A. Case study
A 31-year-old man contacted his doctor. Upon his first visit to the bathroom that morning, he had noticed, in addition to symptoms of a hangover, that his urine was malodorous. He thought that he might have alcohol poisoning. The doctor questioned him about his symptoms other than the malodorous urine, but these appeared to be the same as during previous hangovers. His wife also had a hangover that morning, but had experienced no change in urine smell. The patient was asked to describe the food served at the party the night before. He informed the doctor that there had been a variety of cheeses, pastries, fruit and quite a few unusual foods such as asparagus. The patient mentioned that the night before was the first time since childhood that he had eaten asparagus, as he had not enjoyed its taste before. The doctor told the patient that the smell could be a result of eating asparagus. The patient protested as his wife had eaten the same foods as himself but not experienced any odor change. The doctor, however, informed him that this does not occur in all individuals, it is harmless and that the smell would disappear spontaneously. He asked the patient to contact him if the smell persisted throughout the day. The patient agreed, but the smell completely disappeared by lunchtime.

TIP for Allergy Advisor users: Allergy Advisor offers a search function that is useful in many situations. In this case report, where, at first, one has no clue to what could be causing the malodorous urine, this function can be a shortcut to finding the cause. One can search through the Allergy Advisor database for a specific word. For example, if one chooses the "Search & WWW" bar, and then "Search Database", one can enter the word "malodorous" or "urine and smell". It will bring up the sections of the program where this word is found. In this case, "Asparagus" is found. Reading through the information under Asparagus, one will find that ingestion of asparagus is associated with malodorous urine. Problem solved!

B. More information
In February we discussed beeturia. Now we will cover two more food idiosyncrasies: why urine becomes malodorous after the ingestion of asparagus, and why water tastes sweet after the ingestion of artichoke.

The ingestion of asparagus is associated with the production of malodorous (described as "rotten or boiling cabbage" or "vegetable soup") urine. This occurs in approximately 40-43% of people (a figure of 79% was observed in the United States) within an hour after eating only a few spears of asparagus.

It has been shown to remain with individuals for virtually a lifetime. Those who produce this odor assume that everyone does, and those who do not produce it have no idea of its potential olfactory consequences.1,2,3,4,5

Why does this occur?
This phenomena has been regarded as either the result of an inborn error of metabolism or an inherited (autosomal dominant) trait.^5,6

But this appears to be not true. The urinary excretion of a pungent odorous substance after asparagus is eaten appears to be universal and the variable is the ability to detect the related odor. The detection of the odor constitutes a specific smell hypersensitivity. Those who can smell the odor in their own urine would thus be able to smell it in the urine of anyone who has eaten asparagus, whether or not that person was able to smell it himself. It is possible that this odor sensitivity is a genetic hypersensitivity or general hyperosmia rather than an inborn error of metabolism. Studies have suggested that it is a genetically determined specific hypersensitivity (controlled by a single autosomal dominant gene).^6,7

What is evident is that there also appears to exist a specific hyposmia (hyposphresia) or anosmia, wherein certain individuals are unable to smell the odor even from the most fetid urines. A later study suggested that both phenomena coexist. Some people are excretors while others are nonexcretors; some people are perceivers (able to smell the odor) while others are nonperceivers (do not smell it). But this still needs further investigation.⁷

Several metabolites have been found present in the urine after ingesting asparagus and at least two different ones have been held responsible for the characteristic odor. Specifically six discrete sulphur-containing alkyl compounds have been identified, namely methanethiol, dimethyl sulphide, dimethyl disulphide, bis-(methylthio)methane, dimethyl sulphoxide and dimethyl sulphone. But other have also been found present.^4,7,8

One study has indicated that a substance, namely methylmercaptan, appeared in the urine of 40% of the subjects and suggested that its excretion was an expression of an autosomal dominant gene.⁷

S-methyl thioacrylate and its methanethiol addition product S-methyl-3 (methylthio) thiopropionate have been postulated to be the odor-causing compounds in most studies that have been performed, but the metabolic pathway leading to their formation has not been identified.^2,3,7,9

