MudPhud20XX

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So I get that thiamine (B1) is needed for several metabolic pathways such as TCA cycle, HMP shunt, and for branched-chain amino acid dehydrogenase as well.

So in general, many of the symptoms you would see would be muscle weakness such as ophthalmoplegia, which I am assuming can happen b/c of the lack of ATP production. But why eye muscles among many other muscles?

Also, how do you explain ataxia, memory loss, and cerebral hemorrhage?

Also FA says Wernicke-Korsakoff can lead to damage to medial dorsal nucleus of thalamus and mammilary bodies, I just feel like these are kind of random symptoms that are perhaps irrelevant to metabolic pathways affected by thiamine deficiency.

One explanation I can think of perhaps is the lack of NADPH production since thiamine is needed for transketolase in the PPP (Pentose Phosphate Pathway), but there are many organs that require appropriate NADPH to maintain redox balance, so why damage in medial dorsal nucleus of thalamus and mammilary bodies?

Can anyone enlighten me? Many thanks in advance.
 

ulikedaggers

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There shouldn't be a lack of NADPH production since all the NADPH is produced by the G6PDH reaction, which occurs before the transketolase reaction. There would be decreased production of Ribose-5-P though, and HMP is usually the major source of R5P for nucleotide synthesis.

Besides that, I don't have an answer for you besides the fact that (as you mention) lack of ATP production severely inhibits myelin formation.
 
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MudPhud20XX

MudPhud20XX

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You're absolutely right about the NADPH. (What was I smoking? LOL). I don't think knowing the mechanism will be in USMLE, but it just bothers me to memorize these symptoms without knowing why. Thanks though.
 
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MudPhud20XX

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Okay, so I finally got some clarification.

Wernike-Korsakoff has to do with transketolase being mutated, whereas Beri breri has to do with thiamine deficiency affecting several enzymes (TK, PDH, alph-KG dehydrogenase, branched chain a. a. dehydrogenase) that require thiamine.

So the symptoms you would see from WK have to do with the fact that transketolase is not really working whereas, symptoms you get from beri beri have to do with all those enzymes affected by thiamine.
 

ulikedaggers

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Okay, so I finally got some clarification.

Wernike-Korsakoff has to do with transketolase being mutated, whereas Beri breri has to do with thiamine deficiency affecting several enzymes (TK, PDH, alph-KG dehydrogenase, branched chain a. a. dehydrogenase) that require thiamine.

So the symptoms you would see from WK have to do with the fact that transketolase is not really working whereas, symptoms you get from beri beri have to do with all those enzymes affected by thiamine.
W-K disease is a genetic disease causing a mutated transketolase that has decreased affinity for thiamine. W-K syndrome is the symptoms.. So alcoholics (and any other severe thiamine deficiency) can have WK syndrome with a perfectly normal transketolase.
 

notbobtrustme

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W-K disease is a genetic disease causing a mutated transketolase that has decreased affinity for thiamine. W-K syndrome is the symptoms.. So alcoholics (and any other severe thiamine deficiency) can have WK syndrome with a perfectly normal transketolase.
**** like that drives me nuts
 
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So I get that thiamine (B1) is needed for several metabolic pathways such as TCA cycle, HMP shunt, and for branched-chain amino acid dehydrogenase as well.

So in general, many of the symptoms you would see would be muscle weakness such as ophthalmoplegia, which I am assuming can happen b/c of the lack of ATP production. But why eye muscles among many other muscles?

Also, how do you explain ataxia, memory loss, and cerebral hemorrhage?

Also FA says Wernicke-Korsakoff can lead to damage to medial dorsal nucleus of thalamus and mammilary bodies, I just feel like these are kind of random symptoms that are perhaps irrelevant to metabolic pathways affected by thiamine deficiency.

One explanation I can think of perhaps is the lack of NADPH production since thiamine is needed for transketolase in the PPP (Pentose Phosphate Pathway), but there are many organs that require appropriate NADPH to maintain redox balance, so why damage in medial dorsal nucleus of thalamus and mammilary bodies?

Can anyone enlighten me? Many thanks in advance.
This is actually fairly high yield Mamillary bodies are equisitely ATP dependent. Mamillary bodies are important for memory which is constantly taking place via a dual mechanism of Mg (magnesium) dependent ligand gated channels and voltage gated channels. the creation of these memories is a physical process heavily dependent on ATP.

