The Significance of Dimethyl Sulphide in Extra-Oral, Blood Borne Halitosis

Dimethylsulphidemia: IN BRIEF

• Outlines the prevalence of halitosis in RESEARCH the general population, its classification the significance of dimethyl and psychosocial implications. • Reports that about 10% of genuine halitosis cases are caused by extra-oral sulphide in extra-oral, blood phenomena, giving extra-oral halitosis an estimated prevalence of about 0.5 ‑3% in the general population. borne halitosis • Reviews the causes of extra-oral halitosis and how to differentiate these from intra-oral halitosis. C. N. Harvey-Woodworth1

Halitosis is a symptom and not a diagnosis. Rather, the topic represents a spectrum of disorders, including intra-oral, otorhinolaryngological, metabolic, systemic, pulmonary, psychological and neurological conditions. Halitosis may be the third most common trigger for patients to seek dental care and can cause significant impact on patient quality of life. About 10% of all genuine halitosis cases are attributed to extra-oral processes. Some authorities have reported that the nasal cavity and the oropharynx are the most common sites of origin of extra-oral halitosis. However, recent evidence appears to suggest that blood borne halitosis may be the most common subtype of extra-oral halitosis. Tangerman and Winkel report that dimethyl sulphide was the main volatile implicated in extra-oral blood borne halitosis. They proposed a hitherto unknown metabolic condition by way of explanation for this finding, resulting in systemic presence of dimethyl sulphide in blood and alveolar breath. This paper reviews the knowledge base regarding the behaviour of dimethyl sulphide in physiological systems and those disorders in which blood borne halitosis secondary to dimethylsulphidemia is thought to have an aetiopathological role.

BACKGROUND Non-genuine halitosis (after dental caries and periodontal dis- Several definitions of the term halitosis eases),7,8 showing that patients place great A proportion of patients who present have been offered. It is generally accepted importance on it. complaining of halitosis will not have that odours on the nose breath, as well Halitosis is subject to great societal any detectable breath malodour. Various as the mouth breath, are included within taboo and stigma.6,9 The evolutionary terms have been used to describe this, this topic. Similarly included are those function of olfaction in humans serves to including delusional halitosis, psychogenic conditions that present with more pleas- detect spoiled food sources and potentially halitosis, pseudohalitosis and halitophobia. ant breath odours eg, the ‘fruity’ breath infectious or harmful stimuli.10,11 It also has Estimates of non-genuine halitosis among of diabetic ketoacidosis and also those a role in mate selection.12–16 Unpleasant those complaining of halitosis range from cases where there is no genuine odour in a personal odour triggers repulsion in oth- 5‑72%.6,28–34 There are several possible rea- patient complaining of halitosis, a scenario ers. This is thought to be an evolution- sons why a finding of non-genuine halito- which has a myriad of causes. ary response to avoid mating with sick sis could be made. Some have called for standardisation of individuals.17,18 The need to belong has protocols in halitosis research.1 Perhaps been identified as a fundamental human Assessment errors and symptom transience due to a lack of consensus regarding diag- need.19 Social rejection and ostracism has nostic criteria and assessment methods, the been shown to have profound physical and Malodour may have been present at the reported prevalence varies, but this value psychological effects.20,21 This symptom time of consultation and was not detected. is probably about 20%.2–5 can therefore have significant psychoso- Those involved in the management of As such, it is rightly described as a com- cial implications, including social anxiety patients complaining of halitosis ideally mon symptom6 and may even be the third and avoidance behaviours, problems with would be familiar with the principles of most common trigger to seek dental care, integration, relationships and productivity, organoleptic assessment35,36 or even have depression and reduced quality of life.6,22–25 access to breath analysis apparatus (for 1Scientific Adviser to MEBO Research Inc, and Regional It has been suggested that clinicians are example, the ‘OralChromaTM’).37 It is also Centre for Oral and Maxillofacial Surgery, University Hospitals, Aintree, Liverpool poorly informed about the causes and possible that malodour was not present Correspondence to: Dr Colin Harvey-Woodworth treatments for halitosis, and may even at the time of the assessment but may Email: [email protected] mismanage cases, promoting adverse psy- be present at other times. Clinicians fre- Online article number E20 chological sequalae.8,26 It is also suggested quently fail to recognise the variability of Refereed Paper - accepted 6 July 2012 DOI: 10.1038/sj.bdj.2013.329 that clinicians may need to be updated the presence and strength of the symp- ©British Dental Journal 2013; 214: E20 regarding the current evidence base.27 tom.38 Factors such as hydration, timing

