Supplementing Manganese might unblock the Urea Cycle?

[cristi_b]

My aminoacids results show Ornithine is under the lower limit, I also have had trouble with ammonia being over the limit, but as I understand it ammonia is a problem for people with homozygous MTHFR A1298C mutation so I'm not sure if it's related to the low Ornithine. The trouble is I simply cannot take Ornithine at all, even one pill immediately makes my urination problems worse(urgency, dribbling) so a supplement is not a solution.

Arginine is also mid range so I don't think the problem comes from an urea cycle disorder. Either insufficient Arginine is transformed in Ornithine, or too much Ornithine is transformed in Citrulline, but I'm not sure which one.

While looking at the urea cycle diagrams I've seen that Manganese is used to transform Arginine in Ornithine. So I'm thinking maybe I have extremely low Manganese(I've not done a test yet) and this would seem to fit my profile well: the water I drink has no Manganese(no other heavy metals also), I eat few foods that contain it, I also have a high Ferritin which I understand prohibits Manganese absorption.

So I'm looking on some advice to how much Manganese to try (hopefully if my Ornithine levels go up naturally, not by using a supplement, the urination problems will not get worse).

 

[Judee]

My aminoacids results show Ornithine is under the lower limit, I also have had trouble with ammonia being over the limit,

Can you take yucca to lower your ammonia levels? I think it has to be eaten with meals. ??

 

[cristi_b]

Can you take yucca to lower your ammonia levels? I think it has to be eaten with meals. ??

I have not tried yucca, I've used lactulose and other compounds to get it down: my ammonia levels were 85 umol/L to begin with and brought it down to about 61 umol/L.

I know 61 umol/L is not ideal, but I thought to leave it like that for now, seeing also that some of the ammonia has ended up been transformed to Glutamine(which is right at the upper limit, but not over it).

I'm so new at this medical stuff, I don't have any experience and I actually don't know if I'm doing something wrong, please correct me if you see a mistake in my reasoning.

I've read that manganese should not be taken in high quantities as having too much is just as bad as too little, that's why I've asked for some advice on the quantity. I don't even know if it will help the Ornithine situation at all, it's an hypothesis of mine, I'm sort of shooting in the dark.

 

[Judee]

I'm not super smart on this stuff either. I'm sorry.

Hopefully one of the brainiacs will have more ideas for you.

 

[cristi_b]

Ok, so I've tried Manganese for about 2 weeks and I did not notice a big improvement in how I feel. I have not retested my blood aminoacids, but judging by my symptoms I doubt ornithine level is changed.

So I've done more reading into the various reactions and came across a new hypothesis why my Ornithine level is low: overactive Ornithine Decarboxylase enzyme. It seems this enzyme is also involved in Alzheimer disease(according to a study done in S. Korea) and would explain why a lot of my relatives had an Alzheimer diagnosis and it also could explain my memory problems. The ODC enzyme can be seen in the attached picture, as it can "take out" ornithine from the urea cycle to produce putrescine(a polyamine):

So my next test will be to try Spermidine, regarded as the most potent feedback inhibitor of ODC, to see if I notice any difference. Allicin is an other alternative as an ODC inhibitor, but I don't know if it reaches the brain.

 

[triffid113]

So, I never know there was any connection between citrilline and the urea cycle, but I ran across this: Compared with the baseline, fasting plasma arginine concentrations increased 12% after 3 wk of the lower-dose watermelon treatment; arginine and ornithine concentrations increased 22% and 18%, The article is about watermelon, which contains citrilline. date 2007

Watermelon consumption increases plasma arginine concentration in adults​

I did not read all your posts, but did you test low in Molybdenum? I would never take it. It prevents absorption of copper... and I believe most older people are low in copper... because - grey/white hair. Also, look at your tan...making enough melanin? If not, prolly not enough copper. I know nothing beyond that. I only mention it for consideration.

 

[triffid113]

I also know there is some tie between thyroid hormone and the ornithine cycle...if you get really sick, make sure you have thyroid support because low thyroid will cause low kidney function and, at some point, can ruin your kidneys...as happened during the 2010 flu pandemic. The interaction is not show in the picture above, but I did find it in a study once.

 

[datadragon]

most older people are low in copper... because - grey/white hair. Also, look at your tan...making enough melanin? If not, prolly not enough copper.

