Anemias and Iron Metabolism

Question 1

What is the difference between heme and non-heme iron?

Answer 1

Absorbed differently; heme iron contains a porphyrin ring

Question 2

What are the different kinds of anemias?

Answer 2

Microcytic anemia (<80fL): TAILS
Normocytic anemia (80-100 fL:)
- increased reticulocyte: blood loss, hemolytic anemia
- normal or decreased reticulocyte: aplastic anemia, leukemia
Macrocytic anemia (>100 fL): vit B12/folate deficiency, myelodysplastic syndrome

Question 3

In humans, iron is incorporated into proteins as a component of what 3 things?

Answer 3

1. Heme
2. Iron sulfur clusters
3. other functional groups
   -> these are important for O2 transport, mitochondrial respiration, DNA replication and repair, immune response, cell signaling, etc.

Question 4

What is the difference between heme and non-heme iron absorption?

Answer 4

Heme:
- unregulated uptake
- endocytosed into enterocytes, Fe 2+ is liberated from heme by heme oxygenase

Non-heme:
- highly regulated
- 3+ Fe can’t be taken up directly -> reduced to Fe 2+ first
- Fe 2+ is then bound and transported by divalent metal transporter channels

Question 5

What is the difference between heme and non-heme iron absorption?

Answer 5

Heme:
- unregulated uptake
- endocytosed into enterocytes, Fe is liberated from heme by heme oxygenase

Non-heme:
- highly regulated
- 3+ Fe can’t be taken up directly -> reduced to Fe 2+ first
- Fe 2+ is then bound and transported by divalent metal transporter channels

Question 6

How is iron transferred from cytosol to plasma?

Answer 6

Iron is shuttled by peptides to retain oxidation state. They can be stored as ferritin, or transported through ferroportin
2 pathways for iron transfer to cytosol

Major pathway
- transported by ferroportin into plasma, Fe 2+ oxidized into Fe3+ by hephaestin -> binds to transferrin and transported

Minor pathway
- transmembrane transporter directly transports Fe2+ into plasma, ceruloplasmin oxidizes Fe2+ to Fe3+ -> binds to transferrin

Question 7

What is transferrin?

Answer 7

transferrin is a glycoprotein that transports iron in plasma
- contains 2 high affinity Fe 3+ binding sites

Question 8

How is Iron in plasma taken up by tissue?

Answer 8

transferrin receptor 1 takes up transferrin bound iron
- receptor mediated endocytosis
- acidified vesicle releases transferrin, which is recycled back to cell surface as apotransferrin (unbound transferrin)

Question 9

How is iron stored? Where?

Answer 9

Ferritin
- found in all cells, mostly in liver, spleen, bone marrow
hemosiderin
- denatured form of ferritin
- if cells are overloaded with iron, hemosiderin accumulates in lysosomes (mostly in macrophages)

Question 10

What happens when there is excess iron?

Answer 10

Unbound iron -> generates free radicals -> cause oxidative damage to DNA, lipids, proteins
- if ferritin storage is maxed out, liver cells take up unbound iron from plasma -> liver damage
- iron from dying RBC are stored in macrophages

Question 11

What are the 2 ways of regulating iron absorption?

Answer 11

hepcidin
- inhibits ferroportin

intracellular regulation
- post transcriptional regulation of transferrin receptor (TfR), ferritin, and DMT1
- the mRNA for these proteins contain iron response elements (IREs)

-> in iron depleted cells, iron regulatory protein binds to 5’ IRE of ferritin (inhibited translation), IRP binds to 3’ IRE of TfR mRNA , stabilizing it and increasing translation
-> in iron high cells, ferritin mRNA is normal, TfR mRNA is destabilized and decreasing TfR translation

Question 12

Describe the protein function of:
DMT1
Duodenal cytochrome b (DCYTB)
Ferroportin
Transferrin
Transferrin Receptor 1(TfR1)
Ferritin
Hepcidin

Answer 12

DMT1: transports Fe2+ from gut lumen into enterocyte
Duodenal cytochrome b (DCYTB): reduces Fe3+ in gut lumen to Fe2+ for DMT1
Ferroportin: responsible for iron export out of enterocytes into plasma
Transferrin: major transport protein for iron in circulation
Transferrin Receptor 1(TfR1): uptakes transferrin bound iron into cells
Ferritin: iron storage protein
Hepcidin: iron absorption regulator

Question 13

What is hemochromatosis?

