clueless - 9-2-2011 at 11:26
Hi. I have a nursing degree, but don't understand the indepth stuff in chemistry!
I'm going to explain a hypothetical patient:
This person has had lightheadedness when standing for 5 years. Most labs are normal, a few slight variations here and there, nothing pointing to a
diagnosis. An accompanying symptom is off/on daily vasodilation(flushing)in upper body, and into hands.
The one thing that is odd is that, on rare occasions, urine left in the toilet overnight(rarely longer) has left a blue ring around the top. Reading
up, a blue ring could be due to indole production. This comes from tryptophan metabolism in the gut.
This leads to finding that gut bacteria convert amino acids into various "amines" through decarboxylation. "Amines" are known to cause vasodilation
and/or vasoconstriction.
Does this sound like a plausible pathway back to the initial health problem of orthostatic lightheadedness?
Also, during decarboxylation, CO2 is a by-product. If too much of this is going on, would this translate into higher levels of CO2 in the serum?
Thanks for anyone explaining or correcting me on this. I have spent weeks trying to understand this.
clueless - 9-2-2011 at 11:35
I forgot, I guess what I mean to ask is, can you get bacteria that go "rogue" and overproduce amine levels where they then produce a pathophysiologic
state?
not_important - 9-2-2011 at 13:37
The amount of CO2 from decarboxylating amino acids at the levels needed to produce biologically significant levels of amines would not be very
important or likely detectable, especially as the CO2 has to diffuse from the gut to the bloodstream and is being produced by other bacterial
processes.
There are so many signally agents in metazoa that I'd be hard pressed to comment on your hypothesis, except to say that it is not outlandish. People
occasionally pick up strains of gut microorganisms that are more effective at producing ethanol than the normal flora, as a result they may go about
in a near constant state of mild inebriation and suffer job-wise and socially for being a drunk; much smaller amounts of amines would be needed than
of ethanol.
The daily flush sounds a bit like a histamine dump, which can come from mast cells in the lungs or gut, or possibly bacteria although it's more likely
that they would produce some triggering compound that kicks the mast cells. It seems to me that more or less constant unusually levels of some
signally agent would show in the lab tests, but something that happens occasionally might escape as the tests would be unlikely to be done at just the
right time to catch an event.
clueless - 9-2-2011 at 14:06
Thanks for your input.
Odd that you mention histamine specifically. This hypothetical patient is part of a growing group of this odd group that finds that using
antihistamines(H1 and H2) are seeming to help. Once these are started, the orthostatic issues, along with the vasodilation episodes seem to calm.
Assuming that controlling the histamine keeps the fluid shift from intravascular from happening, thus keeping the vascular volume okay. The problem
is, something is causing a "mast cell activation" and nothing is outright obvious. No mastocytosis.
Was thinking that gut bacteria could be contributing.
entropy51 - 9-2-2011 at 14:23
Has carcinoid syndrome been ruled out? Although many carcioid tumors release serotonin, some release histamine and the flushing is blocked by
histamine antagonists. See for example, this article in the New England Journal.
clueless - 9-2-2011 at 14:37
Carcinoid syndrome is very plausible, but ruled out.
Sedit - 9-2-2011 at 15:53
If you are a care giver for the patiant you should order an Obermeyer test in an attempt to screen for Indoxyl Sulfate. This is the result as you more
then likely already know of the bacteria in the gut reacting with tryptophan.
Perform this test to assure yourself that the blue ring is indeed Indole and not just remenants of an old toilet tab lingering in the bowl(trace
amounts could in theory concentrate overnight to form a ring I assume).
Orthostatic hypotension causes all the symtoms you descibed and the flushing is just his body reacting to the drop in blood pressure when standing in
an attempt to regulate itself by inducing vascoconstriction. Has this patiant ever experienced fainting from it?
Background information would be best to know since medications and heart disease could complicate hypothesis of the causes of his symptoms. Not
knowing the patiants history I wanted to know if he is on diuretics of any kind such as furosemide and if so did that correlate with the appearence of
these symtoms. I also wouldn't rule out diabetes but I would assume test should have already been done to rule that out.
I have never heard of the blue ring = excess Indole explination, would you by any chance have a reference of anykind I could read up on?
clueless - 9-2-2011 at 16:09
I actually did not read that a blue ring is from indole production--I guess I worded that wrong! I had a biochemist acquaintance that when I
mentioned a blue ring in the toilet(no commercial blue things used), he said that sounds like indoles. He didn't elaborate and I didn't ask.
After reading up on indoles, I saw some old 1960s medical articles talking about bacterial overgrowth in the small bowel can lead to indicanuria, thus
having me assume that indoles could leave a blue ring.
The person is in otherwise good health, just homebound due to orthostatic intolerance. No diabetes, in fact a history of low blood sugar. Just takes
thyroid meds and something to sleep. The person has never fainted, just feels like he might if standing for longer than maybe 10 minutes. No history
of heart issues, no diuretic use. Patient tries to consume roughly 100 oz. of fluid a day, and intake=output.
