Microcytic Anaemia - Pathoma

  • 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
Rx
  • 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
Robbins Basic Pathology, Robbins Pathologic Basis of Disease, Robbins Review of Pathology (MCQs - very path-y), Robbins Flash Cards, Baby Robbins, Robbins Atlas - some exact same images come up in the exam, 100 Cases in ClinicalPathology - possibly the best Qbank for the practical