iron-deficient when the
  transferrin saturation (SI ? TIBC x 100) falls
  below 15.

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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 lt1 suggests Anaemia of chronic disease and
  gt2 iron deficiency

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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

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Problems setting the B12 range

• B12 assay curve
• Setting lower end of range is difficult

Normal distribution curve -applies to most lab
tests
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ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS

• B12 gt 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

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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
• lt 100pg/ml - Low B12.
• Advise IM B12 therapy, check response.
• Diagnosis ? PA (check IFA), ? Crohns,
• ? gastric or ileal resection

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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

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ALGORITHM FOR REPORTING B12 AND FOLATE RESULTS

• Folate gt 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
• lt 2.2ng/ml trial of treatment
• ? dietary deficiency.
• Consider coeliac or other small bowel disorder
  or resection, anti-folate medication

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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

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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?

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Further investigations

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

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Blood film
Normal film
Patients film
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More results

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

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Other tests

• Parvovirus serology
• Confirm Hereditary spherocytosis
• Family history?

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Aplastic crisis

• Parvovirus B19 IgM positive
• Treatment
• transfused as very symptomatic
• Folic acid, iron (tests showed iron 9.0)

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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

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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.

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Case 5 Adam MacyBlood film What is causing
his anaemia
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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

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Any Questions?

• Thankyou

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Iron deficiency
Bone Marrow
Blood vessels
Intravascular Haemolysis
Antibodies
Liver and spleen
Causes of Anaemia
Pooling
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Other abnormal Haematology results

• When to refer and when to relax

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Haematology laboratory results

• Haemoglobin (erythrocytosis)
• Hb gt 18.5, Hct gt0.55 (M), Hb gt 16.5, Hct gt 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)

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Haematology laboratory results

• White cells
• Neutrophils lt 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

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Haematology laboratory results

• White cells
• Neutrophils gt 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

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Haematology laboratory results

• White cells
• Lymphocytes gt 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 gt2.0, 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

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Haematology laboratory results

• Platelets
• Platelets gt600, 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 lt50 - consider referral to haematology
  unless cause is clear and/or more relevant to
  another speciality

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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 gt 18 secs
• APTT gt 40 secs - N.B. exclude lupus
  anticoagulant
• Fibrinogen lt1.0g/l
• Any combination of abnormal coagulation results
  accompanied by relevant symptoms