Good article: BB and TMAU

[Larc400]

Extracts from a fresh article I got hold of...

Quite long, but clears out a few misconceptions about TMAU and bad breath etc...


----------------------------------------------------
Human Breath Odors and Their Use
in Diagnosis

CHRIS L. WHITTLE,a STEVEN FAKHARZADEH,b JASON EADES,a
AND GEORGE PRETIa,b
aMonell Chemical Senses Center, 3500 Market Street, Philadelphia,
Pennsylvania 19104, USA

INTRODUCTION
Humans emit a complex array of nonvolatile and volatile molecules. The
metabolic processes of an individual, and hence the compounds emitted into
the environment, may be influenced by genetics, diet, stress, and the immune
status of the individual. Human olfaction is the most ancient of our distal senses
and does provide information from distant sources in real time. Olfactory information
may be used to detect and evaluate food sources and environmental
toxins as well as to recognize kin and potential predators. In addition, many
body odors evolved to be olfactory cues that convey information between individuals.
1 Large numbers of volatile compounds may be emitted from several
areas of the body that are prone to odor production; these include the scalp,
axillae, feet, groin, and oral cavity.2 Consequently, it is not surprising that
physicians have used their olfactory and gustatory senses to aid in the differential
diagnosis of diseases since the beginning of medical practice.3–5
Hippocrates is reported to have used exhaled breath and smelled the breath
of patients as part of his assessment.6 Breath testing as a scientific tool was
pioneered in the 18th century by Lavoisier and Laplace.7 These pioneers established
the presence of CO2 in exhaled breath air. In the second half of the
20th century, the development of more sophisticated analytical techniques,
such as gas chromatography, has allowed the separation and identification of
volatile compounds from complex biological matrices, such as exhaled breath.
In the 1960s, the separating power of gas chromatography was combined with
mass spectrometry to create combined gas chromatography/mass spectrometry
(GC/MS); see Watson for a review.8 This development allowed the separation
of complex mixtures as well as structural identification of separated, volatile
components.

Numerous investigators have captured and concentrated breath and salivary
volatiles. Studies by these researchers have focused upon establishing the normal
breath constituents and searching for biomarkers from the oral cavity to
aid in the diagnosis of illness or severity of disease.9–13
Analysis of exhaled breath provides a unique opportunity to examine the
organic constituents of blood because alveolar breath reflects the concentration
of metabolites that have passively diffused across the pulmonary alveolar
membrane. Breath primarily consists of nitrogen, oxygen, carbon dioxide,
inert gases, water vapor, and a trace amount of volatile organic compounds
(VOCs) (e.g., acetone, isoprene, and pentane) that are present in nano- to
picomolar concentrations.14 Because the organic constituents of exhaled breath
are representative of the blood-borne concentrations of metabolites, breath
analysis provides a noninvasive means to examine blood-borne constituents
relative to using blood and/or urine samples. Some of the advantages of using
exhaled breath include the fact that lung air volatiles reflect the arterial
concentrations of biological substances; also the VOCs are removed from
complex fluid matrices, such as blood and urine; consequently, the complete
sample of all compounds are present in the collected sample with no
work-up required prior to analysis of the sample. However, breath analysis
also has limitations. One issue that hinders routine breath tests in clinical
practice is a lack of standardized collection and analysis methods and
the need for complex and unfamiliar (for clinicians) instrumentation. In
addition, simple and automated chemical tests that are routinely used for
blood and urine analyses are relatively inexpensive when compared to the
most commonly used instrumentation for breath analyses, GC/MS. The latter
requires an expensive initial investment (> $70,000) and maintenance
(>$10,000/year) as well as skilled operators who must be able to interpret
data from large complex data sets.9,15

A large number of studies using modern instrumental analyses have focused
upon analysis of breath volatiles in search of biomarkers for disease
states. The vast majority of these studies have examined respiratory system
diseases such as asthma. Nitric oxide is the most extensively exhaled marker
investigated, and has been linked to a host of respiratory ailments including
chronic obstructive pulmonary disease,16,17 rhinitis,18,19 rhinorrhea,20 chronic
cough (primary),21,22 asthma,23,24 cystic fibrosis,25 bronchiectasis,26,27 and
lung cancer.28,29 Numerous exhaled markers of disease have been studied,
such as several leukotrienes and nitrogenous compounds.30–33
Many recent studies focused upon branched or methylated hydrocarbons or
VOCs with broad diagnostic potential. These have been postulated to increase
in breath effluvia as a function of oxidative stress or damage (see Miekisch et al.
for a review).11 Although hydrocarbons are commonly found in the air of urban
areas, where many of the above-cited studies have taken place, investigators
appear certain that these products are products of human biological activity
and not exogenous, environmental contaminants. These include the straightchained
hydrocarbons, ethane and pentane, which are markers of oxidative
damage and have also been linked to diseases, such as asthma,34,35 lung and
breast cancer,33,36 interstitial lung disease,37 chronic obstructive pulmonary
disease,35 and heart rejection.38 Numerous other volatile compounds have been
found in exhaled breath and have been linked to different diseases.

