Anaemia + B12 and folate metabolism Flashcards
what is anaemia
a haemoglobin concentration lower than the normal range
how can body adjust to the lower concentration of haemoglobin
- increasing cardiac stroke volume to increase blood supply to tissues
- increase concentration of 2,3-bisphosphoglycerate to promote oxygen dissociation
signs of anaemia
- pallor
- tachycardia
- systolic flow murmur
- tachypnoea
- hypotension
specific signs associated with cause of anaemia
- koilonychia (spoon shaped nails) - iton deficiency
- angular stomatitis (inflammation of corners of mouth) - iron deficiency
- glossitis (inflammation + depapillation of tongue) - B12 deficiency
- abnormal facial bone development (expansion of haemopoietic tissue at young age) - thalassaemia
symptoms of anaemia
- shortness of breath
- palpitations
- headaches
- claudication
- angina
- weakness + lethargy
- confusion
life cycle of an erythrocyte
bone marrow (production)
peripheral RBC (function)
reticuloendothelial system (removal)
why might anaemia develop
production
- reduced or dysfunctional erythropoiesis
- abnormal haem synthesis
- abnormal globin chain synthesis
function
- abnormal structure
- mechanical damage
- abnormal metabolism
removal
- excessive bleeding
- increased removal by reticuloendothelial system
classifications of anaemia
- macrocytic
- microcytic
- normocytic
role of erythropoietin (EPO) in hormonal control of erythropoiesis
- pericytes in kidney sense hypoxia and produce EPO
- EPO binds to receptors on erythroblasts in bone marrow and stimulates red cell production
- increased number of RBC
- high blood oxygen acts as negative feedback
reduced or dysfunctional erythropoesis
- chronic kidney disease - lack of response in haemostatic loop or insufficient production of EPO
- marrow unable to respond to EPO - after chemotherapy, ionising radiation, autoimmunity, infection with parvovirus
- marrow infiltrated by cancer cells or fibrous tissue - normal haemopoietic cells reduced
- anaemia of chronic disease - iron not made available to marrow for RBC production
- myelodysplastic syndromes - abnormal clones of marrow stem cells limit capacity to make red and white cells
defects in haemoglobin synthesis
- deficiency in iron, vitamin B12 and folate - lower RBC production as they’re key for Hb synthesis
- mutations in genes encoding globin chain proteins - thalassaemias (alter amount) and sickle cell disease (alter function)
what is sideroblastic anaemia
body has enough iron but unable to use it to produce haemoglobin
what is megaloblastic anaemia
- most common cause of macrocytic anaemia
- erythrocytes large and show oval morphology
- due to deficiency of vitamin B12 and folate as red cell precursors can’t synthesise DNA and divide so nuclear maturation and cell division lag behind cytoplasm development
- large red cell precursors with large nuclei and open chromatin
haemolytic anaemia
destruction of RBCs in blood vessels or spleen faster than they can be replaced
acquired damage to RBCs
- microangiopathic haemolytic anaemias from mechanical damage - shear stress e.g. defective heart valve, cells snagging on fibrin strands e.g. disseminated intravascular coagulation
- heat damage from severe burns - dehydrates RBCs
- osmotic damage
inherited causes of RBC damage
- e.g. hereditary spherocytosis
- mutations in genes coding for proteins involved in interactions between plasma membrane and cytoskeleton
- cells less flexible and more easily damaged
- break up in circulation or removed more quilky by RES
inherited causes of RBC damage
- hereditary spherocytosis
- glucose-6-phosphate dehydrogenase deficiency
hereditary spherocytosis
- RBCs spherical instead of having biconcave shape
- defective cell membrane proteins making them more fragile and easily damaged
- break up in circulation or removed more quicly by RES
defects in red cell metabolism
G6PDH deficiency
- NADPH limited so lower GSH
- more susceptible to oxidative damage
- lipid peroxidation and protein damage lead to haemolysis
- Heinz bodies recognised by RES and removed
pyruvate kinase deficiency
