's case

[Guest guest]

Hi, all.

has given me permission to post an analysis of her recent test

results here:

Hi, .

As you will no doubt recall, I first began trying to understand your

case about six years ago. At various times since then I have

offered hypotheses to explain it or parts of it, but as you know,

all these attempts have been less than completely successful. In

recent months you have been sharing with me data from a new set of

tests that you have taken, including the Yasko genetic variations

panel. Over the past few days I have been studying these results in

the context of other data you have sent me in the past. The file

with your name on it is far and away the thickest file in my

collection, and frankly I owe a great deal of the progress I have

made in understanding CFS in general to your penetrating questions

over the past few years, which have helped to focus my thinking on

significant issues.

I am now prepared to make yet another try at offering a hypothesis

for your case. This time I am optimistic that I have been able to

capture a much bigger part of what has been going on, because of the

wealth of focused data you have sent me, and particularly because we

now have the genetic information and a better understanding of the

role that genetics plays in

CFS. I now believe that this is the key to understanding your case

(and I suspect many other cases as well). As you will see, a lot of

the pieces fit together rather nicely now. I think your case has

the potential to be a textbook case if all of this is ever figured

out and put into a textbook, because you have had so many things

measured!

Genetic Data

Considering first the genetic information, you have sent me a wealth

of relevant data: The Genovations Detoxigenomic Profile, the Yasko

Complete Basic SNP Panel I covering enzymes associated with the

methylation cycle, the Hemex characterization of your hereditary

blood coagulation factors, and the LabCorp HLA DRB, DQB Typing panel

for human leukocyte antigen alleles.

Detoxigenomic Profile

Let's look first at the Detoxigenomic Profile. Compared to those I

have received from other PWCs, you have one of the lowest total

numbers of SNPs in your detox enzymes. You were spared the ones

that make people so sensitive to pharmaceuticals, for example.

However, the ones you have are CYP1B1 (V432L or N453S), COMT V158M

(+/-), NAT2 R197Q (+/-) (slow metabolizer), GSTP1 I105V (+/-), and

SOD2 A16V (+/-).

The CYP1B1 SNPs are upregulations, and CYP1B1 is partly responsible

for detoxing polycyclic aromatic hydrocarbons, which are present in

various kinds of smoke. This, together with the NAT2 SNP would have

made you sensitive to smokes and to charbroiled foods. Another

thing that CYP1B1 does is to convert estradiol to 4-catechol

estradiol, which is capable of auto-oxidizing to form semiquionones

and quinones. These processes produce oxidizing free radicals.

Normally 4-catechol estradiol is processed by the COMT enzyme, but

you have a heterozygous SNP for a downregulation of COMT, which

means that more of the 4-catechol estradiol will go on to

semiquinones and quinones. The latter are normally detoxed by

conjugation with glutathione, and you do have GSTM1 present, but you

have a SNP in GSTP1. I suspect that this will tend to allow the

semiquinones and quinones to oscillate back and forth between each

other more than normal, and that will produce more oxidizing free

radicals. In addition, you have a SNP in SOD2, which is the

mitochondrial form of the superoxide dismutase enzyme. This will

also allow the concentration of oxidizing free radicals to rise.

In summary of your detox SNPs, I think that the combination of detox

SNPs you inherited, together with the fact that you are female and

thus produce high levels of estradiol, biased you toward more

readily developing oxidative stress and glutathione depletion than

the average person, and I suspect that this is one reason you

developed CFS, as we will see further on.

Yasko Panel

Now let's see how this would have interacted with your methylation-

cycle-related SNPs: Looking at the Yasko panel, the first thing to

note is that you are heterozygous for two of the upregulating SNPs

in the CBS enzyme (CBS A360A and CBS C699T). These SNPs would have

tended to cause too much homocysteine to be converted to

cystathionine and to go on down the transsulfuration pathway, giving

elevated production of ammonia, sulfite and hydrogen sulfide, and

less conversion of homocysteine to methionine. Right here I think

we finally have an explanation for the problem of bad-smelling

breath that you have reported having for so many years!

