Methaemoglobinaemia - left-shifted curve

[Phloston]

I'm aware that fetal Hb shifts the curve to the left because 2,3-BPG cannot bind to the gamma chains as easily as they can to the beta.

I'm guessing this means that 2,3-BPG binds to the globin portion of Hb.

I'm also aware that CO shifts the curve to the left because, by binding to Fe2+, it locks the Hb in the relaxed form.

For methaemoglobinaemia, why is the curve left-shifted? O2 cannot bind as readily to Fe3+, so if anything, wouldn't that right-shift the curve? I had thought that maybe the mechanism could be similar, as with fetal Hb, where 2,3-BPG cannot bind as readily, but in this case, the globin isn't changed, just the oxidation state of the oxygen.

Anyone's thoughts?

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[withrye]

Fe3+ has a decreased affinity for O2, but it also has a decreased unloading capacity. Provided you have an appropriate PaO2, you're going to (near) saturate your Hb, whether Hb or metHb. This will seem like a 100% SaO2, but the actual capacity to deliver O2 will be decreased due to the left shift and metHb's desire not to release the O2 to tissue.

 

[Ronin786]

Wiki has the answer apparently:

Methemoglobin is an oxidized form of hemoglobin that has a decreased affinity for oxygen, resulting in an increased affinity of oxygen to other heme sites and overall reduced ability to release oxygen to tissues. The oxygen–hemoglobin dissociation curve is therefore shifted to the left. When methemoglobin concentration is elevated in red blood cells, tissue hypoxia can occur.

Hypoxia occurs due to the decreased oxygen-binding capacity of methemoglobin, as well as the increased oxygen-binding affinity of other subunits in the same hemoglobin molecule which prevents them from releasing oxygen at normal tissue oxygen levels.

http://en.wikipedia.org/wiki/Methemoglobinemia

 

[Belleza156]

Fe3+ can't bind O2 so there will be normal PaO2 with decreased SaO2 because even though MetHb is NOT binding to any O2, normal ferrous (Fe2+) iron is still there, and they won't let go of their O2. Ferric iron groups impair the unloading of O2 by the oxygenated ferrous heme. Thus Left shift in the curve.

That's why Methemoglobinemia is one of the examples in which administration of O2 does not increase SaO2. You have to give methylene blue in order to increase SaO2.

FUN FACT: normal pulse ox will give you a reading that SaO2 is normal. The wavelengths emitted by the pulse ox can't differentiate between deoxyhemoglobin and MetHb..same goes for carxboxyHb. You have to use a special oximeter in order to get the correct reading.

 

[Phloston]

Fe3+ can't bind O2 so there will be normal PaO2 with decreased SaO2 because even though MetHb is NOT binding to any O2, normal ferrous (Fe2+) iron is still there, and they won't let go of their O2. Ferric iron groups impair the unloading of O2 by the oxygenated ferrous heme. Thus Left shift in the curve.

That's why Methemoglobinemia is one of the examples in which administration of O2 does not increase SaO2. You have to give methylene blue in order to increase SaO2.

FUN FACT: normal pulse ox will give you a reading that SaO2 is normal. The wavelengths emitted by the pulse ox can't differentiate between deoxyhemoglobin and MetHb..same goes for carxboxyHb. You have to use a special oximeter in order to get the correct reading.

Could you please be more specific with / elaborate on that bold statement?

 

[MedicalStudent9]

Geez bro. Just buy Harrison's already.

 

[Phloston]

I've looked at Harrison's. I don't really feel the explanations get to the heart of it beyond what we already know.

 

[Belleza156]

That's all I know. The extent of my knowledge goes as deep as Goljan

I'm sure I learned the details first year in physio or biochem, but I can't recall anymore.

Here's what Medscape had to say:

Oxidation of iron to the ferric state reduces the oxygen-carrying capacity of hemoglobin and produces a functional anemia. In addition, a ferric heme group affects nearby ferrous heme groups. Ferric heme groups impair the release of oxygen from nearby ferrous heme groups on the same hemoglobin tetramer. The result of methemoglobinemia is that oxygen delivery to tissues is impaired and the oxygen hemoglobin dissociation curve shifts to the left.

