Hemoglobin synthesis

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What is the normal adult daily iron needed to replace senescent RBCs? Where does most come from? What is avg intake?: Normal adult = 21 mg
most comes from recycling iron.
Pregnant/breast feeding/infants need more.

Avg intake = 10-20 mg/day
how much of the total body iron is present as hemoglobin?: 66%
How much iron is absorbed from diet and lost daily?: both = 1-2 mg
What factors affect daily Fe requirements?: growth spurts
menstruation
pregnancy
lactation
iron deficiency
where is dietary iron absorption regulated?: in the intestinal mucosa of the small bowel
What is the oxidation state of iron in: -diet -stomach -mucosal cells: Dietary is Ferric - 3+
Stomach is Ferrous - 2+
Mucosa - back to 3+, then complexed with apoferritin to form Ferritin - storage form of iron
What is the primary storage form of iron, and where is it found? Why is it primary?: ferritin
-liver, spleen, bone marrow.

Easily mobilized for usage
What is an alternative form of stored iron to ferritin?: hemosiderin
After Fe3+ in mucosal cells is complexed with apoferritin, what is the remaining Ferric iron converted to?: Transferrin, via combination with apotransferrin.
what is Transferrin?: an Iron transporter to the organs in the body.
What forms Heme?: Iron plus Protoporphyrin ring
How is iron absorption regulated by mucosal cells?: they only take up ferrous iron, so it has to be converted by the stomach acid to Fe2+. After uptake, its converted back to Fe3+ - ferric.
What is Fe3+ first complexed with in mucosal cells?: apotransferrin, to be transferred to the blood.
What is apotransferrin?: transferrin without Iron. just a glycoprotein Beta-globulin shell without its prosthetic group
What does transferrin do?: transports iron from the gut to the blood
What are the 2 storage forms of iron?: ferritin
hemosiderin
what is the primary protein used to store iron, but without the prostethic group?: Apoferritin.
what is ferritin?: the storage form of iron - it complexes with Ferric Iron to make it Fe2+
where is ferritin found?: bone marrow
spleen
liver
plasma
intestinal mucosal cells (some)
what is hemosiderin?: a storage form of ferritin - the ferritin is denatured, but there is excess Fe within it.
what does hemosiderin stain with?: prussian blue.
where is the majority of Fe found in the body?: blood - 65% is in hemoglobin

stored - 30% is in ferritin/hemosiderin
what are 5 types of iron studies?: 1. serum iron
2. Total iron binding capacity (TIBC)
3. % saturation of transferrin
4. Serum ferritin
5. Free erythrocyte protoporphyrin (FEP)
What is serum iron? Reference range? What is it used for? How does it vary?: iron bound to protein.

Ref range = 60-160 mg/dl

It has limited use as a single measurement. Diurnal variation - different in the morning vs. night
What is TIBC? what info does it give?: Total Iron Binding Capacity, tells how much transferrin is able to bind Iron.
So, an indirect measurement of transferrin.
What is the ref range of TIBC?: 200-360 mg/dl
what does a high TIBC indicate?: That lots of transferrin is free and capable of binding iron - b/c iron to be transferred is low.
what is the % Saturation of Transferrin test?: meausres serum iron/TIBC x 100 to detect if iron levels are too high.
what is serum ferritin?: an acute phase reactant, increased in inflammation.
What info does serum ferritin measurement give? what is its clinical use? limitations?: measurement of body iron stores.

used for monitoring iron therapy.
an acute phase reactant, can be falsely elevated in inflammation.
What does FEP or ZPP stand for?: Free erythrocyte protoporphyrin, or
Zinc protoporphyrin
What does FEP represent? What is its clinical use?: free erythrocyte protoporphyrin - the non-heme porphyrin in BLOOD. most is actually bound to zinc, so called ZPP.

used to differentiate anemias -ZPP is increased if truly Fe deficient.
what kinds of iron study results are seen in Fe deficiency anemia?: everything is low except
-Iron binding capacity
-Free erythrocyte protoporphyrin
What is characteristic iron study in Anemia of Chronic Infection?: high FEP - no iron is available to bind protoporphyrin so it's bound to zinc.
What is hemociderosis? What causes it?: Disease where ferritin is degenerated, resulting in excess iron levels.

caused by hemolysis/excess Hb breakdown.
What is hemochromatosus? What causes it? What are the symptoms? How is it treated? What iron study results are seen?: the most common genetic abnormality i caucasions. Ferritin problem; Iron accumul up to 4g/day!! daily need is in Millig.
caused by 2-gene mutation: C2824, H63D.

