DEPARTMENT OF NUTRITION AND DIETETICS

Dietary information for adolescents & adults with Trimethylaminuria (TMAU)

Choline Restricted Diet

Metabolic Dietitians Tel: 020 3448 3604 3605 4332 3602 Charlotte Ellerton [email protected] Heidi Chan [email protected] Clare Gray [email protected] Francine Freedman [email protected]

Bleeps: 8197/8198

Updated August 2010

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Updated August 2010

Contents Introduction Symptoms of TMAU What causes TMAU? Clinical diagnosis Clinical management Dietary management

Page no 4 4 4 5 5 6

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Introduction Trimethylaminuria (TMAU) TMAU is a disorder in which the body is unable to break down trimethylamine (TMA), a compound derived from the diet that has a strong odour of rotting fish. It is an inherited condition resulting in a deficiency of the enzyme which changes the odourous trimethylamine (TMA) into the odourless N-oxide trimethylamine (TMA-O) (see Figure 1). TMAU, also known as the Fish malodour syndrome is characterised by the presence of abnormal amounts of TMA in urine, sweat, breath and other bodily secretions. Figure 1: Trimethylamine metabolism

IN T E S T IN E L e c ith in C h o lin e
B a c te ria

L IV E R

TMA
B a c te ria

TMA

T M A -N -O xid e
O d o u rle s s

F is h o d o u r
F ish

T M A -N -o xid e

U rin e

Symptoms of TMAU Malodorous TMA (which gives fish its fishy odour) builds up and is excreted in the urine and body secretions such as sweat, reproductive fluids, saliva and breath, giving off a strong unpleasant body odour similar to rotten fish. The severity is variable. Some individuals have a strong odour all the time but it can be episodic and varies in intensity over time. Sweating, menstruation and a diet high in trimethylamine and its precursors may worsen symptoms.

What causes TMAU? There are various proposed classifications for TMAU. At this centre we classify TMAU into two major subgroups: 1) primary (genetic) and 2) secondary (acquired).

TMAU, in its primary form, is an autosomal recessive disorder. This means two copies of the FMO3 mutation, one from each parent, are needed to inherit TMAU. Any person with one copy of the mutation can pass it on to their children (see Figure 2). Primary TMAU is characterised

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by a high TMA/TMA-O ratio. In patients with primary TMAU, symptoms are usually present from birth and the condition may worsen with puberty. Figure 2: Primary TMAU

Although genetic mutations account for most cases of TMAU, it can also be caused by other factors. A fish-like body odour may result from an excess of certain proteins in the diet or from an increase in bacteria that normally produce TMA in the gut. Secondary TMAU is characterised by a high concentration of TMA in the urine, but a normal urinary TMA/TMA-O ratio. Temporary symptoms of this condition have been reported in a small number of premature infants who are fed a choline-containing infant formula and in some healthy women at the start of menstruation Clinical diagnosis TMAU diagnosis is determined by the ratio of TMA to TMA-O in the urine. Patients are requested to substantially increase choline intake by eating foods such as fish and eggs a day before the urine collection. The test can be repeated to assess changes in urinary TMA excretion after intervention. It usually takes 6 8 weeks for the test results to come back. Gene mutation analysis can confirm primary TMAU. Clinical Management Symptoms may be managed through dietary restrictions, non-dietary methods or a combination of both these approaches. The main treatment strategies are: Choline and lecithin restricted diet Short courses (typically two weeks) of antibiotics: Antibiotics (metronidazole, neomycin, amoxicillin and doxycycline) reduce the activity of the gut microflora and suppress the generation of TMA. Rotation of antibiotics every few months prevents antibiotic resistance.

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Use of probiotics after a short course of antibiotics. All gut bacteria are suppressed by the antibiotics, and by taking probiotics the gut flora can be modified. This will increase the number of Lactobacilli and Bifidobacteria species which are not thought to metabolise choline to TMA. There are numerous types of probiotic supplements available in supermarkets, pharmacies and health food shops. Probiotics in tablet or sachet form tend to contain a greater number of bacteria than drinks or yoghurts, so these may be more effective. It is important to stop taking probiotics whilst you are completing a course of antibiotics. Please check that your supplement does not contain lecithin, soya lecithin or choline. Use of gut absorbers (charcoal / copper Chlorophyllin). These can be useful in the management of TMAU by binding some of the free choline and TMA in the gut and allowing it to be excreted, rather than absorbed into the body. Research has shown that taking these supplements can reduce free urinary TMA, suggesting that they can help with symptom control. The two main supplements are activated charcoal or copper