The isolation of sulfur-containing compounds from the urine after asparagus ingestion is, however, no indication that they themselves contribute to the odor, as they may be insufficiently volatile. Due to many queries about the methods used, more investigations are needed.^7,8

Other odors related to foods and diseases:
Some diseases have been described as having characteristic odors. Patients with diphtheria have a "sweetish" odor, those in a diabetic coma smell "fruity," yellow fever patients smell like a "butcher shop," scurvy gives a "putrid" odor and scrofula the odor of "stale beer," while those with typhoid fever have an odor like "fresh-baked brown bread." It is said that nurses in the past confidently diagnosed enteric fever by sniffing the armpits.¹⁰

By intelligent use of the sense of smell, an astute clinician may make a presumptive diagnosis of a rare metabolic disorder and institute life-saving therapy while awaiting laboratory confirmation. There is a group of disorders in metabolism that lead to unusual odors of the body or urine; they are individually rare, but collectively they make up a sizable portion of acute life-threatening illnesses of infancy.¹¹

a. The characteristic odor of phenylketonuria has been described as "musty," "wolflike," "barny," "mousy," "horsey," and "stale sweaty locker-room towels."^10,11,12

b. In maple syrup urine disease, the odor is described as "caramel-like," "malty," or like "maple syrup."¹⁰ It was determined that 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), a well-known flavor impact compound also present in fenugreek, lovage and buckwheat honey¹³, is responsible for the characteristic odor in the urine of affected individuals. The common name given to the disease is thus quite appropriate, as maple syrup also contains sotolone.¹⁴

Ingestion of fenugreek (a leguminous herb cultivated in southern Europe, northern Africa and India) resulted in a false suspicion of maple syrup urine disease when the doctor noticed the characteristic smell of the patient's urine. It has been reported where the patient was given fenugreek tea¹⁵ or a folk remedy containing the plant.¹⁶ Also, false suspicion arose when the ingestion of fenugreek by mothers in labor resulted in a maple syrup-like odor in their newborn infants.¹⁷

c. Oast-house syndrome (or Oasthouse urine disease or Methionine malabsorption syndrome), which has some resemblances to phenylketonuria, presents with a distinctive dried malt or hops (as in breweries), dried celery or yeast odor.^10,11

d. Individuals with hypermethioninemia have been variously described as having a "fishy," "sweet and fruity," "rancid butter" or "boiled cabbage" odor.¹⁰ It has been suggested that tyrosinosis-tyrosinemia (or rancid butter syndrome) which presents with a strong offensive odor resembling that of rancid butter is the same as hypermethioninemia.¹¹

e. Isovaleric acidemia (or sweaty feet syndrome) often presents with a "cheesy" or "sweaty feet" odor.^10,11

f. Trimethylaminuria (TMAuria) (also known as fish malodor syndrome or fish odor syndrome) is an uncommon disorder that causes an accumulation and massive excretion of the volatile tertiary amine trimethylamine (TMA) in the urine and other bodily fluids (sweat, expired air, saliva, vaginal secretions and other bodily secretions).^18,19,20 (This should not be confused with the fishy odor present in Trichomonas vaginitis. This odor is as a result of anaerobic organisms.) The disease produces a powerful aroma of rotting fish, and this causes the affected person to have an offensive body odor.^18,21 Trimethylamine is derived from the intestinal bacterial degradation of foods rich in choline (egg yolk, liver, etc.) and carnitine. TMA is also formed by reduction of TMA-oxide present in high concentrations in marine fish.^20,22 TMA is normally oxidized by the liver into odorless trimethylamine N-oxide and then excreted in the urine. This oxidization is defective in TMA-uria. The above foods can exacerbate the condition. Dietary adjustments can reduce the excretion of trimethylamine and may reduce the odour.²²

g. Cat's urine syndrome has neurological symptoms resembling Werdnig-Hoffman's disease, and the patient's urine has a cat urine-like odor.¹¹

h. Diabetic keto-acidosis induces a characteristic odor on the breath that has been described as "sweet" or "fruity."¹¹

For more reading on the above conditions, I recommend references 10 and 11.

