Session 7: Intro to anaemia, B12 & folate, megaloblastic anaemia, iron metabolism & microcytic anaemia Flashcards
What substances are required for DNA synthesis?
vitamin B12 & folate
What is macrocytic anaemia and what causes it (5)?
Anaemias where RBCs are greater than average (greater MCV)
- B12 & folate deficiency
- Liver disease
- Excessive alcohol
- Reticulocytotic
- Myelodysplasia
What does MCV stand for?
mean corpuscular volume
What is microcytic anaemia & what causes it? [TAILS]
Anaemias where small RBCs are produced
- Thalassaemia
- Anaemia of chronic disease
- Iron deficiency
- Lead poisoning
- Sideroblastic anaemia
What are the 3 macrocytic anaemias? Give a brief explanation & examples of each of them.
- 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
What is normocytic anaemia & what causes it (4)?
normal sized RBCs but low number
- Sickle cell disease
- Early iron deficiency
- Anaemia of chronic disease
- Blood loss
What is anaemia?
Haemoglobin concentration lower than normal range
What are the symptoms of anaemia? (6)
- Headaches
- Weakness & lethargy
- Claudication (pain in legs/arms occurring when walking or using arms)
- Angina
- Shortness of breath
- Confusion
What are the signs of anaemia? (5)
- Pallor (paleness)
- Tachycardia
- Systolic flow murmur
- Tachypnoea
- Hypotension
What are specific signs associated with the cause of anaemia? (4)
- 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
Explain the different ways in which reduced/dysfunction of erythropoiesis causes anaemia (3 points).
- 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
Explain how defects in haemoglobin synthesis can cause anaemia (4).
-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)
Explain how INHERITED abnormal structure & mechanical damage can cause haemolytic damage.
- 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
Explain how ACQUIRED abnormal structure & mechanical damage can cause haemolytic anaemia to develop (3).
- 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
Explain how defects in RBC metabolism (G6PDH deficiency) can cause the development of anaemia.
- 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
Explain how defects in RBC metabolism (Pyruvate kinase deficiency) can cause the development of anaemia.
- Final step of glycolysis
- RBCs lack mitochondria so rely on glycolysis for energy production
- Deficiency causes deficiency in ATP = undergo haemolysis
What are the 2 reasons for defects in RBC metabolism?
G6PDH deficiency and Pyruvate kinase deficiency
How might anaemia develop through excessive bleeding? (3)
- 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)
How does chronic usage of NSAID drugs cause anaemia?
induces GI bleeding via inhibition of COX activity in platelets (work less efficiently) & direct cytotoxic effects on the epithelium
How does increased removal of RBCs by RES cause anaemia?
- 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
What term is used to describe damage to RBCs within their own cells?
intravascular haemolysis
What term is used to describe damage of RBCs within the RES?
extravascular haemolysis
How does splenomegaly occur from haemolytic anaemia?
spleen doing extra work (macrophages that recognise RBC proteins as foreign)
What is haematinic anaemia?
deficiency of any of the vitamins and minerals (iron, vit b12, folate) essential for normal erythropoiesis = causing reduction in RBCs
What causes iron deficiency? (5)
- 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)
What are the key features of vitamin B12? (8)
- 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
What are good sources of dietary vitamin b12?
animal products eg fish, meat, eggs, and cheese.
Why may vegan people experience vitamin B12 deficiency?
lack of animal products in their diets
What is vitamin B12 deficiency caused by? (6)
- 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
What is pernicious anaemia? What is it caused by?
anaemia caused by vitamin B12 deficiency due to a lack of intrinsic factor prevents b12 from being absorbed
What are the symptoms of vitamin B12 deficiency? (6)
- Anaemia symptoms
- Glossitis & mouth ulcers
- Diarrhoea
- Paraesthesia (burning/tingling in hands, arms, legs or feet)
- Disturbed vision
- Irritability
What are the key features of folate? (6)
- 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
What is folate deficiency caused by? (6)
- 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
What are the symptoms of folate deficiency? (6)
- Anaemia symptoms
- Reduced sense of taste
- Diarrhoea
- Paraesthesia
- Muscle weakness
- Depression
How does folate & B12 deficiency lead to defects in DNA synthesis?
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)
Evaluate the treatment for folate deficiency.
Oral folic acid for folate deficiency
- Well tolerated, cheap & effective
How is pernicious anaemia (B12 deficiency) treated?
Intramuscular hydroxocobalamin (B12 supplements)
Why are B12 supplements for pernicious anaemia administered intramuscularly rather than orally?
intrinsic factor deficiency prevents B12 absorption so oral B12 supplements would not be absorbed
Why may hypokalaemia (low K+ levels) occur at the beginning of treatment for severe pernicious anaemia?
due to increased K+ requirement due to erythropoiesis rate increases back to normal
How is B12 deficiency treated (other reasons NOT pernicious anaemia)
Oral supplements (cyanocobalamin)
How does lead poisoning cause microcytic anaemia?
lead inhibits enzymes involved in haem synthesis
What is haemosiderin? Where does it accumulate?
