Lecture 8 Flashcards
What are the 2 types of microcytic anaemia?
TAILS
Reduced haem synthesis
- Iron deficiency-no iron for Hb
- Lead poisoning-inhibits enzymes involved to make haem
- Sideroblastic anaemia- genetic disease
- Anaemia of chronic disease-hepcidin results in iron deficiency
Reduced globin chain synthesis
-Thalassaemia (alpha/beta globin chain mutations)
What is microcytic anaemia?
- reduced rate of Hb synthesis
- erythrocytes smaller than normal
- cells often paler (hypochromic)
What is iron required for?
Essential element in all living cells
- oxygen carriers (Hb/myoglobin)
- co-factor for many enzymes (cytochromes, Krebs cycle enzymes, CP450, catalase)
What is a problem with iron?
Free iron is very toxic to cells
Complex regulatory systems to ensure homeostasis
How can you excrete iron?
There is no mechanisms in body to regulate excretion.
-Only regulate how much iron enters our body.
What different states are there of iron?
Exist in a range of oxidation states
Ferrous (Fe2+)
- reduced form
- utilise this one
Ferric (Fe3+)
- no mechanisms to absorb this so needs to be converted to reduced form
- most common
- oxidised form
Where do you get haem, or non-haem iron?
Dietary iron consists of haem iron (Fe2+) & non haem iron (mixture of Fe2+/Fe3+)
Haem (readily absorbed)
-liver, kidney, beef, chicken, duck, pork, salmon, tuna
Non-haem (ferrous/ferric:converted to ferrous)
-cereals fortified with iron, raisins, beans, figs, barley, oats, rice, potatoes
Where/how do you absorb iron?
Duodenum/upper jejunum (just after duodenum)
- chyme enters duodenum from stomach
- haem iron is readily absorbed into enterocyte
- any ferric iron is reduced to ferrous iron by reductase enzyme which requires vitamin C as the electron donor
- ferrous can move through DMT1 to enterocyte
- haem is degraded to form Fe2+ by haem oxygenase
- Fe2+ can be stored as ferritin as Fe3+
- or Fe2+ can enter bloodstream via ferroportin in basolateral surface
- ferrous is oxidised to ferric by hephaestin and is transported attached to transferrin (carries 2 Fe3+)
What is hepcidin?
Produced by liver and inhibits ferroportin.
What inhibits absorption of non haem iron?
-tannins (in tea)
-fibre (can bind to iron to prevent it being absorbed)
-phyphates (pulses)
These bind non-haem iron in intestine, reducing absorption
-antacids (require acid environment for conversion of the irons)
What has a positive influence on iron absorption?
-vit C (helps reduce ferric to ferrous iron)
-citrate
(Both prevent formation of insoluble iron compounds)
What is functional iron?
Available iron
- Hb
- Myoglobin
- transported in serum via transferrin
- cytochromes (contain iron)
What are some ways of storing iron?
Ferritin (soluable)
- pores on surface to allow exit/entry of iron
- globular protein with hollow centre
Haemosiderin (insoluble)
- aggregates of clumped ferritin particles, denatured protein, lipids
- accumulates in macrophages, especially in liver/spleen/marrow
- seen as dark precipitates when stained
How do cells take up iron?
- diferric transferrin enters cell via receptor mediated endocytosis into vesicle
- ferric to ferrous (due to acidic environment from H+ pump into endosome) where it can leave vesicle via DMT1
- forming label pool of iron (here iron can be stored as ferritin, used in mitochondria for cytochrome enzymes, or exported via FPN1- ferroportin 1)
Where does our daily total iron usually come from?
Recycled: 80% of iron requirement met via this (only a small amount from our diet)
-macrophages engulf and recycle the iron from the dead/damaged RBC’s
(Mainly splenic macrophages/Kupffer cells)
What can control regulation of iron absorption?
Dietary iron levels sensed by enterocytes
- reguation of transporters (ferroportin)
- regulation of receptors (transferrin receptor & HFE protein)
- hepcidin/cytokines
- cross talk between epithelial cells and other cells
What is the role of hepcidin?
Peptide hormone produced by liver
- causes ferroportin to be internalised
- negative influence on absorption/release (from macrophages and enterocyte)
What is anaemia of chronic disease?
- inflammatory conditions e.g. rheumatoid arthritis/chronic infection
- release of cytokines by immune cells (IL-6)
IL-6
- inhibits erythropoietin production by kidneys
- inhibition of erythropoiesis in bone marrow
- increased hepcidin production (inhibits ferroportin) causing reduced amount of iron , limiting amount of erythropoiesis that can occur
Why is called functional iron deficiency ?
Because the body has stores of iron, but it doesn’t have the mechanisms to use it.
What happens if you have too little iron?