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Intra-oral halitosis (oral malodour) and nature of last food consumption, time phantosmia may report self detection of of day, menstrual status, nature of clini- an odour which others do not seem to About 90% of genuine halitosis cases cal environment and fluctuations in clini- comment on. have a cause within the oral cavity, that cian olfactory acuity possibly affecting the is, intra-oral halitosis (oral malodour).6,28–34 detection threshold on any single occasion. Psychological condition The leading cause of intra-oral halitosis Halitophobia can be defined as follows, is release of volatile sulphur compounds Genuine bad tastes and dysgeusia ‘when there is no physical or social con- (VSC) from halitogenic biofilm on the pos- Although gustation and olfaction are firmation to suggest that halitosis is pre- terior dorsal tongue, and/or within gin- closely related senses, a bad taste often sent, which can persist after therapy for gival crevices/periodontal pockets. The does not necessarily translate to detect- either genuine halitosis or pseudohalito- causative organisms are usually gram- able malodour by others. Disorders of sis’.35 Some consider halitophobia to be negative, anaerobic spp. VSC are generated taste can present as a complaint related to a type of olfactory reference syndrome by bacterial degradation of sulphur con- smell and vice versa. Genuine bad tastes (ORS), where there is preoccupation taining amino acid substrates, for exam- can be caused by any number of factors, with the belief that one emits a foul or ple, methionine, cystine and cysteine.35 including poor oral hygiene, dental caries, offensive odour, although this odour is The main odourants implicated in intra- periodontal diseases (for example, acute not perceived by others.50 These patients oral halitosis are methyl mercaptan (MM, 53 necrotising ulcerative gingivitis), oral can- are said to misinterpret the behaviour of CH3SH) and hydrogen sulphide (H2S). cer, diabetes and uraemia.39 others, reinforcing this preoccupation Intra-oral halitosis has been the subject Patients may also experience dysgeu- and engage in obsessive activities such of increasingly detailed study in recent sia (taste disturbance), which has many as excessive bathing or oral hygiene. ORS times and the symptom could be con- causes, commonly smoking, xerostomia, is not, however, included as a diagnosis in sidered clinically manageable in the vast ageing, infection, trauma involving the DSM-IV, and will only be included under majority of cases, provided a well informed mouth, nose or head, or nerve damage ‘conditions that require further research’ clinician and motivated patient. Readers involving the chorda tympani, lingual or in DSM‑5. The persistence of adverse are directed to the many comprehensive facial nerves, gastro-oesophageal reflux psychosocial sequalae after treatment reviews available on the subject.6,35,36,54–65 disease (GORD) and deficiency states for genuine halitosis is perhaps testa- (B12 or zinc). For a more extensive list ment to the distress it can cause in some Extra-oral halitosis of the rarer causes of dysgeusia, readers patients. Distressed patients may display Some 10% of genuine halitosis cases are are directed to dedicated reviews of the behaviours that inappropriately prompt not caused by intra-oral phenomena, topic.40–43 Iatrogenic effect of various med- clinicians to assume a tendency towards giving extra-oral halitosis an estimated ications may cause both genuine bad tastes delusional symptoms. prevalence of 0.5‑3% in the general popu- and dysgeusia. Recently, Falcão et al. challenged the lation.28,30,32 Extra-oral halitosis is by con- current concepts of pseudohalitosis and trast less well researched and understood Dysosmia (olfactory disturbance) halitophobia, drawing attention to altered and represents a greater diagnostic and Parosmia is the misinterpretation or distor- chemo-sensory function states, but also therapeutic challenge. It has been classi- tion of odour stimuli and may occur with proposed that retronasal olfaction may fied according to location and aetiology upper respiratory tract infections, head offer explanation for halitosis complaints (Table 1).27,35–37,66 trauma or accompany ageing.44 that cannot be detected by others.51 Traditionally, it was thought that the Phantosmia is perception