Abstract



Trimethylaminuria, better known as fish odor syndrome, is a psychologically disabling condition in which a patient emits a foul odor, which resembles that of rotting fish. The disorder is most commonly caused by an inherited deficiency in flavin monooxygenase 3, the vital enzyme for the metabolism of trimethylamine, which is the compound responsible for the unpleasant odor. The condition is uncommon, but there has been recent research to suggest that the diagnosis may often be overlooked. Moreover, it is important to be cognizant of this condition because there are reliable diagnostic tests and the disorder can be devastating from a psychosocial perspective. While there is no cure, many simple treatment options exist that may drastically improve the quality of life of these patients. This article will review the literature with an emphasis on the psychosocial impact and treatment options.

Trimethylaminuria, or fish odor syndrome (FOS), is a condition characterized by the presence of trimethylamine (TMA)—a tertiary amine whose odor is described as resembling that of rotting fish—in the urine, sweat, and expired air. The cause of the syndrome is rooted in the dysfunctional metabolism of TMA,1 which is normally oxidized by flavin monooxygenase 3 (FMO3) into non-odorous trimethylamine-N-oxide (TMAO).2,3 In 1970, Humbert at el4 published the first case report of FOS; however, William Shakespeare’s description of a slave who smelled like fish in The Tempest may indicate that the condition was recognized much eariier. It is difficult to estimate the true prevalence of this syndrome, but a decade ago there were more than 200 cases described, which was considered an underestimate at that time.5 More recently, it has been shown that undiagnosed cases of trimethylaminuria may be fairly common among patients suffering from idiopathic malodor production,6 which supports the thought that this disorder is under recognized. Genetic studies have estimated the incidence of heterozygous carriers to range from 0.5 to 11 percent depending on the ethnicity examined.7,8 Cases have been reported from nearly all parts of the world and in both sexes, although it seems that females, particularly those of African descent, may be over-represented.5,6 In childhood or early adulthood, afflicted individuals usually complain of body odor and/or halitosis and seek care from pediatricians, family doctors, or specialists, such as dermatologists. The odor may not always be pungent as patients may have learned to minimize the smell through simple measures, such as frequent bathing, so it is imperative that healthcare providers be cognizant of this disorder. While not directly Ufe threatening, FOS has a significant psychosocial impact that should not be overlooked.9-11 This article provides a brief review of the literature with an emphasis on the psychosocial impact of the condition and treatment options.



ETIOLOGY



Most patients with FOS are eventually diagnosed with primary trimethylaminuria, which is caused by a deficiency in FMO3 that is inherited in an autosomal recessive fashion.1 Under normal circumstances, dietary TMAO and other TMA precursors, such as choline, are ingested and then reduced to TMA by colonic bacteria. The TMA passively diffuses across cell membranes12-14 and enters the enterohepatic circulation where it is removed by the liver. It is in the liver that FMO3 normally oxidizes TMA into odorless TMAO2,3; however, those afflicted with this condition lack adequate functional FMO3 and therefore experience an excess of foul-smelling TMA. While primary trimethylaminuria accounts for the majority of cases, there also exists secondary or acquired trimethylaminuria where FMO3 may still retain varying degrees of functionality. Secondary cases may occur in the setting of excess precursor burden as occurred after therapeutic administration of choline for the treatment of Huntington’s chorea15 and Alzheimer’s disease.16 Hepatic disease may serve as another cause as demonstrated in cases of apparent viral hepatitis5,17 and in instances of portosystemic shunting and markedly impaired hepatocellular function.18,19 Further, trimethylaminuria has been reported in chronic kidney disease, presumably secondary to bacterial overgrowth in the large intestine.20 FOS has also been described transiently in early childhood21,22 when FMO3 levels are minimal and in the perimenstrual period,10,23–26 when steroid hormones may have caused a reduction in FMO3 expression.27



PSYCHOSOCIAL IMPACT



Regardless of the etiology, FOS is often associated with significant psychosocial disturbances, which must be considered when developing a treatment plan. Patients with FOS are often ridiculed and suffer from low self-esteem. Withdrawing from their peers, they become lonely, which may negatively impact their academic performance.28 Anxiety can also be an issue for these patients, especially if they are unable to detect their odor.10 Patients also admit to experiencing shame and distress over their condition, and cases of attempted suicide have been noted.9–11,29 Ayesh et al10 studied 11 patients with FOS and noted depression, paranoia, career disadvantages, and failure to engage in sustained relationships with members of the opposite sex in addition to the aforementioned psychosocial issues. Interestingly, FMO3 is also responsible for the metabolism of other endogenous amines, such as tyramine, which are present in the brain.30 It is conceivable that the disordered metabolism of these endogenous amines could cause or at least contribute to the mood disorders described in this patient population. At any rate, there is an apparent benefit in providing the patient with a diagnosis as they are then able to research the disorder for themselves, seek help from support foundations, and discuss the disorder with family and friends.9,31



