Managing histamine intolerance

1

Histamine IntoleranceNina Bailey BSc, MSc, PhD RNutr

Adverse reactions to ingested food can be divided into toxic and non-toxic, caused by specific individual intolerance of food which is usually tolerated in healthy individuals

The most common and most severe food allergy is IgE-mediated food allergy, which occurs in predisposed individuals, namely atopics

Food intolerances are non-immune mechanisms and can be a result of disturbance of enzymes of the gastrointestinal system or as a result of pharmacologic effects of vasoactive amines present in food and is dose dependent

Histamine disorders

• Mast cell activation – inappropriate degranulation

• Mastocytosis (rare) – too many mast cells

• Histamine intolerance – histamine specific

• Histamine is a hydrophilic vasoactive amine that plays an essential role in maintaining the health of the body, both in defence against infection and trauma (in inflammation) and in physiological processes in various organ systems, such as stimulating gastric secretions, regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus

• As such, histamine is responsible for a staggering number of biological effects, which vary based on receptor, cell location and target cell

• Histamine is derived from histidine through carboxylation by L-histidine decarboxylase

• Histamine, once formed, can be stored or rapidly undergo deamination or demethylation, which is catalyzed by diamine oxidase (DAO) or histamine-N-methyltransferase (HNMT)

• Histamine intolerance is a dose-dependent condition that occurs when the rate of histamine accumulation exceeds the capacity of histamine degradation

Maintz, L. and Novak, N. Histamine and histamine intolerance. Am J Clin Nutr. 2007; 85: 1185–1196

Function of DAO and HNMT• The primary function of DAO seems to be the elimination of excess histamine

and controlling the amount of histamine entering the body from the digestive tract

–DAO expression is restricted to specific tissues; the highest activities are shown for small intestines, ascending colon, and for placenta and kidney

–DAO break down products imidazole acetaldehyde & imidazole acetic acid

• HNMT primarily functions at the level of histamine receptors where it terminates the biological activity of histamine in a wide range of organs

–HNMT is widely expressed in human tissues; the greatest expression is in kidney and liver, followed by spleen, colon, prostate, ovary, spinal cord cells, bronchi, and trachea

–HNMT is broken down to the methylated products N-methylhistamine & N-methylimidazole acetic acid

Common symptoms associated with histamine intolerance

Skin problems • Skin rashes, itchiness • Eczema• Urticaria (hives)• Acne (pimples)

Chest area /cardiovascular • Asthma • Cardiac arrhythmia, such as a fast beating or irregular heart beat• Low blood pressure

Mood• Sudden psychological changes (e.g. aggressiveness, inattentiveness,

lack of concentration) • Anxiety/depression• Sleep issue (insomnia / early waking)

Common symptoms associated with histamine intolerance

Digestive tract

• Irritable bowel syndrome (constipation / diarrhoea)

• Flatulence and feeling of fullness

• Stomach cramps /stomach ache

• Nausea / vomiting

Symptoms affecting head and face

• Flushing of face and /or chest (very common symptom)

• Headaches / migraine

• Runny nose and weepy eyes (with no clinical sign of allergies)

• Dizziness

• Extreme tiredness, fatigue (often feeling cold/shivery)

• Oedema (swellings mostly appearing around eyes and lips, sometimes in the area of the throat)

Women

• Dysmenorrhoea (severe period pains)

• HIT symptoms go away during pregnancy and return after birth of child

Maintz, L. and Novak, N. Histamine and histamine intolerance. Am J Clin Nutr. 2007; 85: 1185–1196

Maintz L, Yu CF, Rodríguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy. 2011 Jul;66(7):893-902. 1.

Szczepankiewicz A, Bręborowicz A, Sobkowiak P, Popiel A. Polymorphisms of two histamine metabolizing enzymes genes and childhood allergic asthma: a case control study. Clin Mol Allergy. 2010 Nov 1;8:14.

