Microcytic Anaemia

Anaemia with MCV < 80
Causes
- "microcytic cells are STIC thin"
- Sideroblastic anaemia
- Thalassaemias
- Iron deficiency anaemia
- Chronic disease
Erythroblast
- large
- Divides until becomes small RBCs
- So microcytic anaemia due to an "extra division"
Problem is decreased Hb production
- So making this "extra division" means you increase the Hb concentration by decreasing the volume
Hb
- = Haem + Globin
- = (Fe+ protoporphyrin) + (globin)
- So
  - Too low Fe leads to too little haem, Hb and thus small cells
    - e.g. sucked into macrophages in anaemia of chronic disease
    - e.g. not enough in diet or chronic loss
  - Too low protoporhyrin
    - Sideroblastic anaemia
  - Too low globin protein
    - Thalassaemias

Iron deficiency anaemia

Most common anaemia
Dev world - Fe most common deficiency
From diet
- Haem in meat
- Non haem in veg
- Absorbed in duodenum, jejunum
  - "Iron (II) absorbed in two places "
Only absorbed in Fe2+ form (Iron(II) gets into the body)
- Enterocyte exports into blood out of ferroportin channel
- Transferrin binds in blood, delivers to liver + bone marrow macrophages for storage
- RBCs have sTfRs = soluble transferrin receptors - "iron stuffers"
- Store bound to ferritin intracellularly
  - Ferritin
  - Haemosiderin
- Binding prevents fento reaction ROS
Ix
- Serum Fe
- TIBC - Total Iron Binding Capacity
- Transferrin % Saturation
  - 20-50% normal adults, >16% normal kids
- Serum Ferritin
Causes
- Dietary
  - Infants - breast feeding
  - Children - poor diet, drinking cows milk as major component of diet, not enough for growth
  - Adults
    - peptic ulcer disease - most common cause in middle aged men
    - menorrhagia
    - pregnancy
  - Elderly
    - Colon polyps
    - Colon carcinoma
    - Hookworm in developing world
      - Ancylostoma duodenale - ME, NAfrica, India
      - Necator americanus - Americas, SubSahara, SEAsia
  - Malnutrition
- Malabsorption
  - Coeliac - destroys duodenal vili
- Gastrectomy
  - Cut out part stomach so less acid
  - So can't reduce Fe3+ to Fe2+/prevent oxn of Fe2+ to allow efficient absorption
- Blood loss - colon Ca etc
Stages
- ONE Deplete existing stores
  - so serum ferritin dec
  - & inc TIBC as less iron around and liver inc TIBC as recognises that need to try and grab as much iron as possible
  - (ie if ferritin goes down, TIBC goes up)
- TWO Deplete what Fe is in serum
  - dec serum iron
  - Transferrin % Sat dec
- THREE Normocytic anaemia - less iron so make less cells
- FOUR Microcytic, hypochromic anaemia - far too little Fe so make less cells and the cells that are made have less Hb
PresentsIx
- Anaemia
- Koilonychia
- Pica
  - eat dirt etc
  - psych drive to get Fe2+ from any "source" possible

Microcytic
Hypochromic
Inc RDW - red cell distribution width - basically make RBC syn shit so lots of diff shapes
Dec serum ferritinInc TIBC - more made by liver to grab what can
- Best measure
- Less than 15 microgram /L suggestive of deficiency
- But acts as acute phase reactant so well increase if there's coinciding inflammation! Eg infection - body sequesters as much iron as possible so not available for bacteria
- So check CRP, ESR when interpreting
- If ferritin not low but sTfR is, likely deficiency and inflammation - eg infection
Dec serum iron
Dec transferrin saturation
Inc serum sTfRs - RBCs grab what can
- Not routine
- May end up using other tests plus inflammatory markers and a trial of iron supplements
Inc FEP
- Free Erythrocyte Protoporhyrin
- Because less haem to bind to protoporhyrin to make Hb
Bone marrow biopsy
- Little or no iron on marrow when deficient

Underlying cause
Ferrous sulfate

Plummer-Vinson Syndrome

Iron deficiency anaemia with oesophageal web
Atrophic glossitisAnaemia
- Beefy red tongue
Dysphagia

Anaemia of chronic disease

NB may be found at normocytic stage - ie has same stages as iron deficiency
- as slow and chronic, may take long time to reach the microcytic stage
AssocMost common type in hospitalised pts
- Chronic inflammation
- Cancer
- RhA
- etc
Cause - inc acute phase reactants
Causes a microcytic anaemia as dec Fe available for RBC synth
- Hepcidin - sequesters storage into storage sites
  - Meant to prevent bugs getting Fe
  - Stops macrophage to erythroid precursor Fe transfer
  - Suppresses EPO synth
Ix
- Inc ferritin
  - Because hepcidin (an acute phase reactant) has made Fe go into cell storage
  - So behaves as if an acute phase reactant so will be Inc due to the inflammatory state

Dec TIBC

Because liver cells stuffed with iron so thinks plenty around, so makes less TIBC as don't feel the need to grab what's there

Dec serum iron
Dec transferrin saturation
Inc FEP - as less haem made
Rx
Underlying cause
Exogenous EPO in a few pts esp Ca pts

Sideroblastic anaemia

Due to defective protoporhyrin synth
- So make less Hb
- So microcytic
How protoporhyrin is made:
- 8 rxns!
- Some in cytoplasm, some in mitochondria in erythroblasts
- First step
  - SuccinylCoA converted into AminoLevulinic Acid (via ALASynthase)
    - ALAS is RDS in protoporhyrin production
    - use Vit B6 as cofactor
  - ALA converted to Porphobilinogen by ALADehydrogenase
  - then bunch of other rxns
- Final rxn attaches protoporhyrin IX to Fe to make haem
  - by ferrochelatase
  - in mitochondria
Problem:
- Not making enough protoporhyrin, so less haem
- And iron transfer from cytoplasm into microchondria
  - Gets trapped
  - Builds up in mitochondria
  - As these are around nucleus, get a "ring" of mitochondria filled with Fe around nucleus
  - So characteristic erythroblast cell = ring sideroblast on bone marrow biopsy
    - Prussian Blue Stain - makes iron blue