 

[Phloston]

That totally makes sense now.

So we get a degree of unloading at the tissues, with the Hb entering the venous circulation half-saturated. The two free O2-binding sites would then get oxidized to Fe3+, meaning that they can't pick up O2 anymore, but the oxidation locks the Hb in the R-configuration such that the two O2 already bound cannot leave until the two other unbound-oxidized binding sites are reduced again. The net result is that methaemoglobin binds oxygen very strongly at its normal Fe2+ sites and doesn't bind it at all at the Fe3+ sites; this explains why the blood is deoxygenated enough to yield a "blue-brown" or "chocolate brown" color, despite the Hb partially having greater affinity for O2. The misconception would therefore be that all four O2-binding sites would be oxidized in methaemoglobinaemia, when in fact the process must be heterogenous, since it's actually very rare for a Hb molecule to ever have all of its oxygen unloaded such that pan-oxidation (and therefore a right-shift) could take place.

 

[Belleza156]

I dunno if it help you, but I always have to quantitate things in order to visualize.

Each RBC has 200-300 molecules of hemoglobin. Each of those hemoglobins is made up of 4 heme groups plus the 4 globin polypeptide subunits (Actual ratio is like 96% globin chain, 4% heme). Each of those heme groups gets one and only 1 Oxygen molecule. So the way I see it there would have to be a heterogenous mix just given how many heme groups there would be~roughly 800-1200 heme groups.

It always helps me to see the bigger picture.

BTW did you know that there was such a thing as hereditary methemoglobinemia? I think I had seen it before but I didn't realize they were BLUE their whole life!!!
http://www.dartmouth.edu/~rpsmith/bluepeople2.jpg

 

[Phloston]

I dunno if it help you, but I always have to quantitate things in order to visualize.

Each RBC has 200-300 molecules of hemoglobin. Each of those hemoglobins is made up of 4 heme groups plus the 4 globin polypeptide subunits (Actual ratio is like 96% globin chain, 4% heme). Each of those heme groups gets one and only 1 Oxygen molecule. So the way I see it there would have to be a heterogenous mix just given how many heme groups there would be~roughly 800-1200 heme groups.

It always helps me to see the bigger picture.

BTW did you know that there was such a thing as hereditary methemoglobinemia? I think I had seen it before but I didn't realize they were BLUE their whole life!!!
http://www.dartmouth.edu/~rpsmith/bluepeople2.jpg

Hereditary methaemoglobinaemia? That's odd. I always thought the "blue people of Kentucky" had some sort of argyria. Notice if you google "argyria," the same pictures come up as hereditary met.

 

[Belleza156]

Couldn't resist!

Argyria-improper exposure to chemical forms of silver

Hereditary methemoglobinemia- most common cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency

 

[HelpPleaseMD]

That totally makes sense now.

So we get a degree of unloading at the tissues, with the Hb entering the venous circulation half-saturated. The two free O2-binding sites would then get oxidized to Fe3+, meaning that they can't pick up O2 anymore, but the oxidation locks the Hb in the R-configuration such that the two O2 already bound cannot leave until the two other unbound-oxidized binding sites are reduced again. The net result is that methaemoglobin binds oxygen very strongly at its normal Fe2+ sites and doesn't bind it at all at the Fe3+ sites; this explains why the blood is deoxygenated enough to yield a "blue-brown" or "chocolate brown" color, despite the Hb partially having greater affinity for O2. The misconception would therefore be that all four O2-binding sites would be oxidized in methaemoglobinaemia, when in fact the process must be heterogenous, since it's actually very rare for a Hb molecule to ever have all of its oxygen unloaded such that pan-oxidation (and therefore a right-shift) could take place.

whatever you wrote there gave me a headache to read. basicaly in met hemo the Fe+3 sites serve as functionally carrying oxygen when they are not. it therefore logically reduces the oxygen carrying capacity and unloading of oxygen cause there would also be a decrease in coopertivity.