Heme 07: Biochem Of Iron Deficiency And Megaloblastic Anemias

Front 1

What causes iron deficiency anemia?

Back 1

- Inadequate levels of iron for synthesis of various proteins such as hemoglobin and myoglobin
- Also inadequate for use as a cofactor for enzymatic reactions

Front 2

What are the iron sources?

Back 2

Heme Iron
- Red meat
- Shellfish and fish

Non-heme iron
- Enriched cereals
- Beans
- Tofu
- Seeds
- Potatoes
- Green vegetables
- Dried fruits

Front 3

How much iron is absorbed in the diet? Where?

Back 3

- 1 mg
- Duodenum

Front 4

How is heme iron absorbed?

Back 4

Heme iron is taken up by the heme transporter

Front 5

What is required for non-heme iron absorption?

Back 5

Vitamin C is required in diet for efficient uptake of dietary non-heme iron

Front 6

What happens to dietary iron before it can be taken up into the epithelial cells of the duodenum?

Back 6

Duodenal cytochrome B - a ferrireductase - on epithelial cell membrane reduces Fe3+ (ferric) to Fe2+ (ferrous) through a Vitamin C dependent mechanism

Front 7

What happens after ferric iron (Fe3+) is converted to ferrous iron (Fe2+) in the duodenum?

Back 7

Fe2+ is transported into intestinal epithelial cells by DMT1 (divalent metal ion transporter 1)

Front 8

What can happen to Fe2+ after being taken up by DMT1 in duodenum?

Back 8

- Directly transported across basal lateral membrane into portal vein by Ferroportin 1
OR
- Stored until needed in the cells by Ferritin present in the cells

Front 9

How is Fe2+ oxidized back to Fe3+?

Back 9

Hephaestin on basal lateral epithelial cell membrane

Front 10

What happens after Fe3+ is made again by hephaestin?

Back 10

- Fe3+ is transported out of epithelial cell by Ferriportin
- Next, it binds to Transferrin and is distributed to the rest of the body
- All cells that take up Fe3+ use the Transferrin Receptor for uptake through endocytosis

Front 11

What molecule does Fe3+ bind in the plasma for transport through the rest of the body?

Back 11

Transferrin

Front 12

What peptide regulates the release of iron from the duodenal epithelial cells? Where is it synthesized?

Back 12

- Hepcidin
- Synthesized by liver

Front 13

What influences the levels of Hepcidin?

Back 13

When iron levels in the liver increase, Hepcidin is released and binds to Ferroportin inducing endocytosis and degradation of Ferroportin (preventing additional release of iron into the plasma)

Front 14

Where is iron stored?

Back 14

- Liver takes up iron and stores it inside the hollow ball structure of the protein Ferritin
- 1 ferritin can contain ~5000 Fe(OH)3 molecules

- Iron can also be stored in Hemosiderin granules made up of partially degraded ferritin-iron complexes

Front 15

What happens to Hemosiderin under normal iron conditions? Excess iron?

Back 15

- Normal conditions, very little iron is found in Hemosiderin granules
- Iron overload conditions, excess iron is mainly stored in this form

Front 16

What happens to iron in degrading RBCs?

Back 16

- Most of it is recycled
- Macrophages recycle iron back to bone marrow for synthesis of new RBCs

Front 17

What are the ways to lose iron? How much?

Back 17

- Normally through shedding of intestinal and skin cells (~1 mg/day)
- During menstrual cycle, women lose ~0.5 mg iron / day
- During pregnancy, women lose 500-1000 mg of iron
- Abnormal bleeding (variable loss)

Front 18

What are the locations of iron?

Back 18

- Hemoglobin (~60% or ~2500 mg)
- Myoglobin (~8%)
- Ferritin in liver (~25%)
- Remaining is bound to Transferrin or enzymes (eg, cytochromes, catalase, and aconitase)

Front 19

What causes Megaloblastic Anemia?

Back 19

- Inability to synthesize adequate amounts of purines and thymidylate triphosphate for DNA synthesis
- Deficiency of folate, Vitamin B12, or a methionine synthase leads to impaired DNA synthesis

Front 20

How is synthesis of purines and thymidylate triphosphate implicated in the basis of Megaloblastic Anemia?