The small ocular muscles are constantly functioning through a process called saccaded movement. These saccades (separate from nystagmus) are a result of constant eye movements to mantain stereoscopic vision in the presence of two dimensional information- they eye is curved to create as much 3d as possible and to increase peripheral vision. The saccades are constant rapid movements that take place many times a second (30? 15? I forget)- these movements are meant to create a pattern that the brain then synthesizes and transposes to create a 3d mapping of the world. This is how you can tell that the keyboard is infront of the monitor and not a paintaing.

Anyway this is HIGHLY ATP dependent. You can also see how kidney damage can happen as a result of its ATP dependence. Anyway the brain is primarily affected because of its exceedingly high dependence on glucose- without glucose production (inhibited by thiamine def.) you will see a significant impact on brain function.

This is precisely why thiamine should be given before glucose for a glucose depleted alcoholic. Giving glucose will only cause further thiamine loss and worsen the brain's lack of ability to function.

NADPH is not associated.

WK disease is separate from syndrome as explained by the previous poster.
 

ChessMaster3000

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This is actually fairly high yield Mamillary bodies are equisitely ATP dependent. Mamillary bodies are important for memory which is constantly taking place via a dual mechanism of Mg (magnesium) dependent ligand gated channels and voltage gated channels. the creation of these memories is a physical process heavily dependent on ATP.

The small ocular muscles are constantly functioning through a process called saccaded movement. These saccades (separate from nystagmus) are a result of constant eye movements to mantain stereoscopic vision in the presence of two dimensional information- they eye is curved to create as much 3d as possible and to increase peripheral vision. The saccades are constant rapid movements that take place many times a second (30? 15? I forget)- these movements are meant to create a pattern that the brain then synthesizes and transposes to create a 3d mapping of the world. This is how you can tell that the keyboard is infront of the monitor and not a paintaing.

Anyway this is HIGHLY ATP dependent. You can also see how kidney damage can happen as a result of its ATP dependence. Anyway the brain is primarily affected because of its exceedingly high dependence on glucose- without glucose production (inhibited by thiamine def.) you will see a significant impact on brain function.

This is precisely why thiamine should be given before glucose for a glucose depleted alcoholic. Giving glucose will only cause further thiamine loss and worsen the brain's lack of ability to function.

NADPH is not associated.

WK disease is separate from syndrome as explained by the previous poster.
Could you clarify why giving glucose causes further thiamine depletion? Ive never understood which pathways are affected--thiamine is not required in glycolysis. Is it shifting the reaction toward pyruvate dehydrogenase, which does require thiamine?
 
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Could you clarify why giving glucose causes further thiamine depletion? Ive never understood which pathways are affected--thiamine is not required in glycolysis. Is it shifting the reaction toward pyruvate dehydrogenase, which does require thiamine?
Good question. The issue isn't glycolysis itself but the conversion of pyruvate into acetyl COA via pyruvate dehydrogenase. Remember- Thiamine or B1 is necessary for 4 particular enzymes, three of which are in the glycolytic cycle. ATP- alpha ketoglutarate of krebs fame, Transketolase of G6PD fame- which comes straight out of the F6P pathway, and finally pyruvate dehydrogenase the transition enzyme between glycolysis to krebs. Giving glucose will then force the pathway down towards this end using up pyruvate to acetyl Coa and thus use thiamine. Remember, that along with thiamine there are other key enzymes essential in this pathway for these enzymes- Thiamine, Lipase, CoA, Nadh fadh. Loss of thimaine deprives the brain of its use and the glycolytic pathway for sugar productikon- the brain is so dependent on this- in fact hypoxia and glucose deprivation can cause permanent injury within minutes (whereas hours are needed for other tissues).
 

scoKraz4

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Good question. The issue isn't glycolysis itself but the conversion of pyruvate into acetyl COA via pyruvate dehydrogenase. Remember- Thiamine or B1 is necessary for 4 particular enzymes, three of which are in the glycolytic cycle. ATP- alpha ketoglutarate of krebs fame, Transketolase of G6PD fame- which comes straight out of the F6P pathway, and finally pyruvate dehydrogenase the transition enzyme between glycolysis to krebs. Giving glucose will then force the pathway down towards this end using up pyruvate to acetyl Coa and thus use thiamine. Remember, that along with thiamine there are other key enzymes essential in this pathway for these enzymes- Thiamine, Lipase, CoA, Nadh fadh. Loss of thimaine deprives the brain of its use and the glycolytic pathway for sugar productikon- the brain is so dependent on this- in fact hypoxia and glucose deprivation can cause permanent injury within minutes (whereas hours are needed for other tissues).
Lipoic acid, not lipase right?
 
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MudPhud20XX

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Yup! It's lipoic acid.