of a smell The author therefore advises that a find- stomach was responsible for many cases of in the absence of any odour stimuli. ing of non-genuine halitosis not be made halitosis, however, it has now been shown Phantosmia can occur with conditions without a full and competent halitological that only vary rarely is this the case. The such as alcoholic psychosis, pregnancy, consultation, or be based upon the find- oesophagus is a collapsed tube (except chemo- or radiotherapy, Parkinson’s dis- ings of a single occasion. Furthermore, this during deglutition, eructation, or emesis), ease, Alzheimer’s disease, schizophrenia, finding should not serve as a diagnosis, as denying the transit of odourant volatiles temporal lobe epilepsy or lesions impinging it is a symptom in its own right with many through to the aerodigestive tract.66,67 upon the olfactory bulb or tract (for exam- possible causes that may warrant further Gastrointestinal conditions, for example, ple, a meningioma or neuroblastoma).45–48 investigation and management. Helicobacter pylori infection and GORD, Patients with genuine halitosis develop have been investigation with regards a olfactory fatigue when their symptom is Genuine halitosis potential relationship with halitosis.68–82 present, making them poor judges of their Where the malodour is real and detect- Currently, the overall picture appears to be own odour.49 This is the physiological able, this is known as genuine halitosis. a lack of positive correlation or unconvinc- phenomena where a temporary reduced Estimations of the proportion of genuine ing evidence. awareness of an olfactory stimulus follows halitosis cases among those complaining of Otorhinolaryngolocial pathoses are continuous exposure. Often, the only trig- halitosis range from 28‑95%.6,28–34,52 Genuine thought by many researchers to account ger for patients to medical or dental advice halitosis is then sub-classified according to for the majority of extra-oral causes of is the behaviour of those they come into the location of the origin of the malodour, halitosis, especially tonsillar29 and sino- contact with. Conversely, patients with namely, intra- or extra-oral halitosis. nasal conditions.83 Others suggest that

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Table 1 Classification of extra-oral obstructive nasal pathology can second- measurement does not imply its contribu- halitosis with example diagnoses27,35–37,66 arily cause mouth breathing, with result- tion to perceptible malodour. Although Upper respiratory tract (sinonasal, pharyngeal, ant xerostomia and halitosis.84 It is known all odourants are volatile, not all volatiles laryngeal), eg that mouth-breathing is associated with are odourants. An odourant must also be Pharyngitis halitosis.85 With regards the proportion present in high enough concentrations Purulent sinusitis of genuine halitosis cases that secondary to stimulate olfactory detection. For this ‘Post nasal drip’ Ozena (a subtype of chronic atrophic rhinitis) to ear nose and throat (ENT) conditions, to happen, great enough quantities of Tonsilitis, tonsillolithiasis, tonsillar actinomycosis reported estimates range from between the volatile must be liberated from solu- Foreign body in nasal cavity 2.9‑10%.6,30,34,86,87 tion (that is, respiratory tract secretions, Nasopharyngeal abscess However, recent evidence suggests that a saliva). Whether the chemical is liberated Laryngeal carcinoma mechanism known as blood borne halitosis into the gas phase, and in what quantities, Lower respiratory tract may account for the majority of extra-oral is dependent upon such factors as pH and (trachea, bronchi, alveoli), eg halitosis.32 temperature of the solution and the con- Chronic bronchitis centration of the volatile in the solution. Bronchiectasis Blood borne halitosis Pulmonary abscess However, since the blood goes almost Bronchial carcinoma It has long been known that volatile everywhere, blood borne volatiles may Blood borne halitosis (causative odourant chemicals present in the blood can be also be expressed via other routes of volatile(s) in parenthesis) transferred to the exhaled breath. Breath excretion, for example, sweat, saliva and Temporary effects of certain foodstuffs: analysis for trace chemicals offers a non urine. An example of a blood borne vola- • Garlic (mainly allyl methyl sulphide) invasive investigation that can be applied tile being expressed via multiple routes, • Onion (methyl propyl sulphide) Side effects of certain medications: in a huge range of conditions. For exam- and not just the breath, is trimethyl- 94 • Disulphiram (carbon disulphide) ple, hydrogen and/or methane breath amine (TMA), which has a fish-like • Cysteamine (dimethyl sulphide) analysis can be carried out following odour in vitro, becoming ammoniacal