B4 - folate, vit B12, anaemia Flashcards
Vit B12 required for
- Required for nuclear maturation for DNA synthesis
Vit B12 comes from
- From animal products in diet
vit B12 is absorbed in
- Absorbed in ileum (requires intrinsic factor)
Vit B12 stores
- Large stores (years)
- 2 main reactions that require B12
- 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
deficient intake of vit B12
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
Vit B12 absorption process
○ 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
intrinsic factor
○ 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
transcobalamin 2
○ 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
Ingested Vit B12
○ 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
causes of vit B12 deficiency
○ 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
pernicious anaemia
- 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
pernicious anaemia is an autoimmune disease causing reduced secretion of
intrinsic factor
Clinical features of B12 deficiency
- 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
assay for B12
○ 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
holoTransCobalamin assay
§ Eliminated issues of patients with normal B12 levels but with a functional deficiency of B12 - better assay test
bone marrow appearance in low vit B12
○ Hypercellular; megaloblastic erythropoiesis
○ Bone marrow is overworked to make up for ineffective erythropoiesis
folate is gotten from
fruit and vegetables
folate is absorbed in
upper small bowels
folate stores
3 months
folate deficiencies are uncommon because
- Folate deficiency is uncommon because it is found more broadly in diet and a number of foods are fortified with folate
folate is required for
- 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
causes of folate deficiency
- 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
neural tube defects in folate deficiency
- 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
megaloblastic anaemia
- 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
- Enlarged red blood cells or red blood cell precursors in the bone marrow
megaloblastic anaemia haemotology
○ Macrocytic anaemia (oval) ○ MCV > 100 ○ Hypersegmented neutrophils ○ Mild haemolysis ○ Increased bilirubin ○ Hypercellular bone marrow
other microcytic anaemias
- 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
microcytic anaemia due to liver disease
- Liver disease
○ Target cells
○ Acanthocytes - advanced liver disease, spiky cells
reticulocytosis
higher MCV, response to anaemia (large amount of immature red blood cells released from the bone marrow)