Answer 13

hematochromatosis is a disorder of excess iron
- autosomal recessive disorder that leads to toxic iron accumulation in vital organs -> causes liver damage, bone and joint disease, diabetes, heart disease, etc.
- mutation in genes responsible for regulating hepcidin -> hepcidin deficiency = high ferroportin in enterocytes, so lots of iron in plasma

Question 14

What are some clinical features, lab findings, and treatment of hemochromatosis?

Answer 14

Clinical features:
- cirrhosis
- diabetes
- heart diseases
- darkening of skin

Lab findings: high serum iron, serum ferritin, and transferrin saturation; low total iron binding capacity and low transferrin

Treatment: bleed it out (donating blood) ; monitor for organ damage

Question 15

What are the 3 broad classifications of anemias? what are the 3 causes of anemias?

Answer 15

Classification of anemias:
- decreased prod. of RBC (iron def, folate def, kidney disease (decrease EPO))
- increased destruction of RBC
- loss of RBC (bleed)

Question 16

What are the 3 broad classifications of anemias?

Answer 16

Classification of anemias:
- decreased prod. of RBC (iron def, folate def, kidney disease (decrease EPO))
- increased destruction of RBC
- loss of RBC (bleed)

Question 17

What are the 2 most common Anemias? briefly describe them. Compare and contrast them

Answer 17

BOTH ARE MICROCYTIC ANEMIAS (low MCV)

Iron deficiency anemia
- decreased intake (vegan diet, socioeconomic causes, eating disorder)
- increased loss (bleeding, menstruating, GI bleeds
- symptoms of weakness, headache, angular cheilitis (skin condition in corner of mouth)
- diagnostic testing by ferritn
- treat by diet, oral or iv iron

anemia of chronic inflammation
- primarly a disorder of iron distribution
- systemic inflammation (lupus, etc.) causes increase in hepcidin production -> inhibits ferriportin -> reduced iron in plasma -> reduced prod. of RBC
-NOTE serum ferritin is high because ferritin is an acute phase reactant
Similarities:
- both characterized by low serum iron, both are microcytic anemias

differences:
- decreased release of cellular iron in anemia of chronic disease
- iron stores are trapped in macrophages in anemia of chronic disease

Question 18

what are some examples of hemolytic anemias that occur within the cell? (5)

Answer 18

Hereditary spherocytosis: inherited defects in membrane protein of RBC
Hereditary elliptocytosis: mutations in cytoskeleton and membrane protein integrity
RBC enzyme defects: includes G6PD deficiency (lack of G6PD = low NADPH -> RBC susceptible to oxidation by radicals) and PK deficiency (defect in glycolytic RBC metabolism -> less ATP -> more destruction)
Hemoglobinopathies: thalassemias, sickle cell

Question 19

What are some examples of hemolytic anemias outside the cell?

Answer 19

Autoimmune hemolytic anemia: autoantibody mediated destruction (warm/cold variants)
Alloimmune: antibody against transfusions
Fragmentation hemolysis: RBC fragment resulting in schistocytes (ex. thrombotic thrombocytopenic purpura, disseminated intravascular coagulation)

Question 20

What is aplastic anemia

Answer 20

bone marrow replaced by fat cells -> reduced RBC, WBC, and platelets

Question 21

What are the 2 categories of macrocytic anemia? What are some examples of each

Answer 21

Megaloblastic (resulting from inhibition of DNA synth)
- vitamin B12/folate deficiency
- medications (HIV therapy…)
non-megaloblastic
- alcohol abuse
- liver disease
- myelodysplastic syndrome

Question 22

What is myelodysplastic syndrome

Answer 22

Non-megaloblastic macrocytic anemia, characterized by ineffective hematopoiesis with dysplasia of one or more cell lines
- increased risk of developing AML

Question 23

What iron level do you expect in a patient with myelodysplastic syndrome?

Answer 23

Increased
Ineffective production of RBC leads to increased absorption of iron mediated by suppressed hepcidin and upregulation of ferroportin to compensate