at • Dimethyl sulphoxide (dimethyl sulphide) oral administration of poorly absorbable higher concentrations. Indeed when TMA • Suplatast tosilate (dimethyl sulphide) carbohydrate (for example, lactulose).88 is present in the urine, the rare disorder Metabolic states/systemic disease: Hydrogen and methane are products of trimethylaminuria (TMAU) should be con- • Uraemia (ammonia, dimethyl amine, trimethylamine) gut microbiota fermentation, hence this sidered, although there are other causes of • Ketoacidosis (acetone) breath test is thought to be a measure of elevated urine TMA.95 Dimethylglycinuria • Dimethylsulphidemia (dimethyl sulphide) gut microbiological activity. This test- is another rare cause of fish odour.96 • Hypermethioninaemia (dimethyl sulphide) ing is carried out by some in conditions Tangerman and Winkel32 reported that • Trimethylaminuria (trimethylamine) like small intestinal bacterial overgrowth dimethyl sulphide (DMS, CH3SCH3) was the (SIBO),89 although somewhat controversial most common volatile in extra-oral halito- Table 2 Theoretical criteria for any due to imperfect sensitivity. These odour- sis, which could not be attributed to recent particular chemical to cause symptoms of blood borne halitosis less gases have been absorbed from the ingestion of volatile foodstuffs. They esti- 90 Must be able to enter the systemic circulation gut and transferred to the alveolar breath. mated this DMS-related blood borne halito- • Absorption of volatiles (or precursors) via The same VSC that are reported to be the sis may affect some 0.25‑1.5% of the general gastrointestinal lining most important volatiles in halitosis (H2S, population. These estimates were based • Endogenously produced volatiles eg, second- MM and DMS) are implicated as being upon a cohort of 58 patients complaining ary to organ system insufficiency, as in uraemic fetor the greatest contributors to the malodor- of halitosis, and the findings extrapolated 91–93 • Parenteral administration of volatiles (or ous character of flatus and faeces. Of assuming 10‑30% prevalence of halitosis in precursors) that enter the circulation this trio, only DMS is stable in blood and the general population and 5‑10% of genu- Must be stable in blood (usually requires the capable of creating blood borne halitosis. ine halitosis being extra-oral in aetiology.32 chemical to be neutral) The general mechanism involved Must survive or bypass hepatic metabolism in blood borne halitosis is as follows. Multidisciplinary management • Compromise of hepatic metabolism • Substrate overload of the relevant enzymatic Volatiles enter the systemic circulation The classification into intra- and extra- pathway (several routes possible but most usually oral, and the sub-classification of extra- • Portal shunting of blood (congenital or via the portal system following absorption oral halitosis is useful as it guides clinical acquired) bypasses liver and alters the jour- ney of volatiles which would normally imme- from the gut), and are then circulated to practice according to which disciplines diately be subject to first pass metabolism the lungs, where there is intimate associ- may need to be involved,97 eg, ENT for Must be able to be transferred to the exhaled ated between the pulmonary alveoli and upper respiratory tract and respiratory breath during alveolar gas exchange capillary networks. During gas exchange medicine for lower respiratory tract. The Must be an odourant of waste carbon dioxide and inhaled oxy- referral in blood borne halitosis is cause- • Must be volatile (to be carried in the air to the olfactory chemoreceptor cells of other gen, chemicals present in the blood, may related, for example, endocrinology. individuals) also be exchanged, and may be percep- There are in existence a handful of joint • Must be lipid or water soluble tible on the exhaled breath if they fulfil halitosis clinics, sometimes consisting of • Present at high enough concentration to trig- certain criteria (Table 2). The detection specialists in ENT, periodontology and ger the olfactory cells to signal of a volatile on the breath by objective psychiatry. Some suggest that this problem

