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MEH > 4.1 - Anaemia And Vitamin B12 And Folate metabolism > Flashcards

4.1 - Anaemia And Vitamin B12 And Folate metabolism Flashcards

1
Q

What is anaemia?

A

A haemoglobin concentration lower than the normal range. Not a diagnosis but a manifestation of an underlying disease state, important to establish the cause of the anaemia

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2
Q

What is the normal range of haemoglobin?

A

Normal range varies with sex, age, and ethnicity so the point that a patient becomes anaemic depends on these parameters.

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3
Q

What symptoms are usually present in anaemia?

A 
confusion
Tiredness
SOB
Palpitations
Headaches
Claudication
Angina
Weakness or lethargy
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4
Q

What signs are present in an anaemic patient?

A 
Pallor
Tachycardia
Systolic flow murmur
Tachypnoea
Hypotension
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5
Q

What specific signs are associated with the causes of anaemia?

A

Iron deficiency : Koilonychia, angular stomatitis

Vitamin B12 deficiency : Glossitis

Thalassaemia : abnormal facial bone development

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6
Q

Why might anaemia develop?

A
  • Reduced or dysfunctional erythropoiesis
  • Abnormal Haem synthesis
  • Abnormal globin chain synthesis
  • Abnormal structure
  • Mechanical damage
  • Abnormal metabolism
  • excessive bleeding
  • increased removal by reticuloendothelial system
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7
Q

Describe what causes reduced or dysfunctional erythropoiesis?

A

Anaemia can result from lack of response in the haemostatic loop e.g in chronic kidney disease the kidney stops making erythropoietin

Bone marrow not responding to erythropoietin

Number of normal haemopoietic cells reduced.

Anaemia of chronic disease

Myelodysplastic syndromes.

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8
Q

What is claudication?

A

Pain in legs when walking.

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9
Q

What is koilonychia?

A

Spoon shaped nails associated with iron deficiency

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10
Q

What in angular stomatitis?

A

Inflammation of the corners of the mouth associated with iron deficiency

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11
Q

What is gloss it is?

A

Inflammation and depapillation of tongue.

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12
Q

What may cause the bone marrow to stop responding to erythropoietin?

A

chemotherapy, toxic insult or parvovirus infection

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13
Q

What may cause the number of normal maemopoietuc cells in the bone marrow to be reduced?

A

If the marrow is infiltrated by cancer cells or fibrous tissue. (Myelofibrosis)

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14
Q

What is anaemia of chronic disease?

A

When a chronic disease causes anaemia as a secondary symptom. For example, rheumatoid arthritis causes iron to be unavailable to marrow, resulting in a decrease in RBC production

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15
Q

What are myelodysplastic syndromes?

A

Rare forms of blood cancer. Abnormal clones of bone marrow stem cells limit the capacity to make both red and white blood cells.

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16
Q

What might cause a defect in the synthesis of haemoglobin? (4)

A
  1. Mutations in the genes encoding the globin chain proteins
    • α Thalassaemia
    • β Thalassaemia
    • Sickle cell disease
  2. Defects in the haem synthetic pathway can lead to Sideroblastic anaemia
  3. Insufficient iron in diet can lead to iron deficiency anaemia (not enough iron to make Haem)
  4. Anaemia of chronic disease can result in a functional iron deficiency (sufficient iron in body Haemoglobin
    but not made available for erythropoiesis)
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17
Q

How might mechanical damage to RBCs result due to inherited abnormalities?

A

Mutations in the genes coding for
proteins involved in interactions between
the plasma membrane and cytoskeleton.
Cause cells to become less flexible and more easily damaged.
Break up in the circulation or removed more quickly by RES
(Hereditary spherocytosis)

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18
Q

Hw might RBCs acquire damage (not due to inheritance)?

A

Microangiopathic haemolytic anaemias result from mechanical damage e.g.
• Shear stress as cells pass through a defective heart valve (e.g. MAHA in aortic valve stenosis)
• Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred (e.g. in Disseminated Intravascular coagulation)
• Heat damage from severe burns
• Osmotic damage (drowning in freshwater)

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19
Q

Why does G6PDH deficiency result cause defects in red cell metabolism?

A

Decreased G6PDH activity limits amount of NADPH formed in pentose phosphate pathway. RBCs subject to more oxidative damage as glutathione cannot be reduced.
Oxidative stress leads to lipid peroxidation, cell membrane damage, lack of deform ability a dn mechanical stress. Also impacts proteins, resulting in aggregates of cross linked haemoglobin (Heinz bodies)

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20
Q

How does pyruvate kinase deficiency affect RBC metabolism?