Next, you are heterozygous for MTHFR A1298C, and that would have

tended to lower your production of tetrahydrobiopterin. Among other

things, this would have made it more difficult for your urea cycle

to process ammonia, so the combination of the CBS upregulations and

this downregulation would have made ammonia, which is a toxin, an

important issue for you, especially if you consumed a lot of

protein, which produces ammonia when it is broken down. I think

this is consistent with the fact that activated charcoal has been

helpful for you. It is known to bind ammonia in the gut and carry

it out in the stools. Normally an indicator for low

tetrahydrobiopterin would be an elevated ratio of phenylalanine to

tyrosine, but because your plasma essential amino acid levels are

all so low (see below), we can't check that indicator.

Note that you don't have the fairly common MTHFR C677T SNP, and

that's good.

The next things to look at are the MTR and MTRR SNPs. You are

heterozygous for the MTR A2756G upregulation SNP, which would have

meant faster consumption of methyl B12. You are also heterozygous

for one upregulation SNP in MTRR (the S175L SNP), one downregulator

(H595Y) and one whose effect is unknown (K350A). This is a little

difficult to be precise about, but the combination would probably

have made you unable to recycle methyl B12 as well as normal. The

combined effect of the MTR and MTRR SNPs would probably have been

that you would have had a tendency to develop a shortage of methyl

B12.

Moving on to COMT, as the Detoxigenomic Profile had found, you do

have COMT V158M (+/-), which slows the COMT reaction. In addition,

you have another SNP that tends to slow the reaction (H62H), and one

that tends to speed it up (L136L). The net result is probably a

slowing of the COMT reactions. Because of the net slowing of these

reactions, there would be a greater availability of methyl groups

than normal, and the result is that when you supplement B12 (which

you will need to do, as discussed below), you should probably use

the hydroxocobalamin form rather than the methylcobalamin form.

You are homozygous for the MAO A R297R SNP. Since this enzyme

breaks down serotonin, and this SNP slows the reaction, this would

have tended to make your serotonin levels higher than normal.

However, this is complicated by the fact that your

tetrahydrobiopterin would have been low, which would have slowed the

production of both serotonin and dopamine, so these effects would

have been working against each other. I suspect that the net result

would have been that your serotonin levels would not have been

normal, though I'm not sure if they would have been high or low, or

oscillating. Since serotonin is important in controlling gut

motility, I think that this could have contributed to the gut

problems you have had for so many years.

Looking now at your VDR SNPs, you are heterozygous for all of the

ones measured. The VDR Fok SNP would have tended to make your blood

sugar regulation somewhat abnormal. The VDR Bsm/Taq SNP would have

helped to counter the downregulation of the COMT SNPs in terms of

their effect on dopamine levels.

Taking the MTHFR, COMT, MAO A and VDR SNPs together, I think their

overall effect would have been to cause your dopamine and serotonin

levels to be somewhat abnormal.

You are also homozygous for the ACE Del 16 SNP. The effect of this

would have been to elevate your angiotensin converting enzyme, your

angiotensin II, and your aldosterone. If the adrenals are able to

continue secreting aldosterone at high levels, the result is

elevated sodium and decreased potassium in the blood serum. On the

other hand, if this causes the adrenals to become fatigued, the

sodium can drop and the potassium can rise. Together with your

homozygous MAO A, this SNP could have been expected to produce

anxiety and a low frustration threshold.

Putting the Detoxigenomic Profile and the Yasko Panel Together

O.K., let's now look at how your Detoxigenomic Profile results would

have interacted with your Yasko panel results. As we saw from your

Detoxigenomic Profile, you would have been particularly vulnerable

to developing oxidative stress and glutathione depletion. We also

know that you would have had a tendency toward low methyl B12

availability, and we know also that your sulfur metabolism was

biased toward sending too much down the transsulfuration pathway.

