Anaemia that isn’t due to iron
deficiency
Dr Annette Nicolle
Consultant 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
Iron deficiency
EXERCISE
How many causes of anaemia can
you come up with?
Bone Marrow
I’ve started you off
Blood vessels
Intravascular
Haemolysis
Antibodies
Liver and spleen
Causes of
Anaemia
“Pooling”
Anaemia of chronic disease
Shortage of raw materials
Bone Marrow
External insults
Renal system
Reduced
Erythropoeitin
“Abnormal
Genes”
Blood Loss
Intrinsic Marrow
Problems
Blood vessels
Rapid
turnover
Intravascular
Haemolysis
Antibodies
Causes of
Anaemia
Mechanical
damage
Liver and spleen
Extravascular
Haemolysis
“Pooling”
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
– MCH 19.2
– Plt 251
(80-102)
(27-32)
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
Drugs (cytotoxics, anticonvulsants, antiretrovirals )
Prevalence (%)
37
Alcohol (+/- liver disease)
26
Reticulocytosis (haemolysis or bleeding) 8
Vit B12 or folate deficiency
6
Non-alcoholic liver disease
Primary bone marrow disorders (eg
MDS, AML)
6
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
Anaemia
of chronic
disease
Normocytic,
Normal Low
normochromic or
raised
Early Iron Hypochromic, Normal Low
Deficiency mild
or Low
anisocytosis
TIBC
sTfR –
ferritin
ratio
Low
<1
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…
Normal distribution
curve
-applies to most lab
tests
• B12 assay curve
– Setting lower end of
range is difficult
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 7.6
Hb 4.1
Plt 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 Macy
Blood 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
Iron deficiency
Bone Marrow
Blood vessels
Intravascular
Haemolysis
Antibodies
Liver and spleen
Causes of
Anaemia
“Pooling”
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, autoimmune 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