Genetics

Histamine-metabolising enzymes (HNMT and DAO) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation

Genetic variants of HNMT and DAO genes are associated with altered enzyme activity (for example, the genetic variant (C314T) decreases HNMT activity by 30-50%)

“However it is unlikely that genetic variants are themselves sufficient to fully effectuate the potentially associated disease state of histamine intolerance, suggesting an interplay of genetic and environmental factors”

Histamine-rich foods

• Fermented alcoholic beverages, especially wine, champagne and beer• Fermented foods: sauerkraut, vinegar, soy sauce, kefir, yogurt, kombucha, etc• Vinegar-containing foods: pickles, mayonnaise, olives• Cured meats: bacon, salami, pepperoni, luncheon meats and hot dogs• Soured foods: sour cream, sour milk, buttermilk, soured bread, etc• Dried fruit: apricots, prunes, dates, figs, raisins• Most citrus fruits• Aged cheese including goat cheese• Nuts: walnuts, cashews, and peanuts• Vegetables: avocados, eggplant, spinach, tomatoes• Smoked fish and certain species of fish: mackerel, tuna, anchovies, sardines• Leftover meats can quickly accumulate microorganisms which result in histamine

formation• Wheat-based products

Histamine-releasing foods

• Alcohol• Bananas• Chocolate• Milk • Nuts• Papaya• Pineapple• Shellfish• Strawberries• Tomatoes• Gluten• Wheat germ• Sugar• Many artificial preservatives and dyes

Food additives

• A number of food additives have been implicated as potential factors in the release of histamine and triggering urticaria and angioedema:

– tartrazine and other azo dyes

– salicylates

–monosodium glutamate (MSG)

–preservatives such as sulphites, benzoates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)

• Some of these chemicals occur naturally in foods (e.g. salicylates, benzoates and sulphites)

• In order to reduce the possibility of histamine levels being increased by the action of these naturally occurring chemicals and food additives, they should be excluded from the diet

Foods high in histidine

As histidine converts to histamine, foods high in histidine may also be problematic

•Game meat

•Pork including loin, chops or other cuts, ham, bacon

•Soy protein

•Chicken and turkey

•Veal and beef, pastrami

•Lamb

•Fish including tuna & cod

•Cottage cheese

Medications:A number of pharmaceuticals are known to reduce the activity of DAO and/or DNMT

Non-steroidal anti-inflammatory drugsIbuprofen & aspirin

Antidepressants(Cymbalta, Effexor, Prozac, Zoloft)

Immune modulators: Humira & Enbrel: rheumatoid arthritis, psoriatic arthritis, Ankylosing spondylitis, Crohn's disease, ulcerative colitis, chronic psoriasisPlaquenil: Malaria & rheumatoid arthritis

Antiarrhythmics (propanolol, metaprolol, Cardizem, Norvasc)

Antihistamines (Allegra, Zyrtec, Benadryl)

Histamine (H2) blockers: Tagamet: duodenal and benign gastric ulceration Pepcid & Zantac: heartburn

Anti-histamines

Long-term use of anti-histamines - while they block the histamine receptor and prevent binding, the immune system will, over time, see this as a lack of histamine and up-regulate histamine production

With histamine intolerance, over-the-counter and prescription antihistamines will cause of worsening of symptoms

In addition, over-the-counter antihistamines only block the H1 and/or H2 receptors

Dysbiosis – the gut link

•An increase in histamine carboxylase-containing bacteria may increase the amount of histidine from dietary protein that is then converted to histamine

•Therefore growth of histamine-producing bacteria may lead to higher systemic levels of histamine and HIT

•Overuse of antibiotics – not only do antibiotics cause changes in the microbiome, but dysbiosis can increase the numbers of DAO-inhibiting bacteria or histamine-liberating bacteria

•Intestinal Permeability (leaky gut) and SIBO (bacteria imbalance /overgrowth) both lead to disturbances in the gut microbiome that may contribute to histamine intolerance

•Bacteria used to ferment yoghurt and fermented foods could potentially exacerbate histamine production (e.g. Lactobacillus casei, Lactobacillus reuteri & Lactobacillus bulgaricus)

• Leuconostoc mesenteroides

• Leuconostoc sp.

