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MEH - SEM1 > Session 7: Intro to anaemia, B12 & folate, megaloblastic anaemia, iron metabolism & microcytic anaemia > Flashcards

Session 7: Intro to anaemia, B12 & folate, megaloblastic anaemia, iron metabolism & microcytic anaemia Flashcards

1
Q

What substances are required for DNA synthesis?

A

vitamin B12 & folate

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2
Q

What is macrocytic anaemia and what causes it (5)?

A

Anaemias where RBCs are greater than average (greater MCV)

  • B12 & folate deficiency
  • Liver disease
  • Excessive alcohol
  • Reticulocytotic
  • Myelodysplasia
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3
Q

What does MCV stand for?

A

mean corpuscular volume

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4
Q

What is microcytic anaemia & what causes it? [TAILS]

A

Anaemias where small RBCs are produced

  • Thalassaemia
  • Anaemia of chronic disease
  • Iron deficiency
  • Lead poisoning
  • Sideroblastic anaemia
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5
Q

What are the 3 macrocytic anaemias? Give a brief explanation & examples of each of them.

A
  • megaloblastic anaemia -> development of nucleus is slower than maturation of cytoplasm = form megaloblasts = larger RBCs
    => B12/folate deficiency
  • macronormoblastic erythropoiesis -> normal development of nucleus & cytoplasm but erythroblasts = larger than normal
    => liver disease, alcohol toxicity
  • stress erythropoiesis -> high reticulocyte count (reticulocytes have higher MCV than matured RBCs) => increase overall MCV
    => recovery from blood loss due to haemorrhage & recover from haemolytic anemia
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6
Q

What is normocytic anaemia & what causes it (4)?

A

normal sized RBCs but low number

  • Sickle cell disease
  • Early iron deficiency
  • Anaemia of chronic disease
  • Blood loss
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7
Q

What is anaemia?

A

Haemoglobin concentration lower than normal range

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8
Q

What are the symptoms of anaemia? (6)

A
  • Headaches
  • Weakness & lethargy
  • Claudication (pain in legs/arms occurring when walking or using arms)
  • Angina
  • Shortness of breath
  • Confusion
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9
Q

What are the signs of anaemia? (5)

A
  • Pallor (paleness)
  • Tachycardia
  • Systolic flow murmur
  • Tachypnoea
  • Hypotension
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10
Q

What are specific signs associated with the cause of anaemia? (4)

A
  • Koilonychia (spoon-shaped nails) due to iron deficiency
  • Angular stomatitis (inflammation of corners of the mouth) due to iron deficiency
  • Glossitis (inflammation & depapillation of tongue due to Vit B12 deficiency
  • Abnormal facial bone development (rare because preventable with early diagnosis) due to thalassaemia
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11
Q

Explain the different ways in which reduced/dysfunction of erythropoiesis causes anaemia (3 points).

A
  • Lack of response in haemostatic loop eg chronic kidney disease = kidney stops making erythropoietin => body cannot make RBCs
  • Anaemia can occur from bone marrow being unable to respond to EPO (hormone erythropoietin) eg after chemotherapy
  • Marrow infiltrated by cancer cells or fibrous tissue (myelofibrosis) => number of haemopoietic cells is reduced => body cannot make enough RBCs/quality of RBCs is reduced = causing anaemia
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12
Q

Explain how defects in haemoglobin synthesis can cause anaemia (4).

A

-Defects in haemoglobin synthetic pathway => lead to sideroblastic anaemia (able to make enough iron but cannot put it in haemoglobin)

  • Iron deficiency => not enough iron produced for haem synthesis => anaemia
  • Anaemia of chronic disease = results in functional loss of iron = limiting haemoglobin synthesis
  • Mutations in genes encoding the globin (sub-unit of haem) chain proteins can lead to abnormal haemoglobin production => leading to anaemia.
    o Mutations can alter the function of haem (sickle cell)
    o Amount of haem produced (thalassaemia)
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13
Q

Explain how INHERITED abnormal structure & mechanical damage can cause haemolytic damage.