- red cells become deficient in ATP so haemolysis
- lack mitochondria so depend on glycolysis for energy production
autoimmune haemolytic anaemia
- autoantibodies bind to proteins on RBC membrnae causing RBCs to be targeted and destroyed
- diseases like lupus, lymphomas, HIV
- some medications like penicilin
excessive bleeding
acute blood loss
- injury
- surgery
- childbirth
- ruptured blood vessel
chronic bleeding
- heavy menstrual bleeding
- repeated nosebleeds
- haemorrhoids
- occult GI bleeding
- kidney or bladder tumours
chronic NSAID use
- aspirin, ibuprofen, naproxen
- treatment of conditions with pain and inflammation
- induces GI bleeding via inhibtion of COX activity and direct cytotoxic effects on epithelium
removal by reticuloendothelial system
- issue when RBCs destroyed faster than they can be replaced
- overactive RES speeds up process of destruction - seen in hypersplenism
- splenomegaly occurs with haemolytic anaemias due to increased workload
2 features to work out the cause of anaemia
- RBC size (macrocytic, microcytic, normocytic)
- presence or absence of reticulocytes (has marrow responded normally)
where is folate synthesised
bacteria and plants
folate absorption
- mainly in duodenum and jejunum
- converted to tetrahydrofolate (FH4) by intestinal cells
- enters portal circulation and taken up by the liver which acts as a store (enough for 3-4 months)
role of tetrahydrofolate in metabolism
- act as a one-carbon carrier accepting carbon units from different sources
- carbons can be oxidised or reduced to provide carbons for other metabolic reactions
- recipient reactions include synthesis of nucleotide bases required for DNA + RNA synthesis
causes of folate deficiency
- dietary deficiency
- increased requirements - pregnancy, increased erythropoiesis, severe skin disease
- disease of duodenum and jejunum - coeliac, Crohn’s
- drugs inhibiting dihydroflate reductase - methotrexate
- alcoholism - damage to intestinal cells
- urinary loss of folate - liver disease and heart failure
symptoms of folate deficiency
- anaemia symptoms
- reduced sense of taste
- diarrhoea
- numbness and tingling in feet and hands
- muscle weakness
- depression
effects of folate deficiency
- DNA synthesis affected resulting in megaloblastic anaemia
- neural tube defects in developing fetus - folic acid (400μg/day) taken before conception & during 1st 12 weeks of pregnancy
where is vitamin B12 produced
- bacteria
- largely obtained from foods of animal origin
- vegans should take B12 supplement
what is vitamin B12
- water soluble vitamin
- essential cofactor for DNA synthesis
- required for normal eythropoiesis
- essential for normal function and development of CNS
good sources of vitamin B12
- meat
- fish
- milk
- cheese
- eggs
- yeast extract
vitamin B12 absorption
- B12 released from food proteins by preoteolysis in stomach and binds to haptocorrin
- haptocorrin B12 complex digested by pnacreatic proteases in small intestine, releasing B12 which binds to intrinsic factor
- intrinsic factor-B12 complex binds to cubam receptor and taken up by enterocytes by receptor-mediated endocytosis
- lysosomal release allows B12 to exit via basolateral membrane through MDR1
- B12 forms complex with **transcobalamin II **and released into bloodstream for delivery to various tissues with receptors for transcobalamin II-B12 complex
- liver takes up majority of B12 and stores enough for ~3-6 years
haptocorrin production
- salivary glands
- protects B12 from acid degradation
role of vitamin B12 in metabolism
- transfers methyl group from L-methylmalonyl-CoA to form succinyl-CoA
- transfer methyl group from FH4 to homocysteine to form methionine
causes of vitamin B12 deficiency
- dietary deficiency - vegans
- lack of intrinsic factor - pernicious anaemia
- diseases of the ileum - Crohn’s, ileal resection, tropical sprue
- lack of transcobalamin - congenital defect
- chemical inactivation of B12 - frequent nitrous oxide use
- parasitic infestation - tapeworm in fish can trap B12
- drugs can chelate intrinsic factor - hypercholesterolaemia drug Cholestyramine
