erythropoeisis and microcytic anaemia Flashcards
how much iron is in the daily diet?
15mg/day
what is the usual total body iron?
3-5g
how is the total body iron maintained in its normal range?
1mg is absorbed and 1mg is excreted every day
what is most of the iron in the body in the form of?
circulating Hb and some other proteins
in which area of the body is iron absorbed?
duodenum
what cells absorb iron?
enterocytes
what are the 3 main proteins enterocytes use to absorb, store and remove iron
DMT-1 - divalent metal transported 1 - apical transporter
ferritin - intracellular binding protein
ferroportin - basolateral transporter
what is DMT-1 and what does it stand for?
divalent metal transporter 1
apical transporter in the microvilli
in what form is iron absorbed by enterocytes?
free iron - Fe2+ (NOT Fe3+)
iron as part of a protein like haem
where is ferric reductase enzyme found and what does it do?
found on enterocytes’ brush border and changes Fe3+ to Fe2+
what is ferritin?
a big hollow polyprotein made of 24 apoferritin subunits
what is the function of ferritin?
stores inactive Fe3+ and releases it in a controlled way when needed
acts as a buffer for iron deficiency/overload
where is ferritin found?
mostly as a cytosolic protein but some is secreted into serum to be an iron carrier
what is plasma ferritin an in direct marker of?
total amount of iron in the body
what is serum ferritin used as a diagnostic test for?
iron deficiency anaemia
what do ferroportin molecules do?
basolateral iron transporters
what are transferrins and what is their function?
iron binding blood plasma glycoproteins that can carry 2 molecules of Fe3+
regulate free iron levels in the plasma and ecf and transport iron to other cells e.g. bone marrow
explain how iron enters a cell and is stored
iron filled transferrins bind to transferrin receptors on cell surfaces
enter in vesicles via endocytosis
endosome has lower pH than the cell
transferrin releases iron ions for Hb or ferritin molecules
transferrin released from the empty transferrin/receptor complex
when are serum transferrin levels measured?
in cases of suspected iron deficiency and iron overload disorders
what is myeloid tissue?
bone marrow
why do myeloid cells take up a large part of circulating transferrin?
to incorporate iron into Hb in erythrocyte precursor cells
what is yellow marrow composed of?
lots of fat droplets and cells
where does most erythropoiesis occur in adults?
red bone marrow
what are the three stages of of fetal rbc formation?
mesoblastic
hepatic
myeloid
what happens in the mesoblastic stage?
at week 3 nucleated RBCs form in yolk sac and mesothelial layer of the placenta
what happens in the hepatic stage?
at week 6 erythropoiesis happens in the liver and spleen
what happens in the myeloid stage?
3rd month onwards bone marrow becomes primary source of RBCs
where does rbc formation occur up to 5 years?
bone marrow of all bones
where does rbc formation occur from 5-25 years?
bone marrow of the long bones
where does rbc formation occur after 25 years?
bone marrow of membranous bones such as vertebrae, sternum, ribs, cranial bones and ilium
what is a haemocytoblast?
haemopoietic stem cell
what is a proerythroblast?
common myeloid progenitor – stem cell
describe the stages of erythropoiesis?
haemocytoblast –> proerythroblast –> erythroblast –> nucleus shrinks, cytoplasm fills w Hb until nucleus is expelled –> reticulocyte –> mature RBC
what is diapedesis?
RBC squeezes through pores in marrow capillary membrane into blood
what controls erythropoiesis?
erythropoietin (EPO)
where is EPO made?
protein made in fibroblast interstitial cells around PCT of kidneys
why is EPO made in the kidneys?
kidney O2 levels arent altered by exercise/changes in blood pressure - mainly determined by Hb levels in arterial blood so any hypoxia in the kidneys is defo bc of reduced carriage of oxgen
what are EPO secreting cells sensitive to?
hypoxia
what is the function of EPO?
acts on erythropoietic stem cells to increase the speed of maturation of committed bone marrow cells
why do men have higher Hb levels than women?
bc testosterone increases EPO production
why do RBCs need ATP?
membrane Na+ pumps - stop RBCs from swelling and bursting
GLUT1 transporters - take up glucose
explain how RBCs make ATP?
anaerobic glycolysis
pyruvate from glycolysis reacts with NADH to make lactic acid and NAD+ (instead of pyruvate going into the citric acid cycle) which is then used to make ATP
what is done with the lactate made in anaerobic glycolysis in RBCs?
exported by the RBC and taken up by the liver or muscle cells
converted back to glucose which then gets re-exported into the blood
why do RBCs have a negative surface charge?
bc of membrane glycoproteins containing sialic acid
why do RBCs need a negative surface charge?
so they repel each other and dont stick together in capillaries
why does esr increase in inflammatory reactions?
inflammatory reactions/bacteria in the blood increase fibrinogen levels in the plasma
reduces -ve surface charge so RBCs stick together and form rouleaux which increase ESR
define ESR
the distance, in mm, RBCs fall in 1 hour
what is ESR an indicator for?
a non-specific marker for infection in the blood
how do you calculate the normal esr?
age (+10 in female)/2
what is the normal lifespan of RBCs
120 days
how are RBCs removed from the blood?
in the spleen by macrophages
spleen detects lack of deformability of RBCs when they get stuck in capillaries - shows they’re old
macrophages engulf and break open RBCs by osmotic lysis and break down the contents
how is Hb broken down by splenic macrophages?