Since glutathione is needed to convert other forms of B12 to methyl

B12, and since the enzyme MTR (methionine synthase) is inhibited by

oxidizing conditions, the stage was already very well set at your

conception for you to develop CFS at some time in your life, if your

glutathione level was pushed too low. And of course, we now know

that's just what happened. We have your recent red blood cell total

glutathione measurement, which came out quite low (335 compared to a

normal range of 568 to 1048 micromoles per liter). Based on what

you've reported, the main contributors in your case appear to have

been a poor diet, too much exercise, and being " stressed out, " all

of which are known to deplete glutathione. More on all of this

below, but first let's look at the rest of the genetic results.

Hemex Blood Coagulation Test

Next, let's consider the hereditary part of the Hemex blood

coagulation test results. As you know, your Protein C activity was

found to be low (661 compared to a normal range of 700 to 1400).

Assuming that this low activity was in fact genetic in origin, I

think it can explain your varicose veins early on, as well as your

cold hands and feet, your low erythrocyte sedimentation rate

measurements (as low as zero, 2 and 3 mm per hour) and elevated

prothrombin 1+2 and CD62P once you had developed CFS. You were

susceptible to immune system activation of coagulation (ISAC)

because of your inherited Protein C SNP.

LabCorp HLA Type Characterization

Finally, let's look at your LabCorp HLA results. As interpreted by

Friedl, using Dr. Ritchie Shoemaker's table from his book Mold

Warriors, your HLA types are 14-5-52B, which is a multi-susceptible

type, and 15-6-51, which is a post-Lyme type. These results mean

that if you were exposed to toxic molds or to Lyme disease-producing

Borrelia Burgdorferi bacteria, your immune system would not be able

to recognize and destroy the biotoxins produced, and you would

become chronically ill from the biotoxins. You reported that to your

knowledge, you have not been exposed to significant amounts of mold,

that you tested negative for Borrelia and that it is unlikely that

you have been exposed to tick bites. So I suspect that though you

are susceptible to mold and Lyme biotoxins, you have not been

exposed to them.

Creatinine Puzzle

O.K., we have covered the genetic results, and we know that your

glutathione is low, and we can infer that you currently have a

methylation cycle block. Now here is one puzzle that I haven't been

able to resolve: In 2000, you had a 24-hour urine test, which

showed the creatinine excretion to be in the normal range. That

would suggest that you had normal SAMe methylation capacity at that

time, which would argue against a methylation cycle block at that

time. We don't know what your 24-hour creatinine excretion is now,

but I suspect that it would be low. I don't know why it was normal

in 2000, because you were already ill at that time. So this is a

puzzle.

Indicators for Methylation Cycle Block

Looking at other indicators for such a block, we know that your

sarcosine came out very high, and a possible cause of that is a

tetrahydofolate deficiency, which would be consistent with a block

in the methylation cycle and folate cycles, which are coupled. We

also know that your B12 level was measured to be high, and this may

mean that your body is not able to convert it to methyl B12 for use

in the methylation cycle. In looking at sulfur metabolites, we find

that methionine is low, homocystine is low, cystathionine is fairly

high, cysteine is low (from an older test), cystine is low, taurine

is low, and sulfate is low (from an older test). It looks as though

the entire sulfur metabolism is depleted, but cystathionine is

fairly high, probably because of the CBS upregulations. I suspect

that the absorption of protein by your gut is so poor that even

though you are eating protein, not enough is coming in to supply

normal levels of amino acids, including the sulfur-containing amino

acids methionine, cysteine and taurine. This probably also means

that you are not currently challenging your body's current poor

capacity for processing ammonia, and that is consistent with your

normal blood ammonia measurement.

Explaining Long-Standing Questions about your Case

I think the methylation cycle--folate metabolism block provides us

explanations for some puzzles we have had about your case for a long

time. One has been the frequent low counts you have had for both

white blood cells and red blood cells over the years, combined with

a tendency toward oversized red cells. We also know that your total

red blood cell mass measured low. It now seems to me that all of

this has resulted from the block in your folate metabolism, since

the folate metabolism is necessary to supply RNA and DNA to make new

cells.

Two other places where rapid cell production are normally necessary

are in the routine replacement of the cells lining the gut and in

the cloning of lymphocytes particularly needed to fight viral,

intracellular bacterial and fungal infections. We know that you

have had issues with both your gut and your cell-mediated immune

response, and I think this folate block is likely to be at least

part of the cause.