what is pernicious anaemia
- decreased or absent intrinsic factor causing progressive exhaustion of B12 reserves
- autoimmune disease
- blocking antibody blocks binding of B12 to IF
- binding antibody prevent receptor mediated endocytosis
symptoms of B12 deficiency
- anaemia symptoms
- glossitis + mouth ulcers
- diarrhoea
- paraesthesia
- disturbed vision
- irritability
the B12-folate link
- B12 and methyltetrahydrofolate are part of methionine cycle in converting homocysteine to methionine
- lack of B12 traps folate in the stable methyl-FH4 form preventing its use in other reactions like nucleotide synthesis
- functional folate deficiency despite adequate dietary supply of folate
- consequences of B12 and folate deficiency overlap as both have detrimental impact on DNA synthesis
why do B12 and folate deficiency cause megaloblastic anaemia
- thymidine deficiency
- uracil incorporated into DNA
- DNA repair enzymes repair by excision
- asynchronous maturation between nucleus and cytoplasm so nucleus deosn’t fully mature
- large red cell precursors with inappropriately large nuclei and open chromatin
megaloblastic features in a peripheral blood film
- anisopoikilocytosis
- tear drop
- ovalocytes
- hypersegmented neutrophils
- macrocytic
- pancytopenia can develop (low platelets and neutrophils)
investigation of megaloblastic anaemia
- low haemoglobin
- raised MCV
- low erythrocytes
- low reticulocytes
- low/normal leucocytes
- low/normal platelets
- raised serum ferritin
- raised plasma LDH
- raised bilirubin
- hypersegmented neutrophils
- increased cellularity of bone marrow
- check Vitamin B12, serum folate and anti-intrinsic factor antibodies
treatment for B12 deficiency
- pernicious anaemia: hydroxocobalamin intramuscularly for life (not orally because can’t absorb B12 due to intinsic factor deficiency)
- other causes: oral B12 tablets and dietary advice
- transfuse small volumes with care as blood transufucion can cause high output cardiac failure
treatment for folate deficiency
- oral folic acid daily
- dietary advice
- check B12 levels so treatment doesn’t mask underlying B12 deficiency
what is subacute combined degeneration of the cord
- degeneration of posterior and lateral columns of the spinal cord
- gradual onset
- weakness, numbness and tingling in arms, legs and trunk
- changes in mental state
- result in irreversible nervous system damage
what can B12 deficiency result in
- focal demyelination
- reversible peripheral neuropathy
- subacute combined degeneration of the cord
types of macrocytic anaemia
- megaloblastic anaemias
- macronormoblastic erythropoiesis
- “stress” erythropoiesis
causes of macrocytic anaemia
- liver disease
- alcohol consumption
- hypothyroidism
- haemolytic anaemias
- myelodysplasia
- Vitamin B12/folate deficiency
megaloblastic anaemias
- interference with DNA synthesis during erythropoiesis so development of nucleus retarded compared to cytoplasm
- cell division delayed and erythroblasts grow to form megaloblasts
examples
- vitamin B12/folate deficiency
- drugs that interfere with DNA synthesis
- erythroid leukaemias where DNA synthesis is retarded
macronormoblastic erythropoiesis
- normal relationship between development of nucleus and cytoplasm
- erythrocytes larger than normal
examples
- liver disease
- alcohol toxicity
- myelodysplastic syndromes
“stress” erythropoiesis
- conditions associated with a high reticulocyte count (high MCV)
- high level of erythropoietin so expanded and accelerated erythropoiesis
examples
- recovery from blood loss due to haemmorhage
- recovery from haemolytic anaemia
causes of microcytic anaemia (TAILS)
- Thalassaemia
- Anaemia of chronic disease
- Iron deficinecy anaemia
- Lead poisoning
- Sideroblastic anaemia
normocytic anaemia
size of RBCs normal but haematocrit and haemoglobin levels reduced
causes of microcytic anaemias
- anaemia of chronic disease (reduction in serum iron levels as more taken up by cells)
- early stage microcytic anaemia
- combination of microcytic and macrocytic anaemias
- renal failure
- bone marrow failure
- acute blood loss
