F.'s urine amino acids test--analysis and implications for Cheri's case

[Guest guest]

Hi, all.

With Kathy's and her daughter Cheri's permission, I am posting an

analysis of Kathy's Doctor's Data Lab urine amino acids test and

what I think it says in terms of genetics, when compared with

Cheri's. I previously backchanneled this to Kathy, and she may have

some comments on it, also. I'm posting it in hopes that it might be

helpful to others here as well. Thanks to Kathy and Cheri for being

willing to share their data.

First, your 24-hour creatinine excretion was right at normal. What

does this tell us? Well, creatinine is the breakdown product of

creatine, which is found largely in the muscles and is used to store

phosphate groups for exchange with ATP. It sort of acts like a

battery to store energy in the muscles. Normally, the amount

excreted per day is proportional to the lean body mass of the

person. Having a normal value of creatinine excretion suggests that

your body is making creatine at a normal rate, and that you have a

normal amount of muscle. Since the synthesis of creatine is the

main application of methylation by S-adenosylmethionine (SAMe), it

also suggests that your SAMe level is O.K. So this is all good news.

Next, your 24-hour urine volume is high. This suggests either that

you drank a lot of fluids that day, or that you have diabetes

insipidus. Since I know from one of your messages that you did have

a regular problem of heavy urination and thirst, which was helped by

I.V. glutathione, I'm going to guess that this does indicate

diabetes insipidus. I note that Hall also reported that his

D.I. improved when he raised his glutathione, and this seems

consistent with your experience. I think it means that if your

glutathione can be brought back to normal on a steady basis, this

problem will be resolved. I suspect that it results from a direct

effect of glutathione depletion on the hypothalamus.

Next, your ratio of glutamine to glutamate is a little low, but not

bad. Glutamine converts to glutamate in urine samples during

storage, so this is a measure of how much the urine sample might

have degraded during shipping, and it isn't bad.

The ammonia level is also a measure of sample degradation, as the

urea in urine will break down into ammonia and carbon dioxide over

time, especially if bacteria are present. That's why old urine

smells worse than fresh urine. Again, your value indicates that

your sample did not degrade much during shipping.

Methionine is low normal. It's the main source of chemically

reduced sulfur for the body, and it comes in with dietary protein.

The low value suggests either that your diet is low in methionine or

your gut is not absorbing protein as well as it should. I don't

know what your main dietary sources of protein are, but I suspect

from the high value of 1-methylhistidine that you are absorbing

quite a bit of protein from meat. That should contain substantial

methionine, so that doesn't seem to explain the low methionine

value. In looking at the rest of your sulfur-containing amino

acids, though, I can suggest another explanation. I'll get into

this in more detail as we go along, but I think the levels of the

other ones suggest that more of your sulfur metabolite flow than

normal is exiting the methylation cycle at homocysteine, and is

going down the transsulfuration pathway and through both

sulfoxidation to sulfate and to taurine, and thence into the urine,

rather than returning to methionine to complete the methylation

cycle.

The next few are not too far off normal. Isoleucine and leucine are

a little low, and that may suggest that the branched-chain amino

acids are being burned as fuel more than normal. I think that is

consistent with your earlier urine organic acids results that showed

some elevation of citric acid and some lowering of the later Krebs

cycle metabolites, which suggest a partial blockade early in the

Krebs cycle (probably due to a rise in superoxide and perhaps

peroxynitrite as a result of glutathione depletion). Such a partial

blockade will interfere with the oxidative metabolism of

carbohydrates and fats, and will favor the burning of protein. Your

earlier results of elevation of suberic acid suggests difficulties

in burning fats for fuel.

Your phenylalanine is high. I don't know if you drink diet soft

drinks sweetened with Nutrasweet, but that would be one possibility

to explain this, except that aspartate is low, and that is the other

component of Nutrasweet, so I don't think that's it. Another would

be that it appears that the conversion from phenylalanine to

tyrosine is slower than normal, because phenylalanine is rather

high, while tyrosine is close to normal. This could be caused by a

deficiency of iron, niacin (B3) or tetrahydrobiopterin. Since you

are menopausal and should therefore not be losing much iron, and

since you don't seem to have deficiencies of serotonin or dopamine,

based on the symptoms I've heard about from you, and your urea cycle

seems to be working pretty well, I don't think you are too low in

tetrahydrobiopterin, so I'm guessing that it is due to low niacin,

especially since I know that you have not been able to find a

multivitamin/mineral you can tolerate, and you suspect that the B

vitamins are the culprit.

