B4 - folate, vit B12, anaemia

Question 1

Vit B12 required for

Answer 1

• Required for nuclear maturation for DNA synthesis

Question 2

Vit B12 comes from

Answer 2

• From animal products in diet

Question 3

vit B12 is absorbed in

Answer 3

• Absorbed in ileum (requires intrinsic factor)

Question 4

Vit B12 stores

Answer 4

• Large stores (years)

Question 5

• 2 main reactions that require B12

Answer 5

1. Conversion of homocysteine to methionine
   i. Important in methylation of DNA, RNA and proteins
   2. Convert methylmalonyl CoA to succinyl CoA
   i. Important in fatty acid breakdown and energy production

Question 6

deficient intake of vit B12

Answer 6

may take years to manifest
○ Early stages is usually asymptomatic
○ Latter stages causes problems with haematopoiesis (blood cell productions) and neurological complications with peripheral nerves and spinal cord

Question 7

Vit B12 absorption process

Answer 7

○ Ingested Vit B12 is initially dissociated by proteases
○ Binds to r-protein otherwise known as transcobalamin 1
○ Passes through to the first part of the small bowel where it dissociates
○ Vit B12 binds to intrinsic factor (IF) which is required for the stability and safe passage through to the terminal ilium
§ IF secreted by gastric parietal cells
§ IF-B12 complex attaches to receptors in terminal ileum
○ Absorbed across the enterocytes in terminal ilium where it binds to transcobalamin 2
§ Caries B12 in plasma to the liver, BM, tissues
§ Most B12 in plasma is attached to another B12 binding protein (TCI) and is functionally inactive
○ Then delivered through blood stream

Question 8

intrinsic factor

Answer 8

○ Vit B12 binds to intrinsic factor (IF) which is required for the stability and safe passage through to the terminal ilium
§ IF secreted by gastric parietal cells
§ IF-B12 complex attaches to receptors in terminal ileum

Question 9

transcobalamin 2

Answer 9

○ Absorbed across the enterocytes in terminal ilium where it binds to transcobalamin 2
§ Caries B12 in plasma to the liver, BM, tissues
§ Most B12 in plasma is attached to another B12 binding protein (TCI) and is functionally inactive

Question 10

Ingested Vit B12

Answer 10

○ Ingested Vit B12 is initially dissociated by proteases
○ Binds to r-protein otherwise known as transcobalamin 1
○ Passes through to the first part of the small bowel where it dissociates

Question 11

causes of vit B12 deficiency

Answer 11

○ Diet: inadequate intake
§ Vegans: no animal products in diet
§ Infants born to B12-deficient mothers and breastfed
§ Malnutrition, famine, poverty
○ Malabsorption
§ Gastric causes: pernicious anaemia, gastrectomy eg. Chron’s disease
§ Intestinal causes: defects of the ileum (surgical resection: Crohn’s disease), bacterial overgrowth
○ Accelerated loss

Question 12

pernicious anaemia

Answer 12

• Main cause of Vit B12 deficiency
  
  • Auto-immune gastritis: reduced secretion of IF
  • Antibodies to IF or parietal cells, prevents formation of IF-B12 complex
  • Clinical features
    ○ Female: male = 6:1
    ○ Peak age = 60 years
    ○ Family history of auto immune disease
    ○ Greying hair, blue eyes, blood group A - disease associations, not ubiquitous
  • Auto-immune disease
  • Anaemia with ‘lemon yellow’ tint - increased bilirubin due to ineffective erythropoiesis, and a degree of haemolysis
  • Macrocytic anaemia - usually not profound
  • Low vit B12
  • Rx: IM vit B12

Question 13

pernicious anaemia is an autoimmune disease causing reduced secretion of

Answer 13

intrinsic factor

Question 14

Clinical features of B12 deficiency

Answer 14

• Asymptomatic, incidental finding
  
  • Gradual onset anaemia
  • Leucopoenia, thrombocytopaenia
  • Mild jaundice (ineffective erythropoiesis in BM due to lack of vit B12)
  • Neuropathy
    ○ Subacute combined degeneration of the spinal cord - only in profound longstanding B12 deficiency
    ○ Demyelination of the dorsal (posterior) and lateral spinal columns
    ○ Tingling of the hands/feet - peripheral neuropathy
    ○ Difficulty walking