chlorophyllin. Available online at www.Nullo.com / http://www.bodymint.com or at a health food shop. Use of Riboflavin (Vitamin B2). Riboflavin is a co-factor for the FMO3 enzyme, which means it can help to enhance the activity of the enzyme. Riboflavin is often included in many multivitamin supplements but larger doses are required to aid FMO3 enzyme activity. Tablet preparations are available from health food shops as 100mg tablets, and the usual dose is between 90 200mg/day. Although TMAU is not related to personal hygiene it might be useful to use soaps with a moderate pH (5.5-6.5). As TMA is an alkaline compound (pH 9.8), using a lower pH body wash or moisturiser can make the TMA less volatile and easier to remove through washing (see table 1 on page 11) Multivitamins. We do not routinely insist all patients take multivitamins, but if you are concerned that your diet is very strict or that you may be at risk of vitamin and/or mineral deficiencies then please discuss this with your dietitian and/or consultant. One of the reasons we aim to see everyone who is following the diet on a regular basis is to check blood tests for any indication of nutritional deficiencies.

Dietary management It is relatively easy to exclude foods high in TMA, but TMA can also be produced by bacteria in the gut from choline. Choline is present in food, but it can also be synthesised by the body. By reducing the amount of choline (and to a lesser extent, TMA) that enters the body through diet, this reduces the production of TMA in the gut and therefore can help with symptom control

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Aims Restrict intake of food containing large amounts of choline and lecithin, which can lead to a reduction in odour Ensure adequate nutrition status. Dietary management should ensure that individuals meet the daily choline recommendations for age and gender. Maintain appropriate weight and avoid rapid weight loss

Dietary principles Avoid the major sources of choline: eggs, offal, soya and soy products, beans, legumes, nuts, wholegrain cereals, Vitamin supplements, medicines and fortified foods containing choline or fish oils. Read labels of convenience and manufactured foods. Avoid if Lecithin (E3220) or Soy lecithin (E471) is listed. Lecithin, of which choline is a constituent, is a commonly used emulsifier added to foods such as ice-cream, mayonnaise, chocolate and many other manufactured foods and should be avoided. Sea and saltwater fish is the main dietary source of TMA-O and, therefore, should be avoided. Freshwater fish may be eaten freely. Select a wide variety of foods from the GREEN LIST (page 8) - when on a restricted diet it is important to choose food carefully and include a wide range of foods from the freely allowed list Prepare foods freshly fresh foods and basic ingredients are best Dietary supplements take only those dietary supplements recommended by your doctor or dietitian Maintain a healthy weight weight should be monitored on a regular basis Low levels of choline are present in many foods therefore it is impossible to avoid all dietary choline and provide a healthy diet at the same time. All information regarding the choline content of food and drink is obtained from the USDA database for the choline content of common foods, as there is no UK equivalent. Whilst this list continues to expand, it is not exhaustive and there are no details for many foods. Patients are encouraged to try different foods and assess their symptoms (For a more comprehensive list please follow the link below: http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf)

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Traffic light system Green Amber Red Go! These foods contain small quantities of choline Go Cautiously. These foods contain moderate amounts of choline Stop! Eat limited amount of these foods as they contain large amounts of choline

GREEN LIST GO!

Fruit All fruits except those listed in the AMBER LIST (page 9) Vegetables All vegetables except those listed in the AMBER LIST (page 9) Milk and milk products Creamer Cottage cheese Cheddar cheese Fats and Oils Margarines, butter and vegetable oil spreads (without added lecithin or choline) Oils: olive, sunflower, canola, corn Bread, Cereals, Grains, Flours and potatoes White bread (without added soya flour) Plain potato crisps Danish pastry Wheat crackers Biscuits, plain Spaghetti noodles Brown rice Pasta Bagels Corn/tortilla chips Rice noodles Meat, legumes Pork sausage Eggs Egg whites Preserves and confectionery Sugar Updated August 2010 Treacle 8 Turkey sausage Porridge oats Sweet potatoes Frozen chips Cereals Kraft (honey roasted cereal Cereals Kelloggs (Cheerios, Wheaties, Cornflakes, Rice Krispies) White rice Wheat flour, white Crumpets Pitta bread Sour cream Cream cheese Oat, rice or coconut milk