A

Pyruvate kinase is the
final enzyme in glycolysis. Rare genetic defects in
this enzyme occur in
some patients. As red cells lack
mitochondria they depend on glycolysis for energy production. A defective glycolytic pathway causes red cells to rapidly become deficient in ATP and they undergo haemolysis.

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21
Q

How does blood loss cause anaemia?

A

Loss of blood means loss of iron. As iron levels depleted we cannot form anymore RBCs

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22
Q

What incidents result in acute blood loss?

A

Injury
Surgery
Childbirth
Ruptured blood vessel

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23
Q

What causes chronic bleeding?

A 
Heavy menstrual bleeding
Repeated nosebleeds
Haemorrhoids
Occult gastrointestinal bleeding
(blood lost in stool)
- Ulcers (stomach or
small intestine), Diverticulosis, Polyps in large intestine, Intestinal cancer
Kidney or bladder tumours (blood
lost in urine)
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24
Q

What are NSAIDS?

A

Nonsteroidal anti-inflammatory drugs.

Aspirin
Ibuprofen
Naproxen

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25
Q

What are the negative results of chronic NSAID usage?

A

Chronic bleeding, leading to anaemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used for treatment of conditions with pain and inflammation
Induce GI injury/bleeding via:
Inhibition of cyclooxygenase (COX) activity
Direct cytotoxic effects on epithelium

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26
Q

What is autoimmune haemolytic anaemia?

A

When autoantibodies bind to the red cell membrane

proteins causing them to be recognised by macrophages in the spleen and destroyed.

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27
Q

What is a common sign of haemolytic anaemia?

A

Splenomegaly as the spleen is working hard to remove abnormal or damaged RBCs

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28
Q

What are the 2 main organs of the reticuloendothelial system?

A

Liver and spleen

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29
Q

Why does myelofibrosis result in anaemia?

A

Proliferation of mutated haematopoietic stem cells results in reactive bone marrow fibrosis. Fibrotic marrow has little space for haemopoeisis.

These mutated progenitor cells from marrow can also colonise the liver and spleen leading to extramedullary haemopoiesis and hepatosplenomegaly.

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30
Q

How does thalassemia cause anaemia?

A

Inherited disorders resulting from decreased or absent α or β globin chain production (α - and β - thalassaemia respectively). Microtcytic hypochromic RBCs.

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31
Q

What 2 key features can help to work out the cause of an anaemia?

A
  1. The rbc size – macrocytic, microcytic, normocytic (big, small, normal)
  2. The presence or absence of reticulocytosis (has the marrow responded normally?)
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32
Q

What are reticulocytes?

A

Immature red blood cells (i.e. those which have just been released from the marrow into blood)
No nucleus & eliminate remaining mitochondria
Typically compose ~1% of all red blood cells and take ~ 1 day to mature into erythrocytes

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33
Q

How will an increase in reticulocytes affect corpuscular volume?

A

Will increas corpuscular volume (MCV) as reticulocytes are larger than mature RBCs

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34
Q

If the patient is anaemic and the reticulocyte count is normal/low, what does this indicate?

A

That there is a problem with haemopoiesis within the bone marrow

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35
Q

What conditions cause the bone marrow to produce microcytic RBC?

A 
TAILS
Thalassaemia
Anaemaia of chronic disease 
Iron deficinecy
Lead poisoning
Sideroblastic anaemia
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36
Q

What conditions result in macrocytic red blood cell production by the bone marrow?

A 
Vitamin B12 deficinecy
Folate deficiency
Myelodysplasia
Liver disease
Alcohol toxicity
37
Q

What conditions cause anaemia with small number of normocytic RBC produced by bone marrow?

A

Primary bone marrow failure (aplastic anaemia)

Secondary bone marrow failure
ACD, Uraemia, HIV

38
Q

What conditions may cause haemolysis?

A 
Autoimmune conditions
MAHA (microangiopathic haemolytic anaemia)
Haemoglobinopathies
Enzyme defects
Membrane defects (spherocytosis)
39
Q

What conditions could cause anaemia with no haemolysis and normal RBC production?

A

Acute blood loss
Chronic bleeding
NSAID usage
Splenic sequestration

40
Q

What are macrocytic anaemia?

A

Anaemia where the average red cell size is greater than normal
E.g. megaloblastic anaemias, macronormoblastic erythropoiesis and stress erythropoiesis

41
Q

What is megaloblastic anaemia?

A

Interference with DNA synthesis during erythropoiesis causes nucleus to develop slower in relation to maturation of cytoplasm.
Cell division is delayed whilst erythroblasts continue to grow.
Enlarged erythroblast are caused megaloblasts which give rise to larger than normal RBCs

42
Q

What cause megaloblastic anaemias?