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101 is best managed at such multidisciplinary noxious and it is also a mild skin and eye Table 3 Dimethylsulphidemia: centres. Practically, however, general den- irritant,102 although even at the pathologi- differential diagnosis tistry is the primary setting involved, given cal concentrations reported in disease this Metabolic that most patients will first present to the is probably not a feature. Hypermethioninemias dentist and that the majority of causes of In mammals, free DMS is the only form Condition under study32 halitosis are intra-oral. known to be present.91 DMS can be catab- Systemic The role of the dentist in management of olised from dietary precursors in plants Fetor hepaticus halitosis is to take a history and carry out (S-methylmethionine/vitamin U, and Medications a meticulous intra-oral and oropharyngeal dimethylsufoniopropionate).91,103,104 DMS Dimethylsulphoxide examination for halitogenic factors. This can be synthesised from transamination Cysteamine Suplatast tosilate is followed by an organoleptic assess- of methionine,105 or methylation of methyl ment, to ascertain the presence or absence mercaptan (which itself can be methyl- 106,107 of malodour. Absence of any detectable ated from H2S). Methylation of H2S dimethylsulphidemia (DMSE, or hyper- malodour at repeated consultations likely and MM is thought to be a detoxification dimethylsulphidemia) to describe abnor- represents non-genuine halitosis. It is pathway.91 Dimethylsulphoxide (DMSO) mal elevations of DMS in the blood. inappropriate for these patients to receive can be reduced to DMS.102,108 Bacterial DMSE could be defined as >7 nM (nor- treatments aimed at odour reduction. spp. known to synthesise DMS have been mal range <7 nM). The threshold above Simple reassurance may be carried out demonstrated in the human GI tract.109-111 which blood DMS begins to cause blood in general practice, however, as discussed DMS is a component of flatus and fae- borne halitosis is undefined, although above, non-genuine halitosis complaints ces91,112 and it is assumed that this is the there was close correlation between may represent psychiatric or neurological result of intestinal bacterial activity. There blood and breath DMS reported.91,121 conditions and referral may be indicated. is evidence that suggests of all the VSC DMSE, (with corresponding elevated Malodour that is more detectable on the produced in the colon >90% are absorbed breath DMS and ‘dimethylsulphiduria’), mouth breath compared to the nose breath by the lining rather than being emitted as is a feature of several dif erent condi- may indicate intra-oral halitosis, whereas flatus, and H2S and MM are thought to tions (Table 3), and it therefore should the reverse (ie nasal foetor) may indicate be metabolised by caecal lining tissue (to be considered a sign rather than sino-nasal pathology. Malodour that is thiosulphate). DMS, however, is not bro- a diagnosis. equally objectionable on both the nose and ken down here, instead passing straight to Apart from the conditions listed in the mouth breath usually indicates extra- blood.113–115 Free DMS is neutral molecule, Table 3, several curious correlations of oral halitosis. it does not contain a reactive thiol group breath DMS have been reported. Old age,

The dentist may then treat any clinical (unlike MM and H2S), hence it is stable in female gender, HDL cholesterol, history of intra-oral halitosis, or to refer if extra-oral blood as it is unreactive with proteins. MM colon polyps and asthma were all shown halitosis is suspected. Further investiga- and H2S both react rapidly in blood and to correlate with breath DMS above the tion of extra-oral halitosis it is perhaps are therefore not implicated in blood borne organoleptic threshold.123 Elevated MM on more appropriately carried out by rele- halitosis.32 DMS that is absorbed into the the mouth air also correlated with DMS, vant specialities.98 Equally, dentists may bloodstream appears to be a substrate of possibly since MM is methylated to DMS. need to be aware of patients who are both CYP450 and flavin containing mono- When investigating breath DMS attrib- referred from general medical practition- oxygenases (FMO).116,117 uted to DMSE, some researchers work ers and who are found to have signs of DMS is known to be subject to renal and around this artefact by measuring DMS extra-oral halitosis. pulmonary excretion.102,118,119 Dietary load- on both mouth breath and nose breath ing with either methionine or DMS also (the small amount of DMS that could be DIMETHYL SULPHIDE, IN VIVO produced DMS in the milk of cows.120 After attributed to methylation of MM intra- BEHAVIOUR: SYNTHESIS, METABOLISM AND EXCRETION the work of Tangerman’s group, where orally would not be detectable on the Tenax trapping and gas chromatography nose breath). Male pattern baldness was DMS is a volatile organosulphur com- was used to objectively measure free DMS also correlated to elevated breath DMS pound, constituting a sulphur atom cova- concentrations, the normal range can in elderly men and this relationship was lently bonded to two methyl groups. The be taken as <7 nM in peripheral venous stronger in the presence of GI tract and in vitro odour character has been variably blood.121 Breath DMS is also very low in metabolic disorders.124 Interestingly, described as wild radish or cabbage-like,99 health. Normal subjects in one study were