Tender: Thiamine (B1)
Loving: Lipoic acid
Care: Coenzyme A
For: RiboFlavin (B2)
Nancy: Niacin (B3)

Thank you for the detalied explanation sanj238. After hearing your explanation, I think it is clear that you get all those clinical symptoms in the brain in WK.

Step 1 probably requires us to differentiate WK and beriberi.

So the way I understood beriberi is that unlike WK (which is mainly due to genetic disorder such as transketolase deficiency), it is mainly due to many enzymes (TK, PDH, alpha KG dehydrogenase, Branched chani ketoacid dehydorgenase) being affected by thiamine deficiency, right?

FA classifies beriberi into wet and dry beriberi. Can anyone elaborate more on this classiciation and why they would have those particular clinical symptoms?

Dry beriberi: polyneuritis, symmetrical muscle wasting
Wet beribeir: high-output cardiac failure (dilated cardiomyopathy), edema
 
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Yup! It's lipoic acid.

Tender: Thiamine (B1)
Loving: Lipoic acid
Care: Coenzyme A
For: RiboFlavin (B2)
Nancy: Niacin (B3)

Thank you for the detalied explanation sanj238. After hearing your explanation, I think it is clear that you get all those clinical symptoms in the brain in WK.

Step 1 probably requires us to differentiate WK and beriberi.

So the way I understood beriberi is that unlike WK (which is mainly due to genetic disorder such as transketolase deficiency), it is mainly due to many enzymes (TK, PDH, alpha KG dehydrogenase, Branched chani ketoacid dehydorgenase) being affected by thiamine deficiency, right?

FA classifies beriberi into wet and dry beriberi. Can anyone elaborate more on this classiciation and why they would have those particular clinical symptoms?

Dry beriberi: polyneuritis, symmetrical muscle wasting
Wet beribeir: high-output cardiac failure (dilated cardiomyopathy), edema
The reality is that dry beri beri is the same as WK syndrome...just that beri ber is a nutritional disorder so it is distinguished by the cause- lack of thiamine. while alcohol is a depletion of thiamine.

wet beri beri is a result of inadequate atp for the function of the endothelial cells of capillary walls and endocardium of hte heart. the capillaries become dilated- hypotensive- the heart pumps more blood (high out put) - the heart muscle tires, the endocardium weakens- decreased ATP coupled with high activity - the endocardium also dilates (dilated cardiomyopathy) - boom
 

ChessMaster3000

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The reality is that dry beri beri is the same as WK syndrome...just that beri ber is a nutritional disorder so it is distinguished by the cause- lack of thiamine. while alcohol is a depletion of thiamine.

wet beri beri is a result of inadequate atp for the function of the endothelial cells of capillary walls and endocardium of hte heart. the capillaries become dilated- hypotensive- the heart pumps more blood (high out put) - the heart muscle tires, the endocardium weakens- decreased ATP coupled with high activity - the endocardium also dilates (dilated cardiomyopathy) - boom
nailed it. a patient can get both wet and dry, and often wet is considered the symptoms of dry beriberi with superimposed heart failure. you wouldnt have to distinguish btw who would get wet or dry.

mudphud when are you taking your test btw?
 
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MudPhud20XX

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Thanks guys! I got this completely.

I am taking my step 1 next year after my 2nd year. So it will be around May or June in 2015.

I got upset when I looked at FA and Kaplan books to see that stuff we learned in class wouldn't necessarily prepare me for the board exam. For example, not a single biochem teacher explained these concepts in thiamine deficiency. Considering we will probably see a lot of alcoholics, this has to be high yield in step 1. I am hoping they teach this stuff in pathology during my 2nd year.

So I am not waiting until my 2nd year is done next year to prepare for my board. I've decided to put a considerable portion of my time just for the board exam. Otherwise, I will find myself in trouble after my 2nd year.

I just finished Kaplan biochem and started genetics. My plan is to get all the 1st year subjects (biochem, genetics, neuro, anatomy, physio, immunology) done asap and start previewing the 2nd year subjects (pharm, path, micro).

So I really do appreciate you pros help! Always, any advise and heads-up are greatly appreciated.
Many thanks.
 
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Thanks guys! I got this completely.

I am taking my step 1 next year after my 2nd year. So it will be around May or June in 2015.

I got upset when I looked at FA and Kaplan books to see that stuff we learned in class wouldn't necessarily prepare me for the board exam. For example, not a single biochem teacher explained these concepts in thiamine deficiency. Considering we will probably see a lot of alcoholics, this has to be high yield in step 1. I am hoping they teach this stuff in pathology during my 2nd year.

