Glossary of 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?
- How much iron is absorbed from diet and lost daily?
- both = 1-2 mg
- What factors affect daily Fe requirements?
- growth spurts
- where is dietary iron absorption regulated?
- in the intestinal mucosa of the small bowel
- What is the oxidation state of iron in:
- 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?
-liver, spleen, bone marrow.
Easily mobilized for usage
- What is an alternative form of stored iron to ferritin?
- 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?
- what is the primary protein used to store iron, but without the prostethic group?
- what is ferritin?
- the storage form of iron - it complexes with Ferric Iron to make it Fe2+
- where is ferritin found?
- bone marrow
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?
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?
- 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
- 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.
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
- where is Heme synthesized?
- 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?
- 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?
- how is 2,3-dpg generated?
- via anaerobic glycolysis
- what four things cause a LEFT shift of dissoc. curve?
- high Hgb F concentration
meth or carboxyhemoglobin
transfusion of 2,3-DPG depleted blood
- what 3 things cause a RIGHT shift?
- 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 is in mitochondria
globin is in ribosomes.
- what regulates heme synthesis?
- 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?
- 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?
- 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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