cystic fibrosis patients demonstrated a or unpleasantly sweet,32 but invariably reported to have a breath DMS range of lower breath DMS than a healthy control the terms used have unpleasant connota- 0.13‑0.65 nM.122 Urine DMS is reported as arm.125 Perhaps this could be attributed tions. DMS was shown to reduce mood being generally below the 3 nM detection to altered gas exchange efficiency and compared to more pleasant scents.100 DMS minimum for gas chromatography.91 pathological changes in pulmonary and has an exceptionally low odour detection gastrointestinal secretions. Occupational threshold, meaning that it is detectably CONDITIONS WHERE ELEVATED exposure in certain industries can lead BLOOD DMS IS A FEATURE malodorous even at very low concentra- to elevated exposure to DMS, which is tions (24‑100 ppb).53 The gas can be fatally The author suggests the term demonstrable on the breath.126,127

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The hypermethioninemias same study showed correlation of elevated and DMS, which is then subject to renal Methionine is an essential sulphur contain- breath DMS with cerebrovascular disease. and pulmonary excretion.102,163–167 ing amino acid. It is normally metabolised A secondary form of TMAU is also associ- Nephropathic cystinosis, a rare autoso- in a pathway resulting in cysteine. As dis- ated with liver disease, and blood borne mal recessive lysosomal storage condition, cussed previously, DMS can be synthesised TMA may even be contributory to the was previously a death sentence, however, from transamination reactions of methio- odour of foetor hepaticus.146,147 The charac- cysteamine therapy now slows the pro- nine. Thus hypermethioninaemia (HME) will ter of foetor hepaticus has been varyingly gression of the disease and can prevent or accompany DMSE. HME is a sign, rather described as musty, ‘mousy’ or sweetly fae- delay the life threatening complications.168 than a diagnosis, and represents several cal. There are also descriptions likening it Cysteamine removes the accumulated cys- distinct clinical entities, both genetic and to ‘the smell of dead mice’ or ‘the breath of tine from lysosome, however, an unfortu- non-genetic.128 Many of the hyperme- the dead’. Since DMS is the greatest con- nate side effect of this therapy is halitosis,169 thioninemias are syndromes presenting at tributor to the odour of foetor hepaticus, which has been shown to be mostly due to birth and compromise more medically seri- perhaps we can surmise that the in vivo presence of DMS in the blood. Hence, cyst- ous symptoms rather than malodour alone, expression and odour character of DMS inotic patients on this therapy were shown such as brain demyelination.129 Methionine is similar to that described for this condi- to have elevated DMS in urine and breath.170 adenosyltransferase (MAT) I and III are the tion. It is unlikely that DMSE and a related A case report documented elevated two isoenzymes that catalyse a vital stage halitosis would be monosymptomatic for breath DMS in an asthmatic patient being in the methionine cycle, viz. the synthesis portal shunting, since this is frequently a treated with the anti-allergenic drug, of S‑adenosylmethionine from methionine. late feature of decompensated liver cirrho- suplatast tosilate,171 which appears to be MAT I/III deficiency, secondary to mutations sis, which comes with many other seri- metabolised to DMS. in the coding gene, MAT A1, have been ous signs and symptoms. DMSE levels of described.130–133 MAT I/III deficiency may 7‑50 nM and breath DMS of 0.5‑14.1 nM Condition under study be implicated in isolated persistent hyper- were demonstrated in patients with liver The new metabolic condition that has methioninaemia, an idiopathic cause of cirrhosis.142 potentially been identified by Tangerman elevated methionine, in which hepatic MAT and Winkle, awaits further investigation to activity is normal and yet there are few seri- Volatile foodstuffs identify the exact pathogenesis. Whether ous clinical manifestations.134 Blood borne DMS, along with other VSC, contribute to the dimethylsulphidemia is related to halitosis may still be a feature. Since DMSE the flavour of some foodstuffs and bever- defects in the methionine cycle, or indeed accompanies HME, breath DMS can be used ages.104,148–151 The metabolism of methio- another cause remains to be elucidated. to screen for HME.135–137 A breath DMS level nine was previously discussed, as were The prevalence of the potential new con- of 96 nM was reported in a patient with other DMS dietary precursors in plants. dition has been estimated at 0.25‑1.25% isolated persistent hypermethioninaemia DMS in cabbage, among other VSC deriv- of the general population,32 which would secondary to MAT deficiency.122 Since DMSE atives, have been investigated