Urinary Organic Acids Test and Ramifications of the Results

Now let's move on to your urine organic acids test results. These

results date from mid-2002, but I'm going to assume that they are

still relevant, since I gather that your condition has not changed a

great deal since then, and since the results appear to be very

consistent with the above results. First, I note that you had low-

normal pyroglutamic acid (21 compared to 20 to 115). This is an

indicator of low glutathione, and that's consistent with your red

blood cell glutathione measurement. Looking at your Krebs cycle

metabolites, citric acid was high (282.7 compared to 20 to 200).

Also, aconitic acid was high normal and the later Krebs metabolites

(2-oxo-glutaric, succinic and fumaric acids) were very low-normal.

This is also a signature for low glutathione, suggesting a partial

blockade at aconitase. The elevated level of acetoacetic acid (10.9

compared to 0 to 10) is consistent with inability of the Krebs cycle

to process fatty acids as fuel at normal rates, because of the

partial blockade. This is also consistent with your experience of

readily gaining weight if you consume carbohydrates. The block in

the Krebs cycle prevents them from being burned completely to carbon

dioxide and water, and they are thus recycled through

gluconeogenesis and converted to stored fats. Another effect of

this Krebs cycle partial blockade would be lower than normal

production of carbon dioxide, which would cause the respiratory

center in the brain to slow and make shallow the breathing. I think

this accounts for the sleep apnea you have experienced when falling

asleep.

The Krebs cycle block would also mean low production of ATP, and

this would account for the physical fatigue, since ATP is required

to operate the muscles. Another effect would be less ATP to power

the membrane ion pumps, and I will comment on that further below.

I also now suspect that the reason for your low stomach acid is the

Krebs cycle block in the parietal cells in your stomach. It takes a

lot of ATP to power the proton pumps in these cells, because of the

high concentration gradient that they normally work against. The

low stomach acid also means that the iron that comes in with your

food is not made as soluble as it should be, and I suspect that is

the reason for your perennially low iron and low ferritin.

And of course, if the stomach acid is low, there will not be a good

secretin signal sent to the pancreas, and it won't put out digestive

enzymes as it should. I think that explains part of the reason for

your malabsorption, and it also explains why taking digestive

enzymes has helped your digestion and gotten rid of the gas

generation. It also explains the high amylase level in your blood.

Your organic acids test also showed some indications of dysbiosis,

including elevated HPHPA and hippuric acid. The dysbiosis no doubt

results from inability to digest and absorb food properly because of

the factors already mentioned. This leaves nutrients for the

unfriendly bacteria, and they overgrow.

Your high kynurenic acid (2.77 compared to 0 to 2) suggests a

vitamin B6 deficiency at that time. You also had elevated oxalic

acid (162.9 compared to 0 to 100). I think this is consistent with

the two small stones found in your right kidney on ultrasound

examination, since oxalate stones are one of the most common types.

Possible causes of high oxalic acid are B6 deficiency, low calcium

intake (or binding of calcium as soaps in the gut if fat absorption

is poor), or ingesting significant amounts of foods high in oxalate,

such as spinach.

Minerals Tests

Now let's move on to your minerals. You have both buccal cell

intracellular elements analysis and whole blood element analysis,

which is very nice! Looking first at the buccal cells, the six

elements that are measured by the X-ray fluorescence technique were

all found to be in their normal ranges, but all on the low side of

their normal ranges, except calcium. I think that what this

suggests is that the ion pumps are having trouble getting enough ATP

to fuel themselves, because of the Krebs cycle partial blockade that

results from glutathione depletion and the consequent rise in

oxidizing free radicals in the cells. Since there is good

correlation between the intracellular concentration of elements in

the buccal cells and in the heart cells, one might expect that a

somewhat low-normal magnesium level in the buccal cells would

suggest a slightly elongated corrected QT interval on the

electrocardiogram, and that's exactly what is seen: 446

milliseconds, compared to a normal range of less than or equal to

440 milliseconds. The ratio of phosphorus to calcium in the buccal

cells is found to be low. I suspect that this reflects ion pump

energy problems, also.