Copper is required to be attached to ceruloplasmin to be usable by the body for this and its many other functions, otherwise you can have plenty of copper intake but still be deficient at the same time due to the lack of ceruloplasmin to make it usable. Most are not low in intake but low in being able to produce ceruloplasmin allowing both unbound copper and iron to build up and potential deficiency at the same time. . Individuals lacking ceruloplasmin display iron overload in selected tissues, including liver, brain over time. It has been explained that it is kind of like being in the middle of the ocean surrounded by water, yet still starved of usable water to drink.

Ceruloplasmin, a copper-containing acute phase plasma protein, has been shown to be regulated by 13-cis retinoic acid, an active metabolite of Vitamin A in rats https://www.ncbi.nlm.nih.gov/pubmed/3655940 Ceruloplasmin and Vitamin A also require Zinc and thats where problems occur as under inflammation zinc uptake is reduced. Also, The cytokine interleukin 6 (IL6) and others induces the expression of Metallothionein and consequently reduces zinc availability. IL-6 is released during the acute phase of an inflammatory response. Interleukin-6 (IL-6) up-regulates the ZIP14 gene expression, which in turn, is responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute phase response to inflammation and infection. https://www.pnas.org/content/102/19/6843

Its possible to check serum copper and serum ceruloplasmin (the usable copper) and can calculate free copper levels unbound to ceruloplasmin but this is a spot check at the time of the test only and does not reflect any long term accumulation in the tissues that may have also been going on.
https://web.archive.org/web/2021030...ients-families/lab-tracker-copper-calculator/ I mention this also due to the mention of alzheimers which I mentioned briefly here https://forums.phoenixrising.me/thr...lock-il-6-trans-signalling.90433/post-2438840

-David

 

[datadragon]

So I've done more reading into the various reactions and came across a new hypothesis why my Ornithine level is low: overactive Ornithine Decarboxylase enzyme.

Interesting related to this pathway - ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms. ODC Deletion in Macrophages Also Enhances NLRP3-Inflammasome Activation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293075/

So my next test will be to try Spermidine, regarded as the most potent feedback inhibitor of ODC, to see if I notice any difference.

Yes it says Spermidine and spermine are more effective than putrescine at stimulating translation of antizyme mRNA as inhibitor of ODC. ODC is a pyridoxal 5 phosphate (PLP)-dependent amino acid decarboxylase (active B6). https://www.jbc.org/article/S0021-9258(20)72392-6/fulltext

@cristi_b

 

[cristi_b]

I did not read all your posts, but did you test low in Molybdenum? I would never take it. It prevents absorption of copper...

I have tested my copper level back in 2020, it was mid range(my result was 100 whereas the range was 70-140). I don't think it affects the urea cycle as I did not find any information linking copper to urea cycle or Ornithine.

Also, look at your tan...making enough melanin?

My skin is quite white as I do not spend a lot of time outside, but when I do, I seem to get tanned easily in the sun.

Copper is required to be attached to ceruloplasmin to be usable by the body for this and its many other functions, otherwise you can have plenty of copper intake but still be deficient at the same time due to the lack of ceruloplasmin to make it usable.

I have not tested ceruloplasmin, I will test it next time I do some blood tests

I also know there is some tie between thyroid hormone and the ornithine cycle...

I have tested my thyroid function several times as almost all doctors I went to wanted to see for themselves things like TSH, T3, FT4. Never have they found any problem there.

So, I never know there was any connection between citrilline and the urea cycle,

I've tried Citrulline last year, it makes my veins look like they are about to burst. My veins are dilated and visible all the time, but Citrulline definitely made it worse, so I did not continue taking the supplement. I did not find a solution or an explanation to this either(maybe the NOS enzyme is up-regulated or maybe my blood is not that fluid and pushes against the wall of the veins) it's an open issue just like Ornithine creating urinary problems.

ODC is a pyridoxal 5 phosphate (PLP)-dependent amino acid decarboxylase (active B6).

Taking P5P(active B6) makes my urination problems worse, this could be a clue of ODC being up-regulated.

Yes it says Spermidine and spermine are more effective than putrescine at stimulating translation of antizyme mRNA as inhibitor of ODC.

I'm still waiting for my Spermidine supplement to arrive, there seems to be some delay in shipping. I will post here any results I get from taking it.