Exposure of the tongue to artichoke can make water taste sweet. Experiments have shown that exposure of the tongue to the extract from one-forth of an artichoke heart makes water taste as sweet as 2 teaspoons of sucrose dissolved in 6oz (±168g) of water.

Why does this occur?
It was found that this induced sweetness is produced by temporarily altering the tongue so that a normally non-sweet substance tastes sweet. Two substances in artichoke were identified as the major sources of the sweetness. They are chlorogenic acid (3-caffeoylquinic acid) and cynarin (1,5-dicaffeoylquinic acid). It is suspected that there are other substances that also possess similar taste-altering properties, but these substances have not yet been identified.

There have been anecdotal reports of other beverages such as milk and wine tasting sweet after the consumption of artichoke.

Other common food ingredients have also been shown to alter the taste of water when preceding it on the tongue. For example, water tastes bitter-sour after exposure to salt, bitter after sucrose, salty after urea, and sweet after exposure to acids, quinine, caffeine and potassium chlorate. The major difference between the artichoke-induced sweet taste of water and other sweet tastes of water is the duration of the effect. The artichoke-induced sweetness lasts longer than most of the other flavor changes.

Sweetness can be induced by exposing the tongue to another plant, miracle fruit (Synsepalum dulcificum), a small red berry that is native to tropical West African. However, with miracle fruit, sour substances rather than water are sweetened, the sweetness lasts much longer (30 minutes or more) than that produced by artichokes, and fewer individuals fail to observe the effect.

The authors suggested that the sweetening of substances by temporarily modifying the tongue may provide an alternative to currently used nonnutritive sweeteners. They suggested the possibility that research on taste modification may contribute to the improved palatability of food derived from sources such as algae or yeast, which may be needed increasingly in the future.²³

C. Comments by our editors

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D. References

1. Mitchell SC. Asparagus and malodorous urine. Br J Clin Pharmacol 1989 May;27(5):641-2.
2. Richer C, Decker N, Belin J, Imbs JL, Montastruc JL, Giudicelli JF. Odorous urine in man after asparagus. Br J Clin Pharmacol 1989 May;27(5):640-1.
3. White RH. Occurrence of S-methyl thioesters in urines of humans after they have eaten asparagus. Science 1975 Sep 5;189(4205):810-11.
4. Mitchell SC. Food idiosyncrasies: beetroot and asparagus. Drug Metab Dispos 2001;29:539-43.
5. Mitchell SC, Waring RH, Land D, Thorpe WV. Odorous urine following asparagus ingestion in man. Experientia 1987 Apr 15;43(4):382-3.
6. Hoffenberg L. A note on polymorphism: the ability to smell urinary metabolites of asparagus. Diastema 1983;11:37-8.
7. Lison M, Blondheim SH, Melmed RN. A polymorphism of the ability to smell urinary metabolites of asparagus. Br Med J 1980 Dec 20-27;281(6256):1676-8.
8. Waring RH, Mitchell SC, Fenwick GR. The chemical nature of the urinary odour produced by man after asparagus ingestion. Xenobiotica 1987 Nov;17(11):1363-71.
9. Gearhart HL, Pierce SK, Payne-Bose D. Volatile organic components in human urine after ingestion of asparagus. Clin Chem 1977 Oct;23(10):1941.
10. Cone TE Jr. Diagnosis and treatment: some diseases, syndromes, and conditions associated with an unusual odor. Pediatrics 1968 May;41(5):993-5.
11. Mace JW, Goodman SI, Centerwall WR, Chinnock RF. The child with an unusual odor. A clinical resume. Clin Pediatr (Phila) 1976 Jan;15(1):57-62.
12. Beers MH, Berkow R. The Merck Manual of Diagnosis and Therapy Seventeenth edition. Merck Research Laboratories, NJ, 1999.
13. Zhou Q, Wintersteen CL, Cadwallader KR. Identification and quantification of aroma-active components that contribute to the distinct malty flavor of buckwheat honey. J Agric Food Chem 2002 Mar 27;50(7):2016-21.
14. Podebrad F, Heil M, Reichert S, Mosandl A, Sewell AC, Bohles H. 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone)--the odour of maple syrup urine disease. J Inherit Metab Dis 1999 Apr;22(2):107-14.
15. Sewell AC, Mosandl A, Bohles H. False diagnosis of maple syrup urine disease owing to ingestion of herbal tea. N Engl J Med 1999 Sep 2;341(10):769.
16. Bartley GB, Hilty MD, Andreson BD, Clairmont AC, Maschke SP. "Maple-syrup" urine odor due to fenugreek ingestion. N Engl J Med 1981 Aug 20;305(8):467.
17. Korman SH, Cohen E, Preminger A. Pseudo-maple syrup urine disease due to maternal prenatal ingestion of fenugreek. J Paediatr Child Health 2001 Aug;37(4):403-4.
18. Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos 2001 Apr;29(4 Pt 2):517-21.
19. Treacy E, Johnson D, Pitt JJ, Danks DM. Trimethylaminuria, fish odour syndrome: a new method of detection and response to treatment with metronidazole. J Inherit Metab Dis 1995;18(3):306-12.
20. Sela BA, Trau H, Spira A. [Trimethylaminuria: fish-odor syndrome] Harefuah 1993 Feb 1;124(3):138-9, 183.
21. Akerman BR, Lemass H, Chow LM, Lambert DM, Greenberg C, Bibeau C, Mamer OA, Treacy EP. Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort. Mol Genet Metab 1999 Sep;68(1):24-31.
22. Rehman HU. Fish odor syndrome. Postgrad Med J 1999 Aug;75(886):451-2.
23. Bartoshuk LM, Lee CH, Scarpellino R. Sweet taste of water induced by artichoke (Cynara scolymus). Science 1972;178(64):988-90.