• Escherichia faecium sp.group

• Sarcina lutea

Dapkevicius MLNE, Nout MJR, Rombouts FM, Houben JH, Wymenga W. Biogenic amine formation and degradation by potential fish silage starter microorganisms. International Journal of Food Microbiology 2000 57:107-114

Leuschner R, Heidel M, Hammes W. Histamine and tyramine degradation by food fermenting microorganisms. International Journal of Food Microbiology 1998 39:1-10

• Lactobacillus curvatus

• Lactobacillus sakei

• Lactobacillus sp.

• Weisella hellenica

Microorganisms capable of degrading histamine (DAO producers)

• Capable of degrading food sources of histamine and may reduce total histamine load

• Possible future role of probiotics?

Oestrogen and histamine • Oestrogen excess down-regulates DAO = elevated histamine!

• Oestrogen sensitises mast cells that release inflammatory histamine

• Progesterone deficiency - because progesterone is needed to up-regulate DAO

• Hormonal birth control can cause oestrogen excess and progesterone deficiency

• DAO is higher (and histamine lower) early in the luteal phase when progesterone is high

• The placenta produces high amounts of DAO so symptoms of histamine intolerance often subside during pregnancy

Stress and histamine

Mental stress

• Stress results in activation of the HPA-axis

• The more histamine that is released, the more cortisol it takes to control the inflammatory response and the harder the adrenals have to work to produce more cortisol.

• Stress induces gastrointestinal function disturbances by increasing mast cell activation

• Histamine release increases during the periods of panic/anxiety, especially when the adrenergic, fight or flight response is at its peak with H3 histamine receptors in the brain promoting the most "wakeful" firing pattern

Physical stress

• Excessive physical strain, physical exertion/excercise or injuries, may trigger the release of histamine

• L-carnosine released during exercise is converted to histamine

In individuals with histamine intolerance ingestion of food with normal contents of histamine causes histamine-mediated symptoms

Because each person’s level of tolerance to histamine is unique and ever-changing, the approach to reduce dietary sources of histamine needs to be individualised

Using a time-line approach is a useful tool for identifying suspected histamine intolerance:

• Dietary intake in histamine foods/histamine releasing foods

• Medication history

• Dysbiosis?

• Stress exposure?

• Adrenal fatigue?

Histamine and nutritional deficiencies

• When the body is low in B vitamins, vitamin C, and copper, histamine may not break down sufficiently to overcome symptoms of intolerance

• B-vitamins are required for HNMT activity

• Copper and vitamin C are crucial components of the DAO enzyme and B6 is a key cofactor that enables DAO to degrade histamine

Managing histamine intolerance

• Remove high histamine foods /histamine liberators for ~1-3 months (improvements observed 4-6 weeks)

• Stabilise histamine release/accelerate histamine degradation

• Supplement DAO

• Identify the cause for the histamine intolerance (other than the genetics)

– Medications

– Gut dysbiosis and gluten intolerance (leaky gut?)

– Identify chemical sensitivity (i.e. heavy metals, colourings, dyes, paint chemicals, fluoride, chlorine, pesticides)

The low histamine diet

• Randomised, double-blind controlled trials on the effectiveness of a low histamine diet intervention in histamine intolerance are lacking; however, trials in which a low histamine diet is used have demonstrated a benefit for some participants

• For example, in an uncontrolled pilot study of 44 subjects, 80% showed an improvement in symptoms of chronic idiopathic urticaria (CIU) after following a low histamine diet for 4 weeks

• Adopting a low histamine diet is an effective / cost viable method of identifying those individuals with histamine intolerance

• Because of the restrictive nature of the low histamine diet, care must be taken to ensure that nutritional deficiencies do not arise

Joneja, J. V. & Carmona-Silva, C., 2001. Outcome of a histamine-restricted diet based on chart audit. Journal of Nutritional andEnvironmental Medicine, Volume 11, pp. 249-262.

Avoiding meat, poultry & fish

• Fish and shellfish whether fresh, frozen, smoked or canned, if processing is unknown. (If the fish is freshly caught, gutted and cooked within 30 min it may be eaten)

• Processed, smoked and fermented meats such as luncheon meat, sausage, wiener, bologna, salami, pepperoni, smoked ham, cured bacon


Milk and milk products

All fermented milk products, including: – Cheese (any kind of fermented cheese such as Cheddar, Colby, Blue

cheese, Brie, Camembert, Feta, Romano, etc.)

