Anemias and Iron Metabolism Flashcards
What is the difference between heme and non-heme iron?
Absorbed differently; heme iron contains a porphyrin ring
What are the different kinds of anemias?
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
In humans, iron is incorporated into proteins as a component of what 3 things?
- Heme
- Iron sulfur clusters
- other functional groups
-> these are important for O2 transport, mitochondrial respiration, DNA replication and repair, immune response, cell signaling, etc.
What is the difference between heme and non-heme iron absorption?
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
What is the difference between heme and non-heme iron absorption?
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
How is iron transferred from cytosol to plasma?
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
What is transferrin?
transferrin is a glycoprotein that transports iron in plasma
- contains 2 high affinity Fe 3+ binding sites
How is Iron in plasma taken up by tissue?
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)
How is iron stored? Where?
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)
What happens when there is excess iron?
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
What are the 2 ways of regulating iron absorption?
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
Describe the protein function of:
DMT1
Duodenal cytochrome b (DCYTB)
Ferroportin
Transferrin
Transferrin Receptor 1(TfR1)
Ferritin
Hepcidin
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
What is hemochromatosis?
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
What are some clinical features, lab findings, and treatment of hemochromatosis?
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
What are the 3 broad classifications of anemias? what are the 3 causes of anemias?
Classification of anemias:
- decreased prod. of RBC (iron def, folate def, kidney disease (decrease EPO))
- increased destruction of RBC
- loss of RBC (bleed)
What are the 3 broad classifications of anemias?
Classification of anemias:
- decreased prod. of RBC (iron def, folate def, kidney disease (decrease EPO))
- increased destruction of RBC
- loss of RBC (bleed)
What are the 2 most common Anemias? briefly describe them. Compare and contrast them
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
what are some examples of hemolytic anemias that occur within the cell? (5)
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
What are some examples of hemolytic anemias outside the cell?
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)
What is aplastic anemia
bone marrow replaced by fat cells -> reduced RBC, WBC, and platelets
What are the 2 categories of macrocytic anemia? What are some examples of each
Megaloblastic (resulting from inhibition of DNA synth)
- vitamin B12/folate deficiency
- medications (HIV therapy…)
non-megaloblastic
- alcohol abuse
- liver disease
- myelodysplastic syndrome
What is myelodysplastic syndrome
Non-megaloblastic macrocytic anemia, characterized by ineffective hematopoiesis with dysplasia of one or more cell lines
- increased risk of developing AML
What iron level do you expect in a patient with myelodysplastic syndrome?
Increased
Ineffective production of RBC leads to increased absorption of iron mediated by suppressed hepcidin and upregulation of ferroportin to compensate