E. CPD Questions (South Africa, Australia)

This CPD session is now closed. Please contact karen@allergyadvisor.com for more information.

PLEASE ANSWER ALL THE QUESTIONS
1. Which one of the following is not true regarding the malodorous urine associated with asparagus ingestion?
(a.) The smell is described as being like "rotten or boiling cabbage" or "vegetable soup."
(b.) It occurs in approximately 40-43% of people.
(c.) It occurs after eating at least 20 spears of asparagus.
(d.) The tendency has been shown to remain with individuals for virtually a lifetime.

2. True or false: The characteristic odor has been attributed to sulphur-containing compounds in the urine.
(a.) True
(b.) False

3. Which of the following terms has not been used to describe the characteristic odor of phenylketonuria?
(a.) musty
(b.) mousy
(c.) horsey
(d.) dried malt or hops

4. Which food does not contain the compound that contributes to the odor that is characteristic of maple syrup urine disease?
(a.) maple syrup
(b.) fenugreek
(c.) lovage
(d.) wheat

5. Which of the following conditions has not been associated with a "fishy" odor?
(a.) Isovaleric acidemia
(b.) Trimethylaminuria
(c.) Trichomonas vaginitis
(d.) Hypermethioninemia

6. In which of the following bodily fluids is trimethylamine excreted in the disorder trimethylaminuria?
(a.) Urine
(b.) Sweat
(c.) Saliva
(d.) All of the above

7. Which of the following is not true regarding any of the changes in the taste of water due to food ingredients ingested?
(a.) Bitter-sour taste after exposure to salt
(b.) Sweet taste after exposure to sucrose
(c.) Salty after exposure to urea
(d.) Sweet after exposure to acids, quinine, caffeine and potassium chlorate

8. Which of the following is true regarding the effect of miracle fruit on taste sensation?
(a.) Water taste sweeter.
(b.) Sour substances taste sweeter.

Answers

1. c. It occurs after eating at least 20 spears of asparagus.
2. a. True
3. d. dried malt or hops
4. d. wheat
5. a. Isovaleric acidemia
6. d. All of the above
7. b. Sweet taste after exposure to sucrose.
8. b. Sour substances taste sweeter.

Index