– Cheese products such as processed cheese, cheese slices, cheese spreads

– Cottage cheese / ricotta cheese

– Yoghurt

– Buttermilk

– Kefir

Any milk or milk product that is NOT fermented is allowed


Fruits

• Orange

• Grapefruit

• Lemon

• Lime

• Cherries

• Bananas

• Strawberries

• Apricots

• Raspberries

• Pineapple

• Cranberries

• Prunes

• Loganberries

• Dates

• Raisins

• Currants


Vegetables

• Tomatoes, tomato sauces, ketchup

• Soy and soy products

• Spinach

• Red beans

• Aubergine

• Olives in vinegar or brine

• Pumpkin

• Avocados

• Pickles, relishes and other foods containing vinegar


Seasonings

• Cinnamon

• Cloves

• Anise

• Nutmeg

• Curry powder

• Chilli powder

• Vinegar


Miscellaneous

• Fermented soy products (such as soy sauce, miso)

• Fermented foods (such as sauerkraut)

• Tea (regular or green)

• Chocolate, cocoa, and cola drinks

• Alcoholic beverages of all types


Testing for DAO activity Cambridge Nutritional Science offer £66 – home test

Biolab

Genova

TDL Pathology

Medichecks.com offer £99 - home test

• Normal DAO Activity >10U/mL (Histamine Degradation Units)

• SNP analysis? “it is unlikely that genetic variants are themselves sufficient to fully effectuate the potentially associated disease state of histamine intolerance”

Cambridge Nutritional Science

Histamine degrading bacteria:

• Bifidobacterium infantis

• Bifidobacterium longum

• Lactobacillus plantarum

• Studies also suggest that probiotic Lactobacillus rhamnosus reduces activation of mast cells and H4 receptors

• Probiotics can also shift immune activity to a more “intracellular” Th1 response rather than the “extracellular” Th2 response that characterises excessive histamine activity in allergy, asthma, and autoimmune diseases

Capozzi V, Russo P, Ladero V, Fernández M, Fiocco D, Alvarez MA, Grieco F, Spano G. Biogenic Amines Degradation by Lactobacillus plantarum: Toward a Potential Application in Wine. Front Microbiol. 2012 Apr 2;3:122.

Dev S, Mizuguchi H, Das AK, Matsushita C, Maeyama K, Umehara H, Ohtoshi T, Kojima J, Nishida K, Takahashi K, Fukui H. Suppression of histamine signaling by probiotic Lac-B: a possible mechanism of its anti-allergic effect. J Pharmacol Sci. 2008 107(2):159-66.

In addition to a low histamine diet, focus on stabilising histamine release and accelerating histamine degradation via supplemental intervention

Flavonoids Co-factors Probiotics Omega-3 Polyphenols

Methionine recycling

Methionine

SAM: universal methyl donorMethylates: neurotransmitters, proteins, RNA, DHA, catecholamines, phosphatidylcholine, melatonin, myelin, creatine

HNMT!

Homocysteine

SAM

SAH

Methionine synthase

5-methyl THF

THF

FOLIC ACID CYCLE

Processes affectedNeurotransmitter function Fatty acid metabolismAllergic responsesMyelinationCellular energyCell membrane and proteinstructure and function

Cystathionine

Virus fightingInflammation regulationAntioxidant production

DetoxificationIntestinal integrity

Cysteine

Glutathione

MetallathioninesAffects potent metal-

binding and redox capabilities

Cysteinesulflinic acid

Phenol sulfur-transferase

Phenol processing

DigestionDetoxification

Gut barrier

Sulfate

Sulphite

Taurine

Production of bile salts

SULPHATION

TRANSSULFURATION

METHYLATION

Magnesium

Magnesium, vitamin B6, zinc

Vitamin B6

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH ); tetrahydrofolate (THF)

Folate, VitaminsB6 & B12

Vitamin B6

Methionine is required for protein synthesis and provides a methyl group for >50 critical transmethylation reactions