Icing sugar Glucose Jam Honey Golden syrup Beverages and Alcoholic Drinks Brewed Tea Fizzy Drinks Fruit Squash

Chewing gum Boiled sweets Lollies and fruit based ice lollies Marmalade

Mineral Water Fruit Juice

Limit all alcoholic drinks to small amounts and avoid binge drinking White wine Red wine Spirits Miscellaneous Salt Herbs Chutney Soy sauce Cornflour Essences e.g. vanilla Salad dressing (no egg or lecithin E322) Pepper Spices Salsa Mustard Vinegar Baking powder

AMBER LIST - GO CAUTIOUSLY

Fruit Banana Melon, cantaloupe Vegetables Cabbage, cooked Sauerkraut Broccoli, cooked Cauliflower Peas,cooked Spinach, cooked Milk and milk products Whole milk Bread, Cereals, Grains, Flours and potatoes Oat bran Fish and fish products Updated August 2010 9 Wheat bran Yoghurt plain / fruit Kale, cooked Yellow corn Asparagus, cooked Yellow Squash, Cooked Brussels Sprouts, cooked Avocadoes

Fish fingers Meat, legumes and eggs Bacon Tofu, soft Peanuts-all types Peanut butter Canned Beans navy, kidney, baked Nuts - Pistachio and cashew nuts are highest Preserves and confectionery Chocolate if it contains no lecithin (E322) or choline Popcorn Ice-cream if it contains no lecithin or choline Beverages and Alcoholic Drinks Coffee limit to 1-2 cups weak coffee per day Beer Light (360ml)

RED LIST USE WITH CAUTION

Milk and milk products Skimmed milk Soya milk Fats and Oils Butter spreads and margarine with lecithin or choline added (check ingredients) Fish and fish products All other fish incl. shell fish, and fish products e.g. Fish paste, fish pate, fish cakes, fish oils and products containing fish oils. Cod liver oil capsules, Maxepa capsules Meat, legumes and eggs Egg Chicken Beef, trim-cut Pork loin Soyabeans Mutton Preserves and confectionery Chocolate or ice-creams containing choline (1001), lecithin (322) or Soy lecithin (471) Beverages and Alcoholic Drinks Milkshakes Beer, regular (360ml) Updated August 2010 Bovril and any drink containing yeast extract 10 Chicken liver Beef liver Ground Beef Bacon, cooked Veal Semi-skimmed milk Sheep and goats milk

Miscellaneous Yeast extracts e.g. Marmite, Vegemite, Table 1: pH value of soaps Brand name Avene Ultra-rich soap-free - Cleansing bar - Cleansing gel DermaVeen Soap Free wash Allergenics - Face and Body shower gel - Skin lotion - Hair shampoo Sebamed - Liquid Face - Body wash Palmolive Aquarium Hand Wash Paulas Choice - All Over Hair and Body Shampoo - Slip Into Silk Body Lotion - Skin Balancing Cleanser - One Step Face Cleanser Normal to Dry Skin - Skin Balancing Moisture Gel - Moisture Boost Hydrating Treatment Cream Neutrogena Extra Gentle Cleanser Dermalogica - The Bar - Dermal Clay Cleanser - Conditioning Body Wash - All face washes *This information is correct at the time of producing this dietsheet pH 5.5

5.5 5.5

5.5

5.5 6 6 6.3 5.5 6 5.6-6.2

5.5 6.5 46 4-6

Updated August 2010

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Contact details
Senior Specialist Metabolic Dietitians Direct line: 0845 155 5000 Switchboard: 0845 155 5000 Extension: 83605/ 83604/ 84332 Bleep (pager): 8197/ 8198 Fax: 020 7209 2146 Website: www.uclh.nhs.uk

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1 University College Hospital 2 The Heart Hospital 3 Royal London Homoeopathic Hospital 4 Elizabeth Garrett Anderson and Obstetric Hospital 5 Hospital for Tropical Diseases 6 National Hospital for Neurology and Neurosurgery 7 Eastman Dental Hospital

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Space for notes and questions

Publication date:

August 2010

Date last reviewed:

Date next review due: August 2011 Leaflet code: CONTACT THE PATIENT INFORMATION CO-ORDINATOR FOR THE CODE [email protected] FOR THIS LEAFLET

University College London Hospitals NHS Foundation Trust

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