In these studies, however, a subject’s oral health status appears to seldom
be considered. Halitosis is one of the most frequent complaints expressed
by dental patients. Approximately 90% of oral malodor is thought to originate
from the oral cavity, with the remaining 10% originating from distal
points in the digestive and respiratory systems.39–41 Persistent halitosis may
be indicative of underlying medical conditions, such as diabetes, leukemia,
gastrointestinal ulcers, lung cancer, trimethylaminuria (TMAU), and several
other idiopathic conditions.39,42 Even correctly collected alveolar air and saliva
samples must pass over or come in contact with the posterior dorsal surface
of the tongue. This is a site of bacterial plaque development that is a principal source of halitosis-related volatiles.43 The bad breath mixture has been studied
principally for its volatile sulfur compounds (VSCs): hydrogen sulfide,
methylmercaptan, dimethyl sulfide, carbonyl sulfide. These compounds provide
much of the impact odor of halitosis; however, the breath of individuals
with halitosis does contain a variety of volatile organic odorants, not just
VSCs.44,45 Consequently, VSCs as well as many other volatiles may be indicative
of oral-related health issues rather than non-oral disorders and disease.
Studies addressing markers from exhaled breath may want to address the subject’s
oral health status.

Several authors examining exhaled breath of patients with liver diseases
for VSCs have not addressed their subjects’ oral health.46,47 These authors
found elevated levels of VSCs in these patients versus controls. However, the
historical link of liver diseases with foul breath odor (foetor hepaticus) appears
to exclude an oral cause for breath odor in these patients. In addition, Chen
et al. used a methionine challenge to elicit VSC production in their subjects.48
Because of our basic research into the nature and origin of human body
odors, our lab has become the focal point for a large number of referrals of
people with idiopathic malodor production from either the body or oral cavity.
Regardless of presenting symptoms and to help differentiate individuals with
bad breath from other possible disorders, all individuals are examined for
odor production from the oral cavity and upper body by the same protocol
first described by Preti et al.12 A central part of this work-up is the choline
challenge test for TMAU developed by Tjoa and Fennessey.49
Trimethylaminuria was first described by Humbert,50 and is a metabolic
disorder characterized by the inability of individuals to oxidize and convert
dietary derived trimethylamine (TMA) to trimethylamine N-oxide (TMAO)
in the liver. This disorder results from an inherited autosomal recessive trait
in the gene, which codes for the flavin-containing monooxygenase enzyme 3
(FMO3). The genetic changes range from gene mutations associated with the
most severe cases to the more common single nucleotide polymorphic changes
in the FMO3 gene that may be associated with the less severe cases.51,52
Malodorous TMA is formed in the gut by bacterial metabolism of dietary
constituents, mainly choline. In normal individuals, TMA is converted/
oxidized to TMAO at>95% efficiency by FMO3. Individuals that have
FMO3 metabolic capacity<90% conversion ofTMAtoTMAOare considered
positive for TMAU.53,54 TMAO is nonodorous, more polar and water-soluble
than TMA, and readily excreted in the urine.55 Individuals suffering from
TMAU have a reduced capacity to oxidize TMA to TMAO.
TMA is a gas at body temperature and has a foul, rotten fish odor. At low
concentrations it may be perceived as unpleasant or garbage-like. The inability
to efficiently oxidize TMA results in the sporadic production of a body odor
that is perceived as foul, unpleasant, and in its most extreme cases fish-like.
This odor is caused by excess, unmetabolized TMA present in the circulatory
system that is excreted in urine, sweat, breath, and saliva. Because there are
many foods that are rich in choline (i.e., eggs, certain legumes, and organ
meats), TMAU-affected individuals, family members, friends, and physicians
are unlikely to associate the odor with food intake.
Symptoms may include foul body odor, halitosis, and/or dysguesia that can
produce social embarrassment and may only be temporarily relieved by normal
hygienic procedures.56 The main difficulties experienced by TMAU-affected
individuals are psychosocial ones that are caused by sporadic, undiagnosed
odor production.57
To enable an easier diagnosis for TMAU and to examine whether or not elevated
salivary levels of TMA might accompany oral symptoms in our referred
subjects, we began collecting saliva from all subjects reporting to our lab with
malodor production problems to examine this fluid for TMA.