- iron deficiency (not a diagnosis, it is a sign: treat underlying reason)
- most common nutritional disorder
Could be due to
- insufficient intake/poor absorption
- pregnancy due to demands of foetus (physiological reasons)
- pathological reasons (haemorrhage)
What are some causes of iron deficiency?
- insufficient iron in diet (vegan/vegetarian)
- malabsorption of iron (unable to absorb iron)
- bleeding
- increased requirement (pregnancy/rapid growth)
- anaemia of chronic disease
What are the groups most at risk of iron deficiency?
- infants
- children
- women of child bearing age
- geriatric age group
- women whilst mestruation occurs in their life
Signs and symptoms of iron deficiency
- cold hands and feet
- epithelial changes (angular cheilitis, glossy tongue, spoon nails)
- increased resp rate
- tired
- pallor
- tired
- reduced exercise tolerance due to reduced oxygen carrying capacity
- pica (cravings to eat non-nutritional food source e.g. dirt)
- headache/dizzy
- cardiac: angina, palpitations, heart failure
What are the FBC results for someone with iron deficiency anaemia?
- low MCV
- low MCHC (mean corpuscular Hb conc)
- elevated platelet count
- low serum ferritin, serum iron, and transferrin saturation
- low reticulocyte haemoglobin content (CHr)
- normal/elevated white cell count
- high TIBC (total iron binding capacity, as the transferrin needs to have a higher binding ability to iron as there is less iron available)
What do blood smear results in someone with iron deficiency anaemia look like?
- RBC’s microcytic & hypochromic
- pencil cells
- target cells (over abundance of cell membrane forming a bell shape, top of bell is squashed on a smear forming a bulls eye)
- anisopoikilocytosis (change in size and shape_
How do you test for iron deficiency?
Plasma ferritin used as marker
- ferritin usually cytoplasmic, small amounts secreted into blood to carry iron
- low plasma ferritin indicated iron deficiency
- normal/increased ferritin doesn’t exclude iron deficiency as ferritin levels can increase in cancer/alcoholism/liver disease/inflammation/infection
- reticulocyte Hb (CHr) is more widely used but doesn’t test for thalassaemia
- CHr remains low in inflammatory responses
How do you treat iron deficiency?
- dietary advice
- oral supplement (GI side effects so compliance is poor: so may move to IV/intramuscular injections)
- blood transfusion (only used in emergency)
What is the desired response to iron supplements?
- rise in 20g/L in Hb in 3 weeks
- improvement in symptoms
Why is too much iron dangerous?
- excess iron can exceed binding capacity of transferrin
- so deposited in organs as haemosiderin (insoluable deposits)
- promotes free radial formation by Fenton reaction (hydroxyl/hydroperoxyl)
- these cause lipid peroxidation, damage to proteins/DNA
What is transfusion associated haemosiderosis?
-repeated blood transfusions cause accumulation of iron (e.g. in sickle cell, thalassaemia)
What are the diseases causing high iron?
- transfusion associated haemosiderosis
- hereditary haemochromostosis
What is hereditary haemochromatosis?
- autosomal recessive mutation in HFE gene on chromosome 6
- HFE protein normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
- mutated HFE can’t bind to transferrin so negative influence on iron uptake is lost
- HFE leads to reduction of hepcidin so negative influence of iron if further lost
- too much iron therefore enters cells
- iron accumulates in end organs causing damage
What does TAILS stand for? (Associated with microcytic anaemia)
Thalassaemia Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
What conditions are needed to convert between ferrous/ferric iron?
Oxidation of ferrous to ferric
-requires alkaline pH
Reduction of ferric to ferrous
-requires acidic pH
How much iron do you require daily?
10-15 mg/day
Haem iron is the best source
What promotes/reduces hepcidin synthesis?
Iron overload: increases hepcidin synthesis
High erythropoietic activity: decreases hepcidin synthesis
What contributes/removes from the plasma iron pool?
- dietary iron absorption contributes
- iron stores in liver
- loss of iron (mestruation, sweat, pregnancy:no mechanisms to regulate excretion of iron)
What are the epithelial changes in response to iron deficiency?
Angular cheilitis (red swollen patches at corner of lips at an angle)
Glossy tongue
Koilonychia (spoon nails)
How do you treat hereditary haemochromatosis?
Treat with venesection.
What can delay effects of iron overload?
Iron cheating (ring forming) agents E.g. desferrioxamine
What can accumulation of iron in the liver, heart & endocrine organs cause?
- liver cirrhosis
- slate grey colour of skin
- cardiomyopathy (diseases that affect heart muscle)
- diabetes mellitus (type 1)
- hypogonadism (loss of function of testes/ovaries)
What if MCV units?
fL (femtolitres)
10^15 femolitres in a litre