A

things that interfere with DNA synthesis such as:

Vitamin B12/folate deficiency

Drugs that interfere with DNA synthesis (anti-cancer drugs)

Some erythrocyte leukaemias

43
Q

What is a macronormoblastic erythropoiesis?

A

Erythroblasts are larger than normal and give rise to larger than normal red blood cells. Unlike megaloblastic anaemias, Normal relationship between the development of the nucleus and the cytoplasm in maintained.

44
Q

What conditions cause macronormoblastic erythropoiesis?

A

Liver disease
Alcohol toxicity
Some myelodysplastic syndromes

45
Q

What is stress erythropoiesis?

A

Conditions associated with a high reticulocyte count. High level of erythropoietin leads to expanded and accelerated erythropoiesis. Lots of reticulocytes increase the MCV.

46
Q

What causes stress erythropoiesis?

A

Recovery from blood loss due to haemorrhage

Recovery from haemolytic anaemia

47
Q

Where is folate synthesised?

A

In bacteria and plants

48
Q

What food is abundant in folate?

A

Green leafy vegetables

49
Q

Where is folate mainly absorbed in our bodies?

A

Duodenum

Jejunum

50
Q

Where in the body is folate stored?

A

Liver

51
Q

Why is folate essential in our diet?

A

Folate required for synthesis of nucleotide bases which is required for DNA and RNA synthesis

52
Q

What are causes of folate deficiency

A

Dietary deficiency (Poor diet)

Increased requirements
• Pregnancy
• Increased erythropoiesis e.g.
haemolytic anaemia 
• Severe skin disease (e.g.
psoriasis, exfoliative dermatitis)

Disease of the duodenum and
jejunum (e.g. coeliac disease,
Crohn’s disease)

Drugs which inhibit dihydrofolate
reductase (e.g. Methotrexate)

Alcoholism (poor diet and damage
to intestinal cells)

Urinary loss of folate in liver
disease and heart failure

53
Q

How much folate can be stored in the body?

A

Enough folate for 3-4 months requirements stored in the liver.

54
Q

What are the symptoms of folate deficiency?

A 
Those related to anaemia
Reduced sense of taste
Diarrhoea
Numbness and tingling in feet and
hands
Muscle weakness 
Depression
55
Q

What can be given to prevent neural tube defects in babies?

A 
Folic acid (400μg/day) taken before conception & during 1st 12 weeks of pregnancy prevents majority of
neural tube defects in babies
56
Q

Give an example of neural tube defects?

A

Spina bifida

57
Q

What is spina bifida?

A

Spina bifida is when a baby’s spine and spinal cord does not develop properly in the womb, causing a gap in the spine. Spina bifida is a type of neural tube defect.

58
Q

What is vitamin B12?

A

A water soluble vitamin which is an essential cofactor for DNA synthesis, due to its role in folate metabolism.

59
Q

Why is vitamin B12 essential?

A

Essential cofactor for DNA synthesis (due to its role
in folate metabolism)
Required for normal
erythropoiesis
Essential for normal function and development of CNS

60
Q

How is vitamin B12 produced?

A

By bacteria

Not by plants or animals

61
Q

What are good sources of vitamin B12?

A 
Meat 
Fish
Milk
Cheese
Eggs
Yeast extract
62
Q

What supplements must people on a vegan diet take?

A

Vitamin B12

63
Q

Where is vitamin B12 stored?

A

In the liver until needed for haemopoiesis

64
Q

How much vitamin B12 can be stored?

A

3-6 years worth of vitamin B12 can be stored in the liver.

65
Q

What is haptocorrin?

A

A protein released by salivary glands, haptocorrin binds with vitamin B12 (after it has been released from food proteins by proteolysis in stomach) protecting it from acid degradation.

66
Q

How is the haptocorrin B12 digested?

A

Haptocorrin B12 complex digested by pancreatic proteases in small intestine releasing B12 which then
binds intrinsic factor.

67
Q

Where is intrinsic factor produced?

A

produced by

gastric parietal cells in small intestine.

68
Q

What are enterocytes?

A

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines.

69
Q

How is vitamin B12 absorbed into enterocytes?

A

Intrinsic factor–B12 complex binds to
cubam receptor which mediates uptake of complex by receptor- mediated endocytosis into
enterocytes

70
Q

How does vitamin B12 exit enterocytes into the blood?

A

Absorbed into the enterocytes as intrisic factor-B12 complex. Complex broken down by lysosomes in enterocytes. Vitamin B12 can then exit via basolateral membrane through MDR1.

71
Q

How is vitamin B12 transported in the blood

A

Binds to transcobalamin in blood and transported around bloodstream

72
Q

What causes a vitamin B12 deficiency?