Your taurine is very high. Taurine dumping into the urine is known

to be caused by high beta alanine, and your beta alanine is very

high, so that is likely at least part of the explanation for the

high urinary taurine. High beta alanine in turn is known to be

caused by dysbiosis in the gut, and you do have gut problems, so

that seems to be consistent.

Cysteine is close to normal, which is interesting, and will be

discussed further when we get to cystathionine. Glutamate is a

little high, but that could have come from some breakdown of

glutamine during shipping, and it is a little low. Cystine

excretion is a little high, and that may correspond with your

earlier low pyroglutamic acid in the urine organic acids test

(resulting from glutathione depletion), because pyroglutamic acid is

part of the gamma glutamyl cycle in the kidneys, which is normally

used to reabsorb cystine. The rest on the first page are close to

normal.

On the second page, ammonia is a little high, but could have come

from partial breakdown of urea in shipping, as discussed above.

Ethanolamine is high, probably because of dysbiosis, and the

conversion of ethanolamine to phosphoethanolamine appears to be

slow, probably due to magnesium depletion, which is common in CFS.

The high alpha-aminoadipate suggests a deficiency of vitamin B6 or a

yeast infection.

The low threonine suggests an elevated rate of catabolism

(breakdown) of muscle protein. This is consistent with the

discussion above.

The elevation of beta-aminoisobutyrate is due to a benign genetic

variation of an enzyme in the liver. This is not something to be

concerned about.

The somewhat elevated anserine and carnosine are consistent with a

diet containing significant amounts of poultry and meat.

The indetectable urinary gamma aminobutyrate (GABA) is probably not

significant.

The high hydroxyproline may result from gelatin in the diet or from

digestive problems or various other conditions involving collagen,

bone, skin or connective tissue. I can't pin this down with the

information I have.

The somewhat low citrulline probably results from the somewhat low

arginine, since the former is produced from the latter by nitric

oxide synthase. The somewhat low arginine in turn may reflect that

the dietary protein intake is dominated by meat as opposed to beans,

whole grains and nuts.

I don't know the significance of the elevated phosphoserine.

The elevated taurine excretion has already been discussed, but in

addition, if it is resulting in low intracellular taurine, the

result could be magnesium loss from cells, and that would be

consistent with other evidence for low intracellular magnesium,

already discussed above.

The indetectable methionine sulfate suggests that there is not

extreme oxidative stress.

Finally, we come to cystathionine, the one we have been most curious

about, in view of Cheri's result five years ago, and the recent

developments in the understanding of autism, which I am attempting

to apply to chronic fatigue syndrome. The cystathionine level is

indeed high, but not nearly as high as it was in Cheri's urine amino

acids test. The value here is 65 micromoles per 24 hours. In

Cheri's test, by this same laboratory, it came out at 630 micromoles

per 24 hours, nearly ten times as much! What does this mean?

First, the fact that it is moderately high in your test suggests

either that you are deficient in vitamin B6 or its conversion to its

active form P5P, or that you are heterozygous (have one copy) of the

genetic variation in the cystathionine beta synthase (CBS) enzyme

that causes this enzyme to operate more rapidly than normal. I am

guessing that it is the latter, for several reasons: First, I think

this would be consistent with the levels of the other sulfur

containing species and would also explain your sulfur sensitivity.

Second, because I strongly suspect that Cheri is homozygous (has

both copies) of this genetic variation, in view of her very high

cystathionine excretion. In order for this to be true, you, her

mother, must be at least heterozygous for this variation. When

Cheri's genetic test results come back, we will know whether my

suspicion is true.

Here's how I think a fast CBS enzyme would explain your other sulfur

metabolite results: First, we know that your methionine is slightly

low. Then, we know that your SAMe is essentially normal, because

your creatinine is normal, as I explained above. So that means that

the flow from methionine to SAMe must be O.K. Then, we see that

your homocystine is undetectable, and that means that your

homocysteine cannot be very elevated, and might even be below normal

(Homocystine is the oxidized form of homocysteine). That means that

there is no bottleneck at homocysteine. From there, there is a

branch point. One branch goes back to methionine. The fact that

methionine is somewhat low suggests that the flow in this direction

is below normal. On the other hand, the other branch combines

serine with homocysteine to form cystathionine via the CBS enzyme.

The high level of cystathionine suggests that the flow is above

normal in this direction, suggesting a fast CBS enzyme.

