8- Iron Metabolism & Microcytic Anaemias

Question 1

• what are microcytic anaemias?
• give all of them using the acronym TAILS.
• of those, which are due to reduced haem synthesis and which due to reduced globin chain synthesis?
• briefly describe iron & what it’s needed for.

Answer 1

• erythrocytes smaller than normal, reduced rate of Hb synthesis, cells often paler than normal (hypochromic)
• Thalassaemia (alpha and beta), Anaemia of chronic disease, Iron deficiency, Lead poisoning, Sideroblastic anaemia
• alpha and beta thalassaemia are due to reduced globin chain synthesis, rest are due to reduced haem synthesis.
• essential element, needed as they’re O2 carriers, a cofactor in many enzymes eg cytochrome P450s, free iron very toxic (as it forms free radicals), body has no mechanism for excreting iron

Question 2

• what is the difference between ferrous vs ferric iron?
• what is the difference between haem and non haem iron?
• how is iron absorbed from the diet?

Answer 2

• ferrous=Fe2+, the reduced form, dietary iron has both.
• ferric=Fe3+, the oxidised form, this iron must be REDUCED to ferrous to be absorbed from the diet.
• haem iron is just Fe2+, non haem iron is a mix of Fe2+ and Fe3+, must be reduced to be absorbed. Haem sources=liver, kidney. Non haem =fortified cereals, raisins, oats.
• absorption: Fe3+ bound transferrin binds to the transferrin receptor and enters cytosol via receptor mediated endocytosis. Fe3+ inside endosome is released by acidic micro environment and reduced to Fe2+. The Fe2+ is transported to cytosol via DMT1, once in cytosol Fe2+ is stored as ferritin, can be exported by ferroportin (FPN1), or taken up by mitochondria to be used in cytochrome enzymes.

Question 3

• what are some negative and positive influences on absorption of non haem iron from food?
• describe the differences in amount of functional vs stored iron. What are the soluble and insoluble stored forms called?
• how much iron is recycled vs from diet? Where does this recycled iron come from?

Answer 3

• neg=tannins(in tea), phytates (in chapatti), fibre-they can all bind to non haem & reduce absorption, also antacids (reduce acid that is needed for reduction)
• pos=vitamin C and citrate bc they prevent formation of insoluble iron compounds, help w reduction.
• total iron around 3350mg, available=in Hb, myoglobin, enzymes. Stored=around 1000mg, soluble:ferritin, a globular protein w hollow core, pored release iron, insoluble: haemosiderin, aggregates of ferritin, accumulate in macrophages
• most is recycled (>80%), from RBCs that are engulfed by macrophages (splenic or kupffer cells of liver), catabolise haem and exported to blood as transferrin then stored as ferritin.

Question 4

• how is iron absorption regulated? Name the mechanisms by which this happens. name the key negative regulator.
• how does the above regulator problems lead to anaemia of chronic disease?

Answer 4

• depends on diet, body iron stores, erythropoeisis levels. Levels are sensed by enterocytes.
• control mechanisms=regulation of transporters eg ferroportin, regulation of receptors eg transferrin receptor, hepcidin and cytokines
• key negative regulator= hepcidin, synthesised in liver when there’s an iron overload, gets decreased when there’s a high level of erythropoeisis (lots of haem is recycled then). It induces the internalisation and degradation of ferroportin
• an inflammatory condition causes release of cytokines by immune cells, leading to increased production of hepcidin because there is inhibition of erythropoetin production so less RBCs made. Ferroportin is inhibited leading to decreased iron from the RES system and less iron absorption therefore overall there is a functional deficiency of iron which has caused a decrease in erythropoiesis meaning anaemia.

Question 5

• what is iron deficiency!!! give some causes of iron deficiency
• give iron requirements in males vs females age 18-50. What are the at risk groups of iron deficiency
• give the signs and symptoms of iron deficiency.

Answer 5

• it is a SIGN, not a diagnosis, must fund the underlying cause of it. Causes= insufficient intake, malabsorption, bleeding eg menstrual, gastric, increased requirement eg pregnancy, anaemia of chronic disease eg IBD.
• males=8mg/day, females=18mg/day due to mp, increased risk=infants, children, menstruating women, pregnant, geriatrics
• physiological effects=fatigue, increased RR, pallor, reduced exercise tolerance, dizzy. Pica (unusual cravings), cold hands and feet, epithelial changes (angular cheilitis ie broken skin on edges of mouth, glossy tongue, koilonychia ie spoon nails)

Question 6

• what would you see in a FBC of an individual with iron deficiency anaemia?
• what would you see in a peripheral blood smear of an individual with iron deficiency anaemia? (Appearance)
• what is used to test for iron deficiency, why is this method sometimes not the best?
• how do you treat iron deficiency anaemia?

Answer 6

• FBC= low mean corpuscular volume (MCV), low mean corpuscular Hb conc (MCHC), elevated platelets, normal of elevated WBCs, low serum ferritin, iron & transferrin
• blood smear= RBCs are microcytic and hypochromic, anisopoikilocytosis (varied cell shapes and sizes)
• tested using plasma ferritin as a marker, reduction= iron deficiency HOWEVER normal or high ferritin doesn’t exclude iron deficiency bc ferritin can increase in cancer, infection, inflammation etc, CHr (reticulocyte Hb content) used to test for iron deficiency, remains low in inflammation.
• dietary advice, oral supplements, intramuscular injections/IV, then blood transfusion only if severe, should see 20mg/L rise in Hb in 2 weeks.

Question 7

• why is excess iron dangerous? name the reaction

- what are the 2 conditions that are caused by excess iron and describe each.

Answer 7

• excess iron can exceed binding capacity of transferrin, excess is deposited as haemosiderin, iron promoted free radical formation & organ damage via the Fenton reaction (OH. and OOH. cause damage to cells)
  1) transfusion associated haemosiderosis = repeated blood transfusions gradually accumulate iron, problem in patients who are transfusion dependant eg sickle cell, thalassaemia, iron chelatinf agents can delay but not stop the effects (liver cirrhosis, diabetes mellitus, gray skin, cardiomyopathy)
  2) hereditary haemochromatosis=HFE protein normally interacts with transferrin receptor and reduces its affinity for iron bound transferrin, also promotes hepcidin expression via activation of signalling pathways. Mutated HFE causes loss of negative influences, too much iron uptake to cells, accumulation in organs causing damage, treated with venesection (removal of blood)