Iron/ B12 & Folate Flashcards
Biological functions of folate/vit B9?
DNA synthesis, RNA synthesis, DNA methylation, methionine and thymidylate synthesis, theres more cant bother
What is the Folate Trap?
- B12 deficiency cause folate to be trapped in methyl form (methyl THF) and it can escape without being used.
- needs to be in the THF so it can be used
- DNA synthesis is affected, large RBCs with nuclear retention and flimsy membrane are formed-megaloblastic anaemia
Plant foods contain cobalamin. True or False.
FALSE!!! B12 found in animal sources like beef, liver, fish, diary products.
PS. folate is mainly from plant sources
Describe the transport & absorption of Cobalamin (B12).
- Mouth: Haptocorrin/R protein in saliva binds to dietary B12 & carries it to the stomach.
- Stomach: Gastric acid and pepsin cleaves the B12 from haptocorrin (TCI carries it to the duodenum).
- Duodenum & jejenum: pancreatic juices and enzymes degrade the TC I and releases the cobalamin, which is now taken up by intrinsic factor.
- IF protects the cobalamin and carries it to the cubulin in the ileum. - Ileum: the IF-cobalamin complex binds to cubulin and is taken up into the enterocyte (by Ca2+ dependent passive transport)
- Enterocyte: the IF-cobalamin complex is engulfed by lysosomes, where enzymes degrade the IF and release the cobalamin into the cytoplasm where it is taken up by TCII.
- TC II/Cobalamin complex exit the enterocyte into systemic circulation- to the bone marrow & tissues.
B12 is never left unattended. True or False
True- it is always bound to something.
Describe TCI?
- Binds 70% of cobalamin, protects cobalamin from the acid environment of the GI tract, n neutralizes the function of cobalamin- cobalamin appears functionally dead.
- Largely synthesized by granulocytes and macrophages.
- Aka haptocorrin and R protein
Describe TCII?
- Binds 30% of circulating cobalamin, and transports cobalamin to target cells where they are used, like in bone marrow.
- Congenital TC deficiency causes megaloblastic anaemia because of failure of B12 to enter marrow
What is megaloblastic anaemia?
- Caused by a deficiency (or defective metabolism) of B12 and folate which in turn causes impaired DNA synthesis-ineffective erythropoiesis.
- Results in abnormal RBCS; features- anaemia, macrocytosis, hypersegmented neutrophils, red cell fragments, raised LDH and thrombocytopenia.
The dietary forms of B12 and folate are the same as that in the circulation. True or false.
False-the form in circulation is different
Normal dietary intake of B12 and folate?
7-30 micrograms and 200-250 micrograms resp.
Cooking has a little effect on folate. T or F.
F- folate is easily destroyed by over-cooking
Body stores of B12 and folate?
2-3 mg and 10-12 mg resp.
Absorption site for B12 and folate
Ileum and duodenum/jejunum resp.
In order to be absorbed folate is converted to what?
methyltetrahydrofolate- reduced monoglutamate form which circulates the plasma.
Severe deficiency of B12 is usually caused by what?
pernicious anaemia
note: less commonly in veganism
What is pernicious anaemia?
- an autoimmune attack on the gastric mucosa leading to atrophy of the stomach and the secretion of intrinsic factor (IF) is absent.
- Therefore, there is malabsorption of B12 due to lack of IF.
Why do pregnant women require an increased need for folate?
Due to excess cell turnover, because folate is degraded due to an increase in DNA synthesis (thymidylate synthesis).
How does a folate deficiency cause megaloblastic anaemia?
Folate deficiency inhibits thymidylate synthesis which is the rate limiting step of DNA synthesis.
How does B12 deficiency cause megaloblastic anaemia?
B12 deficiency indirectly reduces the amount of folate coenzyme which is necessary for thymidylate synthesis. In turn, affects DNA synthesis.
Iron deficiency is the main cause of what kinda anaemia?
- Microcytic, hypochromic anaemia (red cells are small and pale)
- low MCV and MCH
note: iron deficiency is the main cause of anaemia.
which enzyme other than hephaestin catalyses oxidation of iron to the ferric form?
caeruloplasmin (copper-containing enzyme)
iron is mobilised after what?
reduction to the ferrous form (Fe2+)
transport and storage of iron is largely mediated by which proteins?