Insoluble
aggregates of clumped ferritin particles, denatured protein & lipid.
Accumulates in macrophages esp in liver, spleen & marrow
How does ferritin structure allow iron to enter & be released? is it soluble or insoluble
its pores
soluble
How does iron deficiency cause anaemia?
inadequate supply of iron for haem synthesis to occur
What are the causes of iron deficiency? (5)
- 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
How does iron deficiency cause microcytic anaemia?
insufficient haem synthesis
What are koilonychia & angular cheilitis caused by?
iron deficiency
What is koilonychia & angular cheilitis?
(spoon-shaped nails) & (inflammation of corners of the mouth)
How does sideroblastic anaemia cause microcytic anaemia?
an inherited defect in haem synthesis
How does anaemia of chronic disease cause microcytic anaemia?
hepcidin causes functional iron deficiency
Which of the TAILS causes of microcytic anaemia are caused by reduced haem synthesis and which one is caused by reduced globin chain synthesis?
Reduced haem synthesis = Iron deficiency, lead poisoning, anaemia of chronic disease & sideroblast anaemia
Reduced globin chain = thalassemia
How much dietary iron is needed/day?
10-15mg
Where is iron absorbed?
duodenum & upper jejunum
What are some good sources of haem iron?
liver, kidney, beef steak, beef burger, chicken, duck, pork chop, salmon/tuna
What are some good sources of non-haem iron?
fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes
How is iron absorbed?
- 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
What are the negative influences of iron absorption? How do they inhibit the absorption of iron?
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
What are the positive influences of iron absorption? How do they promote the absorption of iron?
Vitamin C & citrate
prevent formation of insoluble iron compounds eg haemosiderin
Vitamin C helps reduce ferric to ferrous iron
How is iron absorption regulated?
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.
How is iron taken up by cells?
- 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.
What happens to iron once it is in the blood?
bound to transport protein transferrin & transported to bone marrow for erythropoiesis or taken up by macrophages in RES as storage pool
How is iron transported?
Transported by ferroprotein to bloodstream or stored into within enterocytes at ferritin.
What are signs and symptoms of iron deficiency?
- 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)
Why do patients with iron deficiency have cold hands and feet?
poor blood circulation due to reduces amount of RBCs providing oxygen to tissues
What tests are carried out to diagnose iron deficiency?
- FBC
- Blood film
- CHr
- plasma ferritin
What do FBC results of a patient with iron deficiency show?(6)
- 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)
What would the blood film results of a patient with iron deficiency show?
- RBCs = microcytic & hypochromic (less colour than normal)
- Change in size & shape of RBCs
- Sometimes pencil cells & target cells
What is ferritin?
iron carrier/store it is soluble
Would plasma ferritin be high or low?
low and would suggest iron deficiency
Why should a normal/increased plasma ferritin result not exclude iron deficiency?
plasma ferritin may increase due to cancer, infection, inflammation, liver disease, so there could still be iron deficiency
What does CHr (reticulocyte haemoglobin content) test? Why may it be inaccurate?
test for functional iron deficiency
remains low in thalassaemia/inflammatory responses
How and where is iron deposited in iron overload? How does it damage tissues?
deposited as haemosiderin in end organs compromising function tissue
What causes iron overload?
transfusion-associated hemosiderosis & hereditary hemochromatosis (HH)
What are the implications of iron overload?
Promotes free radical formation & organ damage
How is transfusion-associated hemosiderosis caused?
Repeated blood transfusions = cause gradual accumulation (over several years) of iron
400ml blood transfues = 200mg iron
Give examples of transfusion-dependent anaemias.
sickle cell disease and thalassaemia
What are the effects of build up of haemosiderin? (7)
- Liver cirrhosis
- Diabetes mellitus
- Hypogonadism
- Cardiomyopathy
- Arthropathy
- Slate grey colour of skin (transfusion-associated hemosiderosis)
- Increased skin pigmentation from iron (hereditary hemochromatosis)
How is transfusion-associated hemosiderosis delayed?
iron chelating agents
What is Hereditary Hemochromatosis (HH) caused by?
- 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
How is hereditary hemochromatosis treated?
through regular phlebotomy/venesection – regularly draw blood from a patient to remove iron from iron.
When is hepcidin synthesis decreased and when it is increased?
Decreased by high erythropoietic
activity
Increased in iron overload
What full body count results would be expected from a patient with B12 deficiency?
increase mean cell volume (formation of megaloblasts) & low haemoglobin
What does ferroportin do?
transports iron out of cell across basolateral membrane of enterocytes into bloodstream
What is transferrin and what does it do?
an iron binding plasma glycoprotein which acts as a carrier for iron in the bloodstream
Name two intracellular protein-iron complexes that are used to store iron.
ferritin & haemosiderin
Why is there a low RBC count in patients with iron deficiency?
there no iron available for the bone marrow to produce RBC