A
  • mutations in genes coding for proteins involved in interactions between plasma membrane & cytoskeleton
  • Cells become less flexible & more easily damaged
  • Break in circulation or removed by RES
  • Eg RBCs turn into spheres = unable to flex so removed by RES => less RBCs = reduced haemoglobin conc = anaemia
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14
Q

Explain how ACQUIRED abnormal structure & mechanical damage can cause haemolytic anaemia to develop (3).

A
  • Microangiopathic anaemias eg shear stress as cells pass through defective heart valve
  • Heat damage from severe burns => dehydration of RBCs
  • Osmotic damage eg downing in freshwater = massive influx of water causing cells to burst
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15
Q

Explain how defects in RBC metabolism (G6PDH deficiency) can cause the development of anaemia.

A
  • Deficiency lowers the activity of NADPH => less GSH produced = less protection from oxidative stress
  • Aggregates of haemoglobin form (Heinz bodies) => RBCs recognise as defective by RES = removed => reduced number of RBCs = reduced haemoglobin => anaemia
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16
Q

Explain how defects in RBC metabolism (Pyruvate kinase deficiency) can cause the development of anaemia.

A
  • Final step of glycolysis
  • RBCs lack mitochondria so rely on glycolysis for energy production
  • Deficiency causes deficiency in ATP = undergo haemolysis
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17
Q

What are the 2 reasons for defects in RBC metabolism?

A

G6PDH deficiency and Pyruvate kinase deficiency

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18
Q

How might anaemia develop through excessive bleeding? (3)

A
  • Acute blood loss eg childbirth, surgery, injury & ruptured blood vessel
  • Chronic NSAID usage eg aspirin, naproxen & ibuprofen => induces GI bleeding via inhibition of COX activity in platelets (work less efficiently) & direct cytotoxic effects on the epithelium
  • Chronic bleeding – small amount of bleeding continuing over long time => heavy menstrual bleeding, repeated nosebleeds, haemorrhoids, kidney/bladder tumours (blood loss in urine), GI bleeding (blood loss in stool)
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19
Q

How does chronic usage of NSAID drugs cause anaemia?

A

induces GI bleeding via inhibition of COX activity in platelets (work less efficiently) & direct cytotoxic effects on the epithelium

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20
Q

How does increased removal of RBCs by RES cause anaemia?

A
  • Autoimmune haemolytic anaemia = autoantibodies bind to RBC membrane proteins = cause them to be recognised as foreign by macrophages in the spleen => destroyed & removed by RES
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21
Q

What term is used to describe damage to RBCs within their own cells?

A

intravascular haemolysis

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22
Q

What term is used to describe damage of RBCs within the RES?

A

extravascular haemolysis

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23
Q

How does splenomegaly occur from haemolytic anaemia?

A

spleen doing extra work (macrophages that recognise RBC proteins as foreign)

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24
Q

What is haematinic anaemia?

A

deficiency of any of the vitamins and minerals (iron, vit b12, folate) essential for normal erythropoiesis = causing reduction in RBCs

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25
Q

What causes iron deficiency? (5)

A
  • increased blood loss from bleeding eg uterine, GI (eg NSAID usage)
  • increased requirement of iron eg pregnancy, growth spurts in infants, lactation
  • inadequate dietary supply
  • decreased absorption of iron eg due to gastrectomy, coeliac disease
  • anaemia of chronic disease (produce iron but cannot use)
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26
Q

What are the key features of vitamin B12? (8)

A
  • water soluble
  • absorbed in ileum
  • majority is stored in liver => provide B12 for 3-6 years so development of deficiency takes years
  • essential cofactor for DNA synthesis due to its role in folate metabolism
  • required for normal erythropoiesis
  • required for normal function & development of CNS
  • cause increase mean cell volume (formation of megaloblasts) & low haemoglobin
  • produced by bacteria
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27
Q

What are good sources of dietary vitamin b12?