The whole blood elements test also shows low-normal magnesium, as

well as low-normal molybdenum. The low-normal magnesium is

consistent with the buccal cells. The low-normal molybdenum may be

a result of past overload of the sulfite oxidase enzyme as a result

of the CBS upregulation SNPs discussed above. Molybdenum is a

cofactor for sulfite oxidase. In view of the low-normal magnesium,

it is somewhat surprising to see a normal blood urate level, since

the enzyme xanthine oxidase, which produces urate from the breakdown

of purines, also requires molybdenum as a cofactor. Perhaps the

sulfite oxidase is not currently overloaded because protein is not

being well absorbed, and that leaves the available molybdenum for

use by xanthine oxidase.

Plasma Amino Acids Test

Now we come to the plasma amino acids test results. The first thing

that strikes me is that the levels of all the essential amino acids

are either very low-normal or low. Since you have assured me that

you were eating significant amounts of protein prior to taking this

test, I suspect that means that your gut is not digesting and

absorbing protein well. I think this would be consistent with some

of the earlier discussion above. Your alpha aminoadipic acid level

is high-normal to high, which again suggests vitamin B6 deficiency.

I've already discussed the high sarcosine. The high-normal to high

beta aminoisobutyric acid is due to a benign polymorphism. Some of

the other amino acids are fairly low, and I suspect that this may

just reflect an overall low absorption of amino acids because of

poor protein digestion.

Transketolase

In other test results, you had low-normal transketolase, suggesting

low vitamin B1.

Temporary Break-off

I think I've covered your test results now, and my brain is kind of

fried, so I think I'll stop here and see if you have comments on

this before I talk about treatment. Let me know especially if there

is anything here that you know is not correct.

Rich

[Guest guest]

, I can't say much about the rest of your profile, but I can help

you on this one. The HLA tests only indicate a susceptibility to

problems from these toxins, not an absolute. There are some further

tests that you can do that will tell you whether the susceptibility

has been triggered.

These tests are MSH (melanocyte stimulating hormone), MMP-9, Leptin,

and VEGF. The C4a and C3a can also be important. Dr. Shoemaker

actually does many others as well, but these are the most important in

indicating a need for treatment, and also how well you are responding

to treatment.

These tests can be problematic to get done properly. We have had to

train the local Labcorp, as some of the tests require special draws,

or special handling of the blood. Also, Quest is preferred for Leptin

testing. The Labcorp figures always come out three times higher.

Dr. Shoemaker uses a different range of normal than the labs. Most of

it you can find in the book, Mold Warriors, but in general you want

the MSH in normal range, MMP-9 less than 300, Leptin in the very low

end of the range, VEGF around 50 (not high and not low in range or

out), C3a and C4a below 700 (exposures can run up into the tens of

thousands.)

This would be more helpful than any other tests to see if you are

having trouble with the issues Shoemaker works with. While a Lyme test

might be good to do, it will not tell you if your body is reacting to

the toxins, or what treatments would be best for them.

> LabCorp HLA Type Characterization

> Finally, let's look at your LabCorp HLA results. As interpreted by

> Friedl, using Dr. Ritchie Shoemaker's table from his book Mold

> Warriors, your HLA types are 14-5-52B, which is a multi-susceptible

> type, and 15-6-51, which is a post-Lyme type. These results mean

> that if you were exposed to toxic molds or to Lyme disease-producing

> Borrelia Burgdorferi bacteria, your immune system would not be able

> to recognize and destroy the biotoxins produced, and you would

> become chronically ill from the biotoxins. You reported that to your

> knowledge, you have not been exposed to significant amounts of mold,

> that you tested negative for Borrelia and that it is unlikely that

> you have been exposed to tick bites. So I suspect that though you

> are susceptible to mold and Lyme biotoxins, you have not been

> exposed to them.

>

> : This test result concerns me. WE don't really know what impact

> this would have. I have not been exposed to significant amounts of mold

> but aren't we all exposed to mold everyday ? I never did do the

> Borrelia test and I don't think I've been exposed to tick bites. I

> wish I knew more about this and what to do about it (cholestryamine