- haem prosthetic groups are removed from globin proteins
- globin proteins –> amino acids
- haem broken open by haemoxygenase enzyme and iron is removed and collected by transferrin
- opened porphyrin ring w/o iron is biliverdin
where does iron from broken down RBCs go?
transferrins transport it to the liver and then the bone marrow where it’s then reused to make new Hb
what is the difference between biliverdin and bilirubin?
bilirubin has an extra hydrogen atom
how is biliverdin converted to bilirubin?
reduced by biliverdin reductase in the splenic macrophage
what is unconjugated bilirubin?
bilirubin binds to albumin in splenic macrophages
what is conjugated bilirubin and how is it made?
made when unconjugated bilirubin reaches the liver and has glucuronic acid attached by hepatocytes to make it more soluble
how does conjugated bilirubin leave the body?
enters small intestine through the bile
converted to urobilinogen by bacteria
most urobilinogen leaves body through the faeces
10% passes back in the portal vein to the liver where it leaves via venous blood and is excreted in the urine
what gives urine its yellow colour?
urobilinogen from venous blood from the liver
define anaemia
Hb level below the reference range for that age, and gender
list symptoms of anaemia
tiredness, fainting, shortness of breath, worsening angina/claudication, rapid heart beat (palpitations)
list signs of anaemia
pallor e.g. palmar creases, nail bed, conjunctivae (all unreliable), rapid heart rate, bounding pulse, systolic flow murmur, cardiac failure, retinal haemorrhages
what are the main reasons for anaemia?
decreased production of red cells
increased destruction of red cells
increased loss of red cells
what causes decreased production of red cells?
iron deficiency, B12/folate deficiency, marrow infiltration e.g. cancer, any chronic diseases e.g. rheumatoid/cancer, infections e.g. HIV, parvovirus
what causes increased destruction of red cells?
haemolytic anaemia
a. Disorders of RBC membrane/enzyme/haemoglobin
b. Immune destruction
what causes increased loss of red cells?
bleeding
what are the types of anaemia and how are they categorised?
microcytic (<80fl), normocytic (80-96fl) or macrocytic (>96fl)
what is the threshold for microcytic anaemia in 2-12 year olds?
<76fl
what is microcytic anaemia?
iron deficiency anaemia
what are some causes of microcytic anaemia in developed and developing countries?
o Developing countries – linked to nutrition, hookworm infestation etc
Developed societies – GIT bleeding and other sources of blood loss, malabsorption. IDA prevalent in infants/kids, adolescent girls, pregnant/lactating/premenopausal women
how much iron in 1ml of blood?
0.5mg
how much blood loss per day will cause iron deficiency?
10ml/day
describe RBCs and amounts of Hb in microcytic anaemia
RBCs are small
Reduced amounts of Hb - hypochromic
what are some causes of microcytic anaemia?
low iron in diet
reduced RBC synthesis
excess iron loss (bleeding)
what foods are major sources of haem iron?
food of animal origin
what factors enhance iron absorption?
haem iron (meat), ferrous salts (Fe2+), acid stomach pH, iron deficiency, pregnancy, hypoxia
what factors impair iron absorption?
non-haem iron (veg), ferric salts (Fe3+), alkaline stomach pH, iron overload, inflammatory disorders
what are proton pump inhibitors used for?
used for acid reflux or indigestion
what effect can PPIs have on stomach acid and iron absorption?
reduce stomach acid and decrease iron absorption
what are some of the causes of iron deficiency anaemia?
- Reproductive (menorrhagia)
- GI tract bleeding – varices, ulcer, inflamm bowel, cancer
- GI tract malabsorption – coeliac, atrophic gastritis
- Physiological – growth spurts, pregnancy
- Dietary – poor diet in elderly
- Worldwide – hookworm – parasitic worm which inhabits the intestines. Mouth attaches to gut wall, punctures blood vessels and feeds on RBCs and uses up Fe
how can you confirm IDA?
- Full blood count (low RBC number)
- Blood film (microcytic, hypochromic RBCs)
- Serum ferritin (is it low?)
- Serum iron total iron binding capacity (TIBC) (is it low?)
how is iron deficiency anaemia treated?
- Improve Diet (include haem-containing proteins
- Iron tablets (ferrous sulphate)
- Avoid blood transfusion
- Once Hb normal continue iron supplements for ~3 months