A

animal products eg fish, meat, eggs, and cheese.

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28
Q

Why may vegan people experience vitamin B12 deficiency?

A

lack of animal products in their diets

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29
Q

What is vitamin B12 deficiency caused by? (6)

A
  • dietary deficiency (eg vegan diet lacks, fish, meat, eggs, cheese)
  • diseases of ileum (where it is absorbed) eg chron’s
  • lack of intrinsic factor – causes exhaustion on b12 reserve (pernicious anaemia – blocking IF antibody = blocks binding of B12 to IF OR binding Ab prevents receptor mediated endocytosis )
  • chemical inactivation of B12 eg use of gas nitrous oxide often
  • parasitic infestation (eg rare tapeworm can trap B12)
  • drugs can chelate intrinsic factor
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30
Q

What is pernicious anaemia? What is it caused by?

A

anaemia caused by vitamin B12 deficiency due to a lack of intrinsic factor prevents b12 from being absorbed

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31
Q

What are the symptoms of vitamin B12 deficiency? (6)

A
  • Anaemia symptoms
  • Glossitis & mouth ulcers
  • Diarrhoea
  • Paraesthesia (burning/tingling in hands, arms, legs or feet)
  • Disturbed vision
  • Irritability
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32
Q

What are the key features of folate? (6)

A
  • absorbed in duodenum & jejunum
  • taken up by liver used as store
  • synthesised form = folic acid
  • synthesised in bacteria & plants => particularly found in green leafy vegetables
  • converted to tetrahydrofolate (FH4) by intestinal cells
  • required for DNA & RNA synthesis
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33
Q

What is folate deficiency caused by? (6)

A
  • Dietary deficiency (poor diet => leafy greens)
  • Increased requirement eg pregnancy, increased erythropoiesis (haemolytic anaemia), severe skin disease eg psoriasis, exfoliative dermatitis
  • Disease of duodenum & jejunum (eg coeliac disease, chron’s)
  • Drugs that inhibit dihydrofolate reductase (metabolic pathways)
  • Alcoholism (poor diet & damage to intestinal cells)
  • Urinary loss of folate in lover disease & heart failure
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34
Q

What are the symptoms of folate deficiency? (6)

A
  • Anaemia symptoms
  • Reduced sense of taste
  • Diarrhoea
  • Paraesthesia
  • Muscle weakness
  • Depression
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35
Q

How does folate & B12 deficiency lead to defects in DNA synthesis?

A

leads to thymidine deficiency

  • Uracil replaces thymidine & is incorporated in DNA instead
  • DNA repair enzymes detect errors & constantly repair by excision (try to cut out U base)
  • Results in asynchronous maturation between nucleus & cytoplasm:
    o Nucleus doesn’t fully mature (trying to clip out U base)
    o Cytoplasm matures at normal rate
  • Bone marrow produces abnormally large RBCs (megaloblasts)
  • Causes megaloblastic anaemia (type of macrocytic anaemia)
36
Q

Evaluate the treatment for folate deficiency.

A

Oral folic acid for folate deficiency
- Well tolerated, cheap & effective

37
Q

How is pernicious anaemia (B12 deficiency) treated?

A

Intramuscular hydroxocobalamin (B12 supplements)

38
Q

Why are B12 supplements for pernicious anaemia administered intramuscularly rather than orally?

A

intrinsic factor deficiency prevents B12 absorption so oral B12 supplements would not be absorbed

39
Q

Why may hypokalaemia (low K+ levels) occur at the beginning of treatment for severe pernicious anaemia?

A

due to increased K+ requirement due to erythropoiesis rate increases back to normal

40
Q

How is B12 deficiency treated (other reasons NOT pernicious anaemia)

A

Oral supplements (cyanocobalamin)

41
Q

How does lead poisoning cause microcytic anaemia?

A

lead inhibits enzymes involved in haem synthesis

42
Q

What is haemosiderin? Where does it accumulate?