A

Dietary deficiency (Vegan diet lacking B12 supplementation)

Lack of intrinsic factor (Pernicious
anaemia)

Diseases of the ileum (Crohn’s disease,
ileal resection, tropical sprue)

Lack of transcobalamin (congenital
defect)

Chemical inactivation of B12 e.g.
frequent use of anaesthetic gas nitrous
oxide

Parasitic infestation (rare tapeworm
found in fish can trap B12)

Some drugs can chelate intrinsic factor
(e.g. hypercholesterolaemia drug
Cholestyramine)

73
Q

What is pernicious anaemia?

A

An auto immune disease resulting in lack of intrinsic factor. Decreased or absent Intrinsic
factor (IF) causes progressive
exhaustion of B12 reserves.

74
Q

What are the 2 types of antibody that cause pernicious anaemia?

A

2 types of Antibody (Ab) :

Blocking Ab (more common) blocks binding of B12 to IF (intrinsic factor)
Binding Ab prevents receptor mediated endocytosis of Instrinsic factor-B12 into enterocytes.
75
Q

What are symptoms of vitamin B12 deficiency?

A

Those related to anaemia • Glossitis & mouth ulcers • Diarrhoea • Paraesthesia • Disturbed vision • Irritability

76
Q

How can folate affect the nervous system?

A

Folate deficiency in pregnancy can cause neural tube defects (spina bifida)

77
Q

How can vitamin B12 deficiency affect the nervous system?

A 
Vitamin B12 deficiency
associated with focal
demyelination. B12 deficiency more  often results
in a reversible peripheral
neuropathy.
However, can also result in
a serious condition called
Subacute combined
degeneration of the cord
involving degeneration of
posterior and lateral columns of
the spinal cord which can result is irreversible nervous system damage.
78
Q

What are the symptoms o subacute combined degeneration of the cord?

A

Gradual onset weakness,
numbness & tingling in arms, legs & trunk which progressively worsens
Changes in mental state

79
Q

How does vitamin B12 link to folate?

A

B12 is required to transform methyltetrahydrofolate into tetrahydrofolate for use in synthesis of DNA.
Lack of B12 will “trap” folate in the stable methyltetrahydrofolate form preventing its use in other reactions such as synthesis of thymidine for DNA synthesis.

80
Q

Why do B12 and folate deficiency cause megaloblastic anaemia?

A

Both folate and B12 deficiency ultimately lead to thymidine deficiency.
In the absence of thymidine, uracil is incorporated into DNA instead
DNA repair enzymes detect these errors and constantly
repair by excision
Results in asynchronous maturation between nucleus &
cytoplasm.
Nucleus does not fully mature, cytoplasm matures at the
normal rate
When B12 and folate are deficient, nuclear
maturation and cell divisions lag behind
cytoplasm development.

81
Q

How do megaloblasts vary from erthyroblasts?

A

Megaloblasts are large red cell precursors with
inappropriately large nuclei and open
chromatin. Erythroblasts are much smaller. The mature red cells that develop from megaloblasts are also large leading to a macrocytic anaemia

82
Q

Where are megaloblasts located in a patient with vitamin B12 or folate deficiency?

A

Found in bone marrow. As they are a precursor of macrocytic erythrocytes, they do not enter the blood.

83
Q

What are megaloblastic features of RBC in a peripheral blood film?

A 
Anisopoikilocytosis
Tear drop red cells
Ovalocytes 
Hypersegmented neutrophils
Macrocytic erythrocytes

As B12/folate deficiency progresses a pancytopenia can also develop i.e. low platelets and neutrophils as well

84
Q

What can be found in blood cell investigations of a patient with folate or B12 deficiency?

A

Low haemoglobin, erythrocyte count, reticulocyte count

Raised MCV, serum ferritin, plasma lactate dehydrogenase, bilirubin

85
Q

What investigations should be conducted if megaloblastic anaemia is suspected?

A 
Full blood count
Vitamin B12 and serum folate levels 
Plasma total homocysteine 
Plasma mathylmalonc acid
Anti-intrinsic factor antibodies.
86
Q

How do you treat folate deficiency?

A

Oral folic acid supplement

87
Q

How do you treat percinous anaemia?

A

Hydroxycobalamine intramuscular (NOT oral) for life. No point in increasing folic acid orally as the folic acid cannot be absorbed as intrinsic factor is lacking.

88
Q

How do you treat other causes of B12 deficiency (not pernicious anaemia)?

A

Oral cyanocobalamine

89
Q

Why should patients with severe anaemia caused by vitamin B12 deficiency not have blood transfusion?

A

As can cause high output cardiac failure. If absolutely required transfuse smaller volume with care.

As it takes a long time to become b12 deficient due to high stores, heart adapts to deal with physiological changes. Heart under goes hypertrophy.

MEH (23 decks)

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