Symptoms:
Liver cirrhosis, cardiac, diabetic, skin bronzing. BLEED THEM.
EVERYTHING IS ELEVATED except TIBC.
what are 4 examples of disease assocaited with iron deficiency or increase?: -Fe deficiency anemia
-Anemia of chronic infection
-Hemociderosis
-Hemochromatosis
where is Heme synthesized?: Mitochondria
What is heme synthesized from?: glycine and succinyl coenzyme A
In general, how is heme synthesized?: it goes through a biosyntheitc pathway catalyzed by a series of enzymes in both the mitochondria and cytoplasm.

Each enzymatic reaction adds a ring to the heme molecule.
It becomes less H2O soluble as it grows. Lack of an enzyme causes deficiency in heme.
What is the final structure of heme?: a Tetrapyrole ring with Ferrous iron as its core
what controls heme synthesis?: ALA synthase - the rate-limiting step in the pathway.
what affect does Free heme have?: it can be measured in the urine.
What are the porphyrias? What is their clinical effect?: Defects in porphyrin synthesis.
Free porphyrin precursors are excreted in the urine as:
-urobilinogen in organic layer
-prophyrobilinogen in aqueous layer.
Where does globin synthesis occur?: in ribosomes
what are the 4 types of globin chains?: alpha
beta
gamma
delta
when is most alpha globin made?: in the fetus
what regulates globin synthesis?: mostly genetics
what is the structure of hemoglobin, and how is it assembled?: a tetramer

-2 alpha chains, 2 non-alpha. either Beta, delta, or gamma.

Tetramer links to heme via the proximal histadine on the polypeptide chain.
what's the most important factor affecting O2 release to tissues?: 2,3-DPG
how is 2,3-dpg generated?: via anaerobic glycolysis
what four things cause a LEFT shift of dissoc. curve?: high Hgb F concentration
hemoglobinopathies
meth or carboxyhemoglobin
transfusion of 2,3-DPG depleted blood
what 3 things cause a RIGHT shift?: hypoxia
high altitude
severe anemia
what 3 enzymes play a role in Hgb metabolism?: -enzymes of the Embden Meyerhof produce ATP!!

-G-6-PD catalyze reactions in the hexose monophosphate HMP shunt to prevent buildup of bad peroxides. W/out, Heinz bodies

-Cyto b5 reductase reduces methemoglobin.
what organelle is each synth in? -heme -globin: heme is in mitochondria
globin is in ribosomes.
what regulates heme synthesis?: ALA-synthase
what is ALA-synthase?: an enzyme that catalyzes the rate-determining step in the heme production pathway
how is heme production regulated?: by a negative feedback system; when heme is present, expression of ALA synthase is downregulated.
what are siderocytes?: cells with precipitated iron, due to abnormal/faulty incorporation of iron into the heme group.
what symptomology is seen in the porphyrias?: metabolic deficiencies; urinary excretion of urobilinogen (organic layer), and prophyrobilinogen (aqueous)
what type of iron studies are seen in iron def. anemia?: decreased everything except TIBC and FEP.
what iron study results indicate anemia of chronic infection?: decreased serum iron, TIBC, and transferrin saturation.
increased serum ferritin and FEP.
what is wrong in anemia of chronic infection?: no problem with iron absorption/storage, but there is faulty delivery of iron to RBC and no incorporation into heme.
-That explains the incr. serum ferritin - it's all stored.
what is hemochromatosis essentially?: overloaded iron stores - a genetic disease.
what iron study results are seen in hemachromatosis?: increased serum iron, Transferrin saturation, serum ferritin.
decreased TIBC and FEP.
what does 2,3-dpg do?: decreases hemoglobin's affinity for oxygen - makes it release.
at what pressure does hgb release oxygen in tissues? how much is released?: releases 25% of oxygen at 40 mm Hg.
what does temperature increase do to the o2 diss curve? temp decrease?: increase = shift to right

decrease = shift to left
what does ph decrease (acid) do to the o2 diss curve? ph increase (alkaline)?: acid = shift to right

alkaline = shift to left
what does increased CO2 do to the o2 diss curve?: shift to left
what does decrease in 2,3 DPG do to the o2 diss curve?: shift to left
what happens to oxygen affinity when curve shifts?: to the right = lower oxygen affinity

to the left = higher oxygen affinity
through what metabolic pathway do RBCs generate energy?: embden-meyerhof.
what do RBCs need to protect themselves from?: oxidizing agents that are harmful to protein
what shunt is used to defend the RBC against oxidative injury?: Hexose-Monophosphate shunt
what is the role of glutathione in the hexose-monophosphate shunt?: glutathione reduces oxidative agents and neutralizes them.
what does G-6-PD do? what is seen if it's deficient?: an enzyme that reduces NADP to NADPH to keep the shunt going.

If deficient, see Heinz bodies.
What is the purpose of Cytochrome b5 reductase?: reduces methemoglobin to make it capable of o2 transport.
.: ..

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