A

Insoluble
aggregates of clumped ferritin particles, denatured protein & lipid.
Accumulates in macrophages esp in liver, spleen & marrow

43
Q

How does ferritin structure allow iron to enter & be released? is it soluble or insoluble

A

its pores
soluble

44
Q

How does iron deficiency cause anaemia?

A

inadequate supply of iron for haem synthesis to occur

45
Q

What are the causes of iron deficiency? (5)

A
  • increased blood loss from bleeding eg uterine, GI (eg NSAID usage)
  • increased requirement of iron eg pregnancy, growth spurts in infants, lactation
  • inadequate dietary supply
  • decreased absorption of iron eg due to gastrectomy, coeliac disease
  • anaemia of chronic disease (produce iron but cannot use
46
Q

How does iron deficiency cause microcytic anaemia?

A

insufficient haem synthesis

47
Q

What are koilonychia & angular cheilitis caused by?

A

iron deficiency

48
Q

What is koilonychia & angular cheilitis?

A

(spoon-shaped nails) & (inflammation of corners of the mouth)

49
Q

How does sideroblastic anaemia cause microcytic anaemia?

A

an inherited defect in haem synthesis

50
Q

How does anaemia of chronic disease cause microcytic anaemia?

A

hepcidin causes functional iron deficiency

51
Q

Which of the TAILS causes of microcytic anaemia are caused by reduced haem synthesis and which one is caused by reduced globin chain synthesis?

A

Reduced haem synthesis = Iron deficiency, lead poisoning, anaemia of chronic disease & sideroblast anaemia
Reduced globin chain = thalassemia

52
Q

How much dietary iron is needed/day?

A

10-15mg

53
Q

Where is iron absorbed?

A

duodenum & upper jejunum

54
Q

What are some good sources of haem iron?

A

liver, kidney, beef steak, beef burger, chicken, duck, pork chop, salmon/tuna

55
Q

What are some good sources of non-haem iron?

A

fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes

56
Q

How is iron absorbed?

A
  • Absorbed in duodenum & upper jejunum
  • Transporter protein (DMT1) located on apical surface of enterocytes (cell of intestinal lining) => facilitates uptake of non-haem ferrous iron (Fe2+) from intestinal lumen
  • Ferric iron (Fe3+) in intestinal lumen = reduced to ferrous iron by DcytB before uptake by DMT1.
  • Once in enterocyte, haem degraded to release ferrous iron
57
Q

What are the negative influences of iron absorption? How do they inhibit the absorption of iron?

A

Tannins (eg found in tea)
Phytates (eg high in chapattis & pulses)
=> they can bind to non-haem iron inhibiting absorption.
Antacids
Fibre
=> inhibit reduction of ferric to ferrous iron = cannot be absorbed

58
Q

What are the positive influences of iron absorption? How do they promote the absorption of iron?

A

Vitamin C & citrate
prevent formation of insoluble iron compounds eg haemosiderin
Vitamin C helps reduce ferric to ferrous iron

59
Q

How is iron absorption regulated?

A

Regulated by hepcidin which binds to ferroportin causing degradation which prevents iron from leaving the cell & by down-regulating iron uptake by inhibiting transcription of the DMT1 gene.

60
Q

How is iron taken up by cells?

A
  • Fe3+ bound transferrin binds transferrin receptor & enters cytosol (receptor-mediated endocytosis)
  • Fe3+ within endosome released & reduced to Fe2+
  • Fe2+ transported to cytosol via DMT1
  • Fe2+ stored in ferritin, exported by FPN1 (ferroportin) or taken up by mitochondria for use in cytochrome enzymes.
61
Q

What happens to iron once it is in the blood?

A

bound to transport protein transferrin & transported to bone marrow for erythropoiesis or taken up by macrophages in RES as storage pool

62
Q

How is iron transported?

A

Transported by ferroprotein to bloodstream or stored into within enterocytes at ferritin.

63
Q

What are signs and symptoms of iron deficiency?