Flavonoids

• Naturally occurring flavonoids such as quercetin and rutin inhibit histamine release – Increase kale, broccoli, capers, buckwheat, onions, apples

and asparagus

• Mast cell activity is also inhibited by the flavonoid luteolin– Increase carrots, peppers, celery, olive oil, peppermint,

thyme, rosemary, oregano, lettuce, pomegranate, artichoke, chocolate, rooibos tea, buckwheat sprouts, turnip, capers and cucumber

Oligomeric proanthocyanidins

• OPCs are polyphenolic substances with anti-histamine properties (mast cell stability)

• Found in high concentrations in fruits such as apples, pears and grapes, and in chocolate, wine and tea!

OPCs may be more appropriate as nutritional supplements• Grape Seed Extract 50 to 100 mg 2-3 times per day• Pine Bark Extract (Pycnogenol) 100-200 mg daily

Reduce histamine release

A number of foods are rich in nutrients shown to reduce histamine release from mast cells:

Quercetin: found in red onions, red grapes, apples, peppers,

cruciferous vegetables (e.g. broccoli, cabbage, sprouts), dark leafy greens (e.g. kale)

Ellagic acid: found in pomegranate, walnuts, pecans, blackberries

Luteolin: found in celery, parsley, thyme, peppermint, basil

Resveratrol: found in red grapes, red grape juice, blueberries

Curcumin: found in turmeric

Serving size: 2 tablets Per serving %Reference Intake

Vitamin C (ascorbic acid) 240 mg 300

Vitamin B3 (nicotinamide) 48 mg NE 300

Zinc citrate 20 mg 200

Vitamin B5 (pantothenic acid) 18 mg 300

Vitamin B6 (pyridoxal 5-phosphate) 8 mg 570

Iron (ferrous bisglycinate chelate) 7 mg 50

Vitamin B1 (thiamine HCl) 5.5 mg 500

Vitamin B2 (riboflavin 5-phosphate) 4.2 mg 300

Vitamin E D-alpha tocopherol (natural) 2 mg a-TE 16.6

Boron (disodium tetraborate) 2 mg n/a

Manganese bisglycinate 2 mg 100

Copper bisglycinate 1 mg 100

Vitamin A (beta carotene) 800 mg 100

Folate ([6S]-5-methyltetrahydrofolate) 200 mg 100

Selenomethionine 110 mg 200

Iodine (kelp) 150 mg 100

Vitamin B7 (biotin) 100 mg 200

Chromium picolinate 50 mg 125

Molybdenum 50 mg 100

Vitamin K2 (menaquinone) 37.5 mg 50

Vitamin B12 (methylcobalamin) 20 mg 800

Vitamin D3 (cholecalciferol) 10 mg (400 iu) 200

MULTIVITAMIN & MINERALS™provides 22 key essential vitamins & minerals in superior body-ready and active forms for enhanced absorption and utilisation. Our sustained slow release system optimises blood nutrient levels for longer-lasting action.

Serving size: 1 capsule Per serving % RI*

Longvida® optimised curcumin

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DIRECTIONS FOR USEAdults: take 1 capsule daily with food. For intensive support, take 2 capsules daily as a split dose. Do not exceed the dose unless advised by a healthcare practitioner.

NUTRITIONAL INFORMATION

INGREDIENTS: Longvida® optimised curcumin extract; capsule shell (emulsifier: hydroxypropyl methylcellulose); stearic acid; soy lecithin; maltodextrin; ascorbyl palmitate; silicon dioxide.

Free from: dairy, gluten, lactose, soya protein, wheat, yeast, artificial colours and flavours; not tested on animals; non-GMO; suitable for vegetarians & vegans; halal & kosher.

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Product information

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48

Diagnosing mast cell activation disorder

Symptoms indicative of histamine intolerance plus positive:

• N-methylhistamine 24 hour urine test

• Prostaglandin D2

• Heparin

• A rise in urinary n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α (24-hour urine test for any of the three), is considered an alternative for the co-criterion related to a requirement for a mast cell mediator level rise during a systemic mast cell activation event

Health & Medicine

Managing histamine intolerance