Question 15

assay for B12

Answer 15

○ Low serum vit B12
○ HoloTransCobalamin assay: measure active B12
§ Eliminated issues of patients with normal B12 levels but with a functional deficiency of B12 - better assay test
○ Normal serum folate; raised bilirubin and LDH - causing yellow tinge
§ Due to low level haemolysis related to ineffective red blood cell production

Question 16

holoTransCobalamin assay

Answer 16

§ Eliminated issues of patients with normal B12 levels but with a functional deficiency of B12 - better assay test

Question 17

bone marrow appearance in low vit B12

Answer 17

○ Hypercellular; megaloblastic erythropoiesis

○ Bone marrow is overworked to make up for ineffective erythropoiesis

Question 18

folate is gotten from

Answer 18

fruit and vegetables

Question 19

folate is absorbed in

Answer 19

upper small bowels

Question 20

folate stores

Answer 20

3 months

Question 21

folate deficiencies are uncommon because

Answer 21

• Folate deficiency is uncommon because it is found more broadly in diet and a number of foods are fortified with folate

Question 22

folate is required for

Answer 22

• Essential coenzyme
  
  • Required for synthesis of thymidine monophosphate - and therefore DNA
  • Folate is reduced to tetrahydrofolate (THF)
  • THF is important in the synthesis of purines, pyrimidines and metabolism of amino acids

Question 23

causes of folate deficiency

Answer 23

• Reduced diet intake
  
  • Poor absorption
  • Increased requirements: cell turnover
    ○ Physiological: pregnancy, lactation, premature infants
    ○ Pathological: haemolytic anaemia (red blood cells are churning over more quickly and more substrate is required), inflammatory conditions, exfoliative dermatitis, Crohn disease
  • Excess folate loss
    ○ haemodialysis (protein bound)
  • Drugs: anti-convulsants
  • Alcoholism - often deficient in B group vitamins

Question 24

neural tube defects in folate deficiency

Answer 24

• Fetal growth and development are characterised by widespread cell division
  
  • Adequate folate is critical for DNA and RNA
  • Neural tube defects arise from failure of embryonic neural tube closure between 21 and 27 days post conception when most women are unaware of pregnancy - why they should take folic acid before they start trying
  • Malformations include - variable
    ○ Anencephaly - open brain, lack of skull vault
    ○ Encephalocele - herniation of the meninges (and brain)
    ○ Iniencephaly - occipital skull and spine defects with extreme retroflexion of the head
    ○ Craniorachischisis - completely open brain and spinal cord
    ○ Spina bifida, closed spinal dysraphism, meningocele, myelomeningocele

Question 25

megaloblastic anaemia

Answer 25

• Anaemia associated with impaired DNA synthesis
  
  • Enlarged red blood cells or red blood cell precursors in the bone marrow
    Haematology
    ○ Macrocytic anaemia (oval)
    ○ MCV > 100
    ○ Hypersegmented neutrophils
    ○ Mild haemolysis
    ○ Increased bilirubin
    ○ Hypercellular bone marrow
    Biochemistry
    ○ Reduced serum vitamin B12 or RBC folate
    ○ IF or parietal cell antibodies - in pernicious anaemia
  • Abnormal appearance of erythroblasts in the bone marrow (large)
  • Delay in development of nuclear chromatin given open lacy appearance
  • Defect in the DNA synthesis
  • Usually caused by deficiency of B12 or folate

Question 26

megaloblastic anaemia haemotology

Answer 26

○ Macrocytic anaemia (oval) 
		○ MCV > 100 
		○ Hypersegmented neutrophils 
		○ Mild haemolysis
		○ Increased bilirubin
		○ Hypercellular bone marrow

Question 27

other microcytic anaemias

Answer 27

• Anaemia with enlarged red blood cells
  
  • MCV > 100fL
  • Liver disease
    ○ Target cells
    ○ Acanthocytes - advanced liver disease, spiky cells
  • Alcohol
  • Reticulocytosis: higher MCV, response to anaemia (large amount of immature red blood cells released from the bone marrow)
  • Hypothyroidism
  • Myelodysplastic syndrome
    ○ Bone marrow condition
    ○ Affects older aged people
    ○ Ineffective haematopoiesis

Question 28

microcytic anaemia due to liver disease

Answer 28

• Liver disease
  ○ Target cells
  ○ Acanthocytes - advanced liver disease, spiky cells

Question 29

reticulocytosis

Answer 29

higher MCV, response to anaemia (large amount of immature red blood cells released from the bone marrow)