A
  • Symptoms of anaemia
  • Pica (unusual cravings for non-nutritive substances eg dirt, ice)
  • Cold hands & feet
  • Epithelial changes (structural & functions – eg koilonychia, glossy tongue & angular cheilitis)
64
Q

Why do patients with iron deficiency have cold hands and feet?

A

poor blood circulation due to reduces amount of RBCs providing oxygen to tissues

65
Q

What tests are carried out to diagnose iron deficiency?

A
  • FBC
  • Blood film
  • CHr
  • plasma ferritin
66
Q

What do FBC results of a patient with iron deficiency show?(6)

A
  • Low mean corpuscular vol (MCV) => microcytic RBCs
  • Low mean corpuscular haemoglobin concentration (MCHC)
  • Elevated platelet count
  • Normal or elevated WBC count
  • Low serum ferrtin, iron, low %transferrin saturation & raised TIBC
  • Low reticulocyte haemoglobin content (CHr)
67
Q

What would the blood film results of a patient with iron deficiency show?

A
  • RBCs = microcytic & hypochromic (less colour than normal)
  • Change in size & shape of RBCs
  • Sometimes pencil cells & target cells
68
Q

What is ferritin?

A

iron carrier/store it is soluble

69
Q

Would plasma ferritin be high or low?

A

low and would suggest iron deficiency

70
Q

Why should a normal/increased plasma ferritin result not exclude iron deficiency?

A

plasma ferritin may increase due to cancer, infection, inflammation, liver disease, so there could still be iron deficiency

71
Q

What does CHr (reticulocyte haemoglobin content) test? Why may it be inaccurate?

A

test for functional iron deficiency
remains low in thalassaemia/inflammatory responses

72
Q

How and where is iron deposited in iron overload? How does it damage tissues?

A

deposited as haemosiderin in end organs compromising function tissue

73
Q

What causes iron overload?

A

transfusion-associated hemosiderosis & hereditary hemochromatosis (HH)

74
Q

What are the implications of iron overload?

A

Promotes free radical formation & organ damage

75
Q

How is transfusion-associated hemosiderosis caused?

A

Repeated blood transfusions = cause gradual accumulation (over several years) of iron
400ml blood transfues = 200mg iron

76
Q

Give examples of transfusion-dependent anaemias.

A

sickle cell disease and thalassaemia

77
Q

What are the effects of build up of haemosiderin? (7)

A
  • Liver cirrhosis
  • Diabetes mellitus
  • Hypogonadism
  • Cardiomyopathy
  • Arthropathy
  • Slate grey colour of skin (transfusion-associated hemosiderosis)
  • Increased skin pigmentation from iron (hereditary hemochromatosis)
78
Q

How is transfusion-associated hemosiderosis delayed?

A

iron chelating agents

79
Q

What is Hereditary Hemochromatosis (HH) caused by?

A
  • Autosomal recessive disease caused by a mutation in the HFE gene (on Chr 6)
    -HFE = interacts with transferrin receptor reducing the affinity of iron-bound transferrin & promotes hepcidin expression
  • Mutation causes loss of negative influences on iron uptake & absorption
80
Q

How is hereditary hemochromatosis treated?

A

through regular phlebotomy/venesection – regularly draw blood from a patient to remove iron from iron.

81
Q

When is hepcidin synthesis decreased and when it is increased?

A

Decreased by high erythropoietic
activity
Increased in iron overload

82
Q

What full body count results would be expected from a patient with B12 deficiency?

A

increase mean cell volume (formation of megaloblasts) & low haemoglobin

83
Q

What does ferroportin do?

A

transports iron out of cell across basolateral membrane of enterocytes into bloodstream

84
Q

What is transferrin and what does it do?

A

an iron binding plasma glycoprotein which acts as a carrier for iron in the bloodstream

85
Q

Name two intracellular protein-iron complexes that are used to store iron.

A

ferritin & haemosiderin

86
Q

Why is there a low RBC count in patients with iron deficiency?

A

there no iron available for the bone marrow to produce RBC

MEH - SEM1 (6 decks)

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