 

[cristi_b]

Interesting related to this pathway - ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms. ODC Deletion in Macrophages Also Enhances NLRP3-Inflammasome Activation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293075/

The study you provided has an interesting idea:

We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection

I have looked for any study linking H. Pylori to upregulation of ODC and found this: Helicobacter pylori CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases.

There is also a possible link between H. Pylori and urinary problems: Helicobacter Pylori Induced Interstitial Cystitis

I was tested so many times against H. Pylori and came out negative that I abandoned that route, there was just one time when my H. Pylori antibodies were slightly higher but that's about it. I have not done a endoscopy though, as I know doctors can take biopsies with the endoscopy and test for the microbe directly. So if the Spermidine does not help with my problems maybe I should get more tests for H. Pylori.

 

[triffid113]

have tested my thyroid function several times as almost all doctors I went to wanted to see for themselves things like TSH, T3, FT4. Never have they found any problem there.

TSH should be between 1 and 2. Your lab will say it's normal at 5.5, but science says otherwise. Search lifeextension.org tsh reference range. TsH higher than about 2.3 will have noticeable symptoms
.

Also, we will leave copper because it does not affect the ornithine cycle, but I have to point out that a copper blood test us worthless, tells you nothing, since copper is an acute phase reactant.

 

[cristi_b]

Just done a new set of blood tests, even though I had no recommendation from a doctor, but I discovered something: it seems I have a problem with too much iron(not just ferritin like I initially said).

TSH should be between 1 and 2. Your lab will say it's normal at 5.5, but science says otherwise.

TSH measured this morning was 1.93 μUI/mL within normal range.

Copper is required to be attached to ceruloplasmin to be usable by the body for this and its many other functions, otherwise you can have plenty of copper intake but still be deficient at the same time due to the lack of ceruloplasmin to make it usable.

Tested ceruloplasmin this morning: it was 20 mg/dL which is within normal range for the lab(15 - 30 mg/dL).

Now I need to find a doctor to look over my iron results, as far as I've calculated the transferrin saturation is 52%(above 50% it is marked as problematic in medical literature). The trouble over here with doctors is they expect patients to silently listen and believe the advice they are given, especially if their medical opinion is that you are not sick. Whereas I have done the biggest blasphemy of them all: I have done blood tests again without recommendation even though I was told specifically not to do that anymore. This means I will get yelled at and will have to try with several doctors until I find one willing to help.

What I've found seems important as high iron can affect the urea cycle according to this study:

Proteomic analysis of hepatic iron overload in mice suggests dysregulation of urea cycle, impairment of fatty acid oxidation, and changes in the methylation cycle

 

[triffid113]

Did you check your Vitamin D levels and your urinary ph? (Without adequate D you cann't balance your urinary ph, and it will irritate you). Something to check if you have not.

Another angle is - how you considered trying bioidentical hormone replacement? I ask because lack of sufficient estrogen causes urinary problems in some women and it clears up if estrogen is given. idk how they dispense estrogen for that... maybe you take it topically, not sure. It might be a nominal dose. (In other words, maybe you'll never understand, doesn't necessarily mean you can't fix it).

 

[cristi_b]

[...] urinary problems in some women and it clears up if estrogen is given [...]

Just to clear this up: I am not a woman, I am a man so I'm not sure how estrogen would help me.

I'm still waiting for my Spermidine supplement to arrive, there seems to be some delay in shipping. I will post here any results I get from taking it.

I have tried Spermidine for a month, but not continuously since I wanted to see if the effects last. From what I could deduce it helps: my memory becomes better while taking it and so does my urinary troubles. This seems to confirm my problems are related to an overactive ODC enzyme.

While looking for other possible causes of upregulated ODC enzyme I came across an other possibility(in addition to the ones I mentioned): Giardia. I found two studies showing this:

1) The role of arginine and arginine-metabolizing enzymes during Giardia – host cell interactions in vitro

Most genes were constant or down-regulated (e.g. arginase 1 and 2) upon interaction with Giardia, whereas inducible NO synthase (iNOS) and ornithine decarboxylase (ODC) were up-regulated within 6 h of infection

2) Arginine Consumption by the Intestinal Parasite Giardia intestinalis Reduces Proliferation of Intestinal Epithelial Cells

Crucial are also ODC levels that we found to be upregulated 9.5 × after 24 h of parasite-interaction on RNA level

Now the irony is I have had intestinal parasites as a kid, but in the last 15 years that I've been suffering stomach troubles no doctor has ordered a comprehensive stool test for me.

