Transcript Megaloblastic anaemia an Iron deficiency

Senior Academic Half Day
Dr S W Bokhari
Consultant Haematologist
UHCW
Topics to cover
Low blood counts
- Anaemia due to haematinic deficiency
- Some other causes of anaemia
- Thrombocytopenia
Anaemias
MCV
B12/folate def
Haemolytic anaemia with reticulocytosis
Liver disease
Hypothyroidism
Alcohol
Myelodysplasia
Drugs
MCV
Iron deficiency
Thalassemias
Normal MCV
Anaemia of chronic disease
Aplastic anaemia
Anaemias due to haematinic
deficiency
Aim
Outline practical overview of B12, folate
and Iron deficiency
Megaloblastic anaemia
Group of disorders characterised by
presence of distinctive morphological
appearances of red cells in the marrow
Causes
-B12 deficiency
-Folate deficiency
-Abnormal metabolism of these vitamins
-Faults in DNA synthesis not related to B12
and folate
Vitamin B12 deficiency-Causes
Nutritional (vegans)
Malabsorption
- Gastric causes 1.pernicious anaemia
2.Total or partial
gastrectomy
- Intestinal causes
1. Intestinal stagnant loop syndrome (jej diverticulosis,
ileocolic fistula, anatomical blind loop, intestinal
stricture)
2. Ileal resection and chron’s disease
3. Tropical sprue
4. TCII deficiency
5. Fish tapeworm (Diphyllobothrium latum)
Vitamin B12
2 main natural forms (Deoxyadenosyl
cobalamin, Methyl cobalamin)
2 main pharmaceutical forms
(Cyanocobalamin, Hydroxycobalamin)
Dietry source: animal products only
Body stores: 2-3 mg
50% in liver
Sufficient for 2-4 years
Biochemistry
Homocysteine
Methionine
(Methyl B12)
Methyl THF
THF
DNA
dTMP
CYTOSOL
dUMP
Absorption
B12 in average diet 5 -7 ug/day
Doses >1 mg: 1% absorbed passively
R-binder: high level in saliva/gastric juice
ph2 – R:IF ~ 50:1
ph8 – R:IF ~ 3:1
IF: when present >70% B12 absorbed
if absent <1%
Enterohepatic circulation: 5-10 ug/day B12 analogues
bind to R binder
Absorption in terminal ileum.
Transportation: 75% TCI
10-20 % TCII
Mrs KC
55 years
Shortness of breath, sore mouth, tingling and
numbness in hands and feet
Good diet, no GI symptoms, No drugs.
Hb: 4.1 Platelets:85 WCC: 3.1
MCV: 109
LFT: normal; Reticulocytes: 20 LDH: 1100
Blood film:----------------------------------
Blood Film----diagnosis?
Diagnosis?
B12 level: 105
IF antibodies: positive
Pernicious Anaemia
Severe lack of IF due to gastric atrophy
Incidence 25/100,000/year aged over 40years
10 female: 7 male
20% have positive family history
Association with autoimmune disease (30% with
Crohn’s disease)
90% parietal cell antibody positive (~20% in
normal population)
60% IF antibody positive
Clinical features
Symptoms:
Malaise, SOB, Paraesthesia, sore mouth, weight loss,
alopecia/grey hair, irritability, poor memory, depression,
personality change, hallucinations, impotence, postural
hypotension
Signs:
Smooth tongue, angular chellosis, vitiligo, PUO, LVF,
sensory disturbance, subacute combined degenration,
optic atrophy, altered colour vision
Laboratory Abnormalities
Upto 40% not anaemic
Upto 30% not macrocytic (masked by
IDA/thalassaemia)
Pancytopenia
Neutrophil hypersegmentation
Hyposplenism
Howell Jolly bodies
Laboratory Abnormalities Chemistry
Increased serum Iron
Increased Iron stores
Increased bilirubin and LDH
Decreased immunoglobulins
Decreased cholesterol
Presentation and Management
Optic atrophy
Subacute comb.deg.