for their make it more prevalent than other ‘blood can be caused by other conditions, elevated antimicrobial activity.152 Urinary DMS has borne malodour’ conditions previously breath DMS is not specific for HME. been shown to be elevated after asparagus identified. The extra-oral nature of the consumption,153 although DMS was not the halitosis in these patients was deduced Foetor hepaticus major volatile produced. by demonstrating equal levels of DMS on Portal hypertension and resultant porto- the nose and mouth breath. Furthermore, systemic shunting can be caused by con- Medications blood DMS was shown to correlate per- ditions like liver cirrhosis. Blood bypasses Dimethylsulphoxide (DMSO) is used as fectly with breath DMS. Experimentation the portal circulation and hence volatiles vehicle for several drugs,154 as it is able to with solutions of DMS was found to have that are absorbed from the GI tract are penetrate skin and other membranes with- an odour comparable to the character of not immediately exposed to first pass out damage,155 but it can also be used as halitosis in this group. Patients with this metabolism. Traditionally, this foetor has a therapeutic agent in its own right.156–159 proposed metabolic condition are reported been attributed to ketones and ammonia, It has uses as a topical agent, where inter- to have breath DMS levels of 0.5–2.5 nM91 however, more recent evidence suggests estingly its cutaneous administration can and blood DMS levels of 10–80 n mol/l.32 that DMS is the main odourant volatile, lead to a side effect of a garlic taste in Interestingly, a patient in this group although ketones contribute to a lesser the mouth.160 Whether this is due to blood showed significantly raised breath DMS extent.138–141 In vitro experimentation with borne presence of the DMS is unclear. 12 hours after consuming 12 glasses of DMS solutions was reported to produce A similar phenomenon is observed with beer. After this experiment, the patient in an odour very similar to that produced disulphiram, where this is attributed to question was said to switch to drinking in fetor hepaticus.142 Mercaptans do not metabolism of the drug to carbon disul- wine, and reported fewer complaints of 161 66 seem to directly cause hepatic encepha- phide (CS2). CS2, a neurotoxin not bad breath. lopathy, rather they just accumulate sys- thought to be endogenously produced, was These findings could be interpreted with temically.143–144 Awano et al. demonstrated also reported to be raised on the breath caution as they are based on a small sam- elevated breath DMS in patients with of patients with schizophrenia.162 DMSO is ple, and are as yet uncorroborated by other 145 various liver diseases. Interestingly, the metabolised to dimethyl sulphone (DMSO2) researchers.

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DISCUSSION exchange. However, the blood goes just One of these substrates is trimethylamine ‘Systemic candidiasis syndrome’ about everywhere. It is known that in (TMA), which has a fish like odour, becom- other conditions, blood borne volatiles ing ammoniacal at higher concentrations. There is a general belief among some sec- can be expressed via several routes of Genetic mutations of FMO3 that result in tion of the public that Candida overgrowth excretion, leading to the presence of vola- reduced efficiency when acting on the is a leading cause of halitosis, or even body tiles in sweat, saliva and urine etc. This volatile TMA, (normally N‑oxidised to tri- malodour. It is interesting to note the evo- may cause multiple symptoms of malo- methylamine N‑oxide), leading to presence lution of a commercial industry revolving dour in these patients, for example, body of TMA in the systemic circulation. This is around the theory that a so called ‘sys- odour, malodorous urine, etc. Thus, the said to create a fish-like blood borne body temic candidiasis syndrome’ (also termed concept of blood borne volatiles causing odour and halitosis.179 Secondary forms ‘candida hypersensitivity syndrome’) blood borne halitosis monosymptomati- of TMAU, where FMO efficiency may be is widely prevalent. This is a medically cally may be an oversimplification. It is at normal levels and an increase in the unrecognised condition and falls within likely with many of these volatiles that production of volatiles may overload the the realms of pseudoscience and alterna- pulmonary excretion is the main form of pathway, creating a mismatch between the tive medicine. To the author’s knowledge, elimination, since this is a highly effi- substrate work load and the enzymes’ abil- there is no published scientific paper that cient system. The term blood borne body ity to act on them.180 There also appears to has proven Candida albicans or other yeasts odour has been offered, but this again