I will just have to order such a test for myself(Real-Time PCR on stool sample) to see if that shows anything.

I have also ordered a complete genome sequencing test from Nebula Genomics(trying to find any kind of genetic condition that would cause my problems).

 

[cristi_b]

Did you check your Vitamin D levels and your urinary ph? (Without adequate D you cann't balance your urinary ph, and it will irritate you). Something to check if you have not.

Since I've last written in this topic I've checked my Vitamin D level and it's quite low: 14.4 ng/mL. Laboratory says optimal is above 30 ng/mL. I've tried to supplement with vitamin D but it doesn't help with my urinary problems and it causes other issues, so I don't think it's actually the cause.

I will just have to order such a test for myself(Real-Time PCR on stool sample) to see if that shows anything.

Real-Time PCR on stool sample showed no parasites.

I have also ordered a complete genome sequencing test from Nebula Genomics(trying to find any kind of genetic condition that would cause my problems).

Nebula Genomics results came in: I don't have an urea cycle disorder and they did not find any important genetic conditions. To double check I've run the Sequencing.com app on the raw data from Nebula Genomics and nothing important came out of it. Basically I've wasted a lot of money sequencing my whole genome without finding anything.

 

[Alvin2]

My aminoacids results show Ornithine is under the lower limit

What test did you do to determine this?

 

[cristi_b]

What test did you do to determine this?

It's a blood aminoacid test, it was processed in Germany and it gave the levels of 29 aminoacids from a single blood draw. From my results, values relevant to the urea cycle are:
Arginine __________ 15.9 mg/L ______ Normal range is: 2.6 - 22.3 mg/L
Citrulline __________ 4.2 mg/L ______ Normal range is: 2.1 - 9.6 mg/L
Ornithine _________ 6.1 mg/L _______ Normal range is: 6.3 - 25.8 mg/L !!!

 

[Alvin2]

It's a blood aminoacid test, it was processed in Germany and it gave the levels of 29 aminoacids from a single blood draw. From my results, values relevant to the urea cycle are:
Arginine __________ 15.9 mg/L ______ Normal range is: 2.6 - 22.3 mg/L
Citrulline __________ 4.2 mg/L ______ Normal range is: 2.1 - 9.6 mg/L
Ornithine _________ 6.1 mg/L _______ Normal range is: 6.3 - 25.8 mg/L !!!

Interesting, what is this test called?

 

[triffid113]

So do we know if you can get high ammonia from a high protein diet, regardless of if you have the gene making it hard to excrete ammonia? (Do you eat a high protein diet?). I also read that gut bacteria can produce amminia. I recommend, and take, a supplement from Life Extension called GI With Page Technology - it just adds some good microbiota and kills some bad ones. I have that genetic problem excreting ammonia, but I tested myself and I can handle 80g of protein a day, which is plenty. I just cant handle a high protein diet.

I don't think your lab is correct about the D level needed. Most docs/hospitals claim it is 50ng/ml but Life Extension says it is 70 and I believe them. I keep mine between 70 nj/ml-100ng/ml and find I no longer crave dairy products and am able to absorb enough calcium to stave off the diabetes the rest of my family fell prey to (low calcium raises insulin resistance and destroys the Beta cells in the pancreas). idk what problems raising your D level would cause, only that over 100 can make uti easier to get.

So, you are male...men need more citrate and zinc in their prostate. I am wondering if, when you take your D, that you are then absorbing an irritating calcium supplement. I take cal-mag CITRATE. No other form feels good to my body. So maybe look to your cal-mag supplement if raising your D is problematic. Also, I would never take calcium without magnesium. Magnesium helps quench pain, something that may be of interest in CFS/FM.

Did I read you tried P5P? I think of P5P and magnesium together...they are both required for excretion of harmful substances, including homocysteine, in the liver. So if you tried P5P and it was problematic, try that with magnesium and see if it makes a difference.

I used to consult the Roche biochemical database for this nfo, but the program for interacting with it has changed and I don't know what it is called anymore.