Pancytopenia
Urgent referral
Check B12
Treat blind with B12 & folate
Cont…
When to screen:
Unexplained macrocytic anaemia
Unexplained normocytic anaemia (elderly,
GI disease, autoimmune disease, family
h/o of PA)
Dimentia
anaemic or
Unexplained psychiatric illness
not
Cont…
B12 <170 pg/ml
B12 170-200
normal FBC/well
Treat
Neurology or
5 1mg injections
>65/debilitated
1mg every 3 months
<65:
IF Abs
Schillings test
Treat
?improved
?B12 ^
repeat 3-4 mo
Level
normal/static
probably spurious
Assessment of megaloblastic
anaemia
Confirmed megaloblastic BM: Plasma B12
90-95% B12 <200
5-10% B12 200-300
1% B12 > 300
But 50% of patients with B12<200 are not
Megaloblastic
Therefore B12 <100 usually B12 deficient
Only 50% of patients with a B12 100-200 will be
truly deficient; others spurious low B12
Causes of Spurious low B12
Iron deficiency- 30% IDA have low B12 which corrects
with FeSO4 alone
Folate deficiency- 30% folate deficient patients have a
low B12 which corrects with folate alone
Myeloma
Megadose Vit C
Vegetarian diet
Pregnancy
TC I deficiency
Pancreatic disease
Schilling Test
Low B12 (<100) + pos IF Ab +>60yrs = PA
If <60yrs/ IF Ab negative
Schilling test
Requirements:
- Normal renal function
- B12 replete
Schilling Test- Part 1
1 ug B12 (0.5 ug CiCo^57) orally
Gut normal
1000ug B12 IM
IF normal
Absorbed
~30%
Urine
Must collect 24 hr urine
(~25% collections inadequate)
Blocks all binding sites
Schilling test – Part 2
If absorption reduced in part 1
1ug B12(0.5 CiCo^57) + IF orally
No change
Gut disease
1000ug B12 IM
normal excretion= IF deficient
(B12 excretion controls: 11-32%
PA part 1: 0-6%
PA part 2: 3-30%)
If problems with incontinence or renal failure; collect
plasma sample 8 hours after oral B12 Co^57
Folate deficiency
Nutritional esp. old age, institutions, poverty
Malabsorption eg coeliac disease
Excess utilisation
Physiological (pregnancy, lactation)
Pathological eg hemolytic anaemia
Excess urinary folate loss
Active liver disease
CCF
Drugs (anti-convulsants, sulphasalazine)
Alcoholism
ITU
Serum folate
Not sensitive or specific
Spurious low values – anorexia
alcoholism
anticonvulsants
pregnancy
Falsely raised values – acute food intake
Haemolysis
Red cell folate
Levels are 30x greater than serum
Better longer term measure
Raised by – reticulocytosis
haemoconcentration
Lowered by – B12 deficiency (methyl THF
leaks out of RBC)
Response to B12/folate therapy
BM normal by 48 hours but giant
metamyelocytes persist for 14 days
Serum Iron normal by 48 hrs
K drops in first 48 hrs
Uric acid increases and peaks at 96 hrs
Reticulocyte response by D2-D3- peaks by day
7
Hb increased by 1-1.5 gm per week (If MCV <80
?IDA)
Hypersegmented neutrophils persist for 14 days
Bil/LDH correct over 7 days
Response to therapy
Neurology:
If present for < 3/12, usually reverse but
may take upto 6/12
No improvement after >12/12
Spinal cord damage usually irreversible
Only 30% of optic atrophy pts improve
Iron deficiency
3.1% adult men
5.3% adult women
Children upto 14 (non-menstruating
females) 2-3%
Menstruating girls upto 14 yrs age 9%
30% menstruating females have low
ferritin
Symptoms and signs
Anaemia – speed of onset
angina/CCF
Glossitis
Angular stomatitis (~10%)
Postural hypotension
Palpitations
Mild alopecia
Iron deficiency- interesting facts
7mg Fe/1000 kcal diet = Poor iron content
Phytates/phosphates reduce absorption =
reduce Fe availability
Iron losses males 0.5-1 mg/day
females 1-2 mg/day
pregnancy 1.5-3 mg/day
children 1 mg/day (2-3 yrs require 57 mg/day)
Breast milk/Toddlers diet often don’t keep up
with Iron demand
Iron deficiency- Points to remember
1 Aspirin /day – average gut loss 2-3ml/d = 2-3
mg Iron
1 Hookworm – average gut blood loss 0.03
ml/day
Liver disease– get Iron deficiency with a normal
MCV; ferritin likely to be normal or increased,
therefore difficult to diagnose
1/3rd of patients with Fe deficiency have low/
borderline B12
After partial gastrectomy, 50% of patients will be
Iron deficient at 5 years
4%
29%
myoglobin (4%)
transferrin(0.1%)
enzymes(0.2%)
Ferritin
66%
Total body Iron 3-4 gms
6 gms of Hb made per day = 20 mg Fe
Plasma Fe pool= 4 mg, hence large turnover
Haemoglobin
Iron deficiency – helpful film
comments
Microcytes
Anisocytosis
Poikilocytosis
Pencil cells
Target cells: few, not many
Polychromasia = reticulocytes ?bleeding
Neutropenia ; reverts with Iron therapy
Thrombocytosis
Diagnosis
Serum Ferritin
Sensitive
Ferritin
CV <4%
Diurnal variation <10%
Serum Fe
CV >20%
Diurnal variation> 50%
measures Fe stores
Specific
Causes of low ferritin Fe deficiency
Hypothyroid
Causes of low serum Fe Fe def.
Inflammation
Infection
malignancy
trauma
Causes of high TIBC Fe def.
Plasma Ferritin
Low plasma ferritin:
Iron deficiency
Hypothyroidism
Vitamin C deficiency
High plasma ferritin: Iron overload
Acute phase response
Liver damage
Sensitivity 0.23 and specificity 1.0 for diagnosis of
IDA
Haemolytic anaemia
Immune
Non-Immune
Evidence of haemolysis
FBC
Reticulocytes
LFT
LDH
Haptoglobin
Blood film – Schistocytes
-- Spherocytes
Spherocytes
Schistocytes
Immune vs non-Immune
Direct Coomb’s Test
Causes of false positive DCT
Autoimmune conditions
Paraproteinemias e.g myeloma
Post allogeneic transplant
Causes of Immune haemolysis
Autoimmune
Allo-immune (blood transfusion,
mismatched bone marrow transplants)
Drug-induced
Autoimmune haemolysis
Cold AIHA
Warm AIHA
Paroxysmal cold haemoglobinurea
Practical problems
Difficulties in blood grouping
Difficulties in cross-matching blood
Management
Blood transfusion
Steroids
IVIG – less effective
Rituximab
Chemotherapeutic agents