be a lack of consensus regarding the ideal as a cause of oral malodour or extra-oral may be too constrictive and misleading. diagnostic threshold. halitosis. Indeed, one paper reported low The author suggests the term ‘blood borne Reported incidence of heterozygous Candida albicans carriage rates in hali- malodour condition’ to describe these (carrier) TMAU incidence has been esti- tosis patients.33 Candida is a normal oral conditions and to reflect the multiple mated at 0.5‑1% in the white British popu- commensal organism in a high percentage malodour complaints that they may be lation.95,181 Patients with the heterozygote of the general population. Yeasts ferment capable of triggering. phenotype are thought by some to be ‘at carbohydrates to produce ethanol, which There are logistical problems involved in risk’ of having their already compromised has an odour character described as ‘strong breath analysis,173 and its availability may enzyme pathway overloaded easily,180 pos- alcoholic, ethereal or medical’.172 Whether be limited in some areas. The relevance of sibly producing a transient presence of high carriage rates of Candida spp. or even breath analysis in the management of hali- blood borne volatiles and an intermittent clinical evidence of oral candidiasis would tosis is undisputed, but it may be useful to malodour symptom. Evidently, the num- produce a great enough concentration of perform urinalysis or blood biochemistry ber of patients with symptomatic TMAU ethanol or other metabolic by-products to in selected cases, eg, where blood borne is likely lower than these figures. This create a malodour detectable by others is halitosis is suspected and there is a failure notion is supported when one looks at unknown. There is a feasible indirect, but of standard therapy for intra-oral halitosis reported data from a major TMAU testing not causative link between candidiasis and to control the symptom which cannot be centre for over a decade. The number of halitosis. Oral candidiasis frequently devel- better explained. These alternative routes patients receiving a positive diagnosis is ops where there is xerostomia. Decreased may be more available and familiar to cli- low, around 30%. If we assume that a high salivary flow rates will reduce both the anti- nicians. Further research would be needed percentage of these patients have genuine microbial and mechanical cleansing action to validate these methods as being predic- malodour symptoms (since they have been of saliva, resulting in increased growth of tive for malodour symptoms and if so at referred by a clinician for the test), then it bacterial spp. in addition to Candida spp. what threshold concentration in the blood appears that TMAU does not explain the The increased bacterial load could then lead is required to create symptoms. majority of patients with suspected blood to increased VSC levels and hence halitosis. borne malodour conditions. In practice however, there does not seem to Trimethylaminuria Anecdotally, only a minority of TMAU be any link between Candida and halitosis. Trimethylaminuria (TMAU) has domi- positive patients and patients who test The so called ‘systemic candidiasis syn- nated researchers’ interest into blood negatively for TMAU, display the classi- drome’, among its vast range of claimed borne malodour conditions. The impli- cally described fish odour, instead a range symptoms, is described as giving a hali- cated enzyme pathway is the xenobiotic of odours are reported, such as faecu- tosis and/or body odour that is musty, metabolising enzyme (XME) group, flavin lant body odour and halitosis. It is cur- ‘mousy’ or ‘yeasty’. These particular odour containing mono-oxygenases (FMO), par- rently unknown whether other odourant descriptions are reminiscent of the odour ticularly FMO3. FMO has been implicated volatiles normally dealt with by FMO3 character of DMS. as being of perhaps equal importance to could become elevated systemically as a CYP450.174 Evidence suggests that FMO is result of dysfunction or overload of this Blood borne halitosis may also also involved in the metabolism of certain enzyme pathway. It is interesting to note cause other malodour complaints drugs.175–178 The main role of the FMO path- that FMO may be at least partly respon- Blood borne halitosis is caused by odour- way appears to be as a scavenger system sible for metabolism of DMS,117,182,183 and ant volatiles present in the systemic cir- with a low specificity, carrying out oxida- also reports of the potential contribution culation that are then transferred to the tion of thousands of substrates, most nota- of TMA along with DMS in the odour of exhaled breath during pulmonary gas bly nucleophilic amines and sulphides.174 foetor hepaticus.

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