- transferrin
- transferrin receptor 1
- ferritin
What does hepcidin do?
- It’s a hormone produced by the liver that inhibits the release of iron from macrophages and from enterocytes (by closing the ferroportin) into the plasma.
- If increased, it reduces iron absorption
Too much iron leads to an increase in hepcidin, and iron deficiency leads to a decrease in hepcidin. T or F.
T- amt of iron is directly proportional to the amt of hepcidin
Why does ineffective erythropoiesis, increase iron absorption?
Because erythroblasts secrete 2 proteins that suppress the hepcidin synthesis, and a decrease in hepcidin allow for an increase in iron absorption.
note: hypoxia also suppresses hepcidin synthesis
Inflammation, IL-6 and other cytokines increase hepcidin synthesis. T or F.
T- reduces iron absorption
Most dietary iron is absorbed. T or F.
F- most dietary iron remains unabsorbed
- 5-10 % is absorbed normally
- 20-30 % is absorbed in iron deficiency and pregnant women (bcuz 35% of 300 mg of iron is transferred to the fetus)
major causes of iron deficiency?
- chronic blood loss (uterine, gastrointestinal)
- increased demands (pregnancy, growth)
- malabsorption
- poor diet (rarely the sole cause of iron deficiency)
In iron deficiency, the iron stores are completely depleted. T or F.
T- takes a while before it reaches anaemia cuz the iron stores will be used up
what is hemochromatosis?
- disorder in iron metabolism where there is excess iron absorption, saturation of iron-binding proteins and deposition of hemosiderin in the tissues.
- excess iron deposition leads to liver cirrhosis bronze diabetes (bronze skin + diabetes).
iron is absorbed mainly where?
the duodenum
note: in the ferrous state
iron varies directly with what?
rate of erythropoiesis
what factors favour iron absorption? hint: 8
- ferrous form
- inorganic iron
- acids- HCl, vit C
- solubizing agents- sugar, amino acids
- iron deficiency
- ineffective erythropoiesis
- pregnancy
- primary haemochromatosis
*decreasing hepcidin
what factors reduce iron absorption? hint:9
- ferric form
- organic iron
- alkalis- antacids
- precipitating agents-phosphates
- iron excess
- decreased erythropoiesis
- infection/ inflammation
- tea
- desferrioxamine
*increasing hepcidin
describe the process of iron transport/absorption?
- first, dietary iron is reduced from the ferric state (Fe3+) to the ferrous state (Fe2+) by DCYTB.
- Fe2+ can now enter the enterocyte but its transferred in by DMT1
- in the enterocyte, Fe2+ can either be stored as mucosal ferritin then shed as stool or it can be transported through ferroportin into circulation
- Fe2+ outside of the enterocyte is oxidized back to the Fe3+ by hephaestin
- Fe3+ now in the blood vessel is bound to transferrin which carries it either to the bone marrow for erythropoiesis or to the liver to stimulate hepcidin
what does low plasma iron concentrations (hypoferremia) cause?
anaemia (cuz of decreased Hb synthesis)
Iron is transported in the ferric form (Fe3+) by transferrin and absorbed in the ferrous form (Fe2+) by DMT-1. T or F.
T
the majority of storage iron is present as ferritin, and haemosiderin is predominantly found in macrophages rather than hepatocytes. T or F.
T
TC deficiency causes metaloblastic anaemia because of failure of B12 to enter marrow (and other cells) from plasma but the serum B12 level in TC deficiency is normal. T or F.
T
Folate deficiency is thought to cause megaloblastic anaemia by inhibiting the thymidylate synthesis, a rate-limiting step in DNA synthesis. T or F.
T
note: Lack of B12 prevents the demethylation of methyl THF, thus depriving cells of THF and so of folate polyglutamate coenzyme- which is needed for thymidylate synthesis
clinical features of megaloblastic anaemia?
- mild jaundice- excess breakdown of haemoglobin resulting from increased ineffective erythropoiesis in the bone marrow
- Glossitis, angular stomatitis and mild symptoms of malabsorption with loss of weight