I keep going back to thinking about the tryptophan. If bacteria are breaking down the tryptophan, does that mean there will be a shortage of
serotonin downstream? Or is there going to be an increased serotonin production?
chemoleo - 10-2-2011 at 16:08
Without attempting to diagnose- I find it interesting that the blue 'ring' takes time to form (overnight) - meaning that whatever metabolite it is, it
gets slowly oxidised at the surface (where there is oxygen), forming the blue compound. It reminds me of the white levo/leuco form of indigo! http://en.wikipedia.org/wiki/Indigo_dye
And no surprise, indigo has as a core a derivatised indole subunit, which is also in tryptophan.
More interestingly, the oxidised version of indole, indoxyl (middle compound), oxidises readily in air to form indigo 
http://en.wikipedia.org/wiki/File:Indigo_modern_synthesis.pn...
Might be worth checking it out a bit more. Who knows, maybe this patient has that problem due to an uncommon mutation in one of the enzymes used in
tryptophan metabolism....? Biochemists would love this sort of thing - maybe chat to some uni departments specialising in this? A quick LC-MS and
other analyses (i.e. elemental analysis) could nail down this blue metabolite in no time- and potentially the cause of the illness!
[Edited on 11-2-2011 by chemoleo]
Sedit - 10-2-2011 at 16:53
interesting Chemoleo, the indoxyl is what gut bacteria turn tryptophan into so it is possible that this fellow has a gut bacteria however I find it
odd that such a thing would last for 5 years causing Orthostatic hypotension without progressing or the immune system handling it. Perhaps the fellow
has a combination of a couple things that is throwing diagnosis off.
I once spent 5 days in a hospital with my 2 year old son having doctors give me every reason in the book that he was dying while I insisted that what
they thought was scarletina was nothing more then the flu(it was going around and everyone had it) and a rash that he more then likely picked up on
one of our walks in the woods the day before the rash appeared. The doctors looked for every deadly thing they could and I found it interesting that
the only person to mention that it may be a cold and a rash combined was an intern. Fucked up part is as soon as our insurance ran out on day five...
he was fine and only had a rash and a cold and could go home
Go figure. Thanks
for milking my insurace while telling me my kids dying doc. Top things off someone stole my credit card and we found that out when stuck in the city
with our bank accounts drained and 5 dollars in our pockets. What a fun week that was let me tell you.
clueless - 10-2-2011 at 18:25
Thanks to both of you.
So, are biochemists at big universities receptive to phone calls to discuss things like urine that leaves a blue ring?
I agree that there could be a couple of things going on at once. It's possible it is all connected, but it is rather complicated.
Sedit - 10-2-2011 at 19:04
I wouldnt have a clue but to be honest I would have to think they would be delighted to speak with you. See, the way things are people interested in
science have very few people to talk to about it since almost no laymen is on there level and for a professor to further isolate themself by sticking
to a specific branch of science would pretty much isolate him to just speaking with his students at best.. many of whom more thne likely do not share
his passion.
I think thats what results in the popularity of these sort of forums. We have a passion for science and in order to find a freind that shares the same
interest we would have to travel along way just to have a discussion with them. Now we can make virtual freinds and talk about science all day long
without the worry. Hell I wouldnt be suprized to find the professor is a member here
chemoleo - 11-2-2011 at 15:24
Only to be seconded.
If you wish to take this forward and contact some uni departments I would do the following first:
1) get in touch with medical specialists that focus on urinary/renal issues
2) if they have no clue as to what could be the cause (eliminate the obvious diseases first with the specialists in the field), then I'd make a search
and find Unis that specialise in metabolic disorders, in particular regarding Trp metabolism and/or amino acid metabolism.
3) if such a department/prof can be found, then contact him/her! Be prepared to have a urine sample (the evening before, and the following day once
the blue compound has formed) ready.
Good luck!
Btw Sedit - what is the physiological effect of indoxyl at high concentrations? Or any of its subsequent metabolites?
Ps2: with regards to the gut bacteria - did the patient ever take antibiotics that are active on enterobacteria, both the gram -ve/+ve, during the
last 5 years?
[Edited on 11-2-2011 by chemoleo]
clueless - 11-2-2011 at 17:12
Regarding the antibiotics, the only ones have been a Z-pack for a sinus infection a couple of years ago, and then Xifaxin to try and help the stomach
bloating(a year ago).
Thanks for all of your thinking. I really appreciate this. I will see if I can find a biochemistry dept. at my closest university that has someone
who specializes in amino acid/metabolism.
Went to a urologist that didn't really address the issue. The doctor admitted she had no clue.
Sedit - 11-2-2011 at 21:28
@Chemoleo
Im not really sure about high concentrations activity so I ran the structure thru Pub_Chem bioassays and oddly returned nothing. This seems odd since
I figured a metabolite of Tryptophan would have more then a few examples present and given its simple structure someones had to have done a paper on
it. Since I didn't get any hits there I attempted to run it thru the biosystem scans in an attempt to follow its pathway thru the body but that only
produced invivo indigo synthesis of different plants so that wasn't much help.
A quick google returned something of a little value but I dont know jack about the AHR receptors there talking about so give me a couple days since im
trying to wrap my head around something else and I just bought a new kiln to play with and Ill give it a read. The compound is indoxyl-3-sulfate and
it is a uremic toxin.
Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805781/