Back 20

- Synthesis of these molecules involves 1C units attached to folate derivative Tetrahydrofolate
- Deficiency of folate, Vitamin B12, or a methionine synthase

Front 21

How is folate converted to the form which can donate 1C units for DNA synthesis?

Back 21

- Folate is converted to THF by sequential reduction reactions by Dihydrofolate Reductase
- Folate → Dihydrofolate → Tetrahydrofolate

Front 22

How is folate critical to the synthesis of Thymidylate Triphosphate?

Back 22

- Methylene-THF donates a 1C group to dUMP → dTMP using enzyme Thymidylate Synthetase
- THF reductase is oxidized to dihydrofolate, which must be reduced by DHF reductase to form THF

Front 23

What drug inhibits purine and thymidylate synthesis? Implications?

Back 23

Methyltrexate - causes drug induced Megaloblastic Anemia

Front 24

What are the sources of a 1C unit for the folate and S-adenosylmethionine pathways?

Back 24

- Serine is the major source
- Histidine, glycine, and formate can also contribute 1C units

Front 25

How is folate critical to the synthesis of Purines?

Back 25

De novo synthesis of purines (Adenine and Guanine) depends upon donation of two 1C units in the form of formate from formyl-tetrahydrofolate

Front 26

Why is Vitamin B12 critical for the synthesis of purines and dTMP?

Back 26

- Synthesis of methionine requires methyl-THF (from folate pathway) and Vitamin B12 as cofactor
- Without Vitamin B12 methyl-THF is not utilized, methionine synthesis is inhibited, and THF is not regenerated
- Leads to megaloblastic anemia

Front 27

How is Methionine synthesized?

Back 27

- Methionine Synthase - transfers a methyl group for methyl-THF to vitamin B12 which acts as a co-enzyme
- Methyl group is then transferred to Homocysteine forming Methionine
- Methionine Synthase is the only known enzyme to use Methyl-THF as a substrate and thus the only way to regenerate THF

Front 28

What are the implications of deficient Vitamin B12?

Back 28

- Methyl-THF is not utilized
- Methionine synthesis is inhibited
- THF is not regenerated

Front 29

What is the necessity of Methionine?

Back 29

Formation of S-adenosylmethionine required for methylation of DNA, RNA, and for synthesis of creatinine, melatonin, and epinephrine

Front 30

What are the sources of folate in the diet?

Back 30

- Most vegetables (especially dark leafy greens)
- Fruits
- Grains
- Nuts
- Beans
- Dairy products
- Seafood and meats

Since 1998: cereals, flour, rice, and their products are fortified w/ folate

Front 31

What happens to dietary folate (folic acid) once ingested?

Back 31

- Converted from polyglutamic folate to monoglutamic folate in intestine by Folate Hydrolase
- Folate is released into blood in complex w/ Folate Binding Protein as either monoglutamate folate or monoglutamate THF

Front 32

What are the sources of Vitamin B12 in the diet?

Back 32

- Meat
- Shellfish
- Milk
- Eggs

(not at significant levels in vegetables and fruits)

Front 33

How do vegans obtain folate and Vitamin B12 in their diet?

Back 33

Folate through food:
- Most vegetables (especially dark leafy greens)
- Fruits
- Grains
- Nuts
- Beans
- Dairy products

Vitamin B12 often needs to be supplemented because it is not found in significant levels in fruits and vegetables)

Front 34

What happens to dietary Vitamin B12 once ingested?

Back 34

- Vitamin B12 is bound to proteins in diet and released in stomach at acid pH
- Absorbed in process involving salivary Haptocorrin (R-protein), Intrinsic Factor, and Cubulin

Front 35

What can cause a Vitamin B12 deficiency?

Back 35

- Low intake of vitamin
- More often d/t impaired absorption or transport of vitamin (eg, Pernicious Anemia)

Front 36

What happens in Pernicious Anemia?

Back 36

- Lack of intrinsic factor
- Leads to vitamin B12 deficiency