DIAGNOSTIC TESTING



The diagnosis, which often eludes practitioners for years, is made on the basis of the clinical presentation and urinalysis. Urine can be analyzed for the concentration of both TMA and TMAO, and the results may be given as an oxidizing ratio based on the formula TMAO/(TMAO+TMA) x 100%.32 A ratio of less than 84 percent should be observed in an affected individual with two FMO3 inactivating mutations.33 Conversely, individuals not afflicted with FOS should have a ratio of greater than 92 percent.32 Many patients, in an attempt to reduce their odor, may have empirically tailored their diet to exclude TMA precursors, which could cause a false-negative test result. Therefore, it is critical to ensure that adequate substrate has been ingested in order to allow for maximum sensitivity, which may be accomplished by making use of the Nijmegen protocol33 or loading the patient with a 300g marine fish meal.32 Genetic testing is available and Shephard et al27 recommend molecular analysis for any patient excreting greater than 10 percent of total TMA as the free amine.



TREATMENT CONSIDERATIONS



Once the diagnosis has been established, there are a number of potentially helpful treatment options; however, no single regimen seems universally efficacious.34 Furthermore, no systematic study has been performed to test the various recommendations.32 An easy first step for the patient might be to wash frequently with an acidic soap (pH 5.5-6.5)35 and launder clothes on a regular basis.33 It will also be helpful to inform the patient that the malodor will intensify with fever, stress, exercise, or any other cause of increased perspiration.36

Another logical solution to FOS is to exclude or reduce TMAO, a TMA precursor, from the diet, which is found in high concentration in marine fish. While deprivation of marine fish is unlikely to have major repercussions, the same does not apply to choline, another TMA precursor. Choline deficiency may result in hepatocellular injury, neurological disease, and even a predisposition to cancer.37-41 Notably, pregnant women have an increased choline requirement so restricting intake may be even less desirable in this demographic.42,43 Foods with high concentrations of choline include eggs, mustard seeds, chicken and beef liver, and raw soybeans.44 Busby et al45 have developed diets with defined amounts of choline that patients may find useful. Also, limiting the ingestion of Brussels sprouts, among other vegetables, may be beneficial, as they may inhibit the enzyme FMO3.46,47 Carnitine and glycine betaine are two other substrates that may theoretically produce a fishy odor36; however, whether restricting the ingestion of these substances is of benefit in FOS is unknown.32 It would behoove any patient considering dietary restriction as a treatment for FOS to consult a professional dietitian to ensure that all essential nutrients are accounted for prior to beginning a new diet. If restriction is not a viable option, a theoretical benefit may be derived from supplementation with riboflavin since FMO3 has a flavin cofactor; however, this has not been substantiated with any clinical study.32

Yamazaki et al48 studied the ability of sequestering agents to improve FOS as determined by the oxidizing ratio in the urine. In theory, the agents would act to reduce the load of TMA that FMO3 would need to metabolize by binding precursor amines in the colon. Oral activated charcoal was given to two subjects with ratios less than 90 percent and copper chlorophyllin was given to three subjects with similarly low ratios. After the intervention, all of the subjects showed an elevation in their oxidizing ratios to greater than 90 percent. Another treatment, which exerts its effect in the gastrointestinal tract, is the use of antimicrobials. Short courses of oral neomycin, metronidazole, and amoxicillin have been reported to be useful in some cases.36,49,50 The mechanism involves the destruction of gut bacteria, which are responsible for the reduction of TMAO into TMA. However, antimicrobial therapy only moderately alleviated the foul odor36 and presents a number of possible side effects if used chronically, so this modality is best suited for transient cases or in instances where bacterial overgrowth is thought to be a major factor in the pathogenesis of FOS. Lactulose, which also acts in the alimentary canal, is another therapy that has demonstrated an ability to decrease urinary TMA.51 Lastly, it is of great importance to offer a referral to psychiatric counseling and to screen regularly for depression and suicidal ideation.