Then we come to cysteine, which is at a near-normal level. The fact

that it's near normal in the presence of the high cystathionine

means that the additional flow must be passing through cysteine

rapidly. Perhaps some of the extra flow goes from cysteine toward

glutathione, but this does not seem likely, because we have other

evidence that glutathione is depleted. This evidence includes your

earlier organic acids test, which showed low pyroglutamic acid,

somewhat elevated citric acid, and somewhat lowered levels of the

later Krebs metabolites. It also includes the fact that you

experienced several different improvements in symptoms when you got

the I.V. glutathione treatments. Furthermore, you suffer from large

cold sores, which means reactivation of herpes simplex type 1 virus,

and this can only happen if glutathione becomes depleted.

The other path the sulfur metabolite flow can take is toward

taurine. From there, it can either be excreted in the urine as

taurine, or can go through sulfite oxidase to be converted to

sulfate, and then sulfate can be excreted in the urine. We know

that there is a heavy excretion of taurine, so that is consistent.

We also know that you are sensitive to foods and supplements that

contain sulfur, and that means that your sulfite builds up faster

than your sulfite oxidase can handle it. That could be due to low

molybdenum or to genetic variations in molybdopterin or in your

sulfite oxidase enzyme that cause it to run slower than normal, but

I think that the more likely explanation, in view of all this other

evidence, is that too much sulfur metabolite flow is being pushed

toward sulfite oxidase because of an overactive CBS enzyme upstream,

resulting from a genetic variation in it.

Based on all of this, I strongly suspect that you are heterozygous

for the CBS genetic variation, and Cheri will be found to be

homozygous, thus explaining the basis for both your case and her

more severe one.

So where can you go from here?

First, I think your plan to try nebulized glutathione is a good one,

but as I've written before, since you are subject to asthma, and

also since you are sensitive to sulfur-containing substances, I

suggest that you start with a small amount first to see how you

respond, and have your inhaler at the ready in case you experience

any bronchospasm. If it turns out that you don't have bronchospasm

with nebulized glutathione, I think it could help you a lot, in view

of your lung issues. If this works out alright, hopefully you will

also experience other benefits from this, such as a lessening of

your diabetes insipidus.

I think you would experience quite a bit of improvement if your gut

dysbiosis could be corrected. I don't recall what you have done in

the past for this, but I would suggest running the baking soda burp

test that I have described before on the list to see what your

stomach acid situation is like. If your stomach acid is low, I

would suggest taking betaine-HCl with meals, starting with one pill

and adding one at each meal until you feel a warm feeling in your

stomach, and then backing off one pill and holding it at that dose

for each meal, until it feels warm again, and then dropping back as

you need to on the dose. I would also suggest taking digestive

enzymes. After these things have been in place for a few days, then

I would suggest taking probiotics in large enough quantities to

overwhelm the unfriendly bacteria. Hopefully this will get your

G.I. system back in shape.

I understand that you have not been able to find a

multivitamin/mineral that you can tolerate. I think it's worth

continuing the search. It may be that citric acid is the problem.

I heard from Dr. Vrchota that many of the multis contain it, and

some people can't tolerate it.

I don't know if you have tried bathing in Epsom salts, but if not,

that might be a way to build up your magnesium. About two cups in a

tub of water for 20 minutes or so is what I would suggest. If you

can do it daily, it might give your magnesium quite a boost.

The last thing is the CBS enzyme genetic variation. When Cheri's

genetic panel results come back, if they come out as I think they

will, we should know for sure whether you have a copy of this

variation, as discussed above. If you do, some of the things that

may help to compensate for it are to take molybdenum (I think you

could start this now, to help with the sulfur sensitivity, starting

low and working up to 2,000 micrograms per day if it takes that much

to correct the sulfur sensitivity), limit your intake of protein,

take trimethylglycine (betaine) to divert more of the sulfur

metabolite flow from homocysteine toward methionine (starting with a

low dose and working up as high as 2,000 milligrams per day).

Although I strongly suspect that you have one copy of the CBS enzyme

genetic variation, as I've said, I don't know which other genetic

variations you might have. The only way to know that would be to

have them characterized, and as you know, that's fairly costly (750

U.S. dollars, plus shipping, for the panel now offered by

http://www.testing4health.com).

Perhaps you might want to try the above things first, and also see

how Cheri's results come out, and then decide whether to have your

gene variations characterized, too. But if you want to go ahead,

that would be up to you. As you know, this is a new approach, and I

don't have a lot of experience with it yet, so I'm not in a position

to give you a big " sales job. "

Rich