Types
- Congenital
  - Most common: defect in ALAS - rds
- Acquired
  - EtOH+++
  - Pb poisnoning
    - Denatures enzymes inc ALAD and ferrochelatase
  - Vit B6 deficiency
    - Isoniazid - TB Rx
  - Certain haematological malignancies with mitochondrial iron homoeostasis problems - somatic mut in SF3B1
Ix
- "iron overloaded state"
  - Death of overloaded sideroblastic erythroblasts (fenton rxns etc cause death)
  - Some Fe taken up by macrophages - store xs
  - Some spills into blood, so see in serum
  - So watch out - very same iron lab findings in haemochromatosis!
- Inc ferritin
- Dec TIBC
- Inc serum iron
- Inc transferrin saturation
- Pappenheimer bodies (also in haemolytic anaemia and post splenectomy)

Thalassaemia

Dec synthesis of α or β globin chains
- So dec Hb
- So microcytic
- (NB synth is the problem; cf in sickle cell where you can make them but they are shit)
Mostly inherited mutations
- Carriers protected against Plasmodium falciparum
NB normal Hb
- HbF = α2γ2
- HbA = α2β2
- HbA2 = α2ẟ2
- So α in all Hb, β only in HbA
Types - dec prod of α or β chains
- α-thalassaemia
  - Most due to gene deletion
  - 4 alleles of gene
    - 2 on each copy of Chr 16
  - 1 allele deleted = aSx
  - 2 " " = mild anaemia, slight inc RBC count - may be aSx clinically
    - either both on same Chr = cis deletion - worse!
      - assoc with inc risk of severe offspring thalassaemia
      - as pass on 2 deleted muts if pass this Chr on to child
      - More common in Asians - may be cause of higher rate of spontaneous abortion in Asia
    - or on oppposite Chr = trans deletion
      - more common in Africa
  - 3 " " = Severe anaemia
    - after birth, β chains form tetramers (instead of dimers) = HbH
      - HbH mostly seen in SEAsia, Middle East, Med
    - these damage the cell membrane
    - also too high O2 affinity
    - HbH seen on electophoresis
    - Target cells with Heinz bodies (precipitated HbH)

- - microcytic hypochromic anaemia
  - Hepatosplenomegaly
  - May also get Hb Barts (see below)

- 4 " " = lethal in utero

- - - hydrops foetalis
    - γ chains form tetramers = Hb Barts - damage RBCs
      - Barts - Babies
- - - precipitates in RBC
    - has excessive O2 affinity - none delivered to tissues
    - See Hb Barts on electrophoresis
β-thalassaemia
2 β genes on each copy of Chr 11
Mutation lead to (cf α which were deletions)
- zero β production = β° ("null") - note may be a deletion or mut
- dec = β+
- most muts in promoter preceding the gene
get poikilocytosis - abnormal RBCs > 10% of film
- target cells = codocytes

- get a "bleb" in centre where pallor normally is
- so get some Hb building up in the middle
- so get an additional red bit in middle
- happens due to
  - decreased cytoplasm or
  - inc membrane surface area
  - makes cell "flabby"

anisocytosis
elliptocytosis
Hypochromic anemia
schistocyte

wide spectrum of disease
- Minor
  - Mildest
  - β/β+
    - Some target cells
    - Mostly aSx
    - Inc RBC count
    - Microcytic hypochromic
    - Hb electrophoresis
      - Slight dec HbA
      - Inc HbA2 - 5% instead of 2.5%
        May be only finding
      - Inc HbF - 2% instead of 1%
- Major = Cooley's anaemia
  - β°/β°
  - Most severe
  - Mediteraneans
  - Presents as severe anaemis in a few motnhs after birth
    - Survive antenatally as HbF = α2γ2
  - α chains make tetramers
    - precipitate, damage RBC
    - Get ineffective erythropoiesis - precipitates and damages as making cell
    - Spleen recognises that cell is fekked so extravascular haemolysis
    - So severe anaemia
  - get massive erythroid hyperplasia
    - Expansion of haematopoesis into marrow of skull, facial bones
      - (see these two signs in sickle cell too)
      - "crew cut appearance" on X ray

- - Chipmunk facies

Extramedullary haematopoiesis with hepatosplenomegally
- liver, spleen
Risk aplastic crisis if infected with Parvovirus B19
- infects erythroid precursors and shuts it down
- normal people - not really an issue as have major reserve
- usually self limiting to a week or so
- in these pts, no reserve so fekked
Chronic transfusions needed
- But secondary haemochromatosis risk
Blood smear
- microcytic hypochromic anaemia
- target cells
- nucleated red blood cells - due to extramedullary haematopoiesis
  - they "escape" spleen/liver before fully denucleated
  - "as not made in the proper location so bit crap"
Electophoresis
- Little or no HbA
- Inc HbA2, HbF

Basophilic stippling
Rx
- Minor
  - not really needed
  - Poss transfusions if problems in pregnancy
  - Inc risk of gallstones - may need cholecystecomy
- Major
  - Transfusions - haemochromatosis risk, transfusion reaction risk!Splenectomy - reduces transfusions neded as inc t1/2 of RBCs
    - Iron chelation to dec haemochromatosis risk
  - BM Transplant
  - Induce increased HbF
    - Hydroxyurea
    - Butyrates

Microcytic Anaemia - Pathoma