So I am not waiting until my 2nd year is done next year to prepare for my board. I've decided to put a considerable portion of my time just for the board exam. Otherwise, I will find myself in trouble after my 2nd year.

I just finished Kaplan biochem and started genetics. My plan is to get all the 1st year subjects (biochem, genetics, neuro, anatomy, physio, immunology) done asap and start previewing the 2nd year subjects (pharm, path, micro).

So I really do appreciate you pros help! Always, any advise and heads-up are greatly appreciated.
Many thanks.
oh thats a great plan. Absolutely. Are you a US grad or IMG?
 
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MudPhud20XX

MudPhud20XX

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I go to school in NY and did my undergrad in PA. I have my BA in chemistry and I'm thinking about Rad Onc for my specialty. I fell in love with it when I shadowed a Rad Onc doc during my undergrad.

Hopefully my plan works out well.

Good luck to you all and let's keep up the hard work.
 

ChessMaster3000

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I go to school in NY and did my undergrad in PA. I have my BA in chemistry and I'm thinking about Rad Onc for my specialty. I fell in love with it when I shadowed a Rad Onc doc during my undergrad.

Hopefully my plan works out well.

Good luck to you all and let's keep up the hard work.
been loving the concept questions you are posting, so keep em coming.
 

ulikedaggers

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How does alcoho
The reality is that dry beri beri is the same as WK syndrome...just that beri ber is a nutritional disorder so it is distinguished by the cause- lack of thiamine. while alcohol is a depletion of thiamine.

wet beri beri is a result of inadequate atp for the function of the endothelial cells of capillary walls and endocardium of hte heart. the capillaries become dilated- hypotensive- the heart pumps more blood (high out put) - the heart muscle tires, the endocardium weakens- decreased ATP coupled with high activity - the endocardium also dilates (dilated cardiomyopathy) - boom
How does alcohol a depletion of thiamine? We learned in biochem that thiamine deficiency secondary to alcoholism is because alcoholics tend to have **** diets (making it a "nutritional disorder" in your words).
 
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How does alcoho


How does alcohol a depletion of thiamine? We learned in biochem that thiamine deficiency secondary to alcoholism is because alcoholics tend to have **** diets (making it a "nutritional disorder" in your words).
Well- maybe they said that because diet deficiency may be the main cause? I'm not certain- but I think its because alcohol impedes the conversion of thiamine to its active from thiamine phosphate. The issue here is that we are talking about chronic alcohol abusers though I'm sure acute involvement is there. Chronically- the liver becomes fatty its function declines cirrhosis builds up- this leads to decreased ability to utilize liver function. couple that with decreased intake and decrease ability for liver to convert thiamine to thiamine phosphate and you have WK syndrome. I don't know for sure though but this is my understanding- WK syndrome in alcoholics is far more serious effect than that caused by beri beri

From Wiki:

Strong evidence suggests that ethanol interferes directly with thiamine uptake in the gastrointestinal tract. Ethanol also disrupts thiamine storage in the liver and the transformation of thiamine into its active form.[20] The role of alcohol consumption in the development of WKS has been experimentally confirmed through studies in which rats were subjected to alcohol exposure and lower levels thiamine through a low-thiamine diet.[21] In particular, studies have demonstrated that clinical signs of the neurological problems that result from thiamine deficiency develop faster in rats that have received alcohol and were also deficient in thiamine than rats who did not receive alcohol.[21] In another study, it was found that rats that were chronically fed alcohol had significantly lower liver thiamine stores than control rats. This provides an explanation for why alcoholics with liver cirrhosis have a higher incidence of both thiamine deficiency and WKS.[20]
 
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I go to school in NY and did my undergrad in PA. I have my BA in chemistry and I'm thinking about Rad Onc for my specialty. I fell in love with it when I shadowed a Rad Onc doc during my undergrad.

Hopefully my plan works out well.

Good luck to you all and let's keep up the hard work.
are you MD or DO?
 
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MudPhud20XX

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an MD actually a MudPhud (an MD/PhD) LOL!

"Basic research is the lifeline of medicine"
-Arthur Kornberg

I am really just an ordinary guy who agrees with Dr. Kornberg.

You guys are all really smart and hopefully I will be enlightened too.

Thanks for helping me out!
 
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an MD actually a MudPhud (an MD/PhD) LOL!

"Basic research is the lifeline of medicine"
-Arthur Kornberg

I am really just an ordinary guy who agrees with Dr. Kornberg.

You guys are all really smart and hopefully I will be enlightened too.

Thanks for helping me out!
Hey! I know him!
 
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