RESULTS
We have seen and tested more than 300 individuals in our laboratory using
the protocol outlined inTABLE 2. One hundred two of these have been diagnosed
with some form of TMAU using the choline challenge test.49 The presenting symptoms for the TMAU-positive individuals are illustrated in FIGURE 1. A
majority of individuals had oral symptoms, complaining of either bad breath
or bad taste, many in conjunction with body odors.
In addition, as illustrated in FIGURE 2, the majority of our TMAU-positive
individuals were females. However, regardless of gender, in our experience,
TMAU was the largest cause for undiagnosed body odor. The large number of
TMAU-positive individuals who listed oral complaints led us to hypothesize
that salivary concentrations of TMA were responsible for these symptoms.
During most individuals’ visits, saliva was collected in conjunction with
urine as described in TABLE 2. This has resulted in an archive of more than
270 frozen (at –10◦C) saliva samples. However, only a small number of the
saliva samples collected have been examined thus far for TMA levels: six
individuals each from TMAU-positive and -negative categories. We report
these preliminary results here.

Clearly, the saliva of the positive subjects contains far more TMA than the saliva from TMAU-negative individuals, but there is a great deal of variation in the data,
particularly from the positive subjects. Two of the positive subjects account
for much of this variation because they demonstrated more than a 100-fold
increase in salivary TMA levels from their precholine challenge base line to
their highest levels in the 2nd or 3rd 8-h interval: Positive male 3 went from a
base line of 25 ng/mL to 4,812 ng/mL in the 3rd, 8-hour segment; and positive
male 6 went from a base line of 46.7 ng/mL to 4, 511 ng/mL in the 2nd, 8-h
segment. Each of these subjects had a very low conversion of TMA to TMAO,
indicative of one or more genetic mutations present in the gene for FMO3:
male 3 had 25% TMAO conversion; male 6 had only 11% TMAO conversion.
We also measured the volatile sulfur compounds in the oral cavity associated
with each of these subjects. In the subjects chosen for these analyses, we found that, on average, TMAU-negative subjects had greater concentrations of each VSC measured; these concentrations were also converted to parts per billion (ppb) levels and are presented in TABLE 4. The difference in VSC levels between the TMAU-negative and positive individuals is a result of the subjects chosen for these analyses: in our clinical experience, both TMAU-positive and -negative individuals may have halitosis. However,
the two conditions, TMAU and chronic halitosis caused by bacterial tongue plaque, are independent of each other.


DISCUSSION
Our findings regarding the presenting symptoms ofTMAU-affected individuals
are in contrast to results found in most of the medical literature. Articles
discussing TMAU suggest to the reader that all sufferers have a fishy body
odor presentation. In our population, all of whom have been seen in person,
the fish odor presentation was present in only about 10% of individuals who
are TMAU-positive. Further to this point, these individuals emitted a strong
fish odor recognizable at social distances only after choline challenge. Consequently,
the assumption that the individual with TMAU will always smell “like
fish” is incorrect and is often the reason that many TMAU-affected individuals are sent from one clinical specialist to another: quite often they are sent to a
psychiatrist since their reported symptoms are thought to be subjective.
The choline challenge test for TMAU provides a recognized means for diagnosing
this disorder. The diagnosis currently relies upon a 24-h urine collection,
divided into three 8-h aliquots.49 In our initial attempt to extend this diagnosis
to saliva, we collected whole mouth-stimulated saliva to determine salivary
TMA levels. Our hypothesis that the oral symptoms of many TMAU-affected
individuals appears to be supported by the preliminary results presented here,
although the numbers of subjects analyzed is still small. The data in TABLE 3
show much larger variation in the salivary TMA concentrations of TMAUpositive
versus TMAU-negative individuals. TMAU is known to be caused
by a “spectrum” of genetic changes to the gene that codes for FMO3;51 consequently,
this variation may be due, in part, to differences in the genotype
of each of the TMAU-positive individuals. This is supported by our clinical
observations regarding the odor of different individuals as well as genotyping
data. Two of the six TMAU-positive individuals whose saliva was analyzed
presented with overt fish odor from their upper body and oral cavity after
(∼22 h) choline challenge. As noted above, each of these male subjects had a
low conversion of TMA to TMAO (<25%) and documented mutations in their
FMO3 gene (data not shown).51

[TIREDOFIT]

Thanks Larc! Great article!

[spacemonkey84]

i skimmed through the reading and this caught my eye:

"We have seen and tested more than 300 individuals in our laboratory using
the protocol outlined inTABLE 2. One hundred two of these have been diagnosed
with some form of TMAU using the choline challenge test.49 The presenting symptoms for the TMAU-positive individuals are illustrated in FIGURE 1. A
majority of individuals had oral symptoms, complaining of either bad breath
or bad taste, many in conjunction with body odors.
In addition, as illustrated in FIGURE 2, the majority of our TMAU-positive
individuals were females. However, regardless of gender, in our experience,
TMAU was the largest cause for undiagnosed body odor. "

TMAU is probably more widespread than people believe right now (i read it's thought to affect ~1% of the population). Correct me if i'm wrong, but 33% of the people, some who complained of BREATH odors, were tested had some form of TMAU! There are probably many carriers who show less severe symptoms... so people, find ways to see if you suffer from TMAU! it's far easier than removing your tonsils for sure, and it won't hurt to eliminate one possible cause of bb if you don't have it.

[mike987]

it's weird.. because it only hapened recently.. but for the last two or three weeks, every so often my clothes would smell sewery.. i thought it was my breath .. then i thought it was my body.. but i could only smell it in my actual clothing.. it was strange.. i'm still not sure what the dela with that was.. perhaps i do have some mild TMAU

i haven't been exercising this week at all though.. maybe the sewer smell will come back when i start persperating..


though i am not giving up on the tonsils thing.. they MUST BE REMOVED.. these caverns are so digusting.. and everyday i have a horrible taste .. the taste of tonsil stone!.. Even if I continued having bad breath, removing the tonsils will most definitely have a positive effect on my breath.




it's weird really.. i never had a single one of these problems before i came to this site XD .. but ever since the lid was blown open on my bad breath, it's been on thing to the next.. but it's not in my head.. i swear it.. Seems more like it's just been getting worse in the past year and i'm just starting to notice that

[Mico]

Thats a great article Larc. Do you have the whole one or is this all? Finnaly an article that explains BB and TMAU thouroughly.

[Larc400]

That's the most important parts of it...

Yeah those people at Monell Chemical Senses Center who wrote it seem to know what they're talking about. Wouldn't it be great if our entire gang could pay them a visit?

[elliott]

That's the most important parts of it...

Yeah those people at Monell Chemical Senses Center who wrote it seem to know what they're talking about. Wouldn't it be great if our entire gang could pay them a visit?

I like the way you think! One day, maybe I can quit my day job and devote myself to helping find the cure... but they just raised my rent AGAIN!

[emotional rescue]

That's the most important parts of it...

Yeah those people at Monell Chemical Senses Center who wrote it seem to know what they're talking about. Wouldn't it be great if our entire gang could pay them a visit?

Yeah!!! we must do it right now!!! How can we contact with this guys???

Can you post the figures that are mentioned in the article??


And other thing....if the brocoli for example, has a very hight concentration of clholine, if i eat a BIG salad of brocoli, if a hava some kind of TMAU then i should develop a bb more than usual right????
Sounds like a logical homemade way to test it to you guys?? Cause i seriously doubt that someone is whilling to test me in my country....

we must contact this guys and do something one for all!!

i´m getting desperate!!

[Larc400]

I'll contact them and check if they'd be willing to give us a hand...

Probably good if we don't spam them though ... I'm sure they get enough requests without us flooding them ... I'll send one carefully worded message


Statistics from article:

"Presenting Complaints of TMAU Patients:"
(number of subjects)

Bad taste / oral malodor: 24
Body odor: 36
Chronic halitosis: 21
Vaginal / oral odor: 7
Body odor / oral malodor: 15

"Presenting symptoms and the numbers of subjects reporting each symptom,
in the subjects’ own words. “Body odor” is the most common presenting symptom found in
the literature pertaining to these patients. The symptoms were not always confirmed during
subject evaluation."





"TMAU Patients' gender"

M: 23
F: 79

The gender distribution of TMAU-positive subjects seen in our laboratory
is shown in this figure. We do not know whether or not the larger number of females
affected is due to hormonal differences in the regulation of the FMO3 gene. Females report
symptoms before and after menopause.

[Larc400]

...by the way... members of this forum have already been in touch with those guys...

Link

[sweets07]

the fact that an article is even asking questions on this level is amazing to me! i just downloaded a pdf of the article and will read it later, but it seems like a strong possiblity that i have tmau. i didn't realize u could have tmau and not have chronic body odor. crazy.

if anyone wants a copy of the complete article, just email me at: misskim45 at yahoo dot com

[BBNO]

FYI: I tested negative for TMAU. Dr. Preti (Chief Monell Researcher) conjectured that the source of my BB is...drum roll......VSC producing bacteria on the posterior of my tongue. He suggested I try Profresh, several of his patients have had success using it. No great revelation, no exotic diagnosis, just plain 'ol sulfur producing germs in my mouth. By the way my oral hygiene is immaculate and has been for many years. I bought the Profresh kit and followed the procedure for 45 days with minimal (at best) improvement.

Sorry for the pessimism, but I believe once the flora of your mouth becomes stinky, it is more than likely a never ending battle to supress it. I've been battling it for 20 yrs and it seems to get worse with age. The good news is that it seems there is much more credible and scientific research happening these days, so maybe relief will be available
in the near future.

[Mico